Full Text Available In the current model of the mammalian circadian clock, PERIOD (PER represses the activity of the circadian transcription factors BMAL1 and CLOCK, either independently or together with CRYPTOCHROME (CRY. Here, we provide evidence that PER has an entirely different function from that reported previously, namely, that PER inhibits CRY-mediated transcriptional repression through interference with CRY recruitment into the BMAL1-CLOCK complex. This indirect positive function of PER is consistent with previous data from genetic analyses using Per-deficient or mutant mice. Overall, our results support the hypothesis that PER plays different roles in different circadian phases: an early phase in which it suppresses CRY activity, and a later phase in which it acts as a transcriptional repressor with CRY. This buffering effect of PER on CRY might help to prolong the period of rhythmic gene expression. Additional studies are required to carefully examine the promoter- and phase-specific roles of PER.
Kerri L. Kim
Full Text Available Pediatric bipolar disorder (BD rates have notably increased over the past three decades. Given the significant morbidity and mortality associated with BD, efforts are needed to identify factors useful in earlier detection to help address this serious public health concern. Sleep is particularly important to consider given the sequelae of disrupted sleep on normative functioning and that sleep is included in diagnostic criteria for both Major Depressive and Manic Episodes. Here, we examine one component of sleep—i.e., circadian phase preference with the behavioral construct of morningness/eveningness (M/E. In comparing 30 BD and 45 typically developing control (TDC participants, ages 7–17 years, on the Morningness-Eveningness Scale for Children (MESC, no between-group differences emerged. Similar results were found when comparing three groups (BD−ADHD; BD+ADHD; TDC. Consistent with data available on circadian phase preference in adults with BD, however, we found that BD adolescents, ages 13 years and older, endorsed significantly greater eveningness compared to their TDC peers. While the current findings are limited by reliance on subjective report and the high-rate of comorbid ADHD among the BD group, this finding that BD teens demonstrate an exaggerated shift towards eveningness than would be developmentally expected is important. Future studies should compare the circadian rhythms across the lifespan for individuals diagnosed with BD, as well as identify the point at which BD youth part ways with their healthy peers in terms of phase preference. In addition, given our BD sample was overall euthymic, it may be that M/E is more state vs. trait specific in latency age youth. Further work would benefit from assessing circadian functioning using a combination of rating forms and laboratory-based measures. Improved understanding of sleep in BD may identify behavioral targets for inclusion in prevention and intervention protocols.
... to its known regulation of seasonal gonadal cycles, the relative position of two circadian neural oscillations may also affect the rate of gonadal development during the attainment of puberty in mice. Moreover, the present study provides an experimental paradigm to test the coincidence model of circadian oscillations.
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...
Polly Yingshan Hsu
Full Text Available Circadian rhythms are physiological and behavioral cycles with a period of approximately 24 hours that are generated by an endogenous clock, or oscillator. Found in diverse organisms, they are precisely controlled and provide growth and fitness benefits. Numerous microarray studies examining circadian control of gene expression have reported that a substantial fraction of the genomes of many organisms is clock-controlled. Here we show that a long-period mutant in Arabidopsis, rve8-1, has a global alteration in phase of all clock-controlled genes. After several days in constant environmental conditions, at which point the mutant and control plants have very different circadian phases, we found 1557 genes to be differentially expressed in rve8-1, almost all of which are clock-regulated. However, after adjusting for this phase difference, only a handful show overall expression level differences between rve8-1 and wild type. Thus the apparent differential expression is mainly due to the phase difference between these two genotypes. These findings prompted us to examine the effect of phase on gene expression within a single genotype. Using samples of wild-type plants harvested at thirty-minute intervals, we demonstrated that even this small difference in circadian phase significantly influences the results of differential expression analysis. Our study demonstrates the robust influence of the circadian clock on the transcriptome and provides a cautionary note for all biologists performing genome-level expression analysis.
Full Text Available Abstract Background Recent circadian clock studies using gene expression microarray in two different tissues of mouse have revealed not all circadian-related genes are synchronized in phase or peak expression times across tissues in vivo. Instead, some circadian-related genes may be delayed by 4–8 hrs in peak expression in one tissue relative to the other. These interesting biological observations prompt a statistical question regarding how to distinguish the synchronized genes from genes that are systematically lagged in phase/peak expression time across two tissues. Results We propose a set of techniques from circular statistics to analyze phase angles of circadian-related genes in two tissues. We first estimate the phases of a cycling gene separately in each tissue, which are then used to estimate the paired angular difference of the phase angles of the gene in the two tissues. These differences are modeled as a mixture of two von Mises distributions which enables us to cluster genes into two groups; one group having synchronized transcripts with the same phase in the two tissues, the other containing transcripts with a discrepancy in phase between the two tissues. For each cluster of genes we assess the association of phases across the tissue types using circular-circular regression. We also develop a bootstrap methodology based on a circular-circular regression model to evaluate the improvement in fit provided by allowing two components versus a one-component von-Mises model. Conclusion We applied our proposed methodologies to the circadian-related genes common to heart and liver tissues in Storch et al. 2, and found that an estimated 80% of circadian-related transcripts common to heart and liver tissues were synchronized in phase, and the other 20% of transcripts were lagged about 8 hours in liver relative to heart. The bootstrap p-value for being one cluster is 0.063, which suggests the possibility of two clusters. Our methodologies can
Lovato, Nicole; Micic, Gorica; Gradisar, Michael; Ferguson, Sally A; Burgess, Helen J; Kennaway, David J; Lack, Leon
The efficacy of bright light and/or melatonin treatment for Delayed Sleep Wake Phase Disorder (DSWPD) is contingent upon an accurate clinical assessment of the circadian phase. However, the process of determining this circadian phase can be costly and is not yet readily available in the clinical setting. The present study investigated whether more cost-effective and convenient estimates of the circadian phase, such as self-reported sleep timing, can be used to predict the circadian phase and guide the timing of light and/or melatonin treatment (i.e. dim-light melatonin onset, core body temperature minimum and melatonin secretion mid-point) in a sample of individuals with DSWPD. Twenty-four individuals (male = 17; mean age = 21.96, SD = 5.11) with DSWPD were selected on the basis of ICSD-3 criteria from a community-based sample. The first 24-hours of a longer 80-hour constant laboratory ultradian routine were used to determine core body temperature minimum (cBT min ), dim-light melatonin onset (DLMO) and the midpoint of the melatonin secretion period (DLM mid = [DLM° ff -DLMO]/2). Prior to the laboratory session subjective sleep timing was assessed using a 7-day sleep/wake diary, the Pittsburgh Sleep Quality Index (PSQI), and the Delayed Sleep Phase Disorder Sleep Timing Questionnaire (DSPD-STQ). Significant moderate to strong positive correlations were observed between self-reported sleep timing variables and DLMO, cBT min and DLM mid . Regression equations revealed that the circadian phase (DLMO, cBT min and DLM mid ) was estimated within ±1.5 hours of the measured circadian phase most accurately by the combination of sleep timing measures (88% of the sample) followed by sleep diary reported midsleep (83% of the sample) and sleep onset time (79% of the sample). These findings suggest that self-reported sleep timing may be useful clinically to predict a therapeutically relevant circadian phase in DSWPD.
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
Moderie, Christophe; Van der Maren, Solenne; Dumont, Marie
To assess factors that might contribute to a delayed sleep schedule in young adults with sub-clinical features of delayed sleep phase disorder. Two groups of 14 young adults (eight women) were compared: one group complaining of a delayed sleep schedule and a control group with an earlier bedtime and no complaint. For one week, each subject maintained a target bedtime reflecting their habitual sleep schedule. Subjects were then admitted to the laboratory for the assessment of circadian phase (dim light melatonin onset), subjective sleepiness, and non-visual light sensitivity. All measures were timed relative to each participant's target bedtime. Non-visual light sensitivity was evaluated using subjective sleepiness and salivary melatonin during 1.5-h exposure to blue light, starting one hour after target bedtime. Compared to control subjects, delayed subjects had a later circadian phase and a slower increase of subjective sleepiness in the late evening. There was no group difference in non-visual sensitivity to blue light, but we found a positive correlation between melatonin suppression and circadian phase within the delayed group. Our results suggest that a late circadian phase, a slow build-up of sleep need, and an increased circadian sensitivity to blue light contribute to the complaint of a delayed sleep schedule. These findings provide targets for strategies aiming to decreasing the severity of a sleep delay and the negative consequences on daytime functioning and health. Copyright © 2017 Elsevier B.V. All rights reserved.
Fang, Bin; Everett, Logan J.; Jager, Jennifer; Briggs, Erika; Armour, Sean M.; Feng, Dan; Roy, Ankur; Gerhart-Hines, Zachary; Sun, Zheng; Lazar, Mitchell A.
SUMMARY Mammalian transcriptomes display complex circadian rhythms with multiple phases of gene expression that cannot be accounted for by current models of the molecular clock. We have determined the underlying mechanisms by measuring nascent RNA transcription around the clock in mouse liver. Unbiased examination of eRNAs that cluster in specific circadian phases identified functional enhancers driven by distinct transcription factors (TFs). We further identify on a global scale the components of the TF cistromes that function to orchestrate circadian gene expression. Integrated genomic analyses also revealed novel mechanisms by which a single circadian factor controls opposing transcriptional phases. These findings shed new light on the diversity and specificity of TF function in the generation of multiple phases of circadian gene transcription in a mammalian organ. PMID:25416951
Carrie E Mahoney
Full Text Available Cells of the dorsomedial/lateral hypothalamus (DMH/LH that produce hypocretin (HCRT promote arousal in part by activation of cells of the locus coeruleus (LC which express tyrosine hydroxylase (TH. The suprachiasmatic nucleus (SCN drives endogenous daily rhythms, including those of sleep and wakefulness. These circadian oscillations are generated by a transcriptional-translational feedback loop in which the Period (Per genes constitute critical components. This cell-autonomous molecular clock operates not only within the SCN but also in neurons of other brain regions. However, the phenotype of such neurons and the nature of the phase controlling signal from the pacemaker are largely unknown. We used dual fluorescent in situ hybridization to assess clock function in vasopressin, HCRT and TH cells of the SCN, DMH/LH and LC, respectively, of male Syrian hamsters. In the first experiment, we found that Per1 expression in HCRT and TH oscillated in animals held in constant darkness with a peak phase that lagged that in AVP cells of the SCN by several hours. In the second experiment, hamsters induced to split their locomotor rhythms by exposure to constant light had asymmetric Per1 expression within cells of the middle SCN at 6 h before activity onset (AO and in HCRT cells 9 h before and at AO. We did not observe evidence of lateralization of Per1 expression in the LC. We conclude that the SCN communicates circadian phase to HCRT cells via lateralized neural projections, and suggests that Per1 expression in the LC may be regulated by signals of a global or bilateral nature.
Gogenur, I.; Wildschiotz, G.; Rosenberg, J.
Background. It is believed that the severely disturbed night-time sleep architecture after surgery is associated with increased cardiovascular morbidity with rebound of rapid eye movement (REM). The daytime sleep pattern of patients after major general surgery has not been investigated before. We...... decided to study the circadian distribution of sleep phases before and after surgery. Methods. Eleven patients undergoing elective major abdominal surgery were included in the study. Continuous ambulatory polysomnographic monitoring was made 24 h before surgery and 36 h after surgery, thus including two...... time awake (P=0.016) in the postoperative daytime period compared with the preoperative daytime period. Five patients had REM sleep during the daytime after surgery. Three of these patients did not have REM sleep during the preceding postoperative night. There was significantly reduced night-time REM...
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.
Burgess, Helen J; Eastman, Charmane I
In humans, sleep duration often determines the night (dark) length experienced, because we close our eyes when we sleep and are exposed to artificial or natural light when we are awake. Although it is recognized that there is an increasing trend in modern society toward shorter sleep time, it is not known how short nights (long photoperiods) affect the human circadian system. In this study we investigated for the first time the effects of night length on circadian phase shifts to light in humans. Eight young healthy subjects experienced 2 wk of 6-h sleep episodes in the dark (short nights) and 2 wk of long 9-h sleep episodes (long nights) in counterbalanced order. After each series of nights, they were exposed to four 30-min pulses of morning bright light (approximately 5000 lux) that advanced by 1 h/d for 3 consecutive days while night (dark) length was maintained at 6 or 9 h. Circadian phase was determined from the circadian rhythm of melatonin in dim light before and after the 3-d bright light treatments. The phase advance in the melatonin rhythm during the short nights was less than half of that observed during the long nights (P time that people who curtail their sleep may unwittingly reduce their circadian responsiveness to morning light. This finding also demonstrates that sleep length can alter human circadian function and has important implications for enhancing the treatment of circadian rhythm sleep disorders.
Woelders, Tom; Beersma, Domien G M; Gordijn, Marijke C M; Hut, Roelof A; Wams, Emma J
Light is the most potent time cue that synchronizes (entrains) the circadian pacemaker to the 24-h solar cycle. This entrainment process is an interplay between an individual's daily light perception and intrinsic pacemaker period under free-running conditions. Establishing individual estimates of circadian phase and period can be time-consuming. We show that circadian phase can be accurately predicted (SD = 1.1 h for dim light melatonin onset, DLMO) using 9 days of ambulatory light and activity data as an input to Kronauer's limit-cycle model for the human circadian system. This approach also yields an estimated circadian period of 24.2 h (SD = 0.2 h), with longer periods resulting in later DLMOs. A larger amount of daylight exposure resulted in an earlier DLMO. Individuals with a long circadian period also showed shorter intervals between DLMO and sleep timing. When a field-based estimation of tau can be validated under laboratory studies in a wide variety of individuals, the proposed methods may prove to be essential tools for individualized chronotherapy and light treatment for shift work and jetlag applications. These methods may improve our understanding of fundamental properties of human circadian rhythms under daily living conditions.
Motohashi, Hiroaki; Sukigara, Haruna; Tahara, Yu; Saito, Keisuke; Yamazaki, Mayu; Shiraishi, Takuya; Kikuchi, Yosuke; Haraguchi, Atsushi; Shibata, Shigenobu
In mammals, daily physiological events are precisely regulated by an internal circadian clock system. An important function of this system is to readjust the phase of the clock daily. In Japan, traditional herb medicines, so-called crude drugs (Shoyaku), are widely used for many diseases, and some are reported to affect circadian clock impairment, suggesting that some of them might have an ability to modify clock gene expression rhythms. Therefore, from selected 40 crude drugs, finding candidates that control the circadian clock phases was the first purpose of this study. As there are several crude drugs used for liver- and/or kidney-related diseases, the second aim of the present study was to find some crude drugs affecting liver/kidney circadian clock in vivo. To assess phase changes in the daily circadian rhythm, bioluminescence from the core clock gene product Period 2 was continuously monitored in mouse embryonic fibroblasts in vitro and in some peripheral tissues (kidney, liver, and submandibular gland) of PERIOD2::LUCIFERASE knock-in mice in vivo. In our screening, Polyporus and Bupleuri radix were found to be good candidates to effectively manipulate the peripheral circadian clock phase acutely, with stimulation time-of-day dependency in vitro as well as in vivo. Interestingly, Polyporus and Bupleuri radix are traditional herb medicines use for treating edema and promoting diuresis, and for chronic hepatitis, respectively. These crude drugs may be therefore good modulators of the circadian peripheral clocks including liver and kidney, and circadian clock genes become new molecular targets for these crude drugs. Copyright © 2017 Elsevier Inc. All rights reserved.
Taylor, Daniel J; Clay, Kendra C; Bramoweth, Adam D; Sethi, Kevin; Roane, Brandy M
The current study offers a comprehensive assessment of psychosocial functioning and academic performance in relation to circadian phase preference in a US sample of undergraduate college students (N = 838), aged 17-26 (M = 19.78, SD = 1.89). Women had greater morning preference than men, and seniors had greater morning preference than freshmen. Circadian phase preference, fatigue, perceived stress, depression, anxiety, and substance use were assessed cross-sectionally and grade point average (GPA) was assessed prospectively. Evening phase preference was related to higher levels of fatigue, alcohol and caffeine use, and worse academic performance than morning or intermediate phase preferences.
Gumenyuk, Valentina; Roth, Thomas; Drake, Christopher L
Most night workers are unable to adjust their circadian rhythms to the atypical hours of sleep and wake. Between 10% and 30% of shiftworkers report symptoms of excessive sleepiness and/or insomnia consistent with a diagnosis of shift work disorder (SWD). Difficulties in attaining appropriate shifts in circadian phase, in response to night work, may explain why some individuals develop SWD. In the present study, it was hypothesized that disturbances of sleep and wakefulness in shiftworkers are related to the degree of mismatch between their endogenous circadian rhythms and the night-work schedule of sleep during the day and wake activities at night. Five asymptomatic night workers (ANWs) (3 females; [mean ± SD] age: 39.2 ± 12.5 yrs; mean yrs on shift = 9.3) and five night workers meeting diagnostic criteria (International Classification of Sleep Disorders [ICSD]-2) for SWD (3 females; age: 35.6 ± 8.6 yrs; mean years on shift = 8.4) participated. All participants were admitted to the sleep center at 16:00 h, where they stayed in a dim light (individual melatonin profile. Objective sleepiness was assessed using the multiple sleep latency test (MSLT; 13 trials, 2-h intervals starting at 17:00 h). A Mann-Whitney U test was used for evaluation of differences between groups. The DLMO in ANW group was 04:42 ± 3.25 h, whereas in the SWD group it was 20:42 ± 2.21 h (z = 2.4; p groups, except the SWD group showed an earlier bedtime on off days from work relative to that in ANW group. The MSLT corresponding to night work time (01:00-09:00 h) was significantly shorter (3.6 ± .90 min: [M ± SEM]) in the SWD group compared with that in ANW group (6.8 ± .93 min). DLMO was significantly correlated with insomnia severity (r = -.68; p vs. 180 lux [M ± SD], respectively z = -1.7; p individuals with SWD maintain a circadian phase position similar to day workers, leading to a mismatch/conflict between their endogenous rhythms and their sleep-wake schedule.
Burke, Tina M.; Markwald, Rachel R.; Chinoy, Evan D.; Snider, Jesse A.; Bessman, Sara C.; Jung, Christopher M.; Wright, Kenneth P.
Study Objectives: Photic and non-photic stimuli have been shown to shift the phase of the human circadian clock. We examined how photic and non-photic time cues may be combined by the human circadian system by assessing the phase advancing effects of one evening dose of exogenous melatonin, alone and in combination with one session of morning bright light exposure. Design: Randomized placebo-controlled double-blind circadian protocol. The effects of four conditions, dim light (∼1.9 lux, ∼0.6 Watts/m2)-placebo, dim light-melatonin (5 mg), bright light (∼3000 lux, ∼7 Watts/m2)-placebo, and bright light-melatonin on circadian phase was assessed by the change in the salivary dim light melatonin onset (DLMO) prior to and following treatment under constant routine conditions. Melatonin or placebo was administered 5.75 h prior to habitual bedtime and 3 h of bright light exposure started 1 h prior to habitual wake time. Setting: Sleep and chronobiology laboratory environment free of time cues. Participants: Thirty-six healthy participants (18 females) aged 22 ± 4 y (mean ± SD). Results: Morning bright light combined with early evening exogenous melatonin induced a greater phase advance of the DLMO than either treatment alone. Bright light alone and melatonin alone induced similar phase advances. Conclusion: Information from light and melatonin appear to be combined by the human circadian clock. The ability to combine circadian time cues has important implications for understanding fundamental physiological principles of the human circadian timing system. Knowledge of such principles is important for designing effective countermeasures for phase-shifting the human circadian clock to adapt to jet lag, shift work, and for designing effective treatments for circadian sleep-wakefulness disorders. Citation: Burke TM; Markwald RR; Chinoy ED; Snider JA; Bessman SC; Jung CM; Wright Jr KP. Combination of light and melatonin time cues for phase advancing the human circadian
Madeleine V Garren
Full Text Available There have been several studies on the role of circadian clocks in the regulation of associative learning and memory processes in both vertebrate and invertebrate species. The results have been quite variable and at present it is unclear to what extent the variability observed reflects species differences or differences in methodology. Previous results have shown that following differential classical conditioning in the cockroach, Rhyparobia maderae, in an olfactory discrimination task, formation of the short-term and long-term memory is under strict circadian control. In contrast, there appeared to be no circadian regulation of the ability to recall established memories. In the present study, we show that following operant conditioning of the same species in a very similar olfactory discrimination task, there is no impact of the circadian system on either short-term or long-term memory formation. On the other hand, ability to recall established memories is strongly tied to the circadian phase of training. On the basis of these data and those previously reported for phylogenetically diverse species, it is suggested that there may be fundamental differences in the way the circadian system regulates learning and memory in classical and operant conditioning.
Lee, Kwangwon; Shiva Kumar, Prithvi; McQuade, Sean; Lee, Joshua Y; Park, Sohyun; An, Zheming; Piccoli, Benedetto
Circadian rhythms are observed in most organisms on earth and are known to play a major role in successful adaptation to the 24-h cycling environment. Circadian phenotypes are characterized by a free-running period that is observed in constant conditions and an entrained phase that is observed in cyclic conditions. Thus, the relationship between the free-running period and phase of entrainment is of interest. A popular simple rule has been that the entrained phase is the expression of the period in a cycling environment (i.e., that a short period causes an advanced phase and a long period causes a delayed phase). However, there are experimental data that are not explained by this simple relationship, and no systematic study has been done to explore all possible period-phase relationships. Here, we show the existence of stable period-phase relationships that are exceptions to this rule. First, we analyzed period-phase relationships using populations with different degrees of genome complexity. Second, we generated isogenic F1 populations by crossing 14 classical period mutants to the same female and analyzed 2 populations with a short period/delayed phase and a long period/advanced phase. Third, we generated a mathematical model to account for such variable relationships between period and phase. Our analyses support the view that the circadian period of an organism is not the only predictor of the entrained phase.
Ferrante, Andrew; Gellerman, David; Ay, Ahmet; Woods, Kerri Pruitt; Filipowicz, Allan Michael; Jain, Kriti; Bearden, Neil; Ingram, Krista Kenyon
Circadian rhythms play an integral role in human behavior, physiology and health. Individual differences in daily rhythms (chronotypes) can affect individual sleep-wake cycles, activity patterns and behavioral choices. Diurnal preference, the tendency towards morningness or eveningness among individuals, has been associated with interpersonal variation in circadian clock-related output measures, including body temperature, melatonin levels and clock gene mRNA in blood, oral mucosa, and dermal fibroblast cell cultures. Here we report gene expression data from two principal clock genes sampled from hair follicle cells, a peripheral circadian clock. Hair follicle cells from fourteen individuals of extreme morning or evening chronotype were sampled at three time points. RNA was extracted and quantitative PCR assays were used to measure mRNA expression patterns of two clock genes, Per3 and Nr1d2. We found significant differences in clock gene expression over time between chronotype groups, independent of gender or age of participants. Extreme evening chronotypes have a delay in phase of circadian clock gene oscillation relative to extreme morning types. Variation in the molecular clockwork of chronotype groups represents nearly three-hour phase differences (Per3: 2.61 hours; Nr1d2: 3.08 hours, both: 2.86) in circadian oscillations of these clock genes. The measurement of gene expression from hair follicles at three time points allows for a direct, efficient method of estimating phase shifts of a peripheral circadian clock in real-life conditions. The robust phase differences in temporal expression of clock genes associated with diurnal preferences provide the framework for further studies of the molecular mechanisms and gene-by-environment interactions underlying chronotype-specific behavioral phenomena, including social jetlag.
Rüger, Melanie; Gordijn, Marijke C.M.; Beersma, Domien G.M.; de Vries, Bonnie; Daan, Serge
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
Dijk, Derk-Jan; Brunner, Daniel P.; Beersma, Domien G.M.; Borbély, Alexander A.
Human sleep electroencephalograms, recorded in four experiments, were subjected to spectral analysis. Waking prior to sleep varied from 12 to 36 h and sleep was initiated at different circadian phases. Power density of delta and theta frequencies in rapid-eye-movement (REM) sleep and non-REM (NREM)
Van Reen, Eliza; Sharkey, Katherine M; Roane, Brandy M; Barker, David; Seifer, Ronald; Raffray, Tifenn; Bond, Tamara L; Carskadon, Mary A
Sex differences in circadian rhythms have been reported with some conflicting results. The timing of sleep and length of time in bed have not been considered, however, in previous such studies. The current study has 3 major aims: (1) replicate previous studies in a large sample of young adults for sex differences in sleep patterns and dim light melatonin onset (DLMO) phase; (2) in a subsample constrained by matching across sex for bedtime and time in bed, confirm sex differences in DLMO and phase angle of DLMO to bedtime; (3) explore sex differences in the influence of sleep timing and length of time in bed on phase angle. A total of 356 first-year Brown University students (207 women) aged 17.7 to 21.4 years (mean = 18.8 years, SD = 0.4 years) were included in these analyses. Wake time was the only sleep variable that showed a sex difference. DLMO phase was earlier in women than men and phase angle wider in women than men. Shorter time in bed was associated with wider phase angle in women and men. In men, however, a 3-way interaction indicated that phase angles were influenced by both bedtime and time in bed; a complex interaction was not found for women. These analyses in a large sample of young adults on self-selected schedules confirm a sex difference in wake time, circadian phase, and the association between circadian phase and reported bedtime. A complex interaction with length of time in bed occurred for men but not women. We propose that these sex differences likely indicate fundamental differences in the biology of the sleep and circadian timing systems as well as in behavioral choices.
Mark S. Rea
Full Text Available The present study was aimed at further elucidating the relationship between circadian phase, rising time, and the morning cortisol awakening response (CAR. The results presented here are a secondary analysis of experimental data obtained from a study of advanced sleep-wake schedules and light exposures on circadian phase advances measured by dim-light melatonin onset (DLMO. The present results demonstrate that morning CAR is strongly related to rising time and more weakly related to DLMO phase.
Cajochen, C.; Khalsa, S. B.; Wyatt, J. K.; Czeisler, C. A.; Dijk, D. J.
The aim of this study was to quantify the associations between slow eye movements (SEMs), eye blink rate, waking electroencephalogram (EEG) power density, neurobehavioral performance, and the circadian rhythm of plasma melatonin in a cohort of 10 healthy men during up to 32 h of sustained wakefulness. The time course of neurobehavioral performance was characterized by fairly stable levels throughout the first 16 h of wakefulness followed by deterioration during the phase of melatonin secretion. This deterioration was closely associated with an increase in SEMs. Frontal low-frequency EEG activity (1-7 Hz) exhibited a prominent increase with time awake and little circadian modulation. EEG alpha activity exhibited circadian modulation. The dynamics of SEMs and EEG activity were phase locked to changes in neurobehavioral performance and lagged the plasma melatonin rhythm. The data indicate that frontal areas of the brain are more susceptible to sleep loss than occipital areas. Frontal EEG activity and ocular parameters may be used to monitor and predict changes in neurobehavioral performance associated with sleep loss and circadian misalignment.
Rex Katharine M
Full Text Available Abstract Background The phase of a circadian rhythm reflects where the peak and the trough occur, for example, the peak and trough of performance within the 24 h. Light exposure can shift this phase. More extensive knowledge of the human circadian phase response to light is needed to guide light treatment for shiftworkers, air travelers, and people with circadian rhythm phase disorders. This study tested the hypotheses that older adults have absent or weaker phase-shift responses to light (3000 lux, and that women's responses might differ from those of men. Methods After preliminary health screening and home actigraphic recording baselines, 50 young adults (ages 18–31 years and 56 older adults (ages 59–75 years remained in light-controlled laboratory surroundings for 4.7 to 5.6 days, while experiencing a 90-min ultra-short sleep-wake cycle. Following at least 30 h in-lab baseline, over the next 51 h, participants were given 3 treatments with 3000 lux white light, each treatment for 3 h, centered at one of 8 clock times. The circadian rhythms of urinary aMT6s (a melatonin metabolite, free cortisol, oral temperature, and wrist activity were assessed at baseline and after treatment. Results Light (3000 lux for 3 h on 3 days induced maximal phase shifts of about 3 h. Phase shifts did not differ significantly in amplitude among older and young groups or among women and men. At home and at baseline, compared to the young, the older adults were significantly phase-advanced in sleep, cortisol, and aMT6s onset, but not advanced in aMT6s acrophase or the temperature rhythm. The inflection from delays to advances was approximately 1.8 h earlier among older compared to young participants in reference to their aMT6s rhythm peaks, and it was earlier in clock time. Conclusion In these experimental conditions, 3000 lux light could shift the phase of circadian rhythms to about the same extent among older and young adults, but the optimal light timing for
Full Text Available The circadian clock regulates metabolic homeostasis and its disruption predisposes to obesity and other metabolic diseases. However, the effect of phase shifts on metabolism is not completely understood. We examined whether alterations in the circadian rhythm caused by phase shifts induce metabolic changes in crucial genes that would predispose to obesity. Three-month-old rats were maintained on a standard diet under lighting conditions with chronic phase shifts consisting of advances, delays or advances plus delays. Serum leptin, insulin and glucose levels decreased only in rats subjected to advances. The expression of the clock gene Bmal 1 increased in the hypothalamus, white adipose tissue (WAT, brown adipose tissue (BAT and liver of the advanced group compared to control rats. The advanced group showed an increase in hypothalamic AgRP and NPY mRNA, and their lipid metabolism gene profile was altered in liver, WAT and BAT. WAT showed an increase in inflammation and ER stress and brown adipocytes suffered a brown-to-white transformation and decreased UCP-1 expression. Our results indicate that chronic phase advances lead to significant changes in neuropeptides, lipid metabolism, inflammation and ER stress gene profile in metabolically relevant tissues such as the hypothalamus, liver, WAT and BAT. This highlights a link between alteration of the circadian rhythm and metabolism at the transcriptional level.
Schulz, Pierre; Steimer, Thierry
Time is a dimension tightly associated with the biology of living species. There are cycles of varied lengths in biological activities, from very short (ultradian) rhythms to rhythms with a period of approximately one day (circadian) and rhythms with longer cycles, of a week, a month, a season, or even longer. These rhythms are generated by endogenous biological clocks, i.e. time-keeping structures, rather than being passive reactions to external fluctuations. In mammals, the suprachiasmatic nucleus (SCN) is the major pacemaker. The pineal gland, which secretes melatonin, is the major pacemaker in other phyla. There also exist biological clocks generating circadian rhythms in peripheral tissues, for example the liver. A series of clock genes generates the rhythm through positive and negative feedback effect of proteins on their own synthesis, and this system oscillates with a circadian period. External factors serve as indicators of the astronomical (solar) time and are called zeitgebers, literally time-givers. Light is the major zeitgeber, which resets daily the SCN circadian clock. In the absence of zeitgebers, the circadian rhythm is said to be free running; it has a period that differs from 24 hours. The SCN, together with peripheral clocks, enables a time-related homeostasis, which can become disorganized in its regulation by external factors (light, social activities, food intake), in the coordination and relative phase position of rhythms, or in other ways. Disturbances of rhythms are found in everyday life (jet lag, shift work), in sleep disorders, and in several psychiatric disorders including affective disorders. As almost all physiological and behavioural functions in humans occur on a rhythmic basis, the possibility that advances, delays or desynchronization of circadian rhythms might participate in neurological and psychiatric disorders has been a theme of research. In affective disorders, a decreased circadian amplitude of several rhythms as well as a
Silva, Edward J; Duffy, Jeanne F
The purpose of our analysis was to determine if older adults show sleep inertia effects on performance at scheduled wake time, and whether these effects depend on circadian phase or sleep stage at awakening. Using the Digit Symbol Substitution Test, effects of sleep inertia on performance were assessed over the first 30 min after wake time on baseline days and when sleep was scheduled at different circadian phases. Mixed model analyses revealed that performance improved as time awake increased; that beginning levels of performance were poorest when wake time was scheduled to occur during the biological night; and that effects of sleep inertia on performance during the biological night were greater when awaking from non-REM (NREM) sleep than from REM sleep. Based on our current understanding of sleep inertia effects in young subjects, and previous reports that older subjects awaken at an earlier circadian phase and are more likely to have their final awakening from NREM sleep than younger adults, our findings suggest older adults may be more vulnerable to sleep inertia effects than young adults.
Saini, Camille; Morf, Jörg; Stratmann, Markus; Gos, Pascal; Schibler, Ueli
The circadian pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus maintains phase coherence in peripheral cells through metabolic, neuronal, and humoral signaling pathways. Here, we investigated the role of daily body temperature fluctuations as possible systemic cues in the resetting of peripheral oscillators. Using precise temperature devices in conjunction with real-time monitoring of the bioluminescence produced by circadian luciferase reporter genes, we showed that simulated body temperature cycles of mice and even humans, with daily temperature differences of only 3°C and 1°C, respectively, could gradually synchronize circadian gene expression in cultured fibroblasts. The time required for establishing the new steady-state phase depended on the reporter gene, but after a few days, the expression of each gene oscillated with a precise phase relative to that of the temperature cycles. Smooth temperature oscillations with a very small amplitude could synchronize fibroblast clocks over a wide temperature range, and such temperature rhythms were also capable of entraining gene expression cycles to periods significantly longer or shorter than 24 h. As revealed by genetic loss-of-function experiments, heat-shock factor 1 (HSF1), but not HSF2, was required for the efficient synchronization of fibroblast oscillators to simulated body temperature cycles. PMID:22379191
Saini, Camille; Morf, Jörg; Stratmann, Markus; Gos, Pascal; Schibler, Ueli
The circadian pacemaker in the suprachiasmatic nuclei (SCN) of the hypothalamus maintains phase coherence in peripheral cells through metabolic, neuronal, and humoral signaling pathways. Here, we investigated the role of daily body temperature fluctuations as possible systemic cues in the resetting of peripheral oscillators. Using precise temperature devices in conjunction with real-time monitoring of the bioluminescence produced by circadian luciferase reporter genes, we showed that simulated body temperature cycles of mice and even humans, with daily temperature differences of only 3°C and 1°C, respectively, could gradually synchronize circadian gene expression in cultured fibroblasts. The time required for establishing the new steady-state phase depended on the reporter gene, but after a few days, the expression of each gene oscillated with a precise phase relative to that of the temperature cycles. Smooth temperature oscillations with a very small amplitude could synchronize fibroblast clocks over a wide temperature range, and such temperature rhythms were also capable of entraining gene expression cycles to periods significantly longer or shorter than 24 h. As revealed by genetic loss-of-function experiments, heat-shock factor 1 (HSF1), but not HSF2, was required for the efficient synchronization of fibroblast oscillators to simulated body temperature cycles.
Mazzoccoli, Gianluigi; Giuliani, Francesco; Sothern, Robert B
A quantifiable and reliable technique for the determination of body circadian phase applicable to non-laboratory studies would allow the evaluation of circadian dysregulation. In this study we evaluated feasible methodologies to individualize whole body circadian phase in lung cancer patients. Cortisol and melatonin serum levels were measured in blood samples collected every 4 h for 24 h from eleven male controls and nine men suffering from non-small cell lung cancer. Circadian rhythmicity was evaluated and the 4-hourly fractional variations (FV) were calculated to evaluate the dynamics of the rise and fall in serum levels. Overall cortisol serum levels were higher in cancer patients (pmelatonin, but not significantly (p=0.261). Original serum levels of cortisol and melatonin each showed a prominent 24 h oscillation in both study groups, with highest values at night for melatonin and near awakening for cortisol. Using all data after normalization to percent of individual mean, ANOVA detected a significant time-effect (pcortisol in cancer patients and higher for melatonin, but these differences were not significant. FV levels of cortisol and melatonin each showed a prominent 24 h oscillation in both study groups, with highest values prior to darkness onset for melatonin and near mid-dark for cortisol. ANOVA also detected a significant time-effect (pmelatonin and ∼5 h for cortisol. A chronobiological evaluation of serum levels and fractional variations for cortisol and especially melatonin is a valuable methodology to define body circadian phase in lung cancer patients. It is possible to describe the complex process of hormone secretion with a methodology that allows the definition of both temporal characteristics and dynamic components. This kind of analysis might be useful in the study of hormone secretion(s) in cancer patients and other diseases and to guide therapeutic interventions. While lung cancer patients may have a negative prognostic value based upon
Wright, K. P. Jr; Badia, P.; Czeisler, C. A. (Principal Investigator)
The influence of menstrual cycle phase and oral contraceptive use on neurobehavioral function and circadian rhythms were studied in healthy young women (n = 25) using a modified constant routine procedure during 24 h of sleep deprivation. Alertness and performance worsened across sleep deprivation and also varied with circadian phase. Entrained circadian rhythms of melatonin and body temperature were evident in women regardless of menstrual phase or oral contraceptive use. No significant difference in melatonin levels, duration, or phase was observed between women in the luteal and follicular phases, whereas oral contraceptives appeared to increase melatonin levels. Temperature levels were higher in the luteal phase and in oral contraceptive users compared to women in the follicular phase. Alertness on the maintenance of wakefulness test and some tests of cognitive performance were poorest for women in the follicular phase especially near the circadian trough of body temperature. These observations suggest that hormonal changes associated with the menstrual cycle and the use of oral contraceptives contribute to changes in nighttime waking neurobehavioral function and temperature level whereas these factors do not appear to affect circadian phase.
Stone, Julia E; Sletten, Tracey L; Magee, Michelle; Ganesan, Saranea; Mulhall, Megan D; Collins, Allison; Howard, Mark; Lockley, Steven W; Rajaratnam, Shantha M W
Shift work is highly prevalent and is associated with significant adverse health impacts. There is substantial inter-individual variability in the way the circadian clock responds to changing shift cycles. The mechanisms underlying this variability are not well understood. We tested the hypothesis that light-dark exposure is a significant contributor to this variability; when combined with diurnal preference, the relative timing of light exposure accounted for 71% of individual variability in circadian phase response to night shift work. These results will drive development of personalised approaches to manage circadian disruption among shift workers and other vulnerable populations to potentially reduce the increased risk of disease in these populations. Night shift workers show highly variable rates of circadian adaptation. This study examined the relationship between light exposure patterns and the magnitude of circadian phase resetting in response to night shift work. In 21 participants (nursing and medical staff in an intensive care unit) circadian phase was measured using 6-sulphatoxymelatonin at baseline (day/evening shifts or days off) and after 3-4 consecutive night shifts. Daily light exposure was examined relative to individual circadian phase to quantify light intensity in the phase delay and phase advance portions of the light phase response curve (PRC). There was substantial inter-individual variability in the direction and magnitude of phase shift after three or four consecutive night shifts (mean phase delay -1:08 ± 1:31 h; range -3:43 h delay to +3:07 h phase advance). The relative difference in the distribution of light relative to the PRC combined with diurnal preference accounted for 71% of the variability in phase shift. Regression analysis incorporating these factors estimated phase shift to within ±60 min in 85% of participants. No participants met criteria for partial adaptation to night work after three or four consecutive night
Lewy, Alfred J; Rough, Jennifer N; Songer, Jeannine B; Mishra, Neelam; Yuhas, Krista; Emens, Jonathan S
The finding that bright light can suppress melatonin production led to the study of two situations, indeed, models, of light deprivation: totally blind people and winter depressives. The leading hypothesis for winter depression (seasonal affective disorder, or SAD) is the phase shift hypothesis (PSH). The PSH was recently established in a study in which SAD patients were given low-dose melatonin in the afternoon/evening to cause phase advances, or in the morning to cause phase delays, or placebo. The prototypical phase-delayed patient, as well as the smaller subgroup of phase-advanced patients, optimally responded to melatonin given at the correct time. Symptom severity improved as circadian misalignment was corrected. Circadian misalignment is best measured as the time interval between the dim light melatonin onset (DLMO) and mid-sleep. Using the operational definition of the plasma DLMO as the interpolated time when melatonin levels continuously rise above the threshold of 10 pg/mL, the average interval between DLMO and mid-sleep in healthy controls is 6 hours, which is associated with optimal mood in SAD patients.
Steinan, Mette Kvisten; Morken, Gunnar; Lagerberg, Trine V; Melle, Ingrid; Andreassen, Ole A; Vaaler, Arne E; Scott, Jan
Theoretical models of Bipolar Disorder (BD) highlight that sleep disturbances may be a marker of underlying circadian dysregulation. However, few studies of sleep in BD have reported on the most prevalent circadian sleep abnormality, namely Delayed Sleep Phase (DSP). A cross-sectional study of 404 adults with BD who met published clinical criteria for insomnia, hypersomnia or DSP, and who had previously participated in a study of sleep in BD using a comprehensive structured interview assessment. About 10% of BD cases with a sleep problem met criteria for a DSP profile. The DSP group was younger and had a higher mean Body Mass Index (BMI) than the other groups. Also, DSP cases were significantly more likely to be prescribed mood stabilizers and antidepressant than insomnia cases. An exploratory analysis of selected symptom item ratings indicated that DSP was significantly more likely to be associated with impaired energy and activity levels. The cross-sectional design precludes examination of longitudinal changes. DSP is identified by sleep profile, not by diagnostic criteria or objective sleep records such as actigraphy. The study uses data from a previous study to identify and examine the DSP group. The DSP group identified in this study can be differentiated from hypersomnia and insomnia groups on the basis of clinical and demographic features. The association of DSP with younger age, higher BMI and impaired energy and activity also suggest that this clinical profile may be a good proxy for underlying circadian dysregulation. Copyright © 2015 Elsevier B.V. All rights reserved.
Ortiz-Tudela, Elisabet; Martinez-Nicolas, Antonio; Albares, Javier; Segarra, Francesc; Campos, Manuel; Estivill, Eduard; Rol, Maria Angeles; Madrid, Juan Antonio
An integrated variable based on the combination of wrist Temperature, motor Activity and body Position (TAP) was previously developed at our laboratory to evaluate the functioning of the circadian system and sleep-wake rhythm under ambulatory conditions. However, the reliability of TAP needed to be validated with polysomnography (PSG). 22 subjects suffering from sleep disorders were monitored for one night with a temperature sensor (iButton), an actimeter (HOBO) and exploratory PSG. Mean waveforms, sensitivity (SE), specificity (SP), agreement rates (AR) and comparisons between TAP and sleep stages were studied. The TAP variable was optimized for SE, SP and AR with respect to each individual variable (SE: 92%; SP: 78%; AR: 86%). These results improved upon estimates previously published for actigraphy. Furthermore, TAP values tended to decrease as sleep depth increased, reaching the lowest point at phase 3. Finally, TAP estimates for sleep latency (SL: 37±9 min), total sleep time (TST: 367±13 min), sleep efficiency (SE: 86.8±1.9%) and number of awakenings (NA>5 min: 3.3±.4) were not significantly different from those obtained with PSG (SL: 29±4 min; SE: 89.9±1.8%; NA>5 min: 2.3±.4), despite the heterogeneity of the sleep pathologies monitored. The TAP variable is a novel measurement for evaluating circadian system status and sleep-wake rhythms with a level of reliability better to that of actigraphy. Furthermore, it allows the evaluation of a patient's sleep-wake rhythm in his/her normal home environment, and at a much lower cost than PSG. Future studies in specific pathologies would verify the relevance of TAP in those conditions. Copyright © 2014 Elsevier Inc. All rights reserved.
Juárez-Tapia, Cinthia; Miranda-Anaya, Manuel
Recently, the relationship between the circadian system and female reproduction has been of great interest; ovarian hormones can modify the amount and distribution of daily activity differently in rodent species. The volcano mouse Neotomodon alstoni is a species in which it is possible to study the circadian rhythm of locomotion, and it offers comparative information about the influence of ovaries on the circadian system. In this study, we used infrared crossings to compare free movement in intact and sham-operated or ovariectomized mice. We analyzed behavioral and endocrine changes related to the estrous cycle and locomotor circadian rhythm in free-running mice and photic phase shifting. Evidence shows that intact mice present a scalloped pattern of daily activity during the estrous cycle. In constant darkness, the ovariectomy reduces the total amount of activity, shortens the free-running circadian period of locomotion and increases photic phase shifts during the early subjective night. During entrainment, the ovariectomized mice increased the amplitude of total activity during the scotophase, and delay the time of activity onset. These results suggest that ovarian hormones in N. alstoni modulate the circadian rhythm of locomotor activity in a species-specific manner. Copyright © 2017 Elsevier Inc. All rights reserved.
Naismith, Sharon L; Lagopoulos, Jim; Hermens, Daniel F; White, Django; Duffy, Shantel L; Robillard, Rebecca; Scott, Elizabeth M; Hickie, Ian B
While the association between affective disorders and sleep and circadian disturbance is well established, little is known about the neurobiology underpinning these relationships. In this study, we sought to determine the relationship between a marker of circadian rhythm and neuronal integrity (N-Acetyl Aspartate, NAA), oxidative stress (glutathione, GSH) and neuronal-glial dysfunction (Glutamate + Glutamine, Glx). Fifty-three young adults (age range 15-33 years, mean = 21.8, sd = 4.3) with emerging affective disorders were recruited from a specialized tertiary referral service. Participants underwent clinical assessment and actigraphy monitoring, from which sleep midpoint was calculated as a marker of circadian rhythm. Proton magnetic resonance spectroscopy was performed in the anterior cingulate cortex (ACC). The metabolites NAA, GSH and Glx were obtained, and expressed as a ratio to Creatine. Neither NAA or GSH were associated with sleep midpoint. However, higher levels of ACC Glx were associated with later sleep midpoints (rho = 0.35, p = 0.013). This relationship appeared to be independent of age and depression severity. This study is the first to demonstrate that delayed circadian phase is related to altered glutamatergic processes. It is aligned with animal research linking circadian rhythms with glutamatergic neurotransmission as well as clinical studies showing changes in glutamate with sleep interventions. Further studies may seek to examine the role of glutamate modulators for circadian misalignment.
Youngstedt, Shawn D; Kline, Christopher E; Elliott, Jeffrey A; Zielinski, Mark R; Devlin, Tina M; Moore, Teresa A
Limited research has compared the circadian phase-shifting effects of bright light and exercise and additive effects of these stimuli. The aim of this study was to compare the phase-delaying effects of late night bright light, late night exercise, and late evening bright light followed by early morning exercise. In a within-subjects, counterbalanced design, 6 young adults completed each of three 2.5-day protocols. Participants followed a 3-h ultra-short sleep-wake cycle, involving wakefulness in dim light for 2h, followed by attempted sleep in darkness for 1 h, repeated throughout each protocol. On night 2 of each protocol, participants received either (1) bright light alone (5,000 lux) from 2210-2340 h, (2) treadmill exercise alone from 2210-2340 h, or (3) bright light (2210-2340 h) followed by exercise from 0410-0540 h. Urine was collected every 90 min. Shifts in the 6-sulphatoxymelatonin (aMT6s) cosine acrophase from baseline to post-treatment were compared between treatments. Analyses revealed a significant additive phase-delaying effect of bright light + exercise (80.8 ± 11.6 [SD] min) compared with exercise alone (47.3 ± 21.6 min), and a similar phase delay following bright light alone (56.6 ± 15.2 min) and exercise alone administered for the same duration and at the same time of night. Thus, the data suggest that late night bright light followed by early morning exercise can have an additive circadian phase-shifting effect.
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
Micic, Gorica; de Bruyn, Amanda; Lovato, Nicole; Wright, Helen; Gradisar, Michael; Ferguson, Sally; Burgess, Helen J; Lack, Leon
The currently assumed aetiology for delayed sleep phase disorder (DSPD) is a delay of the circadian system. Clinicians have sought to use bright light therapy, exogenous melatonin or chronotherapy to correct the disorder. However, these treatments have achieved unreliable outcomes for DSPD patients and, as such, one suggestion has been that the disorder may be caused by a longer than normal circadian rhythm period length (i.e. tau). The present study investigated this premise using a 78-h ultradian, ultra-short sleep-wake cycle. This constant bedrest routine was used to simulate a series of 1-h long 'days' by alternating 20-min sleep opportunities and 40 min of enforced wakefulness. Thirteen participants were recruited for the study including, six people diagnosed with DSPD according to the International Classification of Sleep Disorders-2 [mean age = 22.0, standard deviation (SD) = 3.3] and seven good sleepers (mean age = 23.1, SD = 3.9) with normal sleep timing. The DSPD participants' core temperature rhythm tau (mean = 24 h 54 min, SD = 23 min) was significantly longer (t = -2.33, P = 0.04, Cohen's d = 1.91) than the good sleepers' (mean 24 h 29 min, SD = 16 min). The temperature rhythm of the DSPD participants delayed more rapidly (i.e. >25 min day(-1) ) than the good sleepers'. These findings provide an explanation for the difficulty that DSPD patients have in phase advancing to a more conventional sleep time and their frequent relapse following treatment. The outcomes of this study support a vigorous and continued application of chronobiological and behavioural therapies to entrain DSPD patients to their desired earlier sleep times. © 2013 European Sleep Research Society.
Burgess, Helen J; Park, Margaret; Wyatt, James K; Rizvydeen, Muneer; Fogg, Louis F
To compare sleep and circadian variability in adults with delayed sleep-wake phase disorder (DSWPD) to healthy controls. Forty participants (22 DSWPD, 18 healthy controls) completed a ten-day protocol, consisting of DLMO assessments on two consecutive nights, a five-day study break, followed by two more DLMO assessments. All participants were instructed to sleep within one hour of their self-reported average sleep schedule for the last four days of the study break. We analyzed the participants' wrist actigraphy data during these four days to examine intraindividual variability in sleep timing, duration and efficiency. We also examined shifts in the DLMO from before and after the study break. Under the same conditions, people with DSWPD had significantly more variable wake times and total sleep time than healthy controls (p ≤ 0.015). Intraindividual variability in sleep onset time and sleep efficiency was similar between the two groups (p ≥ 0.30). The DLMO was relatively stable across the study break, with only 11% of controls but 27% of DSWPDs showed more than a one hour shift in the DLMO. Only in the DSWPD sample was greater sleep variability associated with a larger shift in the DLMO (r = 0.46, p = 0.03). These results suggest that intraindividual variability in sleep can be higher in DSWPD versus healthy controls, and this may impact variability in the DLMO. DSWPD patients with higher intraindividual variability in sleep are more likely to have a shifting DLMO, which could impact sleep symptoms and the optimal timing of light and/or melatonin treatment for DSWPD. Circadian Phase Assessments at Home, http://clinicaltrials.gov/show/NCT01487252, NCT01487252. Copyright © 2017 Elsevier B.V. All rights reserved.
Melo, Irene; Ehrlich, Ingrid
Sleep promotes memory, particularly for declarative learning. However, its role in non-declarative, emotional memories is less well understood. Some studies suggest that sleep may influence fear-related memories, and thus may be an important factor determining the outcome of treatments for emotional disorders such as post-traumatic stress disorder. Here, we investigated the effect of sleep deprivation and time of day on fear extinction memory consolidation. Mice were subjected to a cued Pavlovian fear and extinction paradigm at the beginning of their resting or active phase. Immediate post-extinction learning sleep deprivation for 5h compromised extinction memory when tested 24h after learning. Context-dependent extinction memory recall was completely prevented by sleep-manipulation during the resting phase, while impairment was milder during the active phase and extinction memory retained its context-specificity. Importantly, control experiments excluded confounding factors such as differences in baseline locomotion, fear generalization and stress hormone levels. Together, our findings indicate that post-learning sleep supports cued fear extinction memory consolidation in both circadian phases. The lack of correlation between memory efficacy and sleep time suggests that extinction memory may be influenced by specific sleep events in the early consolidation period. Copyright © 2016 Elsevier Inc. All rights reserved.
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.
Lo, June C.; Groeger, John A.; Santhi, Nayantara; Arbon, Emma L.; Lazar, Alpar S.; Hasan, Sibah; von Schantz, Malcolm; Archer, Simon N.; Dijk, Derk-Jan
Background Cognitive performance deteriorates during extended wakefulness and circadian phase misalignment, and some individuals are more affected than others. Whether performance is affected similarly across cognitive domains, or whether cognitive processes involving Executive Functions are more sensitive to sleep and circadian misalignment than Alertness and Sustained Attention, is a matter of debate. Methodology/Principal Findings We conducted a 2 × 12-day laboratory protocol to characterize the interaction of repeated partial and acute total sleep deprivation and circadian phase on performance across seven cognitive domains in 36 individuals (18 males; mean ± SD of age = 27.6±4.0 years). The sample was stratified for the rs57875989 polymorphism in PER3, which confers cognitive susceptibility to total sleep deprivation. We observed a deterioration of performance during both repeated partial and acute total sleep deprivation. Furthermore, prior partial sleep deprivation led to poorer cognitive performance in a subsequent total sleep deprivation period, but its effect was modulated by circadian phase such that it was virtually absent in the evening wake maintenance zone, and most prominent during early morning hours. A significant effect of PER3 genotype was observed for Subjective Alertness during partial sleep deprivation and on n-back tasks with a high executive load when assessed in the morning hours during total sleep deprivation after partial sleep loss. Overall, however, Subjective Alertness and Sustained Attention were more affected by both partial and total sleep deprivation than other cognitive domains and tasks including n-back tasks of Working Memory, even when implemented with a high executive load. Conclusions/Significance Sleep loss has a primary effect on Sleepiness and Sustained Attention with much smaller effects on challenging Working Memory tasks. These findings have implications for understanding how sleep debt and circadian rhythmicity
Lo, June C; Groeger, John A; Santhi, Nayantara; Arbon, Emma L; Lazar, Alpar S; Hasan, Sibah; von Schantz, Malcolm; Archer, Simon N; Dijk, Derk-Jan
Cognitive performance deteriorates during extended wakefulness and circadian phase misalignment, and some individuals are more affected than others. Whether performance is affected similarly across cognitive domains, or whether cognitive processes involving Executive Functions are more sensitive to sleep and circadian misalignment than Alertness and Sustained Attention, is a matter of debate. We conducted a 2 × 12-day laboratory protocol to characterize the interaction of repeated partial and acute total sleep deprivation and circadian phase on performance across seven cognitive domains in 36 individuals (18 males; mean ± SD of age = 27.6 ± 4.0 years). The sample was stratified for the rs57875989 polymorphism in PER3, which confers cognitive susceptibility to total sleep deprivation. We observed a deterioration of performance during both repeated partial and acute total sleep deprivation. Furthermore, prior partial sleep deprivation led to poorer cognitive performance in a subsequent total sleep deprivation period, but its effect was modulated by circadian phase such that it was virtually absent in the evening wake maintenance zone, and most prominent during early morning hours. A significant effect of PER3 genotype was observed for Subjective Alertness during partial sleep deprivation and on n-back tasks with a high executive load when assessed in the morning hours during total sleep deprivation after partial sleep loss. Overall, however, Subjective Alertness and Sustained Attention were more affected by both partial and total sleep deprivation than other cognitive domains and tasks including n-back tasks of Working Memory, even when implemented with a high executive load. Sleep loss has a primary effect on Sleepiness and Sustained Attention with much smaller effects on challenging Working Memory tasks. These findings have implications for understanding how sleep debt and circadian rhythmicity interact to determine waking performance across cognitive domains
June C Lo
Full Text Available BACKGROUND: Cognitive performance deteriorates during extended wakefulness and circadian phase misalignment, and some individuals are more affected than others. Whether performance is affected similarly across cognitive domains, or whether cognitive processes involving Executive Functions are more sensitive to sleep and circadian misalignment than Alertness and Sustained Attention, is a matter of debate. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a 2 × 12-day laboratory protocol to characterize the interaction of repeated partial and acute total sleep deprivation and circadian phase on performance across seven cognitive domains in 36 individuals (18 males; mean ± SD of age = 27.6 ± 4.0 years. The sample was stratified for the rs57875989 polymorphism in PER3, which confers cognitive susceptibility to total sleep deprivation. We observed a deterioration of performance during both repeated partial and acute total sleep deprivation. Furthermore, prior partial sleep deprivation led to poorer cognitive performance in a subsequent total sleep deprivation period, but its effect was modulated by circadian phase such that it was virtually absent in the evening wake maintenance zone, and most prominent during early morning hours. A significant effect of PER3 genotype was observed for Subjective Alertness during partial sleep deprivation and on n-back tasks with a high executive load when assessed in the morning hours during total sleep deprivation after partial sleep loss. Overall, however, Subjective Alertness and Sustained Attention were more affected by both partial and total sleep deprivation than other cognitive domains and tasks including n-back tasks of Working Memory, even when implemented with a high executive load. CONCLUSIONS/SIGNIFICANCE: Sleep loss has a primary effect on Sleepiness and Sustained Attention with much smaller effects on challenging Working Memory tasks. These findings have implications for understanding how sleep debt and
Figueiro, Mariana G; Plitnick, Barbara; Rea, Mark S
Chronotype characterizes individual differences in sleep/wake rhythm timing, which can also impact light exposure patterns. The present study investigated whether early and late chronotypes respond differently to controlled advancing and delaying light exposure patterns while on a fixed, advanced sleep/wake schedule. In a mixed design, 23 participants (11 late chronotypes and 12 early chronotypes) completed a 2-week, advanced sleep/wake protocol twice, once with an advancing light exposure pattern and once with a delaying light exposure pattern. In the advancing light exposure pattern, the participants received short-wavelength light in the morning and short-wavelength-restricting orange-tinted glasses in the evening. In the delaying light exposure pattern, participants received short-wavelength-restricting orange-tinted glasses in the morning and short-wavelength light in the evening. Light/dark exposures were measured with the Daysimeter. Salivary dim light melatonin onset (DLMO) was also measured. Compared to the baseline week, DLMO was significantly delayed after the delaying light intervention and significantly advanced after the advancing light intervention in both groups. There was no significant difference in how the two chronotype groups responded to the light intervention. The present results demonstrate that circadian phase changes resulting from light interventions are consistent with those predicted by previously published phase response curves (PRCs) for both early and late chronotypes. Copyright © 2014 Elsevier B.V. All rights reserved.
Kocher, Laurence; Brun, Jocelyne; Devillard, Françoise; Azabou, Eric; Claustrat, Bruno
Melatonin secretion is usually increased during the daytime and decreased at night in Smith-Magenis syndrome (SMS) and consequently is not a pertinent marker of the circadian phase of the clock in these cases. No data on temperature rhythm is available in SMS, another reliable marker of circadian clock activity. For this reason, we assessed the 24h profiles of core temperature, sleep-wake cycle, hormones (plasma cortisol and melatonin) and plasma and urine 6sulfatoxy-melatonin, the main hepatic melatonin metabolism in a 31-year-old man diagnosed with a SMS. All circadian rhythms, especially temperature rhythm showed a phase-advance, associated with reverse melatonin secretion. Plasma and urine 6sulfatoxy-melatonin profiles showed normal melatonin catabolism and confirmed the reversed melatonin secretion. Taking in consideration the reverse melatonin secretion and the phase-advanced temperature rhythm, which is driven by the suprachiasmatic nucleus, we hypothesize that the central clock is more sensitive to afternoon than to morning melatonin. This different responsiveness to melatonin according to the time of the day (i.e. chronaesthesia) corroborates the phase response curve of melatonin secretion to exogenous melatonin. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
Full Text Available Recent reports have illustrated a reciprocal relationship between circadian rhythm disruption and mood disorders. The 5-HT7 receptor may provide a crucial link between the two sides of this equation since the receptor plays a critical role in sleep, depression, and circadian rhythm regulation. To further define the role of the 5-HT7 receptor as a potential pharmacotherapy to correct circadian rhythm disruptions, the current study utilized the selective 5-HT7 antagonist JNJ-18038683 (10 mg/kg in three different circadian paradigms. While JNJ-18038683 was ineffective at phase shifting the onset of wheel running activity in mice when administered at different circadian time (CT points across the circadian cycle, pretreatment with JNJ-18038683 blocked non-photic phase advance (CT6 induced by the 5-HT1A/7 receptor agonist 8-OH-DPAT (3 mg/kg. Since light induced phase shifts in mammals are partially mediated via the modulation of the serotonergic system, we determined if JNJ-18038683 altered phase shifts induced by a light pulse at times known to phase delay (CT15 or advance (CT22 wheel running activity in free running mice. Light exposure resulted in a robust shift in the onset of activity in vehicle treated animals at both times tested. Administration of JNJ-18038683 significantly attenuated the light-induced phase delay and completely blocked the phase advance. The current study demonstrates that pharmacological blockade of the 5-HT7 receptor by JNJ-18038683 blunts both non-photic and photic phase shifts of circadian wheel running activity in mice. These findings highlight the importance of the 5-HT7 receptor in modulating circadian rhythms. Due to the opposite modulating effects of light resetting between diurnal and nocturnal species, pharmacotherapy targeting the 5-HT7 receptor in conjunction with bright light therapy may prove therapeutically beneficial by correcting the desynchronization of internal rhythms observed in depressed individuals.
Richardson, Cele E; Gradisar, Michael; Short, Michelle A; Lang, Christin
Adolescents are vulnerable to inadequate sleep due to a unique constellation of risk factors. In particular, the puberty-related phase delay in the timing of the circadian system postpones the onset of sleep. Resultantly, disordered sleep is common among teenagers and young adults, with the most common sleep problem being delayed sleep wake-phase disorder (DSWPD). Although current treatments for DSWPD show promise, novel ways to improve our youth's sleep are needed. The purpose of this review is to critically evaluate the evidence for the role of exercise as a method to shift and/or regulate circadian timing, and thus improve sleep, in adolescents and young adults. A growing body of evidence suggests that nocturnal exercise can delay circadian timing. However, exercise administered at different times of the 24-h day may result in phase advances, particularly when the timing of exercise is gradually advanced in small daily increments. The implications of these results for young people's sleep health are discussed and suggestions are provided for ways that exercise could be used clinically, to improve the treatment of DSWPD. Copyright © 2016 Elsevier Ltd. All rights reserved.
Reid, Kathryn J; Jaksa, Ashley A; Eisengart, Julie B; Baron, Kelly G; Lu, Brandon; Kane, Peter; Kang, Joseph; Zee, Phyllis C
Alterations in circadian rhythms can have profound effects on mental health. High co-morbidity for psychiatric disorders has been observed in patients with circadian rhythm disorders, such as delayed sleep phase disorder (DSPD), and in those with an evening-type circadian preference. The aim of this study was to systematically determine the prevalence and type of Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM IV) Axis-I disorders in those with DSPD compared to evening-type controls. Forty-eight DSPD and 25 evening-type participants took part in this study. Sleep and wake parameters were assessed with actigraphy, diary and questionnaires (Pittsburgh Sleep Quality Index (PSQI) and Functional Outcomes of Sleep Questionnaire (FOSQ). Evening-type preference was defined by the Horne-Ostberg questionnaire. DSPD was determined by an interview according to International Classification of Sleep Disorders criteria. Current and past diagnoses of psychiatric disorders were assessed with a Structured Clinical Interview for DSM-IV disorders. DSPD was associated with a later wake time, longer sleep time, higher PSQI score and lower Horne-Ostberg and FOSQ scores compared to evening-types. There were no significant differences in the prevalence or type of Axis-I disorders between those with DSPD or evening-type preference. Over 70% of participants met criteria for at least one past Axis-I disorder. Approximately 40% of both the DSPD and evening-types met criteria for a past diagnosis of mood, anxiety (most frequently phobia) or substance-use disorders. Evening types were more likely to have a past diagnosis of more than one Axis-I disorder. These results highlight the important link between circadian rhythms and mental disorders. Specifically, an evening circadian chronotype regardless of DSPD status is associated with a risk for anxiety, depressive or substance-use disorders. Copyright © 2012 Elsevier B.V. All rights reserved.
Raymond P Najjar
Full Text Available Studies in Polar Base stations, where personnel have no access to sunlight during winter, have reported circadian misalignment, free-running of the sleep-wake rhythm, and sleep problems. Here we tested light as a countermeasure to circadian misalignment in personnel of the Concordia Polar Base station during the polar winter. We hypothesized that entrainment of the circadian pacemaker to a 24-h light-dark schedule would not occur in all crew members (n = 10 exposed to 100-300 lux of standard fluorescent white (SW light during the daytime, and that chronic non-time restricted daytime exposure to melanopsin-optimized blue-enriched white (BE light would establish an a stable circadian phase, in participants, together with increased cognitive performance and mood levels. The lighting schedule consisted of an alternation between SW lighting (2 weeks, followed by a BE lighting (2 weeks for a total of 9 weeks. Rest-activity cycles assessed by actigraphy showed a stable rest-activity pattern under both SW and BE light. No difference was found between light conditions on the intra-daily stability, variability and amplitude of activity, as assessed by non-parametric circadian analysis. As hypothesized, a significant delay of about 30 minutes in the onset of melatonin secretion occurred with SW, but not with BE light. BE light significantly enhanced well being and alertness compared to SW light. We propose that the superior efficacy of blue-enriched white light versus standard white light involves melanopsin-based mechanisms in the activation of the non-visual functions studied, and that their responses do not dampen with time (over 9-weeks. This work could lead to practical applications of light exposure in working environment where background light intensity is chronically low to moderate (polar base stations, power plants, space missions, etc., and may help design lighting strategies to maintain health, productivity, and personnel safety.
Crowley, Stephanie J.; Eastman, Charmane I.
Rationale We test methods to advance (shift earlier) circadian rhythms without producing misalignment between rhythms and sleep. We previously tested 1) a gradually advancing sleep/dark schedule plus morning bright light and afternoon/evening melatonin; and 2) the same sleep schedule with only morning bright light. Now we report on the same sleep schedule with only afternoon/evening melatonin. Objectives To examine phase advances, sleepiness and performance in response to melatonin compared to placebo. Methods Twelve adults (5 female) aged 20–45 years (mean ± SD = 28.3 ± 7.3 years) completed this within-subjects placebo-controlled counterbalanced study. Participants slept on fixed 8-hour sleep schedules for 9 baseline days. Then, sleep/dark was advanced by 1 h/day for 3 consecutive days of treatment. Participants took 3 mg of melatonin or placebo 11 hours before baseline sleep midpoint (the optimal time to produce phase advances) on the first treatment day and 1 hour earlier each subsequent day. We measured the dim light melatonin onset (DLMO) before and after treatment. Participants rated subjective symptoms throughout the study. They completed the Psychomotor Vigilance Task (PVT) and rated sleepiness from 1 h before pill ingestion until bedtime each treatment day. Results Melatonin produced significantly larger advances (1.3 ± 0.7 h) compared to placebo (0.7 ± 0.7 h); however, in the hours between melatonin ingestion and bed, melatonin caused sleepiness and performance decrements. Conclusions Adding afternoon/evening melatonin to the gradually advancing sleep schedule increased the phase advance, but given the side effects, like sleepiness, it is better to use morning bright light and perhaps a lower dose of melatonin. PMID:23001190
Quirin, Markus; Kazén, Miguel; Rohrmann, Sonja; Kuhl, Julius
Self-report measures assess mental processes or representations that are consciously accessible. In contrast, implicit measures assess automatic processes that often operate outside awareness. Whereas self-report measures have often failed to show expected relationships with endocrine stress responses, little effort has been made to relate implicit measures to endocrine processes. The present work examines whether implicit affectivity as assessed by the Implicit Positive and Negative Affect Test (IPANAT) predicts cortisol regulation. In Study 1, implicit low positive affectivity, but not negative affectivity, significantly predicted circadian cortisol release. In Study 2, implicit negative affectivity, but not positive affectivity, significantly predicted the cortisol response to acute stress. By contrast, cortisol regulation was not predicted by self-reported affectivity. The findings support the use of implicit affectivity measures in studying individual differences in endocrine stress responses and point to a differential role of positive and negative affectivity in baseline versus stress-contingent cortisol release, respectively.
Bandín, C; Martinez-Nicolas, A; Ordovás, J M; Ros Lucas, J A; Castell, P; Silvente, T; Madrid, J A; Garaulet, M
Genetics is behind our circadian machinery. CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C single-nucleotide polymorphism (SNP) has been previously related to obesity and weight loss. However, phenotypic association and functionality of CLOCK 3111 locus is still unknown. The aim of this study was to determine, in free-living conditions, if the presence of CLOCK 3111C in overweight women could be related to (a) circadian disorders, and (b) changes in sleep quality, to improve understanding of the previously demonstrated associations with obesity and reduced weight loss of the C carriers. Wrist temperature, actimetry and position (TAP) and TAP variables were measured as markers of circadian functionality during 8 consecutive days. A rest-activity and food diary was also completed, whereas sleep quality was determined by domiciliary polysomnography. We recruited 85 women who were overweight with body mass index (BMI) of 28.59±4.30 kg m(-2) and age 43±12 years. From this sample, we found that 43 women were carrying the minor allele (C) for CLOCK 3111T/C SNP and 42 women were TT carriers (major allele carriers). Both groups of patients were matched for number, age, obesity parameters and energy intake. Compared with TT subjects, who showed more robust circadian rhythm profiles, patients with the C allele displayed significant circadian abnormalities: lower amplitude and greater fragmentation of the rhythm, a less stable circadian pattern and a significantly weakened circadian function, as assessed by the circadian function index (CFI). C subjects were also less active, started their activities later in the morning and were sleepier during the day, showing a delayed acrophase that characterizes 'evening-type' subjects. C genetic variants in CLOCK 3111T/C display a less robust circadian rhythm than TT and a delayed acrophase that characterizes 'evening-type' subjects. We support the notion that identifying CLOCK genotypes in patients may assist the
Full Text Available The rich mammalian cellular circadian output affects thousands of genes in many cell types and has been the subject of genome-wide transcriptome and proteome studies. The results have been enigmatic because transcript peak abundances do not always follow the peaks of gene-expression activity in time. We posited that circadian degradation of mRNAs and proteins plays a pivotal role in setting their peak times. To establish guiding principles, we derived a theoretical framework that fully describes the amplitudes and phases of biomolecules with circadian half-lives. We were able to explain the circadian transcriptome and proteome studies with the same unifying theory, including cases in which transcripts or proteins appeared before the onset of increased production rates. Furthermore, we estimate that 30% of the circadian transcripts in mouse liver and Drosophila heads are affected by rhythmic posttranscriptional regulation.
Sánchez-Vázquez, F J; Madrid, J A; Zamora, S
The nocturnal versus diurnal feeding patterns of sea bass under controlled experimental conditions were studied in order to investigate the existence of such a dualistic feeding behavior. The animals (six groups of 4 animals and 8 single fish) were held in tanks filled with recirculating salt water and installed in a "chronolab" under constant conditions (23.5 degrees C and 2.4% salinity). The fish were given access to self-demand feeders and first exposed to a photoperiod regime of 12:12 (12 h light, 70 lx, and 12 h dark, complete darkness) and then to light:dark (LD) pulses (40 min light, 40 min dark). The LD 12:12 cycle was reversed by doubling the light period in day 16, and reversed again in day 27 by doubling the dark period. The circadian rhythm of food demand was strongly synchronized with the LD cycle, and fish exhibited both diurnal and nocturnal patterns. In most fish, the shift of the feeding rhythm to the new LD cycle was very fast for each reversal (bringing forward or delaying their feeds 12 h), indicating a weak participation of an endogenous circadian rhythm. However, when submitted to LD pulses, fish began to free-run with a periodicity of about 23 h and kept feeding in the light or dark phase according to their prior behavior. The existence of a dualism in the diel feeding pattern in sea bass was thus clearly demonstrated and it appeared that the diurnal and nocturnal behavior did not depend exclusively on a circadian phase inversion of the feeding rhythms as this pattern of behavior was enhanced under ultradian LD pulses. The ecological implications of such dual capacity and the switch from one type of phasing to another are hitherto unknown and need further field and laboratory investigation.
Narishige, Seira; Kuwahara, Mari; Shinozaki, Ayako; Okada, Satoshi; Ikeda, Yuko; Kamagata, Mayo; Tahara, Yu; Shibata, Shigenobu
Background and Purpose Caffeine is one of the most commonly used psychoactive substances. Circadian rhythms consist of the main suprachiasmatic nucleus (SCN) clocks and peripheral clocks. Although caffeine lengthens circadian rhythms and modifies phase changes in SCN-operated rhythms, the effects on caffeine on the phase, period and amplitude of peripheral organ clocks are not known. In addition, the role of cAMP/Ca2+ signalling in effects of caffeine on rhythm has not been fully elucidated. Experimental Approach We examined whether chronic or transient application of caffeine affects circadian period/amplitude and phase by evaluating bioluminescence rhythm in PER2::LUCIFERASE knock-in mice. Circadian rhythms were monitored in vitro using fibroblasts and ex vivo and in vivo for monitoring of peripheral clocks. Key Results Chronic application of caffeine (0.1–10 mM) increased period and amplitude in vitro. Transient application of caffeine (10 mM) near the bottom of the decreasing phase of bioluminescence rhythm caused phase advance in vitro. Caffeine (0.1%) intake caused a phase delay under light–dark or constant dark conditions, suggesting a period-lengthening effect in vivo. Caffeine (20 mg·kg−1) at daytime or at late night-time caused phase advance or delay in bioluminescence rhythm in the liver and kidney respectively. The complicated roles of cAMP/Ca2+ signalling may be involved in the caffeine-induced increase of period and amplitude in vitro. Conclusions and Implications Caffeine affects circadian rhythm in mice by lengthening the period and causing a phase shift of peripheral clocks. These results suggest that caffeine intake with food/drink may help with food-induced resetting of peripheral circadian clocks. PMID:25160990
Revell, Victoria L; Kim, Hyungsoo; Tseng, Christine Y; Crowley, Stephanie J; Eastman, Charmane I
The aim of this study was to determine whether circadian phase from salivary melatonin profiles is the same when measured in phase assessments 1 wk apart. Eleven healthy young men and women maintained a fixed, home sleep-wake schedule, in bed, in the dark 23:00-07:00 hr on weekdays. On Friday and Saturday nights they were permitted to wake up and go to bed up to 1 hr later, and on Saturdays and Sundays they could nap between 13:30 and 16:30 hr. The study was run in the summer. Subjects wore sunglasses when outside during the day, and went outside for at least 15 min between 08:00 and 09:00 hr each morning. They maintained this schedule for 15 days before the first assessment and the 6 days in between the two assessments. During the assessments subjects remained awake overnight in <5 lux and gave saliva samples every 30 min. A recovery nap (13:00-17:00 hr) followed the first session. The dim light melatonin onset (DLMO), offset (DLMOff) and midpoint were used as phase markers. There was minimal change in their timing between the two phase assessments. The average absolute change in midpoint (the change in phase regardless of direction) was 20 min. There was a small, 30 min delay in the DLMO. Thus, circadian phase can be measured a week in advance of any phase shifting intervention and, as long as the prescribed sleep and morning light schedule is maintained, the phase at the start of treatment can be confidently estimated.
Full Text Available Ectopic expression of the Arabidopsis RESISTANCE TO POWDERY MILDEW8.1 (RPW8.1 boosts pattern-triggered immunity leading to enhanced resistance to different pathogens in Arabidopsis and rice. However, the underlying regulatory mechanism remains largely elusive. Here, we report that XAP5 CIRCADIAN TIMEKEEPER (XCT, At2g21150 positively regulates RPW8.1-mediated cell death and disease resistance. Forward genetic screen identified the b3-17 mutant that exhibited less cell death and susceptibility to powdery mildew and bacterial pathogens. Map-based cloning identified a G-to-A point mutation at the 3′ splice site of the 8th intron, which resulted in splice shift to 8-bp down-stream of the original splice site of XCT in b3-17, and introduced into a stop codon after two codons leading to a truncated XCT. XCT has previously been identified as a circadian clock gene required for small RNA biogenesis and acting down-stream of ETHYLENE-INSENSITIVE3 (EIN3 in the ethylene-signaling pathway. Here we further showed that mutation or down-regulation of XCT by artificial microRNA reduced RPW8.1-mediated immunity in R1Y4, a transgenic line expressing RPW8.1-YFP from the RPW8.1 native promoter. On the contrary, overexpression of XCT in R1Y4 background enhanced RPW8.1-mediated cell death, H2O2 production and resistance against powdery mildew. Consistently, the expression of RPW8.1 was down- and up-regulated in xct mutant and XCT overexpression lines, respectively. Taken together, these results indicate that XCT positively regulates RPW8.1-mediated cell death and disease resistance, and provide new insight into the regulatory mechanism of RPW8.1-mediated immunity.
De Jeu, M.T.G.; Pennartz, C.M.A.
Gramicidin-perforated patch-clamp recordings were made from slices of the suprachiasmatic nucleus (SCN) of adult rats to characterize the role of gamma-amino butyric acid (GABA) in the circadian timing system. During the day, activation of GABA(A) receptors hyperpolarized the membrane of SCN
Elliott Jeffrey A
Full Text Available Abstract Background Our aims were to examine the influence of different bright light schedules on mood, sleep, and circadian organization in older adults (n = 60, ages 60–79 years with insomnia and/or depression, contrasting with responses of young, healthy controls (n = 30, ages 20–40 years. Methods Volunteers were assessed for one week in their home environments. Urine was collected over two 24-hour periods to establish baseline acrophase of 6-sulphatoxymelatonin (aMT6s excretion. Immediately following home recording, volunteers spent five nights and four days in the laboratory. Sleep periods were fixed at eight hours in darkness, consistent with the volunteers' usual sleep periods. Volunteers were randomly assigned to one of three light treatments (four hours per day within the wake period: (A two hours of 3,000 lux at 1–3 hours and 13–15 hours after arising; (B four hours of 3,000 lux at 6–10 hours after arising; (C four hours of dim placebo light at 6–10 hours after arising. Lighting was 50 lux during the remainder of wakefulness. The resulting aMT6s acrophase was determined during the final 30 hours in the laboratory. Results Neither mood nor total melatonin excretion differed significantly by treatment. For the three light treatments, significant and similar phase-response plots were found, indicating that the shift in aMT6s acrophase was dependent upon the circadian time of treatment. The changes in circadian timing were not significantly correlated to changes in sleep or mood. Conclusion The trial failed to demonstrate photoperiodic effects. The results suggest that even low levels of illumination and/or fixed timing of behavior had significant phase-shifting effects.
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 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.
M.P. Engelen (Erik); R. Janssens (Roel); K. Yagita (Kazuhiro); V.A.J. Smits (Veronique); G.T.J. van der Horst (Gijsbertus); F. Tamanini (Filippo)
textabstractThe transcription/translation feedback loop-based molecular oscillator underlying the generation of circadian gene expression is preserved in almost all organisms. Interestingly, the animal circadian clock proteins CRYPTOCHROME (CRY), PERIOD (PER) and TIMELESS (TIM) are strongly
Home; Journals; Resonance – Journal of Science Education; Volume 18; Issue 11. Circadian Rhythms - Circadian Timing Systems: How are they Organized? Koustubh M Vaze Vijay Kumar Sharma. Series Article Volume 18 Issue 11 November 2013 pp 1032-1050 ...
significance. (right) Vijay Kumar Sharma is a Professor at the. Evolutionary and. Organismal Biology Unit,. JNCASR, Bangalore. His major research interests presently are in understand- ing circadian organization of fruit flies and ants, adaptive significance of circadian clocks, neurogenetics of circadian egg-laying rhythm.
Mottram, Victoria; Middleton, Benita; Williams, Peter; Arendt, Josephine
Delayed sleep phase (and sometimes free-run) is common in the Antarctic winter (no natural sunlight) and optimizing the artificial light conditions is desirable. This project evaluated sleep when using 17,000 K blue-enriched lamps compared with standard white lamps (5000 K) for personal and communal illumination. Base personnel, 10 males, five females, 32.5±8 years took part in the study. From 24 March to 21 September 2006 light exposure alternated between 4-5-week periods of standard white (5000 K) and blue-enriched lamps (17,000 K), with a 3-week control before and after extra light. Sleep and light exposure were assessed by actigraphy and sleep diaries. General health (RAND 36-item questionnaire) and circadian phase (urinary 6-sulphatoxymelatonin rhythm) were evaluated at the end of each light condition. Direct comparison (rmanova) of blue-enriched light with white light showed that sleep onset was earlier by 19 min (P=0.022), and sleep latency tended to be shorter by 4 min (P=0.065) with blue-enriched light. Analysing all light conditions, control, blue and white, again provided evidence for greater efficiency of blue-enriched light compared with white (Plight conditions. Circadian phase was earlier on average in midwinter blue compared with midwinter white light by 45 min (PLight condition had no influence on general health. We conclude that the use of blue-enriched light had some beneficial effects, notably earlier sleep, compared with standard white light during the polar winter. © 2010 European Sleep Research Society.
Kalsbeek, A.; Barassin, S.; van Heerikhuize, J. J.; van der Vliet, J.; Buijs, R. M.
It is well established that in the absence of photic cues, the circadian rhythms of rodents can be readily phase-shifted and entrained by various nonphotic stimuli that induce increased levels of locomotor activity (i.e., benzodiazepines, a new running wheel, and limited food access). In the
Canton, Jillian L; Smith, Mark R; Choi, Ho-Sun; Eastman, Charmane I
Light exposure in the late evening and nighttime and a delay of the sleep/dark episode can phase delay the circadian clock. This study assessed the size of the phase delay produced by a single light pulse combined with a moderate delay of the sleep/dark episode for one day. Because iris color or race has been reported to influence light-induced melatonin suppression, and we have recently reported racial differences in free-running circadian period and circadian phase shifting in response to light pulses, we also tested for differences in the magnitude of the phase delay in subjects with blue and brown irises. Subjects (blue-eyed n = 7; brown eyed n = 6) maintained a regular sleep schedule for 1 week before coming to the laboratory for a baseline phase assessment, during which saliva was collected every 30 minutes to determine the time of the dim light melatonin onset (DLMO). Immediately following the baseline phase assessment, which ended 2 hours after baseline bedtime, subjects received a 2-hour bright light pulse (~4,000 lux). An 8-hour sleep episode followed the light pulse (i.e. was delayed 4 hours from baseline). A final phase assessment was conducted the subsequent night to determine the phase shift of the DLMO from the baseline to final phase assessment.Phase delays of the DLMO were compared in subjects with blue and brown irises. Iris color was also quantified from photographs using the three dimensions of red-green-blue color axes, as well as a lightness scale. These variables were correlated with phase shift of the DLMO, with the hypothesis that subjects with lighter irises would have larger phase delays. The average phase delay of the DLMO was -1.3 +/- 0.6 h, with a maximum delay of ~2 hours, and was similar for subjects with blue and brown irises. There were no significant correlations between any of the iris color variables and the magnitude of the phase delay. A single 2-hour bright light pulse combined with a moderate delay of the sleep/dark episode
Full Text Available Abstract Background Light exposure in the late evening and nighttime and a delay of the sleep/dark episode can phase delay the circadian clock. This study assessed the size of the phase delay produced by a single light pulse combined with a moderate delay of the sleep/dark episode for one day. Because iris color or race has been reported to influence light-induced melatonin suppression, and we have recently reported racial differences in free-running circadian period and circadian phase shifting in response to light pulses, we also tested for differences in the magnitude of the phase delay in subjects with blue and brown irises. Methods Subjects (blue-eyed n = 7; brown eyed n = 6 maintained a regular sleep schedule for 1 week before coming to the laboratory for a baseline phase assessment, during which saliva was collected every 30 minutes to determine the time of the dim light melatonin onset (DLMO. Immediately following the baseline phase assessment, which ended 2 hours after baseline bedtime, subjects received a 2-hour bright light pulse (~4,000 lux. An 8-hour sleep episode followed the light pulse (i.e. was delayed 4 hours from baseline. A final phase assessment was conducted the subsequent night to determine the phase shift of the DLMO from the baseline to final phase assessment. Phase delays of the DLMO were compared in subjects with blue and brown irises. Iris color was also quantified from photographs using the three dimensions of red-green-blue color axes, as well as a lightness scale. These variables were correlated with phase shift of the DLMO, with the hypothesis that subjects with lighter irises would have larger phase delays. Results The average phase delay of the DLMO was -1.3 ± 0.6 h, with a maximum delay of ~2 hours, and was similar for subjects with blue and brown irises. There were no significant correlations between any of the iris color variables and the magnitude of the phase delay. Conclusion A single 2-hour bright light
Full Text Available Abstract The present paper reflects a work in progress toward a definition of circadian light, one that should be informed by the thoughtful, century-old evolution of our present definition of light as a stimulus for the human visual system. This work in progress is based upon the functional relationship between optical radiation and its effects on nocturnal melatonin suppression, in large part because the basic data are available in the literature. Discussed here are the fundamental differences between responses by the visual and circadian systems to optical radiation. Brief reviews of photometry, colorimetry, and brightness perception are presented as a foundation for the discussion of circadian light. Finally, circadian light (CLA and circadian stimulus (CS calculation procedures based on a published mathematical model of human circadian phototransduction are presented with an example.
Kuriki, Daisuke; Haraguchi, Atsushi; Shibata, Shigenobu
Circadian clocks in the peripheral tissues of mice are known to be entrained by pulse stimuli such as restricted feeding, novel wheel running, and several other agents. However, there are no reports on high temperature pulse-mediated entrainment on the phase-shift of peripheral clocks in vivo. Here we show that temperature treatment of mice for two days at 41°C, instead of 37°C, for 1–2 h during the inactive period, using a temperature controlled water bath stimulated phase-advance of peripheral clocks in the kidney, liver, and submandibular gland of PER2::LUCIFERASE mice. On the other hand, treatment for 2 days at 35°C ambient room temperature for 2 h did not cause a phase-advance. Maintenance of mice at 41°C in a water bath, sustained the core body temperature at 40–41°C. However, the use of 37°C water bath or the 35°C ambient room temperature elevated the core body temperature to 38.5°C, suggesting that at least a core body temperature of 40–41°C is necessary to cause phase-advance under light-dark cycle conditions. The temperature pulse stimulation at 41°C, instead of 37°C water bath for 2 h led to the elevated expression of Per1 and Hsp70 in the peripheral tissue of mice. In summary, the present study demonstrates that transient high temperature pulse using water bath during daytime causes phase-advance in mouse peripheral clocks in vivo. The present results suggest that hot water bath may affect the phase of peripheral clocks. PMID:24933288
Oster, Henrik; Werner, Claudia; Magnone, Maria Chiara; Mayser, Helmut; Feil, Robert; Seeliger, Mathias W; Hofmann, Franz; Albrecht, Urs
In mammals, the master circadian clock that drives many biochemical, physiological, and behavioral rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus. Generation and maintenance of circadian rhythmicity rely on complex interlocked transcriptional/translational feedback loops involving a set of clock genes. Among the molecular components driving the mammalian circadian clock are the Period 1 and 2 (mPer1 and mPer2) genes. Because the periodicity of the clock is not exactly 24 hr, it has to be adjusted periodically. The major stimulus for adjustment (resetting) of the clock is nocturnal light. It evokes activation of signaling pathways in the SCN that ultimately lead to expression of mPer1 and mPer2 genes conveying adjustment of the clock. We show that mice deficient in cGMP-dependent protein kinase II (cGKII, also known as PKGII), despite regular retinal function, are defective in resetting the circadian clock, as assessed by changes in the onset of wheel running activity after a light pulse. At the molecular level, light induction of mPer2 in the SCN is strongly reduced in the early period of the night, whereas mPer1 induction is elevated in cGKII-deficient mice. Additionally, we show that light induction of cfos and light-dependent phosphorylation of CREB at serine 133 are not affected in these animals. cGKII plays a role in the clock-resetting mechanism. In particular, the ability to delay clock phase is affected in cGKII-deficient mice. It seems that the signaling pathway involving cGKII influences in an opposite manner the light-induced induction of mPer1 and mPer2 genes and thereby influences the direction of a phase shift of the circadian clock.
Voigt, Robin M; Forsyth, Christopher B; Green, Stefan J; Mutlu, Ece; Engen, Phillip; Vitaterna, Martha H; Turek, Fred W; Keshavarzian, Ali
Intestinal dysbiosis and circadian rhythm disruption are associated with similar diseases including obesity, metabolic syndrome, and inflammatory bowel disease. Despite the overlap, the potential relationship between circadian disorganization and dysbiosis is unknown; thus, in the present study, a model of chronic circadian disruption was used to determine the impact on the intestinal microbiome. Male C57BL/6J mice underwent once weekly phase reversals of the light:dark cycle (i.e., circadian rhythm disrupted mice) to determine the impact of circadian rhythm disruption on the intestinal microbiome and were fed either standard chow or a high-fat, high-sugar diet to determine how diet influences circadian disruption-induced effects on the microbiome. Weekly phase reversals of the light:dark (LD) cycle did not alter the microbiome in mice fed standard chow; however, mice fed a high-fat, high-sugar diet in conjunction with phase shifts in the light:dark cycle had significantly altered microbiota. While it is yet to be established if some of the adverse effects associated with circadian disorganization in humans (e.g., shift workers, travelers moving across time zones, and in individuals with social jet lag) are mediated by dysbiosis, the current study demonstrates that circadian disorganization can impact the intestinal microbiota which may have implications for inflammatory diseases.
Home; Journals; Resonance – Journal of Science Education; Volume 18; Issue 7. Circadian Rhythms - From Daily Rhythms to Biological Clocks. Koustubh M Vaze Vijay Kumar Sharma. Series Article Volume 18 Issue 7 July 2013 pp 662- ... Keywords. Circadian rhythms; biological clocks; geophysical cycles; entrainment.
hunger and sleep at the same time as the body would not be in the right state to metabolise food efficiently. Thus, synchronization of internal rhythms is an essential aspect of physiology, and circadian rhythms benefit living beings by bringing about such temporal order. In other words, circadian rhythms are thought to.
Hummer, Daniel L; Ehlen, J Christopher; Larkin, Tony E; McNeill, John K; Pamplin, John R; Walker, Colton A; Walker, Phillip V; Dhanraj, Daryl R; Albers, H Elliott
The suprachiasmatic nucleus (SCN) contains a circadian clock that generates endogenous rhythmicity and entrains that rhythmicity with the day-night cycle. The neurochemical events that transduce photic input within the SCN and mediate entrainment by resetting the molecular clock have yet to be defined. Because GABA is contained in nearly all SCN neurons we tested the hypothesis that GABA serves as this signal in studies employing Syrian hamsters (Mesocricetus auratus). Activation of GABAA receptors was found to be necessary and sufficient for light to induce phase delays of the clock. Remarkably, the sustained activation of GABAA receptors for more than three consecutive hours was necessary to phase-delay the clock. The duration of GABAA receptor activation required to induce phase delays would not have been predicted by either the prevalent theory of circadian entrainment or by expectations regarding the duration of ionotropic receptor activation necessary to produce functional responses. Taken together, these data identify a novel neurochemical mechanism essential for phase-delaying the 'master' circadian clock within the SCN as well as identifying an unprecedented action of an amino acid neurotransmitter involving the sustained activation of ionotropic receptors. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
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.
Crowley, Stephanie J; Eastman, Charmane I
Efficient treatments to phase-advance human circadian rhythms are needed to attenuate circadian misalignment and the associated negative health outcomes that accompany early-morning shift work, early school start times, jet lag, and delayed sleep phase disorder. This study compared three morning bright-light exposure patterns from a single light box (to mimic home treatment) in combination with afternoon melatonin. Fifty adults (27 males) aged 25.9 ± 5.1 years participated. Sleep/dark was advanced 1 h/day for three treatment days. Participants took 0.5 mg of melatonin 5 h before the baseline bedtime on treatment day 1, and an hour earlier each treatment day. They were exposed to one of three bright-light (~5000 lux) patterns upon waking each morning: four 30-min exposures separated by 30 min of room light (2-h group), four 15-min exposures separated by 45 min of room light (1-h group), and one 30-min exposure (0.5-h group). Dim-light melatonin onsets (DLMOs) before and after treatment determined the phase advance. Compared to the 2-h group (phase shift = 2.4 ± 0.8 h), smaller phase-advance shifts were seen in the 1-h (1.7 ± 0.7 h) and 0.5-h (1.8 ± 0.8 h) groups. The 2-h pattern produced the largest phase advance; however, the single 30-min bright-light exposure was as effective as 1 h of bright light spread over 3.25 h, and it produced 75% of the phase shift observed with 2 h of bright light. A 30-min morning bright-light exposure with afternoon melatonin is an efficient treatment to phase-advance human circadian rhythms. Copyright © 2014 Elsevier B.V. All rights reserved.
Crowley, Stephanie J.; Eastman, Charmane I.
OBJECTIVE Efficient treatments to phase advance human circadian rhythms are needed to attenuate circadian misalignment and the associated negative health outcomes that accompany early morning shift work, early school start times, jet lag, and delayed sleep phase disorder. This study compared three morning bright light exposure patterns from a single light box (to mimic home treatment) in combination with afternoon melatonin. METHODS Fifty adults (27 males) aged 25.9±5.1 years participated. Sleep/dark was advanced 1 hour/day for 3 treatment days. Participants took 0.5 mg melatonin 5 hours before baseline bedtime on treatment day 1, and an hour earlier each treatment day. They were exposed to one of three bright light (~5000 lux) patterns upon waking each morning: four 30-minute exposures separated by 30 minutes of room light (2 h group); four 15-minute exposures separated by 45 minutes of room light (1 h group), and one 30-minute exposure (0.5 h group). Dim light melatonin onsets (DLMOs) before and after treatment determined the phase advance. RESULTS Compared to the 2 h group (phase shift=2.4±0.8 h), smaller phase advance shifts were seen in the 1 h (1.7±0.7 h) and 0.5 h (1.8±0.8 h) groups. The 2-hour pattern produced the largest phase advance; however, the single 30-minute bright light exposure was as effective as 1 hour of bright light spread over 3.25 h, and produced 75% of the phase shift observed with 2 hours of bright light. CONCLUSIONS A 30-minute morning bright light exposure with afternoon melatonin is an efficient treatment to phase advance human circadian rhythms. PMID:25620199
Boissin-Agasse, L.; Boissin, J.; Ortavant, R.
Evidence of a circadian photosensitive phase in male mink, whose annual reproductive cycle is characterized by the recrudescence of testicular development in autumn, was based on the study of testicular response after interrupting the dark period by light breaks offered at various times. In this mammal, the experimental short days 4L:20D and 8L:16D stimulated testicular growth. Short photoperiods, including a main light period of 3.5 h and an additional 0.5 h light break 7.5 h after the beginning of the main photoperiod, were as effective as 8L:16D in stimulating testicular development. On the other hand, when a 0.5 h light break occurred 11.5 or 15.5 h after the beginning of the main photoperiod, the same inhibiting effect on testicular activity was obtained as for long photoperiods. However, when 0.5 h light breaks were given 19.5 after the beginning of the main light period, some minks recognized, as, the onset of the shorter of the two light periods offered. Thus our results proved the existence of a special phase in the day cycle in which light inhibited testicular development in the mink which appears to be a short-day animal. One explanation of the difference between long-day and short-day animals would be the following: if for long-day animals exposure to light during the photosensitive phase led to gonadostimulation, in short-day mammals, like mink, it exerted an inhibiting influence on testicular growth.
Evidence of circadian rhythm, oxygen regulation capacity, metabolic repeatability and positive correlations between forced and spontaneous maximal metabolic rates in lake sturgeon Acipenser fulvescens.
Svendsen, Jon C; Genz, Janet; Anderson, W Gary; Stol, Jennifer A; Watkinson, Douglas A; Enders, Eva C
Animal metabolic rate is variable and may be affected by endogenous and exogenous factors, but such relationships remain poorly understood in many primitive fishes, including members of the family Acipenseridae (sturgeons). Using juvenile lake sturgeon (Acipenser fulvescens), the objective of this study was to test four hypotheses: 1) A. fulvescens exhibits a circadian rhythm influencing metabolic rate and behaviour; 2) A. fulvescens has the capacity to regulate metabolic rate when exposed to environmental hypoxia; 3) measurements of forced maximum metabolic rate (MMR(F)) are repeatable in individual fish; and 4) MMR(F) correlates positively with spontaneous maximum metabolic rate (MMR(S)). Metabolic rates were measured using intermittent flow respirometry, and a standard chase protocol was employed to elicit MMR(F). Trials lasting 24 h were used to measure standard metabolic rate (SMR) and MMR(S). Repeatability and correlations between MMR(F) and MMR(S) were analyzed using residual body mass corrected values. Results revealed that A. fulvescens exhibit a circadian rhythm in metabolic rate, with metabolism peaking at dawn. SMR was unaffected by hypoxia (30% air saturation (O(2sat))), demonstrating oxygen regulation. In contrast, MMR(F) was affected by hypoxia and decreased across the range from 100% O(2sat) to 70% O(2sat). MMR(F) was repeatable in individual fish, and MMR(F) correlated positively with MMR(S), but the relationships between MMR(F) and MMR(S) were only revealed in fish exposed to hypoxia or 24 h constant light (i.e. environmental stressor). Our study provides evidence that the physiology of A. fulvescens is influenced by a circadian rhythm and suggests that A. fulvescens is an oxygen regulator, like most teleost fish. Finally, metabolic repeatability and positive correlations between MMR(F) and MMR(S) support the conjecture that MMR(F) represents a measure of organism performance that could be a target of natural selection.
Evidence of circadian rhythm, oxygen regulation capacity, metabolic repeatability and positive correlations between forced and spontaneous maximal metabolic rates in lake sturgeon Acipenser fulvescens.
Jon C Svendsen
Full Text Available Animal metabolic rate is variable and may be affected by endogenous and exogenous factors, but such relationships remain poorly understood in many primitive fishes, including members of the family Acipenseridae (sturgeons. Using juvenile lake sturgeon (Acipenser fulvescens, the objective of this study was to test four hypotheses: 1 A. fulvescens exhibits a circadian rhythm influencing metabolic rate and behaviour; 2 A. fulvescens has the capacity to regulate metabolic rate when exposed to environmental hypoxia; 3 measurements of forced maximum metabolic rate (MMR(F are repeatable in individual fish; and 4 MMR(F correlates positively with spontaneous maximum metabolic rate (MMR(S. Metabolic rates were measured using intermittent flow respirometry, and a standard chase protocol was employed to elicit MMR(F. Trials lasting 24 h were used to measure standard metabolic rate (SMR and MMR(S. Repeatability and correlations between MMR(F and MMR(S were analyzed using residual body mass corrected values. Results revealed that A. fulvescens exhibit a circadian rhythm in metabolic rate, with metabolism peaking at dawn. SMR was unaffected by hypoxia (30% air saturation (O(2sat, demonstrating oxygen regulation. In contrast, MMR(F was affected by hypoxia and decreased across the range from 100% O(2sat to 70% O(2sat. MMR(F was repeatable in individual fish, and MMR(F correlated positively with MMR(S, but the relationships between MMR(F and MMR(S were only revealed in fish exposed to hypoxia or 24 h constant light (i.e. environmental stressor. Our study provides evidence that the physiology of A. fulvescens is influenced by a circadian rhythm and suggests that A. fulvescens is an oxygen regulator, like most teleost fish. Finally, metabolic repeatability and positive correlations between MMR(F and MMR(S support the conjecture that MMR(F represents a measure of organism performance that could be a target of natural selection.
Patton, Andrew P; Chesham, Johanna E; Hastings, Michael H
The suprachiasmatic nucleus (SCN) is the master circadian oscillator encoding time-of-day information. SCN timekeeping is sustained by a cell-autonomous transcriptional-translational feedback loop, whereby expression of the Period and Cryptochrome genes is negatively regulated by their protein products. This loop in turn drives circadian oscillations in gene expression that direct SCN electrical activity and thence behavior. The robustness of SCN timekeeping is further enhanced by interneuronal, circuit-level coupling. The aim of this study was to combine pharmacological and genetic manipulations to push the SCN clockwork toward its limits and, by doing so, probe cell-autonomous and emergent, circuit-level properties. Circadian oscillation of mouse SCN organotypic slice cultures was monitored as PER2::LUC bioluminescence. SCN of three genetic backgrounds-wild-type, short-period CK1ε(Tau/Tau) mutant, and long-period Fbxl3(Afh/Afh) mutant-all responded reversibly to pharmacological manipulation with period-altering compounds: picrotoxin, PF-670462 (4-[1-Cyclohexyl-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinamine dihydrochloride), and KNK437 (N-Formyl-3,4-methylenedioxy-benzylidine-gamma-butyrolactam). This revealed a remarkably wide operating range of sustained periods extending across 25 h, from ≤17 h to >42 h. Moreover, this range was maintained at network and single-cell levels. Development of a new technique for formal analysis of circadian waveform, first derivative analysis (FDA), revealed internal phase patterning to the circadian oscillation at these extreme periods and differential phase sensitivity of the SCN to genetic and pharmacological manipulations. For example, FDA of the CK1ε(Tau/Tau) mutant SCN treated with the CK1ε-specific inhibitor PF-4800567 (3-[(3-Chlorophenoxy)methyl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride) revealed that period acceleration in the mutant is due to inappropriately phased
Home; Journals; Resonance – Journal of Science Education; Volume 19; Issue 2 ... Adaptation; fitness; circadian resonance; latitudinal clines; experimental evolution. ... Chronobiology Laboratory Evolutionary and Organismal Biology Unit Jawaharlal Nehru Centre for Advanced Scientific Research Jakkur, PO Box 6436, ...
Dijk, Derk-Jan; Duffy, Jeanne F; Silva, Edward J; Shanahan, Theresa L; Boivin, Diane B; Czeisler, Charles A
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. 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. 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-work, jet-lag and exposure to artificial light.
Full Text Available Light is a crucial input for circadian clocks. In Drosophila, short light exposure can robustly shift the phase of circadian behavior. The model for this resetting posits that circadian photoreception is cell autonomous: CRYPTOCHROME senses light, binds to TIMELESS (TIM, and promotes its degradation, which is mediated by JETLAG (JET. However, it was recently proposed that interactions between circadian neurons are also required for phase resetting. We identify two groups of neurons critical for circadian photoreception: the morning (M and the evening (E oscillators. These neurons work synergistically to reset rhythmic behavior. JET promotes acute TIM degradation cell autonomously in M and E oscillators but also nonautonomously in E oscillators when expressed in M oscillators. Thus, upon light exposure, the M oscillators communicate with the E oscillators. Because the M oscillators drive circadian behavior, they must also receive inputs from the E oscillators. Hence, although photic TIM degradation is largely cell autonomous, neural cooperation between M and E oscillators is critical for circadian behavioral photoresponses.
Full Text Available Plants need to avoid carbon starvation and resultant growth inhibition under fluctuating light environments to ensure optimal growth and reproduction. As diel patterns of carbon metabolism are influenced by the circadian clock, appropriate regulation of the clock is essential for plants to properly manage their carbon resources. For proper adjustment of the circadian phase, higher plants utilize environmental signals such as light or temperature and metabolic signals such as photosynthetic products; the importance of the latter as phase regulators has been recently elucidated. A mutant of Arabidopsis thaliana that is deficient in phase response to sugar has been shown, under fluctuating light conditions, to be unable to adjust starch turnover and to realize carbon homeostasis. Whereas, the effects of light entrainment on growth and survival of higher plants are well studied, the impact of phase regulation by sugar remains unknown. Here we show that endogenous sugar entrainment facilitates plant growth. We integrated two mathematical models, one describing the dynamics of carbon metabolism in A. thaliana source leaves and the other growth of sink tissues dependent on sucrose translocation from the source. The integrated model predicted that sugar-sensitive plants grow faster than sugar-insensitive plants under constant as well as changing photoperiod conditions. We found that sugar entrainment enables efficient carbon investment for growth by stabilizing sucrose supply to sink tissues. Our results highlight the importance of clock entrainment by both exogenous and endogenous signals for optimizing growth and increasing fitness.
Full Text Available Disrupted circadian rhythms are a core feature of mood and anxiety disorders. Circadian rhythms are coordinated by a light-entrainable master clock located in the suprachiasmatic nucleus. Animal models of mood and anxiety disorders often exhibit blunted rhythms in locomotor activity and clock gene expression. Interestingly, the changes in circadian rhythms correlate with mood-related behaviours. Although animal models of depression and anxiety exhibit aberrant circadian rhythms in physiology and behavior, it is possible that the methodology being used to induce the behavioral phenotype (e.g., brain lesions, chronic stress, global gene deletion affect behavior independently of circadian system. This study investigates the relationship between individual differences in circadian locomotor parameters and mood-related behaviors in healthy rats. The circadian phenotype of male Lewis rats was characterized by analyzing wheel running behavior under standard 12h:12h LD conditions, constant dark, constant light, and rate of re-entrainment to a phase advance. Rats were then tested on a battery of behavioral tests: activity box, restricted feeding, elevated plus maze, forced swim test, and fear conditioning. Under 12h:12h LD conditions, percent of daily activity in the light phase and variability in activity onset were associated with longer latency to immobility in the forced swim test. Variability in onset also correlated positively with anxiety-like behavior in the elevated plus maze. Rate of re-entrainment correlated positively with measures of anxiety in the activity box and elevated plus maze. Lastly, we found that free running period under constant dark was associated with anxiety-like behaviors in the activity box and elevated plus maze. Our results provide a previously uncharacterized relationship between circadian locomotor parameters and mood-related behaviors in healthy rats and provide a basis for future examination into circadian clock
Full Text Available Abstract Circadian rhythms are daily oscillations of multiple biological processes directed by endogenous clocks. The circadian timing system comprises peripheral oscillators located in most tissues of the body and a central pacemaker located in the suprachiasmatic nucleus (SCN of the hypothalamus. Circadian genes and the proteins produced by these genes constitute the molecular components of the circadian oscillator which form positive/negative feedback loops and generate circadian rhythms. The circadian regulation extends beyond clock genes to involve various clock-controlled genes (CCGs including various cell cycle genes. Aberrant expression of circadian clock genes could have important consequences on the transactivation of downstream targets that control the cell cycle and on the ability of cells to undergo apoptosis. This may lead to genomic instability and accelerated cellular proliferation potentially promoting carcinogenesis. Different lines of evidence in mice and humans suggest that cancer may be a circadian-related disorder. The genetic or functional disruption of the molecular circadian clock has been found in various cancers including breast, ovarian, endometrial, prostate and hematological cancers. The acquisition of current data in circadian clock mechanism may help chronotherapy, which takes into consideration the biological time to improve treatments by devising new therapeutic approaches for treating circadian-related disorders, especially cancer.
Keywords. Circadian rhythms, biological clocks, geophysical cycles, en- trainment. Living organisms ranging from bacteria to human beings exhibit 24-h rhythms in various behaviours and physiological processes. Matching of the period of such rhythms with that of the daily environmental cycles gives an impression that.
rhythms especially their endogenous, self-sustained nature, ability to entrain to environmental cycles and. PRCs, greatly resemble those of self-sustained physical oscillators; which led them to propose that circadian rhythms function like physical oscillators and named such biological oscillators as 'endogenous self- ...
Home; Journals; Resonance – Journal of Science Education; Volume 19; Issue 2. Circadian Rhythms: Why do Living Organisms Have Them? Koustubh M Vaze K L Nikhil Vijay Kumar Sharma. Series Article Volume 19 Issue 2 February 2014 pp 175-189 ...
Münch, Mirjam; Nowozin, Claudia; Regente, Johannes; Bes, Frederik; De Zeeuw, Jan; Hädel, Sven; Wahnschaffe, Amely; Kunz, Dieter
Light during the day and darkness at night are crucial factors for proper entrainment of the human circadian system to the solar 24-h day. However, modern life and work styles have led to much more time spent indoors, often with lower daytime and higher evening/nighttime light intensity from electrical lighting than outdoors. Whether this has long-term consequences for human health is being currently investigated. We tested if bright blue-enriched morning light over several days could counteract the detrimental effects of inadequate daytime and evening lighting. In a seminaturalistic, within-between subject study design, 18 young participants were exposed to different lighting conditions on 3 evenings (blue-enriched, bright orange, or dim light), after exposure to 2 lighting conditions (mixed blue-enriched light and control light, for 3 days each) in the mornings. Subjective sleepiness, reaction times, salivary melatonin concentrations, and nighttime sleep were assessed. Exposure to the blue-enriched morning lighting showed acute wake-promoting effects and faster reaction times than with control lighting. Some of these effects persisted until the evening, and performance improved over several days. The magnitude of circadian phase shifts induced by combinations of 3 different evening and 2 morning lighting conditions were significantly smaller with the blue-enriched morning light. During the night, participants had longer total sleep times after orange light exposure than after blue light exposure in the evening. Our results indicate that bright blue-enriched morning light stabilizes circadian phase, and it could be an effective counterstrategy for poor lighting during the day and also light exposure at the wrong time, such as in the late evening. © 2017 S. Karger AG, Basel.
Williams, Stephen R; Zies, Deborah; Mullegama, Sureni V; Grotewiel, Michael S; Elsea, Sarah H
Haploinsufficiency of RAI1 results in Smith-Magenis syndrome (SMS), a disorder characterized by intellectual disability, multiple congenital anomalies, obesity, neurobehavioral abnormalities, and a disrupted circadian sleep-wake pattern. An inverted melatonin rhythm (i.e., melatonin peaks during the day instead of at night) and associated sleep-phase disturbances in individuals with SMS, as well as a short-period circadian rhythm in mice with a chromosomal deletion of Rai1, support SMS as a circadian-rhythm-dysfunction disorder. However, the molecular cause of the circadian defect in SMS has not been described. The circadian oscillator temporally orchestrates metabolism, physiology, and behavior largely through transcriptional modulation. Data support RAI1 as a transcriptional regulator, but the genes it might regulate are largely unknown. Investigation into the role that RAI1 plays in the regulation of gene transcription and circadian maintenance revealed that RAI1 regulates the transcription of circadian locomotor output cycles kaput (CLOCK), a key component of the mammalian circadian oscillator that transcriptionally regulates many critical circadian genes. Data further show that haploinsufficiency of RAI1 and Rai1 in SMS fibroblasts and the mouse hypothalamus, respectively, results in the transcriptional dysregulation of the circadian clock and causes altered expression and regulation of multiple circadian genes, including PER2, PER3, CRY1, BMAL1, and others. These data suggest that heterozygous mutation of RAI1 and Rai1 leads to a disrupted circadian rhythm and thus results in an abnormal sleep-wake cycle, which can contribute to an abnormal feeding pattern and dependent cognitive performance. Finally, we conclude that RAI1 is a positive transcriptional regulator of CLOCK, pinpointing a novel and important role for this gene in the circadian oscillator. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Dijk, Derk-Jan; Duffy, Jeanne F.; Silva, Edward J.; Shanahan, Theresa L.; Boivin, Diane B.; Czeisler, Charles A.
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-work, jet
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
Genetics is behind our circadian machinery. CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C single-nucleotide polymorphism (SNP) has been previously related to obesity and weight loss. However, phenotypic association and functionality of CLOCK 3111 locus is still unknown. The aim of this stu...
Goldbeter, Albert; Gérard, Claude; Leloup, Jean-Christophe
Cellular rhythms represent a field of choice for studies in system biology. The examples of circadian rhythms and of the cell cycle show how the experimental and modeling approaches contribute to clarify the conditions in which periodic behavior spontaneously arises in regulatory networks at the cellular level. Circadian rhythms originate from intertwined positive and negative feedback loops controlling the expression of several clock genes. Models can be used to address the dynamical bases of physiological disorders related to dysfunctions of the mammalian circadian clock. The cell cycle is driven by a network of cyclin-dependent kinases (Cdks). Modeled in the form of four modules coupled through multiple regulatory interactions, the Cdk network operates in an oscillatory manner in the presence of sufficient amounts of growth factor. For circadian rhythms and the cell cycle, as for other recently observed cellular rhythms, periodic behavior represents an emergent property of biological systems related to their regulatory structure.
Alpatov, A. M.; Hoban-Higgins, T. M.; Klimovitsky, V. Y.; Tumurova, E. G.; Fuller, C. A.
Circadian rhythms of primate brain temperature, head and ankle skin temperature, motor activity, and heart rate were studied during spaceflight and on the ground. In space, the circadian rhythms of all the parameters were synchronized with diurnal Zeitgebers. However, in space the brain temperature rhythm showed a significantly more delayed phase angle, which may be ascribed to an increase of the endogenous circadian period.
White, Robert D
Several components of breast milk show circadian variability. It is likely that at least some of these macronutrients, hormones, and micronutrients produce circadian stimuli that enhance the well-being of breast-fed infants. Future research should determine whether high-risk infants benefit if breast milk is given during the same circadian phase as it was expressed.
Fan, Zenghua; Zhao, Meng; Joshi, Parth D; Li, Ping; Zhang, Yan; Guo, Weimin; Xu, Yichi; Wang, Haifang; Zhao, Zhihu; Yan, Jun
Circadian rhythm exerts its influence on animal physiology and behavior by regulating gene expression at various levels. Here we systematically explored circadian long non-coding RNAs (lncRNAs) in mouse liver and examined their circadian regulation. We found that a significant proportion of circadian lncRNAs are expressed at enhancer regions, mostly bound by two key circadian transcription factors, BMAL1 and REV-ERBα. These circadian lncRNAs showed similar circadian phases with their nearby genes. The extent of their nuclear localization is higher than protein coding genes but less than enhancer RNAs. The association between enhancer and circadian lncRNAs is also observed in tissues other than liver. Comparative analysis between mouse and rat circadian liver transcriptomes showed that circadian transcription at lncRNA loci tends to be conserved despite of low sequence conservation of lncRNAs. One such circadian lncRNA termed lnc-Crot led us to identify a super-enhancer region interacting with a cluster of genes involved in circadian regulation of metabolism through long-range interactions. Further experiments showed that lnc-Crot locus has enhancer function independent of lnc-Crot's transcription. Our results suggest that the enhancer-associated circadian lncRNAs mark the genomic loci modulating long-range circadian gene regulation and shed new lights on the evolutionary origin of lncRNAs. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
Griniatsos, John; Michail, Othon P; Theocharis, Stamatios; Arvelakis, Antonios; Papaconstantinou, Ioannis; Felekouras, Evangelos; Pikoulis, Emmanouel; Karavokyros, Ioannis; Bakoyiannis, Chris; Marinos, George; Bramis, John; Michail, Panayiotis O
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 formalin-fixed 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 cyclins (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 - p21 were 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 - p16 were examined, high levels of p16 expression were correlated to low levels of cyclin expression at 00:00, 06:00 and 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
Full Text Available The problem of determination of the phase-change boundary position at the mathematical modeling of continuous ingot temperature field is considered. The description of the heat transfer process takes into account the dependence of the thermal physical characteristics on the temperature, so that the mathematical model is based on the nonlinear partial differential equations. The boundary position between liquid and solid phase is given by the temperatures equality condition and the Stefan condition for the two-dimensional case. The new method of calculation of the phase-change boundary position is proposed. This method based on the finite-differences with using explicit schemes and on the iteration method of solving of non-linear system equations. The proposed method of calculation is many times faster than the real time. So that it amenable to be used for model predictive control of continuous semifinished product solidification.
Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015
Auger, R. Robert; Burgess, Helen J.; Emens, Jonathan S.; Deriy, Ludmila V.; Thomas, Sherene M.; Sharkey, Katherine M.
A systematic literature review and meta-analyses (where appropriate) were performed and the GRADE approach was used to update the previous American Academy of Sleep Medicine Practice Parameters on the treatment of intrinsic circadian rhythm sleep-wake disorders. Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia). Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients, at a second- and first-tier degree of confidence, respectively. No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data. Areas where further research is needed are discussed. Citation: Auger RR, Burgess HJ, Emens JS, Deriy LV, Thomas SM, Sharkey KM. Clinical practice guideline for the treatment of intrinsic circadian rhythm sleep-wake disorders: advanced sleep-wake phase disorder (ASWPD), delayed sleep-wake phase disorder (DSWPD), non-24-hour sleep-wake rhythm disorder (N24SWD), and irregular sleep-wake rhythm disorder (ISWRD). An update for 2015. J Clin Sleep Med 2015;11(10):1199–1236. PMID:26414986
Morris, Christopher J; Yang, Jessica N; Garcia, Joanna I; Myers, Samantha; Bozzi, Isadora; Wang, Wei; Buxton, Orfeu M; Shea, Steven A; Scheer, Frank A J L
Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show--by using two 8-d laboratory protocols--in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.
Watkins, Heath A [Los Alamos National Laboratory; Shurter, Robert B. [Los Alamos National Laboratory; Gilpatrick, John D. [Los Alamos National Laboratory; Kutac, Vincent G. [Los Alamos National Laboratory; Martinez, Derwin [Los Alamos National Laboratory
The Los Alamos Neutron Science Center (LANSCE) deploys many cylindrical beam position and phase monitors (BPPM) throughout the linac to measure the beam central position, phase and bunched-beam current. Each monitor is calibrated and qualified prior to installation to insure it meets LANSCE requirements. The BPPM wire mapping system is used to map the BPPM electrode offset, sensitivity and higher order coefficients. This system uses a three-axis motion table to position the wire antenna structure within the cavity, simulating the beam excitation of a BPPM at a fundamental frequency of 201.25 MHz. RF signal strength is measured and recorded for the four electrodes as the antenna position is updated. An effort is underway to extend the systems service to the LANSCE facility by replacing obsolete electronic hardware and taking advantage of software enhancements. This paper describes the upgraded wire positioning system's new hardware and software capabilities including its revised antenna structure, motion control interface, RF measurement equipment and Labview software upgrades. The main purpose of the wire mapping system at LANSCE is to characterize the amplitude response versus beam central position of BPPMs before they are installed in the beam line. The wire mapping system is able to simulate a beam using a thin wire and measure the signal response as the wire position is varied within the BPPM aperture.
Herz, Rachel S; Van Reen, Eliza; Barker, David H; Hilditch, Cassie J; Bartz, Ashten L; Carskadon, Mary A
Olfactory sensitivity has traditionally been viewed as a trait that varies according to individual differences but is not expected to change with one's momentary state. Recent research has begun to challenge this position and time of day has been shown to alter detection levels. Links between obesity and the timing of food intake further raise the issue of whether odor detection may vary as a function of circadian processes. To investigate this question, 37 (21 male) adolescents (M age = 13.7 years) took part in a 28-h forced desynchrony (FD) protocol with 17.5 h awake and 10.5 h of sleep, for 7 FD cycles. Odor threshold was measured using Sniffin' Sticks 6 times for each FD cycle (total threshold tests = 42). Circadian phase was determined by intrinsic period derived from dim light melatonin onsets. Odor threshold showed a significant effect of circadian phase, with lowest threshold occurring on average slightly after the onset of melatonin production, or about 1.5○ (approximately 21:08 h). Considerable individual variability was observed, however, peak olfactory acuity never occurred between 80.5○ and 197.5○ (~02:22-10:10 h). These data are the first to show that odor threshold is differentially and consistently influenced by circadian timing, and is not a stable trait. Potential biological relevance for connections between circadian phase and olfactory sensitivity are discussed. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: email@example.com.
Krishnan, Harini C.
Circadian clocks evolved under conditions of environmental variation, primarily alternating light dark cycles, to enable organisms to anticipate daily environmental events and coordinate metabolic, physiological, and behavioral activities. However, modern lifestyle and advances in technology have increased the percentage of individuals working in phases misaligned with natural circadian activity rhythms. Endogenous circadian oscillators modulate alertness, the acquisition of learning, memory formation, and the recall of memory with examples of circadian modulation of memory observed across phyla from invertebrates to humans. Cognitive performance and memory are significantly diminished when occurring out of phase with natural circadian rhythms. Disruptions in circadian regulation can lead to impairment in the formation of memories and manifestation of other cognitive deficits. This review explores the types of interactions through which the circadian clock modulates cognition, highlights recent progress in identifying mechanistic interactions between the circadian system and the processes involved in memory formation, and outlines methods used to remediate circadian perturbations and reinforce circadian adaptation. PMID:26286653
Samadi, Nazanin; Bassey, Bassey; Martinson, Mercedes; Belev, George; Dallin, Les; Jong, Mark de; Chapman, Dean
A system has been developed to measure the vertical position and angle of the electron beam at a single location from a synchrotron source. The system uses a monochromator tuned to the absorption edge of a contrast material and has a sensitivity comparable with other beam position monitors. The stability of the photon beam position on synchrotron beamlines is critical for most if not all synchrotron radiation experiments. The position of the beam at the experiment or optical element location is set by the position and angle of the electron beam source as it traverses the magnetic field of the bend-magnet or insertion device. Thus an ideal photon beam monitor would be able to simultaneously measure the photon beam’s position and angle, and thus infer the electron beam’s position in phase space. X-ray diffraction is commonly used to prepare monochromatic beams on X-ray beamlines usually in the form of a double-crystal monochromator. Diffraction couples the photon wavelength or energy to the incident angle on the lattice planes within the crystal. The beam from such a monochromator will contain a spread of energies due to the vertical divergence of the photon beam from the source. This range of energies can easily cover the absorption edge of a filter element such as iodine at 33.17 keV. A vertical profile measurement of the photon beam footprint with and without the filter can be used to determine the vertical centroid position and angle of the photon beam. In the measurements described here an imaging detector is used to measure these vertical profiles with an iodine filter that horizontally covers part of the monochromatic beam. The goal was to investigate the use of a combined monochromator, filter and detector as a phase-space beam position monitor. The system was tested for sensitivity to position and angle under a number of synchrotron operating conditions, such as normal operations and special operating modes where the photon beam is intentionally altered
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
Gil Ponce, Enrique
The circadian system plays a key role in our well-being and its effects can be seen in many aspects of our lives. Our master circadian clock, located deep in our brain, influences various physiological processes such as heart rate, body temperature, energy metabolism, hormones, and sleep, to name a
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.
A prototype rf beam monitor has been tested on the Racetrack Microtron's (RTM) 100 kV injector beam line at the National Bureau of Standards (NBS). This beam monitor is capable of measuring the current, the relative phase, and the position of the beam. The beam is bunched at 2380 MHz for acceleration by the linac in the injector beam line. This train of beam bunches passing through the beam monitor cavities excites the cavities at this resonance frequency of 2380 MHz. Probes in the cavities couple some of the beam-excited rf power out of the cavities. This rf power can be amplified if necessary and then analyzed by a double balanced mixer (DBM). The DBM can also be used as a phase detector. The effective shunt impedance of the cavities was measured with the CW beam. For the position monitor cavity, the shunt impedance is proportional to the displacement from the axis. The measured response of the prototype rf beam current monitor setup is a linear function of beam current. Response of the rf beam-position monitor is also shown
Stukan, R.A.; Vnukova, L.V.; Kil'yanov, Yu.N.; Polyakova, A.V.
Tetragonal phase with the structure of the 123 type with the composition CdBa 2 Cu 2 WO 8 with full and selective substitution of Cu(1) positions for W atoms was synthesized from binary oxides CdWO 4 and BaCuO 2 at 800 Deg C in oxygen flow. Volumetric analysis and thermal gravimetric investigations were conducted. Phase content in the sample was no less than 90%, crystal lattice parameters were: a=b=0.4151(3) nm, c=1.2537(8) nm, peaks of X-ray pattern pointed to the availability of super structure with the twice of all three parameters in crystal cell [ru
Bass, Joseph; Takahashi, Joseph S
Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here, we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes and implications for rational therapeutics for these conditions.
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
Buhr, Ethan D.; Takahashi, Joseph S.
Mammals synchronize their circadian activity primarily to the cycles of light and darkness in the environment. This is achieved by ocular photoreception relaying signals to the suprachiasmatic nucleus (SCN) in the hypothalamus. Signals from the SCN cause the synchronization of independent circadian clocks throughout the body to appropriate phases. Signals that can entrain these peripheral clocks include humoral signals, metabolic factors, and body temperature. At the level of individual tissu...
Gandhi, Avni V; Mosser, Eric A; Oikonomou, Grigorios; Prober, David A
Sleep is an evolutionarily conserved behavioral state whose regulation is poorly understood. A classical model posits that sleep is regulated by homeostatic and circadian mechanisms. Several factors have been implicated in mediating the homeostatic regulation of sleep, but molecules underlying the circadian mechanism are unknown. Here we use animals lacking melatonin due to mutation of arylalkylamine N-acetyltransferase 2 (aanat2) to show that melatonin is required for circadian regulation of sleep in zebrafish. Sleep is dramatically reduced at night in aanat2 mutants maintained in light/dark conditions, and the circadian regulation of sleep is abolished in free-running conditions. We find that melatonin promotes sleep downstream of the circadian clock as it is not required to initiate or maintain circadian rhythms. Additionally, we provide evidence that melatonin may induce sleep in part by promoting adenosine signaling, thus potentially linking circadian and homeostatic control of sleep. Copyright © 2015 Elsevier Inc. All rights reserved.
Micic, Gorica; Lovato, Nicole; Gradisar, Michael; Burgess, Helen J; Ferguson, Sally A; Lack, Leon
Our objectives were to investigate the period lengths (i.e., taus) of the endogenous core body temperature rhythm and melatonin rhythm in delayed sleep-wake phase disorder patients (DSWPD) and non-24-h sleep-wake rhythm disorder patients (N24SWD) compared with normally entrained individuals. Circadian rhythms were measured during an 80-h ultradian modified constant routine consisting of 80 ultrashort 1-h "days" in which participants had 20-min sleep opportunities alternating with 40 min of enforced wakefulness. We recruited a community-based sample of 26 DSWPD patients who met diagnostic criteria (17 males, 9 females; age, 21.85 ± 4.97 years) and 18 healthy controls (10 males, 8 females; age, 23.72 ± 5.10 years). Additionally, 4 full-sighted patients (3 males, 1 female; age, 25.75 ± 4.99 years) were diagnosed with N24SWD and included as a discrete study group. Ingestible core temperature capsules were used to record minute temperatures that were averaged to obtain 80 hourly data points. Salivary melatonin concentration was assessed every half-hour to determine time of dim light melatonin onset at the beginning and end of the 80-h protocol. DSWPD patients had significantly longer melatonin rhythm taus (24 h 34 min ± 17 min) than controls (24 h 22 min ± 15 min, p = 0.03, d = 0.70). These results were further supported by longer temperature rhythm taus in DSWPD patients (24 h 34 min ± 26 min) relative to controls (24 h 13 min ± 15 min, p = 0.01, d = 0.80). N24SWD patients had even longer melatonin (25 h ± 19 min) and temperature (24 h 52 min ± 17 min) taus than both DSWPD (p = 0.007, p = 0.06) and control participants (p sleep timing could be explained by longer taus. This indicates that longer taus of circadian rhythms may contribute to the DSWPD patients' persistent tendency to delay, their frequent failure to respond to treatment, and their relapse following treatment. Additionally, other factors can contribute to misalignments in DSWPD and N24SWD
Patton, Andrew P.; Chesham, Johanna E.; Hastings, Michael H.
The suprachiasmatic nucleus (SCN) is the master circadian oscillator encoding time-of-day information. SCN timekeeping is sustained by a cell-autonomous transcriptional–translational feedback loop, whereby expression of the Period and Cryptochrome genes is negatively regulated by their protein products. This loop in turn drives circadian oscillations in gene expression that direct SCN electrical activity and thence behavior. The robustness of SCN timekeeping is further enhanced by interneuron...
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
Yadav, Suneeta; Chaturvedi, Chandra Mohini
Specific temporal phase relations of neural oscillations are reported to regulate gonadal activity in many avian species but their interaction with photo-sexual response are still unclear. Hence in the present study, 3week old Japanese quail maintained in short days (experiment 1) received normal saline (SD control) or serotonin precursor 5-HTP and dopamine precursor l-DOPA injections at the interval of 12h (SD 12-h) for 13days. At 37week of age, one subgroup of SD 12-h received these drugs at the interval of 8-h (SD 12-h+8-h). In the second experiment, 3week old quail were injected with 5-HTP and l-DOPA 8h apart (LD 8-h) and then maintained under long days. At the age of 37weeks, one subgroup of these LD quail was retreated with 5-HTP and l-DOPA at the interval of 8h (LD 8-h+8-h). Cloacal gland volume was monitored weekly up to 45weeks of age in both experiments and other reproductive parameters were monitored at 23 and 45week of age. These results indicate that 12-h phase relation of neurotransmitter precursors not only initiates early onset of scotorefractoriness i.e., full development of gonad even under short-day length but maintains it continuously (a long lasting effect) unlike control and the 8-h relation dissipates it, making the quail scotosensitive. On the other hand, the 8-h phase relation suppresses the gonado-stimulatory effect of long days but this effect is transitory. Thus the 12-h phase relation is gonado-stimulatory under short day conditions and the 8-h relation is gonado-inhibitory even under long days, inducing scotorefractoriness and photorefractoriness, respectively, it is suggested that effects of specific temporal phase relation of circadian neural oscillations similar to photoperiodic effects, are not only mediated by HPG axis but may also modulate the classical photoperiodic responses of Japanese quail. Copyright © 2015 Elsevier Inc. All rights reserved.
Full Text Available Synchrony of the mammalian circadian clock is achieved by complex transcriptional and translational feedback loops centered on the BMAL1:CLOCK heterodimer. Modulation of circadian feedback loops is essential for maintaining rhythmicity, yet the role of transcriptional coactivators in driving BMAL1:CLOCK transcriptional networks is largely unexplored. Here, we show diurnal hepatic steroid receptor coactivator 2 (SRC-2 recruitment to the genome that extensively overlaps with the BMAL1 cistrome during the light phase, targeting genes that enrich for circadian and metabolic processes. Notably, SRC-2 ablation impairs wheel-running behavior, alters circadian gene expression in several peripheral tissues, alters the rhythmicity of the hepatic metabolome, and deregulates the synchronization of cell-autonomous metabolites. We identify SRC-2 as a potent coregulator of BMAL1:CLOCK and find that SRC-2 targets itself with BMAL1:CLOCK in a feedforward loop. Collectively, our data suggest that SRC-2 is a transcriptional coactivator of the BMAL1:CLOCK oscillators and establish SRC-2 as a critical positive regulator of the mammalian circadian clock.
Full Text Available Abstract Background The central circadian pacemaker is a remarkably robust regulator of daily rhythmic variations of cardiovascular, endocrine, and neural physiology. Environmental lighting conditions are powerful modulators of circadian rhythms, but regulation of circadian rhythms by disease states is less clear. Here, we examine the effect of ischemic stroke on circadian rhythms in rats using high-resolution pineal microdialysis. Methods Rats were housed in LD 12:12 h conditions and monitored by pineal microdialysis to determine baseline melatonin timing profiles. After demonstration that the circadian expression of melatonin was at steady state, rats were subjected to experimental stroke using two-hour intralumenal filament occlusion of the middle cerebral artery. The animals were returned to their cages, and melatonin monitoring was resumed. The timing of onset, offset, and duration of melatonin secretion were calculated before and after stroke to determine changes in circadian rhythms of melatonin secretion. At the end of the monitoring period, brains were analyzed to determine infarct volume. Results Rats demonstrated immediate shifts in melatonin timing after stroke. We observed a broad range of perturbations in melatonin timing in subsequent days, with rats exhibiting onset/offset patterns which included: advance/advance, advance/delay, delay/advance, and delay/delay. Melatonin rhythms displayed prolonged instability several days after stroke, with a majority of rats showing a day-to-day alternation between advance and delay in melatonin onset and duration. Duration of melatonin secretion changed in response to stroke, and this change was strongly determined by the shift in melatonin onset time. There was no correlation between infarct size and the direction or amplitude of melatonin phase shifting. Conclusion This is the first demonstration that stroke induces immediate changes in the timing of pineal melatonin secretion, indicating
Evans, Jennifer A; Suen, Ting-Chung; Callif, Ben L; Mitchell, Andrew S; Castanon-Cervantes, Oscar; Baker, Kimberly M; Kloehn, Ian; Baba, Kenkichi; Teubner, Brett J W; Ehlen, J Christopher; Paul, Ketema N; Bartness, Timothy J; Tosini, Gianluca; Leise, Tanya; Davidson, Alec J
Daily rhythms in mammals are programmed by a master clock in the suprachiasmatic nucleus (SCN). The SCN contains two main compartments (shell and core), but the role of each region in system-level coordination remains ill defined. Herein, we use a functional assay to investigate how downstream tissues interpret region-specific outputs by using in vivo exposure to long day photoperiods to temporally dissociate the SCN. We then analyze resulting changes in the rhythms of clocks located throughout the brain and body to examine whether they maintain phase synchrony with the SCN shell or core. Nearly all of the 17 tissues examined in the brain and body maintain phase synchrony with the SCN shell, but not the SCN core, which indicates that downstream oscillators are set by cues controlled specifically by the SCN shell. Interestingly, we also found that SCN dissociation diminished the amplitude of rhythms in core clock gene and protein expression in brain tissues by 50-75 %, which suggests that light-driven changes in the functional organization of the SCN markedly influence the strength of rhythms in downstream tissues. Overall, our results reveal that body clocks receive time-of-day cues specifically from the SCN shell, which may be an adaptive design principle that serves to maintain system-level phase relationships in a changing environment. Further, we demonstrate that lighting conditions alter the amplitude of the molecular clock in downstream tissues, which uncovers a new form of plasticity that may contribute to seasonal changes in physiology and behavior.
Liu, Fang; Chang, Hung-Chun
Circadian rhythms orchestrate biochemical and physiological processes in living organisms to respond the day/night cycle. In mammals, nearly all cells hold self-sustained circadian clocks meanwhile couple the intrinsic rhythms to systemic changes in a hierarchical manner. The suprachiasmatic nucleus (SCN) of the hypothalamus functions as the master pacemaker to initiate daily synchronization according to the photoperiod, in turn determines the phase of peripheral cellular clocks through a variety of signaling relays, including endocrine rhythms and metabolic cycles. With aging, circadian desynchrony occurs at the expense of peripheral metabolic pathologies and central neurodegenerative disorders with sleep symptoms, and genetic ablation of circadian genes in model organisms resembled the aging-related features. Notably, a number of studies have linked longevity nutrient sensing pathways in modulating circadian clocks. Therapeutic strategies that bridge the nutrient sensing pathways and circadian clock might be rational designs to defy aging.
Jamie E. M. Byrne
Full Text Available Sleep quality, circadian phase, and mood are highly interdependent processes. Remarkably, there is currently no self-report questionnaire that measures all three of these clinically significant functions: The aim of this project was to address this deficit. In Study 1, 720 participants completed a set of potential items was generated from existing questionnaires in each of the three domains and refined to follow a single presentation format. Study 2 used an independent sample (N = 498 to interrogate the latent structure. Exploratory factor analysis was used to identify a parsimonious, three-factor latent structure. Following item reduction, the optimal representation of sleep quality, circadian phase, and mood was captured by a questionnaire with three 5-item scales: Depressed Mood, Morningness, and Good Sleep. Confirmatory factor analysis found the three-scale structure provided adequate fit. In both samples, Morningness and Good Sleep were positively associated, and each was negatively associated with the Depressed Mood scale. Further research is now required to quantify the convergent and discriminant validity of its three face-valid and structurally replicated scales. The new sleep, circadian rhythms, and mood (SCRAM questionnaire is the first instrument to conjointly measure sleep quality, circadian phase, and mood processes, and has significant potential as a clinical tool.
Smith, Shari E; Ramos, Rafaela Andrade; Refinetti, Roberto; Farthing, Jonathan P; Paterson, Phyllis G
Protein-energy malnutrition (PEM), present in 12%-19% of stroke patients upon hospital admission, appears to be a detrimental comorbidity factor that impairs functional outcome, but the mechanisms are not fully elucidated. Because ischemic brain injury is highly temperature-sensitive, the objectives of this study were to investigate whether PEM causes sustained changes in temperature that are associated with an inflammatory response. Activity levels were recorded as a possible explanation for the immediate elevation in temperature upon introduction to a low protein diet. Male, Sprague-Dawley rats (7 weeks old) were fed a control diet (18% protein) or a low protein diet (PEM, 2% protein) for either 7 or 28 days. Continuous core temperature recordings from bioelectrical sensor transmitters demonstrated a rapid increase in temperature amplitude, sustained over 28 days, in response to a low protein diet. Daily mean temperature rose transiently by day 2 (p = 0.01), falling to normal by day 4 (p = 0.08), after which mean temperature continually declined as malnutrition progressed. There were no alterations in activity mean (p = 0.3) or amplitude (p = 0.2) that were associated with the early rise in mean temperature. Increased serum alpha-2-macroglobulin (p protein diet had no effect on the signaling pathway of the pro-inflammatory transcription factor, NFκB, in the hippocampus. In conclusion, PEM induces an aberrant and sustained acute-phase response coupled with long-lasting effects on body temperature.
Karen A. Hudson
Full Text Available A number of metabolic and physiological processes in plants are controlled by the circadian clock, which enables a plant to anticipate daily changes in the environment. Relatively little is known about circadian rhythms in developing seeds, which may be important for determining the extent and timing of nutrient storage in grain. Microarray expression profiling was used to identify genes expressed in developing soybean ( seeds that are controlled by the circadian clock. Genes with predicted functions in protein synthesis, fatty acid metabolism, and photosynthesis totaling 1.8% of the mRNAs detected in seed were found to be expressed in a circadian rhythm. Known circadian and light-controlled promoter elements were identified as over-represented in the promoters of clock-controlled seed genes, with the over-represented elements varying according to the phase of circadian expression. A subset of circadian-regulated genes were found to be expressed in different phases in developing seeds with respect to leaves from the same plants, many of which have roles in photosynthesis and carbon metabolism. These results help to characterize the genes and processes in seeds that may be regulated by the circadian clock, and provide some insight into organ-specific phasing of clock controlled gene expression.
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.
Bailey, Matthew; Silver, Rae
Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic-pituitary-gonadal axis (HPG), the hypothalamicadrenal-pituitary (HPA) axis, and sleep-arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions. PMID:24287074
Tataroglu, Ozgur; Zhao, Xiaohu; Busza, Ania; Ling, Jinli; O’Neill, John S.; Emery, Patrick
Summary Circadian clocks integrate light and temperature input to remain synchronized with the day/night cycle. Although light input to the clock is well studied, the molecular mechanisms by which circadian clocks respond to temperature remain poorly understood. We found that temperature phase shifts Drosophila circadian clocks through degradation of the pacemaker protein TIM. This degradation is mechanistically distinct from photic CRY-dependent TIM degradation. Thermal TIM degradation is triggered by cytosolic calcium increase and CALMODULIN binding to TIM and is mediated by the atypical calpain protease SOL. This thermal input pathway and CRY-dependent light input thus converge on TIM, providing a molecular mechanism for the integration of circadian light and temperature inputs. Mammals use body temperature cycles to keep peripheral clocks synchronized with their brain pacemaker. Interestingly, downregulating the mammalian SOL homolog SOLH blocks thermal mPER2 degradation and phase shifts. Thus, we propose that circadian thermosensation in insects and mammals share common principles. PMID:26590423
Yan, Lily; Silver, Rae
There are compelling reasons to study the role of steroids and sex differences in the circadian timing system. A solid history of research demonstrates the ubiquity of circadian changes that impact virtually all behavioral and biological responses. Furthermore, steroid hormones can modulate every attribute of circadian responses including the period, amplitude and phase. Finally, desynchronization of circadian rhythmicity, and either enhancing or damping amplitude of various circadian responses can produce different effects in the sexes. Studies of the neuroendocrine underpinnings of circadian timing systems and underlying sex differences have paralleled the overall development of the field as a whole. Early experimental studies established the ubiquity of circadian rhythms by cataloging daily and seasonal changes in whole organism responses. The next generation of experiments demonstrated that daily changes are not a result of environmental synchronizing cues, and are internally orchestrated, and that these differ in the sexes. This work was followed by the revelation of molecular circadian rhythms within individual cells. At present, there is a proliferation of work on the consequences of these daily oscillations in health and in disease, and awareness that these may differ in the sexes. In the present discourse we describe the paradigms used to examine circadian oscillation, to characterize how these internal timing signals are synchronized to local environmental conditions, and how hormones of gonadal and/or adrenal origin modulate circadian responses. Evidence pointing to endocrinologically and genetically mediated sex differences in circadian timing systems can be seen at many levels of the neuroendocrine and endocrine systems, from the cell, the gland and organ, and to whole animal behavior, including sleep/wake or rest/activity cycles, responses to external stimuli, and responses to drugs. We review evidence indicating that the analysis of the circadian
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
Paine, Sarah-Jane; Gander, Philippa H
Factors contributing to sleep timing and sleep restriction in daily life include chronotype and less flexibility in times available for sleep on scheduled days versus free days. There is some evidence that these two factors interact, with morning types and evening types reporting similar sleep need, but evening types being more likely to accumulate a sleep debt during the week and to have greater sleep extension on weekend nights. The aim of the present study was to evaluate the independent contributions of circadian phase and weekend-to-weekday variability to sleep timing in daily life. The study included 14 morning types and 14 evening types recruited from a community-based sample of New Zealand adults (mean age 41.1 ± 4.7 years). On days 1-15, the participants followed their usual routines in their own homes and daily sleep start, midpoint and end times were determined by actigraphy and sleep diaries. Days 16-17 involved a 17 h modified constant routine protocol in the laboratory (17:00 to 10:00, morning types. Similarly on weekend days, evening types had later sleep start times (mean = 00:14 versus 23:07, p = .0032) and end times (mean = 08:56 versus 07:04, p morning types. Evening types also had later DLMO (22:06 versus 20:46, p = .0002) than morning types (mean difference = 80.4 min, SE = 18.6 min). The ANCOVA models found that later sleep start times were associated with later DLMO (p = .0172) and weekend-to-weekday sleep timing variability (p morning types and evening types, the estimated contributions of the DLMO to the mean observed differences in sleep timing were on weekdays, 39% for sleep start times and 49% for sleep end times; and on weekends, 41% for sleep start times and 34% of sleep end times. We conclude that differences in sleep timing between morning types and evening types were much greater than would be predicted on the basis of the independent contribution of the difference in DLMO on both weekdays and weekend days. The timing of sleep in
Shanahan, T. L.; Czeisler, C. A.
The physiology of the human circadian pacemaker and its influence and on the daily organization of sleep, endocrine and behavioral processes is an emerging interest in science and medicine. Understanding the development, organization and fundamental properties underlying the circadian timing system may provide insight for the application of circadian principles to the practice of clinical medicine, both diagnostically (interpretation of certain clinical tests are dependent on time of day) and therapeutically (certain pharmacological responses vary with the time of day). The light-dark cycle is the most powerful external influence acting upon the human circadian pacemaker. It has been shown that timed exposure to light can both synchronize and reset the phase of the circadian pacemaker in a predictable manner. The emergence of detectable circadian rhythmicity in the neonatal period is under investigation (as described elsewhere in this issue). Therefore, the pattern of light exposure provided in the neonatal intensive care setting has implications. One recent study identified differences in both amount of sleep time and weight gain in infants maintained in a neonatal intensive care environment that controlled the light-dark cycle. Unfortunately, neither circadian phase nor the time of day has been considered in most clinical investigations. Further studies with knowledge of principles characterizing the human circadian timing system, which governs a wide array of physiological processes, are required to integrate these findings with the practice of clinical medicine.
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.
Carolin F Reichert
Full Text Available Sleep is regulated in a time-of-day dependent manner and profits working memory. However, the impact of the circadian timing system as well as contributions of specific sleep properties to this beneficial effect remains largely unexplored. Moreover, it is unclear to which extent inter-individual differences in sleep-wake regulation depend on circadian phase and modulate the association between sleep and working memory. Here, sleep electroencephalography (EEG was recorded during a 40-h multiple nap protocol, and working memory performance was assessed by the n-back task 10 times before and after each scheduled nap sleep episode. Twenty-four participants were genotyped regarding a functional polymorphism in adenosine deaminase (rs73598374, 12 G/A-, 12 G/G-allele carriers, previously associated with differences in sleep-wake regulation. Our results indicate that genotype-driven differences in sleep depend on circadian phase: heterozygous participants were awake longer and slept less at the end of the biological day, while they exhibited longer non rapid eye movement (NREM sleep and slow wave sleep concomitant with reduced power between 8-16 Hz at the end of the biological night. Slow wave sleep and NREM sleep delta EEG activity covaried positively with overall working memory performance, independent of circadian phase and genotype. Moreover, REM sleep duration benefitted working memory particularly when occurring in the early morning hours and specifically in heterozygous individuals. Even though based on a small sample size and thus requiring replication, our results suggest genotype-dependent differences in circadian sleep regulation. They further indicate that REM sleep, being under strong circadian control, boosts working memory performance according to genotype in a time-of-day dependent manner. Finally, our data provide first evidence that slow wave sleep and NREM sleep delta activity, majorly regulated by sleep homeostatic mechanisms, is
Reichert, Carolin F; Maire, Micheline; Gabel, Virginie; Hofstetter, Marcel; Viola, Antoine U; Kolodyazhniy, Vitaliy; Strobel, Werner; Goetz, Thomas; Bachmann, Valérie; Landolt, Hans-Peter; Cajochen, Christian; Schmidt, Christina
Sleep is regulated in a time-of-day dependent manner and profits working memory. However, the impact of the circadian timing system as well as contributions of specific sleep properties to this beneficial effect remains largely unexplored. Moreover, it is unclear to which extent inter-individual differences in sleep-wake regulation depend on circadian phase and modulate the association between sleep and working memory. Here, sleep electroencephalography (EEG) was recorded during a 40-h multiple nap protocol, and working memory performance was assessed by the n-back task 10 times before and after each scheduled nap sleep episode. Twenty-four participants were genotyped regarding a functional polymorphism in adenosine deaminase (rs73598374, 12 G/A-, 12 G/G-allele carriers), previously associated with differences in sleep-wake regulation. Our results indicate that genotype-driven differences in sleep depend on circadian phase: heterozygous participants were awake longer and slept less at the end of the biological day, while they exhibited longer non rapid eye movement (NREM) sleep and slow wave sleep concomitant with reduced power between 8-16 Hz at the end of the biological night. Slow wave sleep and NREM sleep delta EEG activity covaried positively with overall working memory performance, independent of circadian phase and genotype. Moreover, REM sleep duration benefitted working memory particularly when occurring in the early morning hours and specifically in heterozygous individuals. Even though based on a small sample size and thus requiring replication, our results suggest genotype-dependent differences in circadian sleep regulation. They further indicate that REM sleep, being under strong circadian control, boosts working memory performance according to genotype in a time-of-day dependent manner. Finally, our data provide first evidence that slow wave sleep and NREM sleep delta activity, majorly regulated by sleep homeostatic mechanisms, is linked to working
Rajaratnam, SMW; Dijk, D-J; Middleton, B; Stone, BM; Arendt, J
The pineal hormone melatonin is a popular treatment for sleep and circadian rhythm disruption. Melatonin administered at optimal times of the day for treatment often results in a prolonged melatonin profile. In photoperiodic (day length-dependent) species, changes in melatonin profile duration influence the timing of seasonal rhythms. We investigated the effects of an artificially prolonged melatonin profile on endogenous melatonin and cortisol rhythms, wrist actigraphy, and reproductive horm...
Circadian rhythm is an internal biological clock which initiates and monitors various physiological processes with a fixed time-related schedule. The master circadian pacemaker is located in the suprachiasmatic nucleus in the hypothalamus. The circadian clock undergoes significant changes throughout the life span, at both the physiological and molecular levels. This cyclical physiological process, which is very complex and multifactorial, may be associated with metabolic alterations, atherosclerosis, impaired cognition, mood disturbances and even development of cancer. Sex differences do exist, and the well-known sleep disturbances associated with menopause are a good example. Circadian rhythm was detected in the daily pattern of hot flushes, with a peak in the afternoons. Endogenous secretion of melatonin decreases with aging across genders, and, among women, menopause is associated with a significant reduction of melatonin levels, affecting sleep. Although it might seem that hot flushes and melatonin secretion are likely related, there are not enough data to support such a hypothesis.
Marcolino-Gomes, Juliana; Rodrigues, Fabiana Aparecida; Fuganti-Pagliarini, Renata; Bendix, Claire; Nakayama, Thiago Jonas; Celaya, Brandon; Molinari, Hugo Bruno Correa; de Oliveira, Maria Cristina Neves; Harmon, Frank G.; Nepomuceno, Alexandre
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. PMID:24475115
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.
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.
Golden, Susan S.
SUMMARY Life on earth is subject to daily and predictable fluctuations in light intensity, temperature, and humidity created by rotation of the earth. Circadian rhythms, generated by a circadian clock, control temporal programs of cellular physiology to facilitate adaptation to daily environmental changes. Circadian rhythms are nearly ubiquitous and are found in both prokaryotic and eukaryotic organisms. Here we introduce the molecular mechanism of the circadian clock in the model cyanobacterium Synechococcus elongatus PCC 7942. We review the current understanding of the cyanobacterial clock, emphasizing recent work that has generated a more comprehensive understanding of how the circadian oscillator becomes synchronized with the external environment and how information from the oscillator is transmitted to generate rhythms of biological activity. These results have changed how we think about the clock, shifting away from a linear model to one in which the clock is viewed as an interactive network of multifunctional components that are integrated into the context of the cell in order to pace and reset the oscillator. We conclude with a discussion of how this basic timekeeping mechanism differs in other cyanobacterial species and how information gleaned from work in cyanobacteria can be translated to understanding rhythmic phenomena in other prokaryotic systems. PMID:26335718
Full Text Available The relevance of a synchronized temporal order for adaptation and homeostasis is discussed in this review. We present evidence suggesting that an altered temporal order between the biological clock and external temporal signals leads to disease. Evidence mainly based on a rodent model of “night work” using forced activity during the sleep phase suggests that altered activity and feeding schedules, out of phase from the light/dark cycle, may be the main cause for the loss of circadian synchrony and disease. It is proposed that by avoiding food intake during sleep hours the circadian misalignment and adverse consequences can be prevented. This review does not attempt to present a thorough revision of the literature, but instead it aims to highlight the association between circadian disruption and disease with special emphasis on the contribution of feeding schedules in circadian synchrony.
Aubin, Sébrina; Jennum, Poul; Nielsen, Tore
-running circadian rhythms, we controlled for circadian phase by a measure of melatonin onset timing. When circadian rhythm was entrained and melatonin onset occurred at normal times, sleep structure did not differ between blind and sighted individuals. On the other hand, an abnormal timing of the circadian phase......, including delayed, shifted and unclassifiable melatonin onsets, led to larger rapid eye movement sleep latencies and increased wake times. No differences were observed for stages of non-rapid eye movement sleep, either between congenital and late blind and sighted individuals, or across the different......We examined the structure, duration and quality of sleep, including non-rapid eye movement sleep and rapid eye movement sleep, in 11 blind individuals without conscious light perception and 11 age- and sex-matched sighted controls. Because blindness is associated with a greater incidence of free...
Brown, Steven A; Zumbrunn, Gottlieb; Fleury-Olela, Fabienne; Preitner, Nicolas; Schibler, Ueli
Low-amplitude temperature oscillations can entrain the phase of circadian rhythms in several unicellular and multicellular organisms, including Neurospora and Drosophila. Because mammalian body temperature is subject to circadian variations of 1 degrees C-4 degrees C, we wished to determine whether these temperature cycles could serve as a Zeitgeber for circadian gene expression in peripheral cell types. In RAT1 fibroblasts cultured in vitro, circadian gene expression could be established by a square wave temperature rhythm with a (Delta)T of 4 degrees C (12 hr 37 degrees C/12 hr 33 degrees C). To examine whether natural body temperature rhythms can also affect circadian gene expression, we first measured core body temperature cycles in the peritoneal cavities of mice by radiotelemetry. We then reproduced these rhythms with high precision in the liquid medium of cultured fibroblasts for several days by means of a homemade computer-driven incubator. While these "in vivo" temperature rhythms were incapable of establishing circadian gene expression de novo, they could maintain previously induced rhythms for multiple days; by contrast, the rhythms of control cells kept at constant temperature rapidly dampened. Moreover, circadian oscillations of environmental temperature could reentrain circadian clocks in the livers of mice, probably via the changes they imposed upon both body temperature and feeding behavior. Interestingly, these changes in ambient temperature did not affect the phase of the central circadian pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. We postulate that both endogenous and environmental temperature cycles can participate in the synchronization of peripheral clocks in mammals.
parameters, and if pharmacological administration of chronobiotics could improve postoperative recovery. Circadian rhythm disturbances were found in all the examined endogenous rhythms. A delay was found in the endogenous rhythm of plasma melatonin and excretion of the metabolite of melatonin (AMT6s...... in 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...
Ding, Ling; Guo, Zhimou; Hu, Zhuo; Liang, Xinmiao
A mixed-mode reversed phase/positively charged repulsion stationary phase C8PN composed of octyl and amino group has been developed for separation of intact protein. Before the separation of proteins, a set of probe compounds were employed to evaluate the chromatographic properties of C8PN, demonstrating typical reversed phase/positively charged repulsion interaction on this stationary phase as estimated. Then the new C8PN stationary phase was used to separate a standard protein mixture on the reversed phase mode. Compared with a commercial C4 stationary phase, it showed different selectivity for some proteins. In order to better understand the properties of C8PN, the effect of acetonitrile content was investigated based on retention equation. Higher values of the equation parameters on C8PN demonstrated that the protein retentions were more sensitive to the change of acetonitrile content. Besides, the influences of buffer salt additives on the protein retentions were also studied. The retention factors of the proteins got larger with the increase of buffer salt concentration, which confirmed the positively charged repulsion interaction on the column. Finally, the C8PN was further applied to separate oxidized- and reduced- forms of Recombinant Human Growth Hormone. Our study indicated the advantages and application potential of mixed-mode reversed phase/positively charged repulsion stationary phase for intact protein separation. Copyright © 2017 Elsevier B.V. All rights reserved.
Mitsutake, G; Otsuka, K; Cornélissen, G; Herold, M; Günther, R; Dawes, C; Burch, J B; Watson, D; Halberg, F
The aim of this study was to assess any variation in positive, negative and total affect recorded longitudinally; to compare the results with those from prior transverse or hybrid population studies, based on the same or a different method of mood rating; and to test for any association of mood with cardiovascular, hormonal and geophysical variables monitored concomitantly. The study approach was as follows. A clinically healthy 34-year-old man filled out the positive and negative affective scale (PANAS) questionnaire five times a day for 86 days. Systolic (S) and diastolic (D) blood pressure (BP) and heart rate (HR) were also measured automatically at 30-minute intervals with an ambulatory monitor from May 19 to June 29, 2000, while different endpoints of heart rate variability (HRV) were also determined at 5-minute intervals from beat-to-beat electrocardiogram (ECG) monitoring for 42 days between May 3 and June 14, 2000, with only short interruptions while the subject took a shower and changed ECG tapes. Saliva samples were collected at the times of mood ratings for one month for later determination of melatonin and cortisol concentrations. Intervals of 24 hours of the record of each variable displaced in increments of 24 hours were analyzed by chronobiologic serial section at a trial period of 24 hours to assess the circadian characteristics as they changed from one day to another. Estimates of the midline-estimating statistic of rhythm (MESOR) and circadian amplitude and acrophase obtained on consecutive days were correlated among variables to assess any associations. The findings were as follows. Overall, a circadian rhythm was demonstrated for all variables. A positive association was noteworthy between the circadian amplitude of negative affect and the MESOR of both SBP (r= 0.363; P= 0.029) and DBP (r= 0.389; P= 0.019), suggesting that BP is raised in the presence of large swings in negative affect. Needing further validation was a weak association between
Full Text Available This paper presents a phase-inductance-based position estimation method for interior permanent magnet synchronous motors (IPMSMs. According to the characteristics of phase induction of IPMSMs, the corresponding relationship of the rotor position and the phase inductance is obtained. In order to eliminate the effect of the zero-sequence component of phase inductance and reduce the rotor position estimation error, the phase inductance difference is employed. With the iterative computation of inductance vectors, the position plane is further subdivided, and the rotor position is extracted by comparing the amplitudes of inductance vectors. To decrease the consumption of computer resources and increase the practicability, a simplified implementation is also investigated. In this method, the rotor position information is achieved easily, with several basic math operations and logical comparisons of phase inductances, without any coordinate transformation or trigonometric function calculation. Based on this position estimation method, the field orientated control (FOC strategy is established, and the detailed implementation is also provided. A series of experiment results from a prototype demonstrate the correctness and feasibility of the proposed method.
Žižka, Zdeněk; Gabriel, Jiří
Roč. 60, č. 6 (2015), s. 545-550 ISSN 0015-5632 Institutional support: RVO:61388971 Keywords : polarization microscopy * microbial cells * positive phase contrast Subject RIV: EE - Microbiology, Virology Impact factor: 1.335, year: 2015
Boivin, Diane B; James, Francine O
In this combined field and laboratory investigation, the authors tested the efficacy of an intervention designed to promote circadian adaptation to night-shift work. Fifteen nurses working permanent night schedules (> or = 8 shifts/ 15 days) were recruited from area hospitals. Following avacation period of > or = 10 days on a regular daytime schedule, workers were admitted to the laboratory for the assessment of circadian phase via a 36-h constant routine. They returned to work approximately 12 night shifts on their regular schedules under one of two conditions. Treatment group workers (n = 10, mean age +/- SD = 41.7 +/- 8.8 years) received an intervention including 6 h of intermittent bright-light exposure in the workplace (approximately 3,243 lux) and shielding from bright morning outdoor light with tinted goggles (15% visual light transmission). Control group workers (n = 9, mean age +/- SD = 42.0 +/- 7.2 years) were observed in their habitual work environments. On work days, participants maintained regular sleep/wake schedules including a single 8-h sleep/darkness episode beginning 2 h after the end of the night shift. A second 36-h constant routine was performed following the series of night shifts. In the presence of the intervention, circadian rhythms of core body temperature and salivary melatonin cycles were delayed by an average (+/- SEM) of -9.32 +/- 1.06 h and -11.31 +/- 1.13 h, respectively. These were significantly greater than the phase delays of -4.09 +/- 1.94 h and -5.08 +/- 2.32 h displayed by the control group (p = 0.03 and p = 0.02, respectively). The phase angle between circadian markers and the shifted schedule was reestablished to its baseline position only in the treatment group of workers. These results support the efficacy of a practical intervention for promoting circadian adaptation to night-shift work under field conditions. They also underline the importance of controlling the overall pattern of exposure to light and darkness in
Robertson, Laura; Jones, M. Gail
The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian…
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
ten Thij, M.C.; Kampstra, P.; Bhulai, S.; Laux, F.; Pardalos, P.M.; Crolotte, A.
In this paper, we study activity on the microblogging platform Twitter. We analyse two separate aspects of activity on Twitter. First, we analyse the daily and weekly number of posts, through which we find clear circadian (daily) patterns emerging in the use of Twitter for multiple languages. We see
Frank A J L Scheer
Full Text Available 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.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.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 final common pathway of platelet aggregation, suggests that endogenous
Westerterp-Plantenga, Margriet S
Circadian alignment is crucial for body-weight management, and for metabolic health. In this context, circadian alignment consists of alignment of sleep, meal patterns and physical activity. During puberty a significant reduction in sleep duration occurs, and pubertal status is inversely associated with sleep duration. A consistent inverse association between habitual sleep duration and body-weight development occurs, independent of possible confounders. Research on misalignment reveals that circadian misalignment affects sleep-architecture and subsequently disturbs glucose-insulin metabolism, substrate oxidation, leptin- and ghrelin concentrations, appetite, food reward, hypothalamic-pituitary-adrenal-axis activity and gut-peptide concentrations enhancing positive energy balance and metabolic disturbance. Not only aligning meals and sleep in a circadian way is crucial, also regular physical activity during the day strongly promotes the stability and amplitude of circadian rhythm, and thus may serve as an instrument to restore poor circadian rhythms. Endogenicity may play a role in interaction of these environmental variables with a genetic predisposition. In conclusion, notwithstanding the separate favourable effects of sufficient daily physical activity, regular meal patterns, sufficient sleep duration and quality sleep on energy balance, the overall effect of the amplitude and stability of the circadian rhythm, perhaps including genetic predisposition, may integrate the separate effects in an additive way.
Skene, D J; Lockley, S W; Arendt, J
Assessment of sleep patterns in blind people demonstrates a high prevalence of sleep disorders. Our studies have shown that subjects with no conscious light perception (NPL) have a higher occurrence and more severe sleep disorders than those with some degree of light perception (LP). A detailed study of 49 blind individuals showed that those with NPL are likely to have free-running (FR) circadian rhythms (aMT6s, cortisol) including sleep. Non-24-hour (or FR) sleep-wake disorder, characterised by periods of good and bad sleep is a condition that may benefit from melatonin treatment. Melatonin has been administered to NPL subjects with FR circadian rhythms and compared with placebo (or the no-treatment baseline) sleep parameters improved. The results suggest that prior knowledge of the subject's type of circadian rhythm, and timing of treatment in relation to the individual's circadian phase, may improve the efficacy of melatonin.
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.
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.
Hasler, Brant P; Clark, Duncan B
Developmental changes in sleep and circadian rhythms that occur during adolescence may contribute to reward-related brain dysfunction, and consequently increase the risk of alcohol use disorders (AUDs). This review (i) describes marked changes in circadian rhythms, reward-related behavior and brain function, and alcohol involvement that occur during adolescence, (ii) offers evidence that these parallel developmental changes are associated, and (iii) posits a conceptual model by which misalignment between sleep-wake timing and endogenous circadian timing may increase the risk of adolescent AUDs by altering reward-related brain function. The timing of sleep shifts later throughout adolescence, in part due to developmental changes in endogenous circadian rhythms, which tend to become more delayed. This tendency for delayed sleep and circadian rhythms is at odds with early school start times during secondary education, leading to misalignment between many adolescents' sleep-wake schedules and their internal circadian timing. Circadian misalignment is associated with increased alcohol use and other risk-taking behaviors, as well as sleep loss and sleep disturbance. Growing evidence indicates that circadian rhythms modulate the reward system, suggesting that circadian misalignment may impact adolescent alcohol involvement by altering reward-related brain function. Neurocognitive function is also subject to sleep and circadian influence, and thus circadian misalignment may also impair inhibitory control and other cognitive processes relevant to alcohol use. Specifically, circadian misalignment may further exacerbate the cortical-subcortical imbalance within the reward circuit, an imbalance thought to explain increased risk-taking and sensation-seeking during adolescence. Adolescent alcohol use is highly contextualized, however, and thus studies testing this model will also need to consider factors that may influence both circadian misalignment and alcohol use. This review
Choi, Jungzae; Choi, Mooyoung; Yoon, Byunggook
We investigate numerically the dynamics of traveling clusters in systems of phase oscillators, some of which possess positive couplings and others negative couplings. The phase distribution, speed of traveling, and average separation between clusters, as well as the order parameters for positive and negative oscillators, are computed as the ratio of the two coupling constants and the fraction of positive oscillators are varied. The dependence of the traveling speed on these parameters is obtained and is observed to fit well with the numerical data of the systems. With the help of this, we describe the conditions for the traveling state to appear in the systems with and without a periodic driving field.
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.
This experiment identifies and models phases during the positioning of graphical objects (called cursors in this article) on computer displays. The human computer-interaction community has traditionally used Fitts' law to model selection in graphical user interfaces, whereas human factors experiments have found the single-component Fitts' law inadequate to model positioning of real objects. Participants (N=145) repeatedly positioned variably sized square cursors within variably sized rectangular targets using computer mice. The times for the cursor to just touch the target, for the cursor to enter the target, and for participants to indicate positioning completion were observed. The positioning tolerances were varied from very precise and difficult to imprecise and easy. The time for the cursor to touch the target was proportional to the initial cursor-target distance. The time for the cursor to completely enter the target after touching was proportional to the logarithms of cursor size divided by target tolerances. The time for participants to indicate positioning after entering was inversely proportional to the tolerance. A three-phase model defined by regions--distant, proximate, and inside the target--was proposed and could model the positioning tasks. The three-phase model provides a framework for ergonomists to evaluate new positioning techniques and can explain their deficiencies. The model provides a means to analyze tasks and enhance interaction during positioning.
Komatsuzaki, Akitomo; Miki, Ichiro
Switched reluctance motor (SRM) drives are suitable for variable speed industrial applications because of the simple structure and high-speed capability. However, it is necessary to detect the rotor position with a position sensor attached to the motor shaft. The use of the sensor increases the cost of the drive system and machine size, and furthermore the reliability of the system is reduced. Therefore, several approaches to eliminate the position sensor have already been reported. In this paper, a position sensorless control method based on the variation of the phase inductance is described. The phase inductance regularly varies with the rotor position. The SRM is controlled without the position sensor using the de-fluxing period and the phase inductance. The turn-off timing is determined by computing the difference of angle between the sampling point and the aligned point and the variation of angle during the de-fluxing period. In the magnetic saturation region, the phase inductance at the current when the effect of the saturation starts is computed and the sensorless control can be carried out using this inductance. Experimental results show that the SRM is well controlled without the position sensor using the proposed method.
Rossetti, Stefano; Corlazzoli, Francesca; Gregorski, Alex; Azmi, Nurul Hidayah A.; Sacchi, Nicoletta
Altered estrogen receptor α (ERA) signaling and altered circadian rhythms are both features of breast cancer. By using a method to entrain circadian oscillations in human cultured cells, we recently reported that the expression of key clock genes oscillates in a circadian fashion in ERA-positive breast epithelial cells but not in breast cancer cells, regardless of their ERA status. Moreover, we reported that ERA mRNA oscillates in a circadian fashion in ERA-positive breast epithelial cells, but not in ERA-positive breast cancer cells. By using ERA-positive HME1 breast epithelial cells, which can be both entrained in vitro and can form mammary gland-like acinar structures in three-dimensional (3D) culture, first we identified a circuit encompassing ERA and an estrogen-regulated loop consisting of two circadian clock genes, PER2 and BMAL1. Further, we demonstrated that this estrogen-regulated circuit is necessary for breast epithelial acinar morphogenesis. Disruption of this circuit due to ERA-knockdown, negatively affects the estrogen-sustained circadian PER2-BMAL1 mechanism as well as the formation of 3D HME1 acini. Conversely, knockdown of either PER2 or BMAL1, by hampering the PER2-BMAL1 loop of the circadian clock, negatively affects ERA circadian oscillations and 3D breast acinar morphogenesis. To our knowledge, this study provides the first evidence of the implication of an ERA-circadian clock mechanism in the breast acinar morphogenetic process. PMID:22935699
Lazar, Alpar S; Santhi, Nayantara; Hasan, Sibah; Lo, June C-Y; Johnston, Jonathan D; Von Schantz, Malcolm; Archer, Simon N; Dijk, Derk-Jan
Sleep complaints and irregular sleep patterns, such as curtailed sleep during workdays and longer and later sleep during weekends, are common. It is often implied that differences in circadian period and in entrained phase contribute to these patterns, but few data are available. We assessed parameters of the circadian rhythm of melatonin at baseline and in a forced desynchrony protocol in 35 participants (18 women) with no sleep disorders. Circadian period varied between 23 h 50 min and 24 h 31 min, and correlated positively (n = 31, rs = 0.43, P = 0.017) with the timing of the melatonin rhythm relative to habitual bedtime. The phase of the melatonin rhythm correlated with the Insomnia Severity Index (n = 35, rs = 0.47, P = 0.004). Self-reported time in bed during free days also correlated with the timing of the melatonin rhythm (n = 35, rs = 0.43, P = 0.01) as well as with the circadian period (n = 31, rs = 0.47, P = 0.007), such that individuals with a more delayed melatonin rhythm or a longer circadian period reported longer sleep during the weekend. The increase in time in bed during the free days correlated positively with circadian period (n = 31, rs = 0.54, P = 0.002). Polysomnographically assessed latency to persistent sleep (n = 34, rs = 0.48, P = 0.004) correlated with the timing of the melatonin rhythm when participants were sleeping at their habitual bedtimes in the laboratory. This correlation was significantly stronger in women than in men (Z = 2.38, P = 0.017). The findings show that individual differences in circadian period and phase of the melatonin rhythm associate with differences in sleep, and suggest that individuals with a long circadian period may be at risk of developing sleep problems. © 2012 European Sleep Research Society.
Takeda, Norihiko; Maemura, Koji
Cardiovascular functions, including blood pressure and vascular functions, show diurnal oscillation. Circadian variations have been clearly shown in the occurrence of cardiovascular events such as acute myocardial infarction. Circadian rhythm strongly influences human biology and pathology. The identification and characterization of mammalian clock genes revealed that they are expressed almost everywhere throughout the body in a circadian manner. In contrast to the central clock in the suprac...
Fekete, Mátyás; Ree, J.M. van; Niesink, Raymond J.M.; Wied, D. de
Disrupting circadian organization in rats by phase-shifting the illumination cycle or by exposure to a reversed day/night cycle or to continuous light, resulted in retrograde amnesia for passive avoidance behavior. This retrograde amnesia induced by phase-shifting lasted at least 2 days, and
Komatsuzaki, Akitomo; Bamba, Tatsunori; Miki, Ichiro
Switched reluctance motors (SRMs) are widely employed as industrial drives because they are inexpensive, simple, and sturdy, further, they deliver a robust and reliable performance. SRMs are controlled with a rotor position sensor attached to the motor shaft. Normally, encoders, resolvers, or Hall sensors are used as position sensors. The use of these sensors, however, increases the size and cost of the machine and degrades its performance. Therefore, to overcome these difficulties, several sensorless drive techniques have been reported. In this paper, a method for estimating the position of a rotor in an SRM; this method is based on calculation of the space vector of phase inductance at standstill and low speeds. The position at standstill is obtained simply without making use of the magnetic characteristics of the motor or any additional hardware. Assuming the inductance waveform to be a sine wave, the position of rotor at standstill is obtained from the phase inductance vectors of all phases. At low speeds, position estimation is carried out by applying a DC link voltage to the unenergized phases. The validity of the proposed method is experimentally verified.
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.
Full Text Available Parkinson's disease (PD is the second most common neurodegenerative disorder that affects over one million individuals in the US alone. PD is characterized by a plethora of motor and non-motor manifestations, resulting from a progressive degeneration of dopaminergic neurons and disbalance of several other neurotransmitters. A growing body of evidence points to significant alterations of the circadian system in PD. This is not surprising given the pivotal role that dopamine plays in circadian regulation as well as the role of circadian influences in dopamine metabolism. In this review we present basic and clinical investigations that examined the function of the circadian system in PD.
Arble, Deanna M; Bass, Joseph; Laposky, Aaron D; Vitaterna, Martha H; Turek, Fred W
Studies of body weight regulation have focused almost entirely on caloric intake and energy expenditure. However, a number of recent studies in animals linking energy regulation and the circadian clock at the molecular, physiological, and behavioral levels raise the possibility that the timing of food intake itself may play a significant role in weight gain. The present study focused on the role of the circadian phase of food consumption in weight gain. We provide evidence that nocturnal mice fed a high-fat diet only during the 12-h light phase gain significantly more weight than mice fed only during the 12-h dark phase. A better understanding of the role of the circadian system for weight gain could have important implications for developing new therapeutic strategies for combating the obesity epidemic facing the human population today.
Dahl, Jens Peder; Springborg, Michael
functions are to be calculated. The wave and phase space functions are displayed in a series of curves and contour diagrams. An Appendix discusses the calculation of the modified Bessel functions of real, positive argument and complex order, which is required for calculating the phase space functions......We present a unified description of the position-space wave functions, the momentum-space wave functions, and the phase-space Wigner functions for the bound states of a Morse oscillator. By comparing with the functions for the harmonic oscillator the effects of anharmonicity are visualized....... Analytical expressions for the wave functions and the phase space functions are given, and it is demonstrated how a numerical problem arising from the summation of an alternating series in evaluating Laguerre functions can be circumvented. The method is applicable also for other problems where Laguerre...
Schnell, R C; Bozigian, H P; Davies, M H; Merrick, B A; Park, K S; McMillan, D A
Experiments were conducted to examine the effects of changes in lighting schedules and food consumption on circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice. Under a normal lighting schedule (light: 06.00-18.00 h), male mice exhibited a circadian rhythm in acetaminophen lethality (peak: 18.00 h; nadir: 06.00, 10.00 h) and an inverse rhythm in hepatic glutathione concentrations (peak: 06.00, 10.00 h; nadir: 18.00 h). Under a reversed lighting schedule (light: 18.00-06.00 h) the glutathione rhythm was reversed and the rhythm in acetaminophen lethality was altered showing greater sensitivity to the drug. Under continuous light, there was a shift in the acetaminophen lethality and the hepatic glutathione rhythms. Under continuous dark, both rhythms were abolished. Under a normal lighting regimen, hepatic glutathione levels were closely correlated with food consumption; i.e., both were increased during the dark phase and decreased during the light phase. Fasting the mice for 12 h abolished the rhythms in acetaminophen lethality and hepatic glutathione levels; moreover, the lethality was increased and the hepatic glutathione levels were decreased. These experiments show that both lighting schedules and feeding can alter the circadian rhythms in acetaminophen lethality and hepatic glutathione levels in male mice.
Cassone, Vincent M
In birds, biological clock function pervades all aspects of biology, controlling daily changes in sleep: wake, visual function, song, migratory patterns and orientation, as well as seasonal patterns of reproduction, song and migration. The molecular bases for circadian clocks are highly conserved, and it is likely the avian molecular mechanisms are similar to those expressed in mammals, including humans. The central pacemakers in the avian pineal gland, retinae and SCN dynamically interact to maintain stable phase relationships and then influence downstream rhythms through entrainment of peripheral oscillators in the brain controlling behavior and peripheral tissues. Birds represent an excellent model for the role played by biological clocks in human neurobiology; unlike most rodent models, they are diurnal, they exhibit cognitively complex social interactions, and their circadian clocks are more sensitive to the hormone melatonin than are those of nocturnal rodents. PMID:24157655
Sarma, Ashapurna; Sharma, Vishal P.; Sarkar, Arindam B.; Sekar, M. Chandra; Samuel, Karunakar; Geusz, Michael E.
Curcuminoids of the spice turmeric and their enhanced derivatives have much potential as cancer treatments. They act on a wide variety of biological pathways, including those regulating cell division and circadian rhythms. It is known that circadian clocks can modify cancer therapy effectiveness, according to studies aimed at optimizing treatments based on the circadian cycle. It is therefore important to determine whether treatments with curcumin or similar chemotherapeutic agents are regulated by circadian timing. Similarly, it is important to characterize any effects of curcumin on timing abilities of the circadian clocks within cancer cells. We examined the circadian clock’s impact on the timing of cell death and cell division in curcumin-treated C6 rat glioma cells through continuous video microscopy for several days. To evaluate its persistence and distribution in cancer cells, curcumin was localized within cell compartments by imaging its autofluorescence. Finally, HPLC and spectroscopy were used to determine the relative stabilities of the curcumin congeners demethoxycurcumin and bisdemethoxycurcumin that are present in turmeric. Circadian rhythms in cell death were observed in response to low (5 μM) curcumin, reaching a peak several hours before the peak in rhythmic expression of mPER2 protein, a major circadian clock component. These results revealed a sensitive phase of the circadian cycle that could be effectively targeted in patient therapies based on curcumin or its analogs. Curcumin fluorescence was observed in cell compartments at least 24 h after treatment, and the two congeners displayed greater stability than curcumin in cell culture medium. We propose a mechanism whereby curcuminoids act in a sustained manner, over several days, despite their tendency to degrade rapidly in blood and other aqueous media. During cancer therapy, curcumin or its analogs should be delivered to tumor cells at the optimal phase for highest efficacy after identifying
Poulsen, Raewyn C; Warman, Guy R; Sleigh, Jamie; Ludin, Nicola M; Cheeseman, James F
Post-operative patients experience sleep disturbances. Animal studies demonstrate that general anaesthesia (GA) can disrupt circadian rhythms and cause changes in the molecular clock, indicating that anaesthesia contributes to post-operative circadian disruption. Here we review the effect of anaesthesia on the circadian clock and its rhythms in order to summarise current findings outline commonalities between studies and propose mechanisms by which effects may be mediated. 1) GA has strong effects on the main neurotransmitter systems linked with circadian control (Gamma aminobutyric acid/N-methyl-D-aspartate (GABA/NMDA)) and may act by interfering with light-entrainment of the clock. 2) Expression of the core clock gene per2 is inhibited by GA (possibly via a NMDA/glycogen synthase kinase 3β (GSK3β) pathway). 3) GA's effect on circadian rhythms appears greatest when administered during animals' active phases 4) GA may have different effects when administered under free-running and entrained conditions. 5) Anaesthesia may mimic the mechanism involved in adaptation of the clock to changes in daylength. There is agreement that GA can strongly affect the circadian clock. How anaesthesia-induced changes in the molecular clock lead to changes in behaviour remains unclear. The answer, and what it may mean for patients post-operatively, will rely on systematic studies at molecular, behavioural, and clinical levels using standardised protocols. Copyright © 2016 Elsevier Ltd. All rights reserved.
Merrow, Martha; Roenneberg, Till
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
Van der Zee, Eddy A.; Boersma, Gretha J.; Hut, Roelof A.
Purpose of review There is growing awareness of the importance of circadian rhythmicity in various research fields. Exciting developments are ongoing in the field of circadian neurobiology linked to sleep, food intake, and memory. With the current knowledge of critical clock genes' (genes found to
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
Park, Junghea; Lee, Choogon; Takahashi, Joseph S.
In animals circadian behavior can be analyzed as an integrated system - beginning with genes leading ultimately to behavioral outputs. In the last decade, the molecular mechanism of circadian clocks has been unraveled primarily by the use of phenotype-driven (forward) genetic analysis in a number of model systems. Circadian oscillations are generated by a set of genes forming a transcriptional autoregulatory feedback loop. In mammals, there is a “core” set of circadian genes that form the primary negative feedback loop of the clock mechanism (Clock/Npas2, Bmal1, Per1, Per2, Cry1, Cry2 and CK1ε). Another dozen candidate genes have been identified and play additional roles in the circadian gene network such as the feedback loop involving Rev-erbα. Despite this remarkable progress, it is clear that a significant number of genes that strongly influence and regulate circadian rhythms in mammals remain to be discovered and identified. As part of a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen using a wide range of nervous system and behavioral phenotypes, we have identified a number of new circadian mutants in mice. Here we describe a new short period circadian mutant, part-time (prtm), which is caused by a loss-of-function mutation in the Cryptochrome1 gene. We also describe a long period circadian mutant named Overtime (Ovtm). Positional cloning and genetic complementation reveal that Ovtm is encoded by the F-box protein FBXL3 a component of the SKP1-CUL1-F-box-protein (SCF) E3 ubiquitin ligase complex. The Ovtm mutation causes an isoleucine to threonine (I364T) substitution leading to a loss-of-function in FBXL3 which interacts specifically with the CRYPTOCHROME (CRY) proteins. In Ovtm mice, expression of the PERIOD proteins PER1 and PER2 is reduced; however, the CRY proteins CRY1 and CRY2 are unchanged. The loss of FBXL3 function leads to a stabilization of the CRY proteins, which in turn leads to a global transcriptional repression of the Per and
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.
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.
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.
Zhao, Lei; Gao, Xingshun; Hu, Xiaofang; Liu, Shubin; An, Qi
A prototype of a beam position and phase measurement system is designed for the proton accelerator in the China Accelerator Driven Sub-critical system (ADS). The signals from the Beam Position Monitor (BPM) detector are narrow pulses with a repetition frequency of 162.5 MHz and the input amplitude would vary for more than 40 dB. By applying the high-speed high-resolution analog-to-digital conversion technique, the input radio-frequency (RF) signals are directly under sampled to orthogonal streams by precisely adjusting the sampling clock frequency. Compared with the traditional method to obtain the in-phase and quadrature-phase (IQ) data, it simplifies both the analog and digital processing circuits. All signal processing algorithms are integrated within one field programmable gate array (FPGA) chip for a good system simplicity. Initial testing results indicate that this prototype achieves a phase resolution better than 0.03° and a position resolution better than 5 μm over the input amplitude range from -44 dBm to -4 dBm, well beyond the requirement.
Meehl, G. A.; Hu, A.; Teng, H.
The negative phase of the Interdecadal Pacific Oscillation (IPO), a dominant mode of multi-decadal variability of sea surface temperatures (SSTs) in the Pacific, contributed to the reduced rate of global surface temperature warming in the early 2000s. A proposed mechanism for IPO multidecadal variability indicates that the presence of decadal timescale upper ocean heat content in the off-equatorial western tropical Pacific can provide conditions for an interannual El Niño/Southern Oscillation event to trigger a transition of tropical Pacific SSTs to the opposite IPO phase. Here we show that a decadal prediction initialized in 2013 simulates predicted Niño3.4 SSTs that have qualitatively tracked the observations through 2015. The year 3-7 average prediction (2015-2019) from the 2013 initial state shows a transition to the positive phase of the IPO from the previous negative phase, and a resumption of larger rates of global warming over the 2013-2022 period consistent with a positive IPO phase.
This thesis explores the methods for enhancing the performance of using low cost, single frequency Carrier phase Differential Global Navigation Satellite System (CDGNSS) in real-time, safety or liability critical applications. This is done by improving the integer ambiguity resolution performance and carrier phase error modeling. CDGNSS is considered for a broad range of real-time applications which require both a high precision relative positioning and attitude determination system. This is because of the drift-free nature of the GNSS measurement errors and the precise nature of the carrier phase measurement. The key to making full use of the precise nature of the carrier phase measurement is to fix the integer ambiguity quickly and reliably. This poses the biggest challenge for a low cost single frequency system. For the attitude determination problem, the precisely known baseline lengths can be used to improve the integer ambiguity resolution performance. Traditionally, the relative positioning problem was solved independently of the attitude determination problem and, thus could not leverage the precisely known baseline lengths of the attitude determination system. However, by integrating the two systems together, the precisely known baseline lengths can be used to improve the relative positioning system as well. The first part of the thesis develops an integration framework to improve the integer ambiguity resolution performance for the relative positioning system and the attitude determination system simultaneously. The second part of the thesis provides a GNSS antenna Phase Center Variation (PCV) error model development to improve the accuracy of the integrated system. It also examines the feasibility analysis of using the developed error model for a real-time dynamic application. The challenging of using this in the real time lies in the fact that PCV error magnitude is small (less than 2cm) and the developed error model is a function of unknown parameter
Coriolis flowmeters (CFM) are forced to vibrate by a periodic excitation usually applied midpipe through an electromagnetic actuator. From hands-on experience with industrial CFMs it appears, that the electromagnetic actuator has to be located as symmetric as possible. For CFM design and trouble-shooting...... position, e.g. due to manufacturing variations or improper handling of the CFM, induces a phase shift that leads to changes of the meter’s sensitivity, and could therefore result into erroneous measurements of the mass flow. This phase shift depends on the mass flow and does not contribute to a lacking...
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.
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.
Eastman, Charmane I; Tomaka, Victoria A; Crowley, Stephanie J
The endogenous, free-running circadian period (τ) determines the phase relationship that an organism assumes when entrained to the 24-h day. We found a shorter circadian period in African Americans compared to non-Hispanic European Americans (24.07 versus 24.33 h). We speculate that a short circadian period, closer to 24 h, was advantageous to humans living around the equator, but when humans migrated North out of Africa, where the photoperiod changes with seasons, natural selection favoured people with longer circadian periods. Recently, in evolutionary terms, immigrants came from Europe and Africa to America ('the New World'). The Europeans were descendents of people who had lived in Europe for thousands of years with changing photoperiods (and presumably longer periods), whereas Africans had ancestors who had always lived around the equator (with shorter periods). It may have been advantageous to have a longer circadian period while living in Europe early in the evolution of humans. In our modern world, however, it is better to have a shorter period, because it helps make our circadian rhythms earlier, which is adaptive in our early-bird-dominated society. European American women had a shorter circadian period than men (24.24 versus 24.41), but there was no sex difference in African Americans (24.07 for both men and women). We speculate that selection pressures in Europe made men develop a slightly longer period than women to help them track dawn which could be useful for hunters, but less important for women as gatherers. © 2017 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.
Lepure, Liviu I.; Andreescu, Gheorghe-Daniel; Iles, Doris
A novel position and speed estimator for single phase permanent magnet brushless d.c. (PMBLDC) motor drives, based on flux integration and prior knowledge of ΨPM (θ) is proposed here and an adequate correction algorithm is adopted in order to increase the robustness to noise and to reduce...... the sensitivity to accuracy of flux linkage estimation. A speed and current close loop control is employed based on the Hall signal and the motor is controlled at different speeds in order to validate the proposed estimation algorithm with satisfying results. The position correction effect is analyzed...
Weinberg, Irving N.
The aims of this work were to design and build a human-directed imaging device incorporating position sensing, perform experimental phantom studies with the device, and prepare for clinical trials to be performed in Phase III. All aims were accomplished. Novel algorithms were developed that were capable of handling flexible prescriptions with respect to detector position, and of providing real-time feedback to operators of the device. Extension of the original SPECT concept was made to the case of PET, and a bench-top experiment demonstrated that a workable prostate imaging device could be constructed using the reconstruction principles evaluated in this effort. Preparation for Phase III was accomplished, as evidenced by equity financing of the company for construction of commercial devices for the field of medicine.
Shirai, Hidenori; Oishi, Katsutaka; Kudo, Takashi; Shibata, Shigenobu; Ishida, Norio
Recent progress at the molecular level has revealed that nuclear receptors play an important role in the generation of mammalian circadian rhythms. To examine whether peroxisome proliferator-activated receptor alpha (PPARα) is involved in the regulation of circadian behavioral rhythms in mammals, we evaluated the locomotor activity of mice administered with the hypolipidemic PPARα ligand, bezafibrate. Circadian locomotor activity was phase-advanced about 3 h in mice given bezafibrate under light-dark (LD) conditions. Transfer from LD to constant darkness did not change the onset of activity in these mice, suggesting that bezafibrate advanced the phase of the endogenous clock. Surprisingly, bezafibrate also advanced the phase in mice with lesions of the suprachiasmatic nucleus (SCN; the central clock in mammals). The circadian expression of clock genes such as period2, BMAL1, and Rev-erbα was also phase-advanced in various tissues (cortex, liver, and fat) without affecting the SCN. Bezafibrate also phase-advanced the activity phase that is delayed in model mice with delayed sleep phase syndrome (DSPS) due to a Clock gene mutation. Our results indicated that PPARα is involved in circadian clock control independently of the SCN and that PPARα could be a potent target of drugs to treat circadian rhythm sleep disorders including DSPS
Full Text Available By continued improvement of measurement methods producers of GPS (Global Positioning System apparatus will be maybe once upon a time effective to minimize a difference of the phase centre from the geometrical one, because it is probably impossible to make the GPS receiver antenna with zero eccentricity of the phase centre. In the last analysis, we do not prevent from a manufacturing error by any way in eliminate of the possible measurement errors.In the paper there is presented the measurement testing practice with aim of the phase centre real position determining of several in a market available GPS receivers in the paper. Investigation up to what standard the GPS receiver antenna phase centre variation achieves to float in an inaccuracy into GPS measurements. Testing was realized on the temporary testing baseline closely village Badín at Banská Bystrica in the Central Slovak Region. GPS receivers Locus Survey System (Ashtech, ProMark2 (Ashtech were tested.
Gilpatrick, John D [Los Alamos National Laboratory; Kutac, Vincent G. [Los Alamos National Laboratory; Martinez, Derwin [Los Alamos National Laboratory; McCrady, Rodney C. [Los Alamos National Laboratory; O' Hara, James F. [Los Alamos National Laboratory; Olivas, Felix R. [Los Alamos National Laboratory; Shurter, Robert B. [Los Alamos National Laboratory; Watkins, Heath A. [Los Alamos National Laboratory
The Los Alamos Neutron Science Center - Risk Mitigation Project is in the process of replacing older Coupled-Cavity-Linac (CCL) Beam-Position Monitors (BPMs) with newer Beam Position and Phase Monitors (BPPMs) and their associated electronics and cable plants. In many locations, these older BPMs include a separate Delta-T loop for measuring the beam's central phase and energy. Thirty-one BPPMs have been installed and many have monitored the charged particle beam. The installation of these newer BPPMs is the first step to installing complete BPPM measurement systems. Prior to the installation, a characterization of each BPPM took place. The characterization procedure includes a mechanical inspection, a vacuum testing, and associated electrical tests. The BPPM electrical tests for all four electrodes include contact resistance measurements, Time Domain Reflectometer (TDR) measurements, relative 201.25-MHz phase measurements, and finally a set of position-sensitive mapping measurements were performed which included associated fitting routines. This paper will show these data for a typical characterized BPPM.
Souto, M; Llanos, J M
Standardized (light from 0600 to 1800) C3HS mice, hepatectomized at different circadian stages, were killed at 1400 (the peak time of mitotic activity in intact mice). The higher values of mitotic index were those of mice operated at 1400, 48 hr before. The curve of mitotic activity of the regenerating liver of mice operated at 1400 and that of mice operated at 0200 (an opposite time in the circadian stage) are, both, grossly in phase with the curves of mitotic index in young and adult mice liver. The amplitude of the first peak of mitotic activity in mice operated at 0200 was dramatically lower than that of animals operated at 1400. The same applies to hepatocytes as well as to the sinusoid litoral population of cells. It is concluded that 1400 hr, as contrast to 0200 hr, is an optimal time for hepatectomy if one wants to obtain the highest mitotic index first peak during regeneration in a normal phase position (the position of the mitotic index peak in the liver of normal young and adult mice).
Bockisch, Christopher J.; Khojasteh, Elham; Straumann, Dominik; Hegemann, Stefan C. A.
The nystagmus in patients with vestibular disorders often has an eye position dependency, called Alexander’s law, where the slow phase velocity is higher with gaze in the fast phase direction compared with gaze in the slow phase direction. Alexander’s law has been hypothesized to arise either due to adaptive changes in the velocity-to-position neural integrator, or as a consequence of processing of the vestibular-ocular reflex. We tested whether Alexander’s law arises only as a consequence of non-physiologic vestibular stimulation. We measured the time course of the development of Alexander’s law in healthy humans with nystagmus caused by three types of caloric vestibular stimulation: cold (unilateral inhibition), warm (unilateral excitation), and simultaneous bilateral bithermal (one side cold, the other warm) stimulation, mimicking the normal push-pull pattern of vestibular stimulation. Alexander’s law, measured as a negative slope of the velocity versus position curve, was observed in all conditions. A reversed pattern of eye position dependency (positive slope) was found <10% of the time. The slope often changed with nystagmus velocity (cross-correlation of nystagmus speed and slope was significant in 50% of cases), and the average lag of the slope with the speed was not significantly different from zero. Our results do not support the hypothesis that Alexander’s law can only be observed with non-physiologic vestibular stimulation. Further, the rapid development of Alexander’s law, while possible for an adaptive mechanism, is nonetheless quite fast compared to most other ocular motor adaptations. These results suggest that Alexander’s law may not be a consequence of a true adaptive mechanism. PMID:23251522
Christopher J Bockisch
Full Text Available The nystagmus in patients with vestibular disorders often has an eye position dependency, called Alexander's law, where the slow phase velocity is higher with gaze in the fast phase direction compared with gaze in the slow phase direction. Alexander's law has been hypothesized to arise either due to adaptive changes in the velocity-to-position neural integrator, or as a consequence of processing of the vestibular-ocular reflex. We tested whether Alexander's law arises only as a consequence of non-physiologic vestibular stimulation. We measured the time course of the development of Alexander's law in healthy humans with nystagmus caused by three types of caloric vestibular stimulation: cold (unilateral inhibition, warm (unilateral excitation, and simultaneous bilateral bithermal (one side cold, the other warm stimulation, mimicking the normal push-pull pattern of vestibular stimulation. Alexander's law, measured as a negative slope of the velocity versus position curve, was observed in all conditions. A reversed pattern of eye position dependency (positive slope was found <10% of the time. The slope often changed with nystagmus velocity (cross-correlation of nystagmus speed and slope was significant in 50% of cases, and the average lag of the slope with the speed was not significantly different from zero. Our results do not support the hypothesis that Alexander's law can only be observed with non-physiologic vestibular stimulation. Further, the rapid development of Alexander's law, while possible for an adaptive mechanism, is nonetheless quite fast compared to most other ocular motor adaptations. These results suggest that Alexander's law may not be a consequence of a true adaptive mechanism.
Xue, Yongbo; Zhang, Yong
The circadian clock, which operates within an approximately 24-h period, is closely linked to the survival and fitness of almost all living organisms. The circadian clock is generated through a negative transcription-translation feedback loop. microRNAs (miRNAs) are small non-coding RNAs comprised of approximately 22 nucleotides that post-transcriptionally regulate target mRNA by either inducing mRNA degradation or inhibiting translation. In recent years, miRNAs have been found to play important roles in the regulation of the circadian clock, especially in Drosophila. In this review, we will use fruit flies as an example, and summarize the progress achieved in the study of miRNA-mediated clock regulation. Three main aspects of the circadian clock, namely, the free-running period, locomotion phase, and circadian amplitude, are discussed in detail in the context of how miRNAs are involved in these regulations. In addition, approaches regarding the discovery of circadian-related miRNAs and their targets are also discussed. Research in the last decade suggests that miRNA-mediated post-transcriptional regulation is crucial to the generation and maintenance of a robust circadian clock in animals. In flies, miRNAs are known to modulate circadian rhythmicity and the free-running period, as well as circadian outputs. Further characterization of miRNAs, especially in the circadian input, will be a vital step toward a more comprehensive understanding of the functions underlying miRNA-control of the circadian clock.
M.A. Quera Salva
Full Text Available Recent advances in the understanding of circadian rhythms have led to an interest in the treatment of major depressive disorder with chronobiotic agents. Many tissues have autonomous circadian rhythms, which are orchestrated by the master clock, situated in the suprachiasmatic nucleus (SNC. Melatonin (N-acetyl-5-hydroxytryptamine is secreted from the pineal gland during darkness. Melatonin acts mainly on MT1 and MT2 receptors, which are present in the SNC, regulating physiological and neuroendocrine functions, including circadian entrainment, referred to as the chronobiotic effet. Circadian rhythms has been shown to be either misaligned or phase shifted or decreased in amplitude in both acute episodes and relapse of major depressive disorder (MDD and bipolar disorder. Manipulation of circadian rhythms either using physical treatments (such as high intensity light or behavioral therapy has shown promise in improving symptoms. Pharmacotherapy using melatonin and pure melatonin receptor agonists, while improving sleep, has not been shown to improve symptoms of depression. A novel antidepressant, agomelatine, combines 5HT2c antagonist and melatonin agonist action, and has shown promise in both acute treatment of MDD and in preventing relapse.
Koike, Nobuya; Yoo, Seung-Hee; Huang, Hung-Chung; Kumar, Vivek; Lee, Choogon; Kim, Tae-Kyung; Takahashi, Joseph S
The mammalian circadian clock involves a transcriptional feed back loop in which CLOCK and BMAL1 activate the Period and Cryptochrome genes, which then feedback and repress their own transcription. We have interrogated the transcriptional architecture of the circadian transcriptional regulatory loop on a genome scale in mouse liver and find a stereotyped, time-dependent pattern of transcription factor binding, RNA polymerase II (RNAPII) recruitment, RNA expression, and chromatin states. We find that the circadian transcriptional cycle of the clock consists of three distinct phases: a poised state, a coordinated de novo transcriptional activation state, and a repressed state. Only 22% of messenger RNA (mRNA) cycling genes are driven by de novo transcription, suggesting that both transcriptional and posttranscriptional mechanisms underlie the mammalian circadian clock. We also find that circadian modulation of RNAPII recruitment and chromatin remodeling occurs on a genome-wide scale far greater than that seen previously by gene expression profiling.
Seki, Motohide; Ohara, Takayuki; Hearn, Timothy J; Frank, Alexander; da Silva, Viviane C H; Caldana, Camila; Webb, Alex A R; Satake, Akiko
Arabidopsis plants store part of the carbon fixed by photosynthesis as starch to sustain growth at night. Two competing hypotheses have been proposed to explain this diel starch turnover based on either the measurement of starch abundance with respect to circadian time, or the sensing of sugars to feedback to the circadian oscillator to dynamically adjust the timing of starch turnover. We report a phase oscillator model that permitted derivation of the ideal responses of the circadian regulation of starch breakdown to maintain sucrose homeostasis. Testing the model predictions using a sugar-unresponsive mutant of Arabidopsis demonstrated that the dynamics of starch turnover arise from the circadian clock measuring and responding to the rate of change of cellular sucrose. Our theory and experiments suggest that starch turnover is controlled by the circadian clock acting as a dynamic homeostat responding to sucrose signals to maintain carbon homeostasis.
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...
Durrington, Hannah J; Farrow, Stuart N; Loudon, Andrew S; Ray, David W
It is characteristic of asthma that symptoms worsen overnight, particularly in the early hours of the morning. Nocturnal symptoms in asthma are common and are an important indicator for escalation of treatment. An extensive body of research has demonstrated that nocturnal symptoms of cough and dyspnea are accompanied by circadian variations in airway inflammation and physiologic variables, including airflow limitation and airways hyper-responsiveness. The molecular apparatus that underpins circadian variations, controlled by so called 'clock' genes, has recently been characterised. Clock genes control circadian rhythms both centrally, in the suprachiasmatic nucleus of the brain and peripherally, within every organ of the body. Here, we will discuss how clock genes regulate circadian rhythms. We will focus particularly on the peripheral lung clock and the peripheral immune clock and discuss how these might relate to both the pathogenesis and treatment of asthma.
Full Text Available Alcohol use disorder (AUD is a debilitating condition marked by cyclic patterns of craving, use, and withdrawal. These pathological behaviors are mediated by multiple neurotransmitter systems utilizing glutamate, GABA, dopamine, ATP, and adenosine. In particular, purines such as ATP and adenosine have been demonstrated to alter the phase and function of the circadian clock and are reciprocally regulated by the clock itself. Importantly, chronic ethanol intake has been demonstrated to disrupt the molecular circadian clock and is associated with altered circadian patterns of activity and sleep. Moreover, ethanol has been demonstrated to disrupt purinergic signaling, while dysfunction of the purinergic system has been implicated in conditions of drug abuse such as AUD. In this review, we summarize our current knowledge regarding circadian disruption by ethanol, focusing on the reciprocal relationship that exists between oscillatory neurotransmission and the molecular circadian clock. In particular, we offer detailed explanations and hypotheses regarding the concerted regulation of purinergic signaling and circadian oscillations by neurons and astrocytes, and review the diverse mechanisms by which purinergic dysfuction may contribute to circadian disruption or alcohol abuse. Finally, we describe the mechanisms by which ethanol may disrupt or hijack endogenous circadian rhythms to induce the maladaptive behavioral patterns associated with AUD.
Žižka, Zdeněk; Gabriel, Jiří
Polarization and positive phase contrast microscope were concomitantly used in the study of the internal structure of microbial cells. Positive phase contrast allowed us to view even the fine cell structure with a refractive index approaching that of the surrounding environment, e.g., the cytoplasm, and transferred the invisible phase image to a visible amplitude image. With polarization microscopy, crossed polarizing filters together with compensators and a rotary stage showed the birefringence of different cell structures. Material containing algae was collected in ponds in Sýkořice and Zbečno villages (Křivoklát region). The objects were studied in laboratory microscopes LOMO MIN-8 Sankt Petersburg and Polmi A Carl Zeiss Jena fitted with special optics for positive phase contrast, polarizers, analyzers, compensators, rotary stages, and digital SLR camera Nikon D 70 for image capture. Anisotropic granules were found in the cells of flagellates of the order Euglenales, in green algae of the orders Chlorococcales and Chlorellales, and in desmid algae of the order Desmidiales. The cell walls of filamentous algae of the orders Zygnematales and Ulotrichales were found to exhibit significant birefringence; in addition, relatively small amounts of small granules were found in the cytoplasm. A typical shape-related birefringence of the cylindrical walls and the septa between the cells differed in intensity, which was especially apparent when using a Zeiss compensator RI-c during its successive double setting. In conclusion, the anisotropic granules found in the investigated algae mostly showed strong birefringence and varied in number, size, and location of the cells. Representatives of the order Chlorococcales contained the highest number of granules per cell, and the size of these granules was almost double than that of the other monitored microorganisms. Very strong birefringence was exhibited by cell walls of filamentous algae; it differed in the intensity
Cortes, J.E.; Kim, D.-W.; Pinilla-Ibarz, J.; le Coutre, P.; Paquette, R.; Chuah, C.; Nicolini, F.E.; Apperley, J.F.; Khoury, H.J.; Talpaz, M.; DiPersio, J.; DeAngelo, D.J.; Abruzzese, E.; Rea, D.; Baccarani, M.; Müller, M.C.; Gambacorti-Passerini, C.; Wong, S.; Lustgarten, S.; Rivera, V.M.; Clackson, T.; Turner, C.D.; Haluska, F.G.; Guilhot, F.; Deininger, M.W.; Hochhaus, A.; Hughes, T.; Goldman, J.M.; Shah, N.P.; Kantarjian, H.
BACKGROUND Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3
Cortes, J E; Kim, D-W; Pinilla-Ibarz, J; le Coutre, P; Paquette, R; Chuah, C; Nicolini, F E; Apperley, J F; Khoury, H J; Talpaz, M; DiPersio, J; DeAngelo, D J; Abruzzese, E; Rea, D; Baccarani, M; Müller, M C; Gambacorti-Passerini, C; Wong, S; Lustgarten, S; Rivera, V M; Clackson, T; Turner, C D; Haluska, F G; Guilhot, F; Deininger, M W; Hochhaus, A; Hughes, T; Goldman, J M; Shah, N P; Kantarjian, H
Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients
Hutzel, W.J.; Hill, J.L. III; Foster, E.L.
The POLO System is a major enhancement to the state of the art for subsurface environmental restoration equipment. The system locate s the tip position of penetrometer probes as they are placed underground while meeting the rigid constraints of environmental restoration applications. POLO is applicable to small diameter probes, does not obstruct the center of the probe, is rugged, is unaffected by the presence of steel or other magnetic material, and is capable of remote operation beneath underground tanks or foundations. The development and adaptation of the POLO System for use with penetrometers has progressed through three development phases prior to commercialization. Phases I and II of the contract included the design, testing, and integration of all components of the POLO device. Efforts were made to simulate field conditions in terms of the scale of the components as well as the operating environment. The preestablished success criterion, which has been maintained throughout the research, was to demonstrate path tracking with a total error of less than 0.50% of the distance traveled for distances less than 70 meters. The results tests on individual POLO components showed that the equipment met or exceeded the success criterion. Phase II laboratory scale path tracking experiments also met the success criterion. Phase III moved the POLO System into the field. The full-scale field demonstration tested the ability of the new POLO Module to track the path of a small diameter probe as it moved underground
Hutzel, W.J.; Hill, J.L. III; Foster, E.L.
The POLO System is a major enhancement to the state of the art for subsurface environmental restoration equipment. The system locate s the tip position of penetrometer probes as they are placed underground while meeting the rigid constraints of environmental restoration applications. POLO is applicable to small diameter probes, does not obstruct the center of the probe, is rugged, is unaffected by the presence of steel or other magnetic material, and is capable of remote operation beneath underground tanks or foundations. The development and adaptation of the POLO System for use with penetrometers has progressed through three development phases prior to commercialization. Phases I and II of the contract included the design, testing, and integration of all components of the POLO device. Efforts were made to simulate field conditions in terms of the scale of the components as well as the operating environment. The preestablished success criterion, which has been maintained throughout the research, was to demonstrate path tracking with a total error of less than 0.50% of the distance traveled for distances less than 70 meters. The results tests on individual POLO components showed that the equipment met or exceeded the success criterion. Phase II laboratory scale path tracking experiments also met the success criterion. Phase III moved the POLO System into the field. The full-scale field demonstration tested the ability of the new POLO Module to track the path of a small diameter probe as it moved underground.
An, Shuai; Yuan, Suozhong
This paper proposes the design of the relative position-keeping control of the receiver unmanned aerial vehicle (UAV) with the time-varying mass in the refueling phase utilizing an inner-outer loop structure. Firstly, the model of the receiver in the refueling phase is established. And then tank model is set up to analyze the influence of fuel transfer on the receiver. Subsequently, double power reaching law based sliding mode controller is designed to control receiver translational motion relative to tanker aircraft in the outer loop while active disturbance rejection control technique is applied to the inner loop to stabilize the receiver. In addition, the closed-loop stabilities of the subsystems are established, respectively. Finally, an aerial refueling model under various refueling strategies is utilized. Simulations and comparative analysis demonstrate the effectiveness and robustness of the proposed controllers. Copyright © 2017 ISA. Published by Elsevier Ltd. All rights reserved.
Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline.
Auger, R Robert; Burgess, Helen J; Emens, Jonathan S; Deriy, Ludmila V; Thomas, Sherene M; Sharkey, Katherine M
A systematic literature review and meta-analyses (where appropriate) were performed and the GRADE approach was used to update the previous American Academy of Sleep Medicine Practice Parameters on the treatment of intrinsic circadian rhythm sleep-wake disorders. Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia). Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients, at a second- and first-tier degree of confidence, respectively. No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data. Areas where further research is needed are discussed. © 2015 American Academy of Sleep Medicine.
Blume, Christine; Lechinger, Julia; Santhi, Nayantara; del Giudice, Renata; Gnjezda, Maria-Teresa; Pichler, Gerald; Scarpatetti, Monika; Donis, Johann; Michitsch, Gabriele; Schabus, Manuel
To investigate the relationship between the presence of a circadian body temperature rhythm and behaviorally assessed consciousness levels in patients with disorders of consciousness (DOC; i.e., vegetative state/unresponsive wakefulness syndrome or minimally conscious state). In a cross-sectional study, we investigated the presence of circadian temperature rhythms across 6 to 7 days using external skin temperature sensors in 18 patients with DOC. Beyond this, we examined the relationship between behaviorally assessed consciousness levels and circadian rhythmicity. Analyses with Lomb-Scargle periodograms revealed significant circadian rhythmicity in all patients (range 23.5-26.3 hours). We found that especially scores on the arousal subscale of the Coma Recovery Scale-Revised were closely linked to the integrity of circadian variations in body temperature. Finally, we piloted whether bright light stimulation could boost circadian rhythmicity and found positive evidence in 2 out of 8 patients. The study provides evidence for an association between circadian body temperature rhythms and arousal as a necessary precondition for consciousness. Our findings also make a case for circadian rhythms as a target for treatment as well as the application of diagnostic and therapeutic means at times when cognitive performance is expected to peak. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Weide, Lineke van der; Soernsen de Koste, John R. van; Lagerwaard, Frank J.; Vincent, Andrew; Triest, Baukelien van; Slotman, Ben J.; Senan, Suresh
Purpose: Respiratory gating can mitigate the effect of tumor mobility in radiotherapy (RT) for lung cancer. Because the tumor is generally not visualized, external surrogates of tumor position are used to trigger respiration-gated RT. We evaluated the suitability of the carina position as a surrogate in respiration-gated RT. Methods and Materials: A total of 30 four-dimensional (4D) computed tomography (CT) scans from 14 patients with lung cancer were retrospectively analyzed. Both uncoached (free breathing) and audio-coached 4D-CT scans were acquired from 9 patients, and 12 uncoached 4D-CT scans were acquired from 5 other patients during a 2-4-week period of stereotactic RT. The repeat scans were co-registered. The carina position was identified on the coronal cut planes in all 4D-CT phases. The correlation between the carina position and the total lung volume for each phase was determined, and the reproducibility of the carina position was studied in the 5 patients with repeat uncoached 4D-CT scans. Results: The mean extent of carina motion in 21 uncoached scans was 5.3 ± 1.6 mm in the craniocaudal (CC), 2.3 ± 1.4 mm in the anteroposterior, and 1.5 ± 0.7 mm in the mediolateral direction. Audio coaching resulted in a twofold increase in carina mobility in all directions. The CC carina position correlated with changes in the total lung volume (R = 0.89 ± 0.14), but the correlation was better for the audio-coached than for the uncoached 4D-CT scans (R = 0.93 ± 0.08 vs. R = 0.85 ± 0.17; paired t test, p = 0.034). Preliminary data from the 5 patients indicated that the CC carina motion correlated better with tumor motion than did the motion of the diaphragm. Conclusions: The CC position of the carina correlated well with the total lung volume, indicating that the carina is a good surrogate for verifying the total lung volume during respiration-gated RT
Guan-Ren Chen; Shih-Chin Yang; Yu-Liang Hsu; Kang Li
In conventional position sensorless permanent magnet (PM) machine drives, the rotor position is obtained from the phase-locked loop (PLL) with the regulation of spatial signal in estimated back electromotive force (EMF) voltages. Due to the sinusoidal distribution of back-EMF voltages, a small-signal approximation is assumed in the PLL in order to estimate the position. That is, the estimated position is almost equal to the actual position per sample instant. However, at high speed when the r...
Full Text Available For the problem of easily losing track target when obstacles appear in intelligent robot target tracking, this paper proposes a target tracking algorithm integrating reduced dimension optimal Kalman filtering algorithm based on phase-path volume integral with Camshift algorithm. After analyzing the defects of Camshift algorithm, compare the performance with the SIFT algorithm and Mean Shift algorithm, and Kalman filtering algorithm is used for fusion optimization aiming at the defects. Then aiming at the increasing amount of calculation in integrated algorithm, reduce dimension with the phase-path volume integral instead of the Gaussian integral in Kalman algorithm and reduce the number of sampling points in the filtering process without influencing the operational precision of the original algorithm. Finally set the target centroid position from the Camshift algorithm iteration as the observation value of the improved Kalman filtering algorithm to fix predictive value; thus to make optimal estimation of target centroid position and keep the target tracking so that the robot can understand the environmental scene and react in time correctly according to the changes. The experiments show that the improved algorithm proposed in this paper shows good performance in target tracking with obstructions and reduces the computational complexity of the algorithm through the dimension reduction.
Borisova, Marina; Gaupp, Rosmarie; Duckworth, Amanda; Schneider, Alexander; Dalügge, Désirée; Mühleck, Maraike; Deubel, Denise; Unsleber, Sandra; Yu, Wenqi; Muth, Günther; Bischoff, Markus; Götz, Friedrich
ABSTRACT Peptidoglycan recycling is a metabolic process by which Gram-negative bacteria reutilize up to half of their cell wall within one generation during vegetative growth. Whether peptidoglycan recycling also occurs in Gram-positive bacteria has so far remained unclear. We show here that three Gram-positive model organisms, Staphylococcus aureus, Bacillus subtilis, and Streptomyces coelicolor, all recycle the sugar N-acetylmuramic acid (MurNAc) of their peptidoglycan during growth in rich medium. They possess MurNAc-6-phosphate (MurNAc-6P) etherase (MurQ in E. coli) enzymes, which are responsible for the intracellular conversion of MurNAc-6P to N-acetylglucosamine-6-phosphate and d-lactate. By applying mass spectrometry, we observed accumulation of MurNAc-6P in MurNAc-6P etherase deletion mutants but not in either the isogenic parental strains or complemented strains, suggesting that MurQ orthologs are required for the recycling of cell wall-derived MurNAc in these bacteria. Quantification of MurNAc-6P in ΔmurQ cells of S. aureus and B. subtilis revealed small amounts during exponential growth phase (0.19 nmol and 0.03 nmol, respectively, per ml of cells at an optical density at 600 nm [OD600] of 1) but large amounts during transition (0.56 nmol and 0.52 nmol) and stationary (0.53 nmol and 1.36 nmol) phases. The addition of MurNAc to ΔmurQ cultures greatly increased the levels of intracellular MurNAc-6P in all growth phases. The ΔmurQ mutants of S. aureus and B. subtilis showed no growth deficiency in rich medium compared to the growth of the respective parental strains, but intriguingly, they had a severe survival disadvantage in late stationary phase. Thus, although peptidoglycan recycling is apparently not essential for the growth of Gram-positive bacteria, it provides a benefit for long-term survival. PMID:27729505
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 partition incompatible physiological processes. At the helm of this system is a master clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN are primarily synchronised to the 24 hour day by the light/dark cycle; however, feeding/fasting cycles are the primary time cues for clocks in peripheral tissues. Aligning feeding/fasting cycles with clock-regulated metabolic changes optimises metabolism, and studies of other animals suggest that feeding at inappropriate times disrupts circadian system organisation and thereby contributes to adverse metabolic consequences and chronic disease development. ‘High-fat diets’ (HFDs) produce particularly deleterious effects on circadian system organisation in rodents by blunting feeding/fasting cycles. Time-of-day-restricted feeding, where food availability is restricted to a period of several hours, offsets many adverse consequences of HFDs in these animals; however, further evidence is required to assess whether the same is true in humans. Several nutritional compounds have robust effects on the circadian system. Caffeine, for example, can speed synchronisation to new time zones after jetlag. An appreciation of the circadian system has many implications for nutritional science and may ultimately help reduce the burden of chronic diseases. PMID:27221157
Nirvani, Minou; Khuu, Cuong; Utheim, Tor Paaske; Sand, Lars Peter; Sehic, Amer
The circadian clock is comprised of a master component situated in the hypothalamic suprachiasmatic nucleus and subordinate clock genes in almost every cell of the body. The circadian clock genes and their encoded proteins govern the organism to follow the natural signals of time, and adapt to external changes in the environment. The majority of physiological processes in mammals exhibit variable circadian rhythms, which are generated and coordinated by an oscillation in the expression of the clock genes. A number of studies have reported that alteration in the expression level of clock genes is correlated with several pathological conditions, including cancer. However, little is known about the role of clock genes in homeostasis of the oral epithelium and their disturbances in oral carcinogenesis. The present review summarizes the current state of knowledge of the implications of clock genes in oral cancer. It has been demonstrated that the development of oral squamous cell carcinoma undergoes circadian oscillation in relation to tumor volume and proliferation rate. The circadian clock gene period ( PER)1 has been associated with oral cancer pathogenesis and it is suggested that changes in the expression of PER1 may exhibit an important role in the development, invasion, and metastasis of oral squamous cell carcinoma. However, its role remains elusive and there is a need for further research in order to understand the underlying mechanisms of the clock genes in oral cancer pathogenesis.
Dauchy, Robert T; Wren-Dail, Melissa A; Hoffman, Aaron E; Hanifin, John P; Warfield, Benjamin; Brainard, George C; Hill, Steven M; Belancio, Victoria P; Dauchy, Erin M; Blask, David E
Regular cycles of exposure to light and dark control pineal melatonin production and temporally coordinate circadian rhythms of metabolism and physiology in mammals. Previously we demonstrated that the peak circadian amplitude of nocturnal blood melatonin levels of rats were more than 6-fold higher after exposure to cool white fluorescent (CWF) light through blue-tinted (compared with clear) rodent cages. Here, we evaluated the effects of light-phase exposure of rats to white light-emitting diodes (LED), which emit light rich in the blue-appearing portion of the visible spectrum (465-485 nm), compared with standard broadspectrum CWF light, on melatonin levels during the subsequent dark phase and on plasma measures of metabolism and physiology. Compared with those in male rats under a 12:12-h light:dark cycle in CWF light, peak plasma melatonin levels at the middark phase (time, 2400) in rats under daytime LED light were over 7-fold higher, whereas midlight phase levels (1200) were low in both groups. Food and water intakes, body growth rate, and total fatty acid content of major metabolic tissues were markedly lower, whereas protein content was higher, in the LED group compared with CWF group. Circadian rhythms of arterial plasma levels of total fatty acids, glucose, lactic acid, pO 2 , pCO 2 , insulin, leptin, and corticosterone were generally lower in LED-exposed rats. Therefore, daytime exposure of rats to LED light with high blue emissions has a marked positive effect on the circadian regulation of neuroendocrine, metabolic, and physiologic parameters associated with the promotion of animal health and wellbeing and thus may influence scientific outcomes.
Ángeles-Velázquez, Jorge Luis; Hurtado-Monroy, Rafael; Vargas-Viveros, Pablo; Carrillo-Muñoz, Silvia; Candelaria-Hernández, Myrna
Over the past years, the survival of patients with Philadelphia-positive chronic myeloid leukemia (CML Ph(+)) has increased as a result of therapy with tyrosin kinase inhibitors (TKIs). Intolerance to TKIs has been described in approximately 20% of patients receiving treatment. We studied the incidence of imatinib intolerance in patients with CML Ph(+) and their outcome in our CML reference site, as there is no information about the evolution of patients intolerant to TKIs. A group of 86 patients with CML Ph(+) receiving imatinib monotherapy who abandoned treatment were the basis for this study. We present the trends of their disease evolution. The median of age at diagnosis was 42 years. Within a year, 19 (22%) of 86 patients developed imatinib intolerance, all of them with grade III or IV disease that required imatinib dose reduction or discontinuation. Of these patients, 16 (84%) of 19 developed transformation to blastic phase. The cumulative incidences of blastic phase development were 47% in the nonintolerant group and 84% in the intolerant group. There was a relative risk for those with imatinib intolerance to develop blastic phase of 1.78 (95% confidence interval, 1.28 to 2.42) (P < .05). Most imatinib-intolerant patients develop blastic phase transformation, with a poor survival of 3 to 6 months; no effective rescue treatment is available. Future research should to determine whether the origin of this evolution is really due to the intolerance itself or whether it is due to a more aggressive form of the disease, perhaps related to genetic transformation. Copyright © 2016 Elsevier Inc. All rights reserved.
Bagri, Durgadas S.; Majid, Walid
At present spacecraft angular position with Deep Space Network (DSN) is determined using group delay estimates from very long baseline interferometer (VLBI) phase measurements employing differential one way ranging (DOR) tones. As an alternative to this approach, we propose estimating position of a spacecraft to half a fringe cycle accuracy using time variations between measured and calculated phases as the Earth rotates using DSN VLBI baseline(s). Combining fringe location of the target with the phase allows high accuracy for spacecraft angular position estimate. This can be achieved using telemetry signals of at least 4-8 MSamples/sec data rate or DOR tones.
The circadian clock is a global regulatory system that interfaces with most other regulatory systems and pathways in mammalian organisms. Investigations of the circadian clock–DNA damage response connections have revealed that nucleotide excision repair, DNA damage checkpoints, and apoptosis are appreciably influenced by the clock. Although several epidemiological studies in humans and a limited number of genetic studies in mouse model systems have indicated that clock disruption may predispose mammals to cancer, well-controlled genetic studies in mice have not supported the commonly held view that circadian clock disruption is a cancer risk factor. In fact, in the appropriate genetic background, clock disruption may instead aid in cancer regression by promoting intrinsic and extrinsic apoptosis. Finally, the clock may affect the efficacy of cancer treatment (chronochemotherapy) by modulating the pharmacokinetics and pharmacodynamics of chemotherapeutic drugs as well as the activity of the DNA repair enzymes that repair the DNA damage caused by anticancer drugs. PMID:25302769
Wehr, T A; Aeschbach, D; Duncan, W C
Because individuals differ in the phase angle at which their circadian rhythms are entrained to external time cues, averaging group data relative to clock time sometimes obscures abrupt changes that are characteristic of waveforms of the rhythms in individuals. Such changes may have important implications for the temporal organization of human circadian physiology. To control for variance in phase angle of entrainment, we used dual internal reference points – onset and offset of the nocturnal period of melatonin secretion – to calculate average profiles of circadian rhythm data from five previously published studies. Onset and/or offset of melatonin secretion were found to coincide with switch-like transitions between distinct diurnal and nocturnal periods of circadian rhythms in core body temperature, sleepiness, power in the theta band of the wake EEG, sleep propensity and rapid eye movement (REM) sleep propensity. Transitions between diurnal and nocturnal periods of sleep–wake and cortisol circadian rhythms were found to lag the other transitions by 1–3 h. When the duration of the daily light period was manipulated experimentally, melatonin-onset-related transitions in circadian rhythms appeared to be entrained to the light-to-dark transition, while melatonin-offset-related transitions appeared to be entrained to the dark-to-light transition. These results suggest a model of the human circadian timing system in which two states, one diurnal and one nocturnal, alternate with one another, and in which transitions between the states are switch-like and are separately entrained to dawn and dusk. This description of the human circadian system is similar to the Pittendrigh–Daan model of the rodent circadian system, and it suggests that core features of the system in other mammals are conserved in humans. PMID:11559786
This paper presents a detailed critical review of the knowledge accumulated in the last three decades concerning research on sleep, work-rest schedules, and circadian rhythms in space. The focus of the paper is preceded by a brief review of the basic principles of the human circadian system and the physiology of the sleep-wake cycle, relevant to understanding the problem of astronaut work-rest scheduling. Much of what is known is based on anecdotal reports, mission log books, and debriefing of astronauts after flights. The broad literature reviewed, which includes studies from American and Soviet space missions, as well as some studies conducted under simulated weightlessness, offers just a handful of objective studies on the physiology of sleep and circadian rhythms in space. Nevertheless, the data are remarkably consistent, and indicate that sleep can be of reasonably good quality in space. The risk of sleep loss and associated performance degradation appears to be a manageable one. However, one clear conclusion arises from this review: whatever the type of mission of flight plan, its success will depend on whether the principles of circadian and sleep-wake regulation have been taken into account during the planning phase of work-rest schedules. That is, satisfactory sleep and alertness is more likely to occur if crews maintain a reasonable (i.e., constant) relation with their normal terrestrial rhythm. This is not as easy a task as it may appear; indeed, unexpected, high-intensity operational demands have been the major cause of acute problems of sleep loss and performance degradation in space. Moreover, the growing complexity of space missions indicate that emergencies will never disappear. Therefore, one of the most important research challenges for future space missions is the development of strategies that could permit astronauts to function closest to maximal efficiency during intensive and prolonged work. Countermeasures for optimizing astronaut
Dai, Wujiao; Shi, Qiang; Cai, Changsheng
The carrier phase multipath effect is one of the most significant error sources in the precise positioning of BeiDou Navigation Satellite System (BDS). We analyzed the characteristics of BDS multipath, and found the multipath errors of geostationary earth orbit (GEO) satellite signals are systematic, whereas those of inclined geosynchronous orbit (IGSO) or medium earth orbit (MEO) satellites are both systematic and random. The modified multipath mitigation methods, including sidereal filtering algorithm and multipath hemispherical map (MHM) model, were used to improve BDS dynamic deformation monitoring. The results indicate that the sidereal filtering methods can reduce the root mean square (RMS) of positioning errors in the east, north and vertical coordinate directions by 15%, 37%, 25% and 18%, 51%, 27% in the coordinate and observation domains, respectively. By contrast, the MHM method can reduce the RMS by 22%, 52% and 27% on average. In addition, the BDS multipath errors in static baseline solutions are a few centimeters in multipath-rich environments, which is different from that of Global Positioning System (GPS) multipath. Therefore, we add a parameter representing the GEO multipath error in observation equation to the adjustment model to improve the precision of BDS static baseline solutions. And the results show that the modified model can achieve an average precision improvement of 82%, 54% and 68% in the east, north and up coordinate directions, respectively.
Kroupa, Daniel M.; Vörös, Márton; Brawand, Nicholas P.; McNichols, Brett W.; Miller, Elisa M.; Gu, Jing; Nozik, Arthur J.; Sellinger, Alan; Galli, Giulia; Beard, Matthew C.
Band edge positions of semiconductors determine their functionality in many optoelectronic applications such as photovoltaics, photoelectrochemical cells and light emitting diodes. Here we show that band edge positions of lead sulfide (PbS) colloidal semiconductor nanocrystals, specifically quantum dots (QDs), can be tuned over 2.0 eV through surface chemistry modification. We achieved this remarkable control through the development of simple, robust and scalable solution-phase ligand exchange methods, which completely replace native ligands with functionalized cinnamate ligands, allowing for well-defined, highly tunable chemical systems. By combining experiments and ab initio simulations, we establish clear relationships between QD surface chemistry and the band edge positions of ligand/QD hybrid systems. We find that in addition to ligand dipole, inter-QD ligand shell inter-digitization contributes to the band edge shifts. We expect that our established relationships and principles can help guide future optimization of functional organic/inorganic hybrid nanostructures for diverse optoelectronic applications.
Fu, Jianxin; Yang, Liwen; Dai, Silan
In Arabidopsis, circadian clock genes play important roles in photoperiod pathway by regulating the daytime expression of CONSTANS (CO), but related reports for chrysanthemum are notably limited. In this study, we isolated eleven circadian clock genes, which lie in the three interconnected negative and positive feedback loops in a wild diploid chrysanthemum, Chrysanthemum lavandulifolium. With the exception of ClELF3, ClPRR1 and ClPRR73, most of the circadian clock genes are expressed more highly in leaves than in other tested tissues. The diurnal rhythms of these circadian clock genes are similar to those of their homologs in Arabidopsis. ClELF3 and ClZTL are constitutively expressed at all time points in both assessed photoperiods. The expression succession from morning to night of the PSEUDO RESPONSE REGULATOR (PRR) gene family occurs in the order ClPRR73/ClPRR37, ClPRR5, and then ClPRR1. ClLHY is expressed during the dawn period, and ClGIs is expressed during the dusk period. The peak expression levels of ClFKF1 and ClGIs are synchronous in the inductive photoperiod. However, in the non-inductive night break (NB) condition or non-24 h photoperiod, the peak expression level of ClFKF1 is significantly changed, indicating that ClFKF1 itself or the synchronous expression of ClFKF1 and ClGIs might be essential to initiate the flowering of C. lavandulifolium. This study provides the first extensive evaluation of circadian clock genes, and it presents a useful foundation for dissecting the functions of circadian clock genes in C. lavandulifolium. Copyright © 2014. Published by Elsevier Masson SAS.
Burke, Tina M.; Scheer, Frank A. J. L.; Ronda, Joseph M.; Czeisler, Charles A.; Wright, Kenneth P.
Sleep inertia, sleep homeostatic, and circadian processes modulate cognition, including reaction time, memory, mood, and alertness. How these processes influence higher-order cognitive functions is not well known. Six participants completed a 73-daylong study that included two 14-daylong 28h forced desynchrony protocols, to examine separate and interacting influences of sleep inertia, sleep homeostasis, and circadian phase on higher-order cognitive functions of inhibitory control and selectiv...
Daan, S; Oklejewicz, M
Locomotor activity recordings of Syrian hamsters were systematically analyzed to estimate the precision of the overt circadian activity rhythm in constant darkness. Phase variation, i.e., the standard deviation of phase markers around the regression line, varied with the definition of phase.
Ivan M Roitt
Full Text Available Bioimpedance measurements are of great use and can provide considerable insight into biological processes. However, there are a number of possible sources of measurement error that must be considered. The most dominant source of error is found in bipolar measurements where electrode polarisation effects are superimposed on the true impedance of the sample. Even with the tetrapolar approach that is commonly used to circumvent this issue, other errors can persist. Here we characterise the positive phase and rise in impedance magnitude with frequency that can result from the presence of any parallel conductive pathways in the measurement set-up. It is shown that fitting experimental data to an equivalent electrical circuit model allows for accurate determination of the true sample impedance as validated through finite element modelling (FEM of the measurement chamber. Finally, the model is used to extract dispersion information from cell cultures to characterise their growth.
Yan, Jie; Kang, Xiaxia; Yang, Ling
Circadian clock is an autonomous oscillator which orchestrates the daily rhythms of physiology and behaviors. This study is devoted to explore how a positive feedback loop affects the dynamics of mammalian circadian clock. We simplify an experimentally validated mathematical model in our previous work, to a nonlinear differential equation with two time delays. This simplified mathematical model incorporates the pacemaker of mammalian circadian clock, a negative primary feedback loop, and a critical positive auxiliary feedback loop, Rev-erbα/Cry1 loop. We perform analytical studies of the system. Delay-dependent conditions for the asymptotic stability of the nontrivial positive steady state of the model are investigated. We also prove the existence of Hopf bifurcation, which leads to self-sustained oscillation of mammalian circadian clock. Our theoretical analyses show that the oscillatory regime is reduced upon the participation of the delayed positive auxiliary loop. However, further simulations reveal that the auxiliary loop can enable the circadian clock gain widely adjustable amplitudes and robust period. Thus, the positive auxiliary feedback loop may provide a trade-off mechanism, to use the small loss in the robustness of oscillation in exchange for adaptable flexibility in mammalian circadian clock. The results obtained from the model may gain new insights into the dynamics of biological oscillators with interlocked feedback loops.
Czeisler, Charles A.; Chiasera, August J.; Duffy, Jeanne F.
Disorders of sleep and circadian rhythmicity are characteristic of both advancing age and manned spaceflight. Sleep fragmentation, reduced nocturnal sleep tendency and sleep efficiency, reduced daytime alertness, and increased daytime napping are common to both of these conditions. Recent research on the pathophysiology and treatment of disrupted sleep in older people has led to a better understanding of how the human circadian pacemaker regulates the timing of the daily sleep-wake cycle and how it responds to the periodic changes in the light-dark cycle to which we are ordinarily exposed. These findings have led to new treatments for some of the sleep disorders common to older individuals, using carefully timed exposure to bright light and darkness to manipulate the phase and/or amplitude of the circadian timing system. These insights and treatment approaches have direct applications in the design of countermeasures allowing astronauts to overcome some of the challenges which manned spaceflight poses for the human circadian timing system. We have conducted an operational feasibility study on the use of scheduled exposure to bright light and darkness prior to launch in order to facilitate adaptation of the circadian system of a NASA Space Shuttle crew to the altered sleep-wake schedule required for their mission. The results of this study illustrate how an understanding of the properties of the human circadian timing system and the consequences of circadian disruption can be applied to manned spaceflight.
Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis. PMID:23303907
Full Text Available In mammals, molecular circadian clocks are present in most cells of the body, and this circadian network plays an important role in synchronizing physiological processes and behaviors to the appropriate time of day. The hypothalamic-pituitary-adrenal endocrine axis regulates the response to acute and chronic stress, acting through its final effectors – glucocorticoids – released from the adrenal cortex. Glucocorticoid secretion, characterized by its circadian rhythm, has an important role in synchronizing peripheral clocks and rhythms downstream of the master circadian pacemaker in the suprachiasmatic nucleus. Finally, glucocorticoids are powerfully anti-inflammatory, and recent work has implicated the circadian clock in various aspects and cells of the immune system, suggesting a tight interplay of stress and circadian systems in the regulation of immunity. This mini-review summarizes our current understanding of the role of the circadian clock network in both, the HPA axis and the immune system, and discusses their interactions.
Irina V Zhdanova
Full Text Available In view of the inverse temporal relationship of central clock activity to physiological or behavioral outputs in diurnal and nocturnal species, understanding the mechanisms and physiological consequences of circadian disorders in humans would benefit from studies in a diurnal animal model, phylogenetically close to humans. Here we report the discovery of the first intrinsic circadian disorder in a family of diurnal non-human primates, the rhesus monkey. The disorder is characterized by a combination of delayed sleep phase, relative to light-dark cycle, mutual desynchrony of intrinsic rhythms of activity, food intake and cognitive performance, enhanced nighttime feeding or, in the extreme case, intrinsic asynchrony. The phenotype is associated with normal length of intrinsic circadian period and requires an intact central clock, as demonstrated by an SCN lesion. Entrainment to different photoperiods or melatonin administration does not eliminate internal desynchrony, though melatonin can temporarily reinstate intrinsic activity rhythms in the animal with intrinsic asynchrony. Entrainment to restricted feeding is highly effective in animals with intrinsic or SCN lesion-induced asynchrony. The large isolated family of rhesus macaques harboring the disorder provides a powerful new tool for translational research of regulatory circuits underlying circadian disorders and their effective treatment.
Full Text Available Mark R Smith, Charmane I EastmanBiological Rhythms Research Laboratory, Rush University Medical Center, Chicago, IL, USAAbstract: There are three mechanisms that may contribute to the health, performance, and safety problems associated with night-shift work: (1 circadian misalignment between the internal circadian clock and activities such as work, sleep, and eating, (2 chronic, partial sleep deprivation, and (3 melatonin suppression by light at night. The typical countermeasures, such as caffeine, naps, and melatonin (for its sleep-promoting effect, along with education about sleep and circadian rhythms, are the components of most fatigue risk-management plans. We contend that these, while better than nothing, are not enough because they do not address the underlying cause of the problems, which is circadian misalignment. We explain how to reset (phase-shift the circadian clock to partially align with the night-work, day-sleep schedule, and thus reduce circadian misalignment while preserving sleep and functioning on days off. This involves controlling light and dark using outdoor light exposure, sunglasses, sleep in the dark, and a little bright light during night work. We present a diagram of a sleep-and-light schedule to reduce circadian misalignment in permanent night work, or a rotation between evenings and nights, and give practical advice on how to implement this type of plan.Keywords: circadian rhythms, night work, bright light, phase-shifting, sleep, melatonin
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.
Kerri L. Kim; Alexandra B. Weissman; Megan E. Puzia; Grace K. Cushman; Karen E. Seymour; Ezra Wegbreit; Mary A. Carskadon; Daniel P. Dickstein
Pediatric bipolar disorder (BD) rates have notably increased over the past three decades. Given the significant morbidity and mortality associated with BD, efforts are needed to identify factors useful in earlier detection to help address this serious public health concern. Sleep is particularly important to consider given the sequelae of disrupted sleep on normative functioning and that sleep is included in diagnostic criteria for both Major Depressive and Manic Episodes. Here, we examine on...
Full Text Available The influence of the mammalian retinal circadian clock on retinal physiology and function is widely recognized, yet the cellular elements and neural regulation of retinal circadian pacemaking remain unclear due to the challenge of long-term culture of adult mammalian retina and the lack of an ideal experimental measure of the retinal circadian clock. In the current study, we developed a protocol for long-term culture of intact mouse retinas, which allows retinal circadian rhythms to be monitored in real time as luminescence rhythms from a PERIOD2::LUCIFERASE (PER2::LUC clock gene reporter. With this in vitro assay, we studied the characteristics and location within the retina of circadian PER2::LUC rhythms, the influence of major retinal neurotransmitters, and the resetting of the retinal circadian clock by light. Retinal PER2::LUC rhythms were routinely measured from whole-mount retinal explants for 10 d and for up to 30 d. Imaging of vertical retinal slices demonstrated that the rhythmic luminescence signals were concentrated in the inner nuclear layer. Interruption of cell communication via the major neurotransmitter systems of photoreceptors and ganglion cells (melatonin and glutamate and the inner nuclear layer (dopamine, acetylcholine, GABA, glycine, and glutamate did not disrupt generation of retinal circadian PER2::LUC rhythms, nor did interruption of intercellular communication through sodium-dependent action potentials or connexin 36 (cx36-containing gap junctions, indicating that PER2::LUC rhythms generation in the inner nuclear layer is likely cell autonomous. However, dopamine, acting through D1 receptors, and GABA, acting through membrane hyperpolarization and casein kinase, set the phase and amplitude of retinal PER2::LUC rhythms, respectively. Light pulses reset the phase of the in vitro retinal oscillator and dopamine D1 receptor antagonists attenuated these phase shifts. Thus, dopamine and GABA act at the molecular level of PER
Full Text Available Abstract When hormones during the ovulatory cycle are shown in phase plane graphs, reported FSH and estrogen values form a specific pattern that resembles the leaning “&" symbol, while LH and progesterone (Pg values form a "boomerang" shape. Graphs in this paper were made using data reported by Stricker et al. [Clin Chem Lab Med 2006;44:883–887]. These patterns were used to construct a simplistic model of the ovulatory cycle without the conventional "positive feedback" phenomenon. The model is based on few well-established relations: hypothalamic GnRH secretion is increased under estrogen exposure during two weeks that start before the ovulatory surge and lasts till lutheolysis. the pituitary GnRH receptors are so prone to downregulation through ligand binding that this must be important for their function. in several estrogen target tissue progesterone receptor (PgR expression depends on previous estrogen binding to functional estrogen receptors (ER, while Pg binding to the expressed PgRs reduces both ER and PgR expression. Some key features of the presented model are here listed: High GnRH secretion induced by the recovered estrogen exposure starts in the late follicular phase and lasts till lutheolysis. The LH and FSH surges start due to combination of accumulated pituitary GnRH receptors and increased GnRH secretion. The surges quickly end due to partial downregulation of the pituitary GnRH receptors (64% reduction of the follicular phase pituitary GnRH receptors is needed to explain the reported LH drop after the surge. A strong increase in the lutheal Pg blood level, despite modest decline in LH levels, is explained as delayed expression of pituitary PgRs. Postponed pituitary PgRs expression enforces a negative feedback loop between Pg levels and LH secretions not before the mid lutheal phase. Lutheolysis is explained as a consequence of Pg binding to hypothalamic and pituitary PgRs that reduces local ER expression. When hypothalamic
bifida occulta , and sarcoidosis, all show loss of the melatonin circadian rhythm, with psoriasis vulgaris, spina bifida occulta , and sarcoidosis...autonomic neuro- pathy show decreased nocturnal melatonin (Checkley and Palazidou, 1988). Klinefelter’s syndrome, Turners syndrome, psoriasis vulgaris, spina
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
Majidi, Keivan; Brankov, Jovan G; Li, Jun; Muehleman, Carol
The analyzer-based phase-contrast x-ray imaging (ABI) method is emerging as a potential alternative to conventional radiography. Like many of the modern imaging techniques, ABI is a computed imaging method (meaning that images are calculated from raw data). ABI can simultaneously generate a number of planar parametric images containing information about absorption, refraction, and scattering properties of an object. These images are estimated from raw data acquired by measuring (sampling) the angular intensity profile of the x-ray beam passed through the object at different angular positions of the analyzer crystal. The noise in the estimated ABI parametric images depends upon imaging conditions like the source intensity (flux), measurements angular positions, object properties, and the estimation method. In this paper, we use the Cramér–Rao lower bound (CRLB) to quantify the noise properties in parametric images and to investigate the effect of source intensity, different analyzer-crystal angular positions and object properties on this bound, assuming a fixed radiation dose delivered to an object. The CRLB is the minimum bound for the variance of an unbiased estimator and defines the best noise performance that one can obtain regardless of which estimation method is used to estimate ABI parametric images. The main result of this paper is that the variance (hence the noise) in parametric images is directly proportional to the source intensity and only a limited number of analyzer-crystal angular measurements (eleven for uniform and three for optimal non-uniform) are required to get the best parametric images. The following angular measurements only spread the total dose to the measurements without improving or worsening CRLB, but the added measurements may improve parametric images by reducing estimation bias. Next, using CRLB we evaluate the multiple-image radiography, diffraction enhanced imaging and scatter diffraction enhanced imaging estimation techniques
Sean R. Moore
Full Text Available Disruption of circadian rhythms is a risk factor for several human gastrointestinal (GI diseases, ranging from diarrhea to ulcers to cancer. Four-dimensional tissue culture models that faithfully mimic the circadian clock of the GI epithelium would provide an invaluable tool to understand circadian regulation of GI health and disease. We hypothesized that rhythmicity of a key circadian component, PERIOD2 (PER2, would diminish along a continuum from ex vivo intestinal organoids (epithelial ‘miniguts’, nontransformed mouse small intestinal epithelial (MSIE cells and transformed human colorectal adenocarcinoma (Caco-2 cells. Here, we show that bioluminescent jejunal explants from PERIOD2::LUCIFERASE (PER2::LUC mice displayed robust circadian rhythms for >72 hours post-excision. Circadian rhythms in primary or passaged PER2::LUC jejunal organoids were similarly robust; they also synchronized upon serum shock and persisted beyond 2 weeks in culture. Remarkably, unshocked organoids autonomously synchronized rhythms within 12 hours of recording. The onset of this autonomous synchronization was slowed by >2 hours in the presence of the glucocorticoid receptor antagonist RU486 (20 μM. Doubling standard concentrations of the organoid growth factors EGF, Noggin and R-spondin enhanced PER2 oscillations, whereas subtraction of these factors individually at 24 hours following serum shock produced no detectable effects on PER2 oscillations. Growth factor pulses induced modest phase delays in unshocked, but not serum-shocked, organoids. Circadian oscillations of PER2::LUC bioluminescence aligned with Per2 mRNA expression upon analysis using quantitative PCR. Concordant findings of robust circadian rhythms in bioluminescent jejunal explants and organoids provide further evidence for a peripheral clock that is intrinsic to the intestinal epithelium. The rhythmic and organotypic features of organoids should offer unprecedented advantages as a resource for
Caroline H Ko
Full Text Available Bmal1 is an essential transcriptional activator within the mammalian circadian clock. We report here that the suprachiasmatic nucleus (SCN of Bmal1-null mutant mice, unexpectedly, generates stochastic oscillations with periods that overlap the circadian range. Dissociated SCN neurons expressed fluctuating levels of PER2 detected by bioluminescence imaging but could not generate circadian oscillations intrinsically. Inhibition of intercellular communication or cyclic-AMP signaling in SCN slices, which provide a positive feed-forward signal to drive the intracellular negative feedback loop, abolished the stochastic oscillations. Propagation of this feed-forward signal between SCN neurons then promotes quasi-circadian oscillations that arise as an emergent property of the SCN network. Experimental analysis and mathematical modeling argue that both intercellular coupling and molecular noise are required for the stochastic rhythms, providing a novel biological example of noise-induced oscillations. The emergence of stochastic circadian oscillations from the SCN network in the absence of cell-autonomous circadian oscillatory function highlights a previously unrecognized level of circadian organization.
Hirano, Arisa; Braas, Daniel; Fu, Ying-Hui; Ptáček, Louis J.
The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD) binding pocket of CRYPTOCHROME2 (CRY2), a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin ki...
Full Text Available In mammals, the suprachiasmatic nucleus (SCN functions as a circadian clock that drives 24-hour rhythms in both physiology and behavior. The SCN is a multicellular oscillator in which individual neurons function as cell-autonomous oscillators. The production of a coherent output rhythm is dependent upon mutual synchronization among single cells and requires both synaptic communication and gap junctions. Changes in phase synchronization between individual cells have consequences on the amplitude of the SCN’s electrical activity rhythm, and these changes play a major role in the ability to adapt to seasonal changes. Both aging and sleep deprivation negatively affect the circadian amplitude of the SCN, whereas behavioral activity (i.e., exercise has a positive effect on amplitude. Given that the amplitude of the SCN’s electrical activity rhythm is essential for achieving robust rhythmicity in physiology and behavior, the mechanisms that underlie neuronal synchronization warrant further study. A growing body of evidence suggests that the functional integrity of the SCN contributes to health, well-being, cognitive performance, and alertness; in contrast, deterioration of the 24-hour rhythm is a risk factor for neurodegenerative disease, cancer, depression, and sleep disorders.
Sabath, E; Báez-Ruiz, A; Buijs, R M
The circadian system, headed by the suprachiasmatic nucleus, synchronizes behaviour and metabolism according to the external light-dark cycle through neuroendocrine and autonomic signals. Metabolic diseases, such as steatosis, obesity and glucose intolerance, have been associated with conditions of circadian misalignment wherein the feeding schedule has been moved to the resting phase. Here we describe the physiological processes involved in liver lipid accumulation and show how they follow a circadian pattern importantly regulated by both the autonomic nervous system and the feeding-fasting cycle. We propose that an unbalanced activity of the sympathetic-parasympathetic branches between organs induced by circadian misalignment provides the conditions for the development and progression of non-alcoholic fatty liver disease. © 2015 World Obesity.
Yamamotová, Anna; Papezová, Hana; Vevera, Jan
Light and food are important synchronizers of circadian rhythmicity. In eating disorders, the circadian rhythms of food intake and temperature are abnormal. We analyzed the effect of the morning light application on the circadian rhythm of tympanic temperature and its association with hunger and mood changes in the sample of 25 female patients hospitalized with DSM-IV diagnosis of eating disorders (14 bulimia nervosa and 11 anorexia nervosa) and in 6 healthy women. Light therapy reduced interindividual variability of the temperature acrophase, synchronized the temperature and hunger rhythms and showed an antidepressant effect on patients with eating disorders. Bright light therapy normalized the circadian rhythm of body temperature in both anorexic and bulimic patients: phase advanced rhythm was delayed and phase delayed rhythm was advanced. In contrast with anorexic patients, the majority of bulimic patients had normal temperature rhythm before the therapy and this rhythm was not changed by the therapy. The light therapy normalized temperature circadian rhythm in patient with eating disorders. We hypothesize that the light therapy can also contribute to improvement of pathological eating pattern because of the functional connections between light and food entrained oscillators. The light may help to restore the irregular circadian rhythmicity induced by chaotic food intake.
Stowie, A C; Amicarelli, M J; Prosser, R A; Glass, J D
The disruptive effects of cocaine on physiological, behavioral and genetic processes are well established. However, few studies have focused on the actions of cocaine on the adult circadian timekeeping system, and none have explored the circadian implications of long-term (weeks to months) cocaine exposure. The present study was undertaken to explore the actions of such long-term cocaine administration on core circadian parameters in mice, including rhythm period, length of the nocturnal activity period and photic entrainment. For cocaine dosing over extended periods, cocaine was provided in drinking water using continuous and scheduled regimens. The impact of chronic cocaine on circadian regulation was evidenced by disruptions of the period of circadian entrainment and intrinsic free-running circadian period. Specifically, mice under a skeleton photoperiod (1-min pulse of dim light delivered daily) receiving continuous ad libitum cocaine entrained rapidly to the light pulse at activity onset. Conversely, water controls entrained more slowly at activity offset through a process of phase-delays, which resulted in their activity rhythms being entrained 147° out of phase with the cocaine group. This pattern persisted after cocaine withdrawal. Next, mice exposed to scheduled daily cocaine presentations exhibited free-running periods under constant darkness that were significantly longer than water controls and which also persisted after cocaine withdrawal. These cocaine-induced perturbations of clock timing could produce chronic psychological and physiological stress, contributing to increased cocaine use and dependence. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.
Lopes, C; deLyra, J L; Markus, R P; Mariano, M
Biological rhythms are detected in a variety of physiological and pathological conditions in man and animals, such as rheumatoid arthritis and asthma. Here we describe a circadian rhythm in experimental infectious and non-infectious granuloma. After 30 days of BCG (Bacillus Calmette-Guerin) or nystatin inoculation in the left hind foot of C57B1/6 mice, there is an oscillation with a period of approximately 24 hr in the variation of paw thickness, indicating a circadian rhythm. The acrophase occurred during the light phase, between 9:00 and 13:00 hr, while the nadir occurred in the dark phase, between 21:00 and 01:00 hr. The vascular permeability around the granulomatous lesions was higher at 12:00 hr than at 24:00 hr. This is in agreement with the observation that the thickness of a paw with granulomatous lesion is larger during the light phase. This rhythmic variation was eliminated by either pinealectomy or superior cervical ganglionectomy, which greatly reduce melatonin levels in the blood. Nocturnal replacement of melatonin in pinealectomized mice led to the re-establishment of the circadian rhythm. Thus, the rhythm of the granulomatous lesion is due to the rhythmic melatonin release by the pineal gland. This approach opens new questions regarding the modulation of chronic inflammation in inflammatory diseases that present rhythmic symptoms throughout the day.
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.
Kunst, Michael; Hughes, Michael E; Raccuglia, Davide; Felix, Mario; Li, Michael; Barnett, Gregory; Duah, Janelle; Nitabach, Michael N
Imbalances in amount and timing of sleep are harmful to physical and mental health. Therefore, the study of the underlying mechanisms is of great biological importance. Proper timing and amount of sleep are regulated by both the circadian clock and homeostatic sleep drive. However, very little is known about the cellular and molecular mechanisms by which the circadian clock regulates sleep. In this study, we describe a novel role for diuretic hormone 31 (DH31), the fly homolog of the vertebrate neuropeptide calcitonin gene-related peptide, as a circadian wake-promoting signal that awakens the fly in anticipation of dawn. Analysis of loss-of-function and gain-of-function Drosophila mutants demonstrates that DH31 suppresses sleep late at night. DH31 is expressed by a subset of dorsal circadian clock neurons that also express the receptor for the circadian neuropeptide pigment-dispersing factor (PDF). PDF secreted by the ventral pacemaker subset of circadian clock neurons acts on PDF receptors in the DH31-expressing dorsal clock neurons to increase DH31 secretion before dawn. Activation of PDF receptors in DH31-positive DN1 specifically affects sleep and has no effect on circadian rhythms, thus constituting a dedicated locus for circadian regulation of sleep. We identified a novel signaling molecule (DH31) as part of a neuropeptide relay mechanism for circadian control of sleep. Our results indicate that outputs of the clock controlling sleep and locomotor rhythms are mediated via distinct neuronal pathways. Copyright © 2014 Elsevier Ltd. All rights reserved.
Harrison, Elizabeth M; Gorman, Michael R
Daily rhythms in mammalian physiology and behavior are generated by a central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN), the timing of which is set by light from the environment. When the ambient light-dark cycle is shifted, as occurs with travel across time zones, the SCN and its output rhythms must reset or re-entrain their phases to match the new schedule-a sluggish process requiring about 1 day per hour shift. Using a global assay of circadian resetting to 6 equidistant time-zone meridians, we document this characteristically slow and distance-dependent resetting of Syrian hamsters under typical laboratory lighting conditions, which mimic summer day lengths. The circadian pacemaker, however, is additionally entrainable with respect to its waveform (i.e., the shape of the 24-h oscillation) allowing for tracking of seasonally varying day lengths. We here demonstrate an unprecedented, light exposure-based acceleration in phase resetting following 2 manipulations of circadian waveform. Adaptation of circadian waveforms to long winter nights (8 h light, 16 h dark) doubled the shift response in the first 3 days after the shift. Moreover, a bifurcated waveform induced by exposure to a novel 24-h light-dark-light-dark cycle permitted nearly instant resetting to phase shifts from 4 to 12 h in magnitude, representing a 71% reduction in the mismatch between the activity rhythm and the new photocycle. Thus, a marked enhancement of phase shifting can be induced via nonpharmacological, noninvasive manipulation of the circadian pacemaker waveform in a model species for mammalian circadian rhythmicity. Given the evidence of conserved flexibility in the human pacemaker waveform, these findings raise the promise of flexible resetting applicable to circadian disruption in shift workers, frequent time-zone travelers, and any individual forced to adjust to challenging schedules. © 2015 The Author(s).
It has been well established that the circadian clock plays a crucial role in the regulation of almost every physiological process. It also plays a critical role in pathophysiological states including those of obesity and diabetes. Recent evidence has highlighted the potential for targeting the circadian clock as a potential drug target. New studies have also demonstrated the existence of “clock-independent effects” of the circadian proteins, leading to exciting new avenues of research in the circadian clock field in physiology. The goal of this review is to provide an introduction to and overview of the circadian clock in physiology, including mechanisms, targets, and role in disease states. The role of the circadian clocks in the regulation of the cardiovascular system, renal function, metabolism, the endocrine system, immune, and reproductive systems will be discussed. PMID:23576606
Gannon, Robert L
The synchronization of circadian rhythms in sleep, endocrine and metabolic functions with the environmental light cycle is essential for health, and dysfunction of this synchrony is thought to play a part in the development of many neurological disorders. There is a demonstrable need to develop new therapeutics for the treatment of neurological disorders such as depression and schizophrenia, and oxytocin is currently being investigated for this purpose. There are no published reports describing activity of oxytocin receptor ligands on mammalian circadian rhythms and that, then, is the purpose of this study. Non-peptide oxytocin receptor ligands that cross the blood brain barrier were systemically injected in hamsters to determine their ability to modulate light-induced phase advances and delays of circadian wheel running rhythms. The oxytocin receptor agonist WAY267464 (10 mg/kg) inhibited light induced phase advances of wheel running rhythms by 55%, but had no effect on light-induced phase delays. In contrast, the oxytocin receptor antagonist WAY162720 (10 mg/kg) inhibited light-induced phase delays by nearly 75%, but had no effect on light-induced phase advances. Additionally, WAY162720 was able to antagonize the inhibitory effects of WAY267464 on light-induced phase advances. These results are consistent for a role of oxytocin in the phase-delaying effects of light on circadian activity rhythms early in the night. Therefore, oxytocin may prove to be useful in developing therapeutics for the treatment of mood disorders with a concomitant dysfunction in circadian rhythms. Investigators should also be cognizant that oxytocin ligands may negatively affect circadian rhythms during clinical trials for other conditions. Copyright © 2014 Elsevier B.V. All rights reserved.
Steensel, Mariska van
In order to cope with and to predict 24-hour rhythms in the environment, most, if not all, organisms have a circadian timing system. The most important mammalian circadian pacemaker is located in the suprachiasmatic nucleus at the base of the hypothalamus in the brain. Over the years, it has become clear that the circadian system is complex and that additional oscillators exist, both within and outside the central nervous system. The aim of this thesis was to obtain insight in the hierarchica...
Kalsbeek, Andries; Strubbe, JH
To investigate whether there is a circadian regulation of insulin secretion, rats were adapted to a feeding regimen of six meals equally distributed over 24 h. Under these conditions basal glucose and insulin levels increased during the light phase and decreased during the dark phase. Maximal blood
Full Text Available Abstract Background Circadian clocks are internal daily time keeping mechanisms that allow organisms to anticipate daily changes in their environment and to organize their behavior and physiology in a coherent schedule. Although circadian clocks use temperature compensation mechanisms to maintain the same pace over a range of temperatures, they are also capable of synchronizing to daily temperature cycles. This study identifies key properties of this process. Results Gradually ramping daily temperature cycles are shown here to synchronize behavioral and molecular daily rhythms in Drosophila with a remarkable efficiency. Entrainment to daily temperature gradients of amplitudes as low as 4°C persisted even in the context of environmental profiles that also included continuous gradual increases or decreases in absolute temperature. To determine which elements of daily temperature gradients acted as the key determinants of circadian activity phase, comparative analyses of daily temperature gradients with different wave forms were performed. The phases of ascending and descending temperature acted together as key determinants of entrained circadian phase. In addition, circadian phase was found to be modulated by the relative temperature of release into free running conditions. Release at or close to the trough temperature of entrainment consistently resulted in phase advances. Re-entrainment to daily temperature gradients after large phase shifts occurred relatively slowly and required several cycles, allowing flies to selectively respond to periodic rather than anecdotal signals. The temperature-entrained phase relationship between clock gene expression rhythms and locomotor activity rhythms strongly resembled that previously observed for light entrainment. Moreover, daily temperature gradient and light/dark entrainment reinforced each other if the phases of ascending and descending temperature were in their natural alignment with the light and
We prove that a Symanzik--Nelson positive quantum field theory, i.e., a quantum field theory derived from a Euclidean field theory, has a unique decomposition into pure phases which preserves Symanzik--Nelson positivity and Poincare covariance. We derive useful sufficient conditions for the breakdown of an internal symmetry of such a theory in its pure phases, for the self-adjointness and nontrivially (in the sense of Borchers classes) of its quantum fields, and the existence of time-ordered and retarded products. All these general results are then applied to the P (phi) 2 and the phi 3 4 quantum field models
Tucker, Matthew A; Morris, Christopher J; Morgan, Alexandra; Yang, Jessica; Myers, Samantha; Pierce, Joanna Garcia; Stickgold, Robert; Scheer, Frank A J L
Sleep during the biological night facilitates memory consolidation. Here we determined the impact of sleep and wake on motor skill learning (acquisition) and subsequent off-line skill improvement (memory consolidation), independent of circadian phase, and compared this to the impact of the endogenous circadian system, independent of whether sleep occurred during the biological night or day. Participants completed two 8-day sleep laboratory visits, adhering on one visit to a circadian aligned ("normal") sleep schedule for the full duration of the protocol, and on the other to a circadian misaligned (12-hour inverted) schedule, with alignment during the first 3 days, a 12-hour 'slam shift' on Day 4, followed by circadian misalignment during the last 4 days of the protocol. Participants were repeatedly trained and tested on different versions of the finger-tapping motor sequence task across each visit. Sleep facilitated offline memory consolidation regardless of whether it occurred during the biological day or night, while circadian phase had no significant impact. These sleep-related benefits remained after accounting for general motor speed, measured in the absence of learning. In addition, motor skill acquisition was facilitated when the training session followed shortly after sleep, without significant impact of circadian phase (biological morning vs. evening). This effect was largely driven by heightened acquisition in participants who slept during the day and were trained shortly thereafter, that is, when acquisition occurred during the biological evening. These benefits were also retained after controlling for general motor speed. Sleep benefits both the acquisition and consolidation of motor skill regardless of whether they occur during the biological day or night. After controlling for general motor speed, a critical adjustment that few studies perform, these sleep benefits remain intact. Our findings have clear implications for night shift workers who obtain
Glou, Eric Le; Seugnet, Laurent; Shaw, Paul J.; Preat, Thomas; Goguel, Valérie
Objectives: Several lines of evidence indicate that sleep plays a critical role in learning and memory. The aim of this study was to evaluate anesthesia resistant memory following sleep deprivation in Drosophila. Design: Four to 16 h after aversive olfactory training, flies were sleep deprived for 4 h. Memory was assessed 24 h after training. Training, sleep deprivation, and memory tests were performed at different times during the day to evaluate the importance of the time of day for memory formation. The role of circadian rhythms was further evaluated using circadian clock mutants. Results Memory was disrupted when flies were exposed to 4 h of sleep deprivation during the consolidation phase. Interestingly, normal memory was observed following sleep deprivation when the memory test was performed during the 2 h preceding lights-off, a period characterized by maximum wake in flies. We also show that anesthesia resistant memory was less sensitive to sleep deprivation in flies with disrupted circadian rhythms. Conclusions Our results indicate that anesthesia resistant memory, a consolidated memory less costly than long-term memory, is sensitive to sleep deprivation. In addition, we provide evidence that circadian factors influence memory vulnerability to sleep deprivation and memory retrieval. Taken together, the data show that memories weakened by sleep deprivation can be retrieved if the animals are tested at the optimal circadian time. Citation: Le Glou E; Seugnet L; Shaw PJ; Preat T; Goguel V. Circadian modulation of consolidated memory retrieval following sleep deprivation in Drosophila. SLEEP 2012;35(10):1377-1384. PMID:23024436
Lavoie, Joëlle; Hébert, Marc; Beaulieu, Jean-Martin
The mood stabiliser drug lithium has been reported to impact circadian rhythms in vertebrates. Among several putative therapeutic molecular targets, direct inhibition of glycogen synthase kinase-3 beta (GSK3β) by lithium has been proposed to underlie its effects on circadian physiology. Here we study the effect of GSK3β haploinsufficiency on the circadian locomotor activity in mice during a free-running period in comparison to wildtype littermates (WT). Mice were housed individually to record their circadian wheel running activity and were entrained to a 12h light/12h dark cycle for 14 days and then placed under constant darkness for 14 days to allow free-running. During the free-running phase, the circadian locomotor activity period of GSK3β(+/-) was significantly lengthened (23.83±0.05h) when compared to the WT mice (23.54±0.10h; p=0.0374). No significant difference in locomotor activity was observed. Knowing that GSK3β interacts with most of the core clock components, these data suggest that GSK3β acts as a critical intrinsic regulator of the circadian clock and plays an important role in regulating its period in response to lithium treatment. Copyright © 2013 Elsevier B.V. All rights reserved.
Full Text Available Essentially all biological processes depend on protein-protein interactions (PPIs. Timing of such interactions is crucial for regulatory function. Although circadian (~24-hour clocks constitute fundamental cellular timing mechanisms regulating important physiological processes, PPI dynamics on this timescale are largely unknown. Here, we identified 109 novel PPIs among circadian clock proteins via a yeast-two-hybrid approach. Among them, the interaction of protein phosphatase 1 and CLOCK/BMAL1 was found to result in BMAL1 destabilization. We constructed a dynamic circadian PPI network predicting the PPI timing using circadian expression data. Systematic circadian phenotyping (RNAi and overexpression suggests a crucial role for components involved in dynamic interactions. Systems analysis of a global dynamic network in liver revealed that interacting proteins are expressed at similar times likely to restrict regulatory interactions to specific phases. Moreover, we predict that circadian PPIs dynamically connect many important cellular processes (signal transduction, cell cycle, etc. contributing to temporal organization of cellular physiology in an unprecedented manner.
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.
Todd P Michael
Full Text Available WHITE COLLAR-1 (WC-1 mediates interactions between the circadian clock and the environment by acting as both a core clock component and as a blue light photoreceptor in Neurospora crassa. Loss of the amino-terminal polyglutamine (NpolyQ domain in WC-1 results in an arrhythmic circadian clock; this data is consistent with this simple sequence repeat (SSR being essential for clock function.Since SSRs are often polymorphic in length across natural populations, we reasoned that investigating natural variation of the WC-1 NpolyQ may provide insight into its role in the circadian clock. We observed significant phenotypic variation in the period, phase and temperature compensation of circadian regulated asexual conidiation across 143 N. crassa accessions. In addition to the NpolyQ, we identified two other simple sequence repeats in WC-1. The sizes of all three WC-1 SSRs correlated with polymorphisms in other clock genes, latitude and circadian period length. Furthermore, in a cross between two N. crassa accessions, the WC-1 NpolyQ co-segregated with period length.Natural variation of the WC-1 NpolyQ suggests a mechanism by which period length can be varied and selected for by the local environment that does not deleteriously affect WC-1 activity. Understanding natural variation in the N.crassa circadian clock will facilitate an understanding of how fungi exploit their environments.
Larina, Olga; Bekker, Anna
Studies performed at space flights and earth-based simulation models detected the plasma indices of acute phase reaction (APR), i.e. the increase of APR cytokine mediators and alterations in the production of blood acute phase proteins (APP) at the initial stages of adaptation to altered gravity conditions. Acute phase response is the principal constituent of the functional activity of innate immunity system. Changes in plasma APPs contents are considered to serve the restoration of homeostasis state. According to trends of their concentration shifts at the evolving of acute phase reaction APPs are denoted as positive, neutral, or negative. Plasma concentrations of positive acute phase proteins α1-acid glycoprotein (α1-AGP), α1-antitrypsin (α1-AT), and neutral α2-macroglobulin (α2-M) were measured in human study at 12-hour antiorthostatic position (AOP) with 15° head down tilt and hypoxia experiments at 14% oxygen in pressure chamber. Both of these impacts were shown to produce alterations in the APP levels indicative for acute phase response. Nevertheless, in AOP experiment noticeable decrease in α1-AGP concentration occurred by hour 12, and even more pronounced decline of α1-AGP and α1-AT were found on hypoxia hours 12 and 36. Acute phase proteins α1-AGP and α2-M possess the features of proteinase inhibitors. This function is implemented by the formation of complexes with the molecules of proteolytic enzymes which subsequently are removed from the blood flow. Transient decrease in plasma concentrations of protease inhibitors on early phases of APR development was reported to result from the growth of plasma protease activity due to cathepsin release from activated leukocytes, which had not yet been compensated by enhanced APP synthesis. Being a carrier protein for positively charged and neutral substances, α1-AGP shows pronounced elevation in its blood content during APR development. As assumed, it is required for the transportation of the increased
Full Text Available Circadian rhythms in pacemaker cells persist for weeks in constant darkness, while in other types of cells the molecular oscillations that underlie circadian rhythms damp rapidly under the same conditions. Although much progress has been made in understanding the biochemical and cellular basis of circadian rhythms, the mechanisms leading to damped or self-sustained oscillations remain largely unknown. There exist many mathematical models that reproduce the circadian rhythms in the case of a single cell of the Drosophila fly. However, not much is known about the mechanisms leading to coherent circadian oscillation in clock neuron networks. In this work we have implemented a model for a network of interacting clock neurons to describe the emergence (or damping of circadian rhythms in Drosophila fly, in the absence of zeitgebers. Our model consists of an array of pacemakers that interact through the modulation of some parameters by a network feedback. The individual pacemakers are described by a well-known biochemical model for circadian oscillation, to which we have added degradation of PER protein by light and multiplicative noise. The network feedback is the PER protein level averaged over the whole network. In particular, we have investigated the effect of modulation of the parameters associated with (i the control of net entrance of PER into the nucleus and (ii the non-photic degradation of PER. Our results indicate that the modulation of PER entrance into the nucleus allows the synchronization of clock neurons, leading to coherent circadian oscillations under constant dark condition. On the other hand, the modulation of non-photic degradation cannot reset the phases of individual clocks subjected to intrinsic biochemical noise.
Shao, Xiaolu; Song, Jie; Li, Shuanglin
Based on a simplified nonlinear model and reanalysis data, the lagged connection of the North Atlantic Oscillation (NAO) with the Madden-Julian Oscillation (MJO) in boreal winters is investigated. The positive NAO is observed to occur more frequently about 8-20 days after the onset of the MJO phase 3. A series of heating forcing experiments and initial-value experiments are conducted by utilizing the Geophysical Fluid Dynamics Laboratory (GFDL) dynamical core atmospheric model. The extratropical responses to the tropical heating associated with the MJO phase 3 are characterized by a wave train over the Pacific-North American region with an anticyclone anomaly over the northeastern Pacific and then followed by a positive-NAO-like pattern over the North Atlantic sector. These circulation anomalies generally match the observed lagged-connection well. At the earlier stage, the Rossby wave train excited by the MJO convection propagates into the North Atlantic, leading to a planetary wave anomaly with a low-over-high dipole prior to the positive NAO. At the later stage, the anomalous synoptic eddy vorticity forcing (EVF) streamfunction tendency has a negative-over-positive dipole, which plays a key role in the development of the positive NAO. Further analysis of the initial-value experiments indicates that, for the subsequent formation of the positive NAO, the anomalous circulation over the Indian Ocean aroused by the MJO phase 3 is more crucial than that over the northeastern Pacific.
Akman Ozgur E
Full Text Available Abstract Background Robustness is a central property of living systems, enabling function to be maintained against environmental perturbations. A key challenge is to identify the structures in biological circuits that confer system-level properties such as robustness. Circadian clocks allow organisms to adapt to the predictable changes of the 24-hour day/night cycle by generating endogenous rhythms that can be entrained to the external cycle. In all organisms, the clock circuits typically comprise multiple interlocked feedback loops controlling the rhythmic expression of key genes. Previously, we showed that such architectures increase the flexibility of the clock's rhythmic behaviour. We now test the relationship between flexibility and robustness, using a mathematical model of the circuit controlling conidiation in the fungus Neurospora crassa. Results The circuit modelled in this work consists of a central negative feedback loop, in which the frequency (frq gene inhibits its transcriptional activator white collar-1 (wc-1, interlocked with a positive feedback loop in which FRQ protein upregulates WC-1 production. Importantly, our model reproduces the observed entrainment of this circuit under light/dark cycles with varying photoperiod and cycle duration. Our simulations show that whilst the level of frq mRNA is driven directly by the light input, the falling phase of FRQ protein, a molecular correlate of conidiation, maintains a constant phase that is uncoupled from the times of dawn and dusk. The model predicts the behaviour of mutants that uncouple WC-1 production from FRQ's positive feedback, and shows that the positive loop enhances the buffering of conidiation phase against seasonal photoperiod changes. This property is quantified using Kitano's measure for the overall robustness of a regulated system output. Further analysis demonstrates that this functional robustness is a consequence of the greater evolutionary flexibility conferred on
Ribas-Latre, Aleix; Eckel-Mahan, Kristin
Background While additional research is needed, a number of large epidemiological studies show an association between circadian disruption and metabolic disorders. Specifically, obesity, insulin resistance, cardiovascular disease, and other signs of metabolic syndrome all have been linked to circadian disruption in humans. Studies in other species support this association and generally reveal that feeding that is not in phase with the external light/dark cycle, as often occurs with night or rotating shift workers, is disadvantageous in terms of energy balance. As food is a strong driver of circadian rhythms in the periphery, understanding how nutrient metabolism drives clocks across the body is important for dissecting out why circadian misalignment may produce such metabolic effects. A number of circadian clock proteins as well as their accessory proteins (such as nuclear receptors) are highly sensitive to nutrient metabolism. Macronutrients and micronutrients can function as zeitgebers for the clock in a tissue-specific way and can thus impair synchrony between clocks across the body, or potentially restore synchrony in the case of circadian misalignment. Circadian nuclear receptors are particularly sensitive to nutrient metabolism and can alter tissue-specific rhythms in response to changes in the diet. Finally, SNPs in human clock genes appear to be correlated with diet-specific responses and along with chronotype eventually may provide valuable information from a clinical perspective on how to use diet and nutrition to treat metabolic disorders. Scope of review This article presents a background of the circadian clock components and their interrelated metabolic and transcriptional feedback loops, followed by a review of some recent studies in humans and rodents that address the effects of nutrient metabolism on the circadian clock and vice versa. We focus on studies in which results suggest that nutrients provide an opportunity to restore or, alternatively
Bamne, Mikhil N; Ponder, Christine A; Wood, Joel A; Mansour, Hader; Frank, Ellen; Kupfer, David J; Young, Michael W; Nimgaonkar, Vishwajit L
Disruption of circadian function has been observed in several human disorders, including bipolar disorder (BD). Research into these disorders can be facilitated by human cellular models that evaluate external factors (zeitgebers) that impact circadian pacemaker activity. Incorporating a firefly luciferase reporter system into human fibroblasts provides a facile, bioluminescent readout that estimates circadian phase, while leaving the cells intact. We evaluated whether this system can be adapted to clinical BD research and whether it can incorporate zeitgeber challenge paradigms. Fibroblasts from patients with bipolar I disorder (BD-I) (n = 13) and controls (n = 12) were infected ex vivo with a lentiviral reporter incorporating the promoter sequences for Bmal1, a circadian gene to drive expression of the firefly luciferase gene. Following synchronization, the bioluminescence was used to estimate period length. Phase response curves (PRCs) were also generated following forskolin challenge and the phase response patterns were characterized. Period length and PRCs could be estimated reliably from the constructs. There were no significant case-control differences in period length, with a nonsignificant trend for differences in PRCs following the phase-setting experiments. An ex vivo cellular fibroblast-based model can be used to investigate circadian function in BD-I. It can be generated from specific individuals and this could usefully complement ongoing circadian clinical research. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Burke, Tina M; Scheer, Frank A J L; Ronda, Joseph M; Czeisler, Charles A; Wright, Kenneth P
Sleep inertia, sleep homeostatic and circadian processes modulate cognition, including reaction time, memory, mood and alertness. How these processes influence higher-order cognitive functions is not well known. Six participants completed a 73-day-long study that included two 14-day-long 28-h forced desynchrony protocols to examine separate and interacting influences of sleep inertia, sleep homeostasis and circadian phase on higher-order cognitive functions of inhibitory control and selective visual attention. Cognitive performance for most measures was impaired immediately after scheduled awakening and improved during the first ~2-4 h of wakefulness (decreasing sleep inertia); worsened thereafter until scheduled bedtime (increasing sleep homeostasis); and was worst at ~60° and best at ~240° (circadian modulation, with worst and best phases corresponding to ~09:00 and ~21:00 hours, respectively, in individuals with a habitual wake time of 07:00 hours). The relative influences of sleep inertia, sleep homeostasis and circadian phase depended on the specific higher-order cognitive function task examined. Inhibitory control appeared to be modulated most strongly by circadian phase, whereas selective visual attention for a spatial-configuration search task was modulated most strongly by sleep inertia. These findings demonstrate that some higher-order cognitive processes are differentially sensitive to different sleep-wake regulatory processes. Differential modulation of cognitive functions by different sleep-wake regulatory processes has important implications for understanding mechanisms contributing to performance impairments during adverse circadian phases, sleep deprivation and/or upon awakening from sleep. © 2015 European Sleep Research Society.
Aug 26, 2016 ... 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.
Dec 7, 2008 ... system for the study of circadian rhythms primarily due to the availability of molecular genetic tools that enabled iden- tification of genes, proteins and neuronal groups that are es- sential components of the circadian machinery. Further, D. melanogaster exhibits robust and relatively easily measur-.
Steensel, Mariska van
In order to cope with and to predict 24-hour rhythms in the environment, most, if not all, organisms have a circadian timing system. The most important mammalian circadian pacemaker is located in the suprachiasmatic nucleus at the base of the hypothalamus in the brain. Over the years, it has become
Bell-Pedersen, Deborah; Crosthwaite, Susan K.; Lakin-Thomas, Patricia L.; Merrow, Martha; Økland, Merete
The fungus Neurospora crassa is being used by a number of research groups as a model organism to investigate circadian (daily) rhythmicity. In this review we concentrate on recent work relating to the complexity of the circadian system in this organism. We discuss: the advantages of Neurospora as a
Dec 7, 2008 ... large variety of tissues in the fly such as the eye, brain, pro- boscis, antennae, wings, abdomen, Malpighian tubules and testes (Plautz et al. 1997; Giebultowicz 2001). Although cell-autonomous circadian function is attributed to several tissues in Drosophila, circadian pacemaker neurons located in the brain ...
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
Salathia, Neeraj; Lynn, James R; Millar, Andrew J; King, Graham J
Circadian rhythms regulate many aspects of plant growth, fitness and vigour. The components and detailed mechanism of circadian regulation to date have been dissected in the reference species Arabidopsis thaliana. To determine the genetic basis and range of natural allelic variation for intrinsic circadian period in the closest crop relatives, we used an accurate and high throughput data capture system to record rhythmic cotyledon movement in two immortal segregating populations of Brassica oleracea, derived from parent lines representing different crop types. Periods varied between 24.4 and 26.1 h between the parent lines, with transgressive segregation between extreme recombinant lines in both populations of approximately 3.5 h. The additive effect of individual QTL identified in each population varied from 0.17 to 0.36 h. QTL detected in one doubled haploid population were verified and the mapping intervals further resolved by determining circadian period in genomic substitution lines derived from the parental lines. Comparative genomic analysis based on collinearity between Brassica and Arabidopsis also allowed identification of candidate orthologous genes known to regulate period in Arabidopsis, that may account for the additive circadian effects of specific QTL. The distinct QTL positions detected in the two populations, and the extent of transgressive segregation suggest that there is likely to be considerable scope for modulating the range of available circadian periods in natural populations and crop species of Brassica. This may provide adaptive advantage for optimising growth and development in different latitudes, seasons or climate conditions.
Li, Qianshu; Lang, Xiufeng
Circadian rhythmic processes, mainly regulated by gene expression at the molecular level, have inherent stochasticity. Their robustness or resistance to internal noise has been extensively investigated by most of the previous studies. This work focuses on the constructive roles of internal noise in a reduced Drosophila model, which incorporates negative and positive feedback loops, each with a time delay. It is shown that internal noise sustains reliable oscillations with periods close to 24 h in a region of parameter space, where the deterministic kinetics would evolve to a stable steady state. The amplitudes of noise-sustained oscillations are significantly affected by the variation of internal noise level, and the best performance of the oscillations could be found at an optimal noise intensity, indicating the occurrence of intrinsic coherence resonance. In the oscillatory region of the deterministic model, the coherence of noisy circadian oscillations is suppressed by internal noise, while the period remains nearly constant over a large range of noise intensity, demonstrating robustness of the Drosophila model for circadian rhythms to intrinsic noise. In addition, the effects of time delay in the positive feedback on the oscillations are also investigated. It is found that the time delay could efficiently tune the performance of the noise-sustained oscillations. These results might aid understanding of the exploitation of intracellular noise in biochemical and genetic regulatory systems.
Rath, Martin F; Rovsing, Louise; Møller, Morten
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...... 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...
Burke, Tina M.; Markwald, Rachel R.; McHill, Andrew W.; Chinoy, Evan D.; Snider, Jesse A.; Bessman, Sara C.; Jung, Christopher M.; O’Neill, John S.; Wright, Kenneth P.
Caffeine’s wakefulness-promoting and sleep-disrupting effects are well established, yet whether caffeine affects human circadian timing is unknown. Here we show that evening caffeine consumption delays the human circadian melatonin rhythm in vivo, and chronic application of caffeine lengthens the circadian period of molecular oscillations in vitro primarily via an adenosine receptor/cyclic AMP-dependent mechanism. In a double-blind, placebo controlled, ~49-day long within-subject study, we found the equivalent amount of caffeine as that in a double espresso 3 hours before habitual bedtime induced a phase delay of the circadian melatonin rhythm in humans by ~40 minutes. This magnitude of delay was nearly half of the magnitude of the phase-delaying response induced by exposure to 3-hours of evening bright-light (~3000 lux; ~7 Watts/m2) that began at habitual bedtime. Furthermore, using human osteosarcoma U2OS cells expressing clock gene luciferase reporters, we found a dose-dependent lengthening of circadian period by caffeine. By pharmacological dissection and siRNA knockdown we established that perturbation of adenosine receptor signaling, but not ryanodine receptor or phosphodiesterase activity, is sufficient to account for caffeine’s effects on cellular timekeeping. We also used a cyclic AMP biosensor to show that caffeine increased cyclic AMP levels, indicating that caffeine can influence a core component of the cellular circadian clock. Taken together, our findings demonstrate that caffeine influences human circadian timing and gives new insight into how the world’s most widely consumed psychoactive drug impacts upon human physiology. PMID:26378246
Touitou, Yvan; Mauvieux, Benoit; Reinberg, Alain; Dispersyn, Garance
The circadian time structure of an organism can be desynchronized in a large number of instances, including the intake of specific drugs. We have previously found that propofol, which is a general anesthetic, induces a desynchronization of the circadian time structure in rats, with a 60-80 min significant phase advance of body temperature circadian rhythm. We thus deemed it worthwhile to examine whether this phase shift of body temperature was related to a modification of the circadian period Tau. Propofol was administered at three different Zeitgeber Times (ZTs): ZT6 (middle of the rest period), ZT10 (2 h prior to the beginning of activity period), ZT16 (4 h after the beginning of the activity period), with ZT0 being the beginning of the rest period (light onset) and ZT12 being the beginning of the activity period (light offset). Control rats (n = 20) were injected at the same ZTs with 10% intralipid, which is a control lipidic solution. Whereas no modification of the circadian period of body temperature was observed in the control rats, propofol administration resulted in a significant shortening of the period by 96 and 180 min at ZT6 and ZT10, respectively. By contrast, the period was significantly lengthened by 90 min at ZT16. We also found differences in the time it took for the rats to readjust their body temperature to the original 24-h rhythm. At ZT16, the speed of readjustment was more rapid than at the two other ZTs that we investigated. This study hence shows (i) the disruptive effects of the anesthetic propofol on the body temperature circadian rhythm, and it points out that (ii) the period Tau for body temperature responds to this anesthetic drug according to a Tau-response curve. By sustaining postoperative sleep-wake disorders, the disruptive effects of propofol on circadian time structure might have important implications for the use of this drug in humans.
Barraco, Gloria Maria; Martínez-Lozano, Nuria; Vales-Villamarín, Claudia; Del Carmen Blaya, María; Rios, Rafael; Madrid, Juan Antonio; Fardy, Paul; Garaulet, Marta
Assessment of circadian health is confined to adults. However, understanding circadian status of school-aged children is necessary due to its health implications. The aim was to develop 1) a protocol to assess circadian function in school-aged children by combining the best non-invasive tools previously validated in adults; 2) a score to capture circadian function in children including food timing. This protocol will allow to explore gender differences and to compare the circadian function of school-aged children with adults from the same Mediterranean area. Healthy children (8-12 y) from 3 schools in a Mediterranean area of Spain were recruited (n = 248; 125 males and 123 females). Several non-invasive tools were used: a) 7-day-diaries of food timing and food intake, physical-activity and sleep, b) Munich-chronotype-self-reported-questionnaire; c) cortisol and melatonin saliva determinations; d) 7-day-rhythms of wrist temperature (T), activity (A), position (P) and the integrative variable TAP e) 7-day-light exposure. We have constructed the first school-aged children population for the assessment of circadian function (ONTIME-Jr) and a new circadian score has been developed. Among circadian-related measures, TAP was the most suitable and reliable to determine circadian system characteristics. Circadian function was better in girls than in boys [circadian score (AU) Mean ± SD (girls, 1216 ± 153 vs. 1159 ± 173 boys, P = 0.012)], and also in school-aged children than in adults from the same Mediterranean area (Circadian-Function-Index: children 0.47 ± 0.06 vs. adults 0.45 ± 0.06 P = 0.001). A new protocol, including TAP and food timing, demonstrated to be reliable in assessing circadian function in children. These non-invasive techniques provide the wherewithal for paediatricians to assess circadian function in clinical practice. Chronobiology and childhood obesity (ONTIME-Jr: Obesity, Nutrigenetics, Timing and Mediterranean, Junior). Clinical
Masum, Shah Md; Li, Shu Jie; Awad, Tarek S; Yamazaki, Masahito
To elucidate the stability and phase transition of cubic phases of biomembranes with infinite periodic minimal surface is indispensable from biological and physicochemical aspects. In this report, we investigated the effect of positively charged peptide-3K (LLKKK) and poly(L-lysine) on the phase stability of monoolein (MO) membranes containing negatively charged dioleoylphosphatidic acid (DOPA) (i.e., DOPA/MO membranes) using small-angle X-ray scattering. At first, the effect of peptide-3K on 10% DOPA/90% MO membrane in excess water, which is in the Q229 phase, was investigated. At 3.4 mM peptide-3K, a Q229 to Q230 phase transition occurred, and at >3.4 mM peptide-3K, the membrane was in the Q230 phase. Poly(L-lysine) (M(w) 1K-4K) also induced the Q230 phase, but peptide-2K (LLKK) could not induce it in the same membrane. We also investigated the effect of peptide-3K on the multilamellar vesicle (MLV) of 25% DOPA/75% MO membrane, which is in L(alpha) phase. In the absence of peptide, the spacing of MLV was very large (11.3 nm), but at > or = 8 mM peptide-3K, it greatly decreased to a constant value (5.2 nm), irrespective of the peptide concentration, indicating that peptide-3K and the membranes form an electrostatically stabilized aggregation with low water content. Poly(L-lysine) also decreased greatly the spacing of the 25% DOPA/75% MO MLV, indicating the formation of a similar aggregation. To compare the effects of peptide-3K and poly(L-lysine) with that of osmotic stress on stability of the cubic phase, we investigated the effect of poly(ethylene glycol) with molecular weight 7500 (PEG-6K) on the phase stability of 10% DOPA/90% MO membrane. With an increase in PEG-6K concentration, i.e., with an increase in osmotic stress, the most stable phase changed as follows; Q229 (Schwartz's P surface) --> Q224 (D) --> Q230 (G). On the basis of these results, we discuss the mechanism of the effects of the positively charged short peptides (peptide-3K) and poly
Andrey A Ptitsyn
Full Text Available In mammals, circadian periodicity has been described for gene expression in the hypothalamus and multiple peripheral tissues. It is accepted that 10%-15% of all genes oscillate in a daily rhythm, regulated by an intrinsic molecular clock. Statistical analyses of periodicity are limited by the small size of datasets and high levels of stochastic noise. Here, we propose a new approach applying digital signal processing algorithms separately to each group of genes oscillating in the same phase. Combined with the statistical tests for periodicity, this method identifies circadian baseline oscillation in almost 100% of all expressed genes. Consequently, circadian oscillation in gene expression should be evaluated in any study related to biological pathways. Changes in gene expression caused by mutations or regulation of environmental factors (such as photic stimuli or feeding should be considered in the context of changes in the amplitude and phase of genetic oscillations.
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
Phillips, Andrew J. K.; Clerx, William M.; O?Brien, Conor S.; Sano, Akane; Barger, Laura K.; Picard, Rosalind W.; Lockley, Steven W.; Klerman, Elizabeth B.; Czeisler, Charles A.
The association of irregular sleep schedules with circadian timing and academic performance has not been systematically examined. We studied 61 undergraduates for 30 days using sleep diaries, and quantified sleep regularity using a novel metric, the sleep regularity index (SRI). In the most and least regular quintiles, circadian phase and light exposure were assessed using salivary dim-light melatonin onset (DLMO) and wrist-worn photometry, respectively. DLMO occurred later (00:08 ± 1:54 vs. ...
Hirano, Arisa; Braas, Daniel; Fu, Ying-Hui; Ptáček, Louis J
The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD) binding pocket of CRYPTOCHROME2 (CRY2), a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin kinase (Rfk), an FAD biosynthetic enzyme, enhanced CRY degradation. RFK protein levels and FAD concentrations oscillate in the nucleus, suggesting that they are subject to circadian control. Knockdown of Rfk combined with a riboflavin-deficient diet altered the CRY levels in mouse liver and the expression profiles of clock and clock-controlled genes (especially those related to metabolism including glucose homeostasis). We conclude that light-independent mechanisms of FAD regulate CRY and contribute to proper circadian oscillation of metabolic genes in mammals. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.
Full Text Available The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD binding pocket of CRYPTOCHROME2 (CRY2, a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin kinase (Rfk, an FAD biosynthetic enzyme, enhanced CRY degradation. RFK protein levels and FAD concentrations oscillate in the nucleus, suggesting that they are subject to circadian control. Knockdown of Rfk combined with a riboflavin-deficient diet altered the CRY levels in mouse liver and the expression profiles of clock and clock-controlled genes (especially those related to metabolism including glucose homeostasis. We conclude that light-independent mechanisms of FAD regulate CRY and contribute to proper circadian oscillation of metabolic genes in mammals.
Price, Luke L A
The effects lighting has on health through modulation of circadian rhythms are becoming increasingly well documented. Data are still needed to show how light exposures are influenced by architecture and lighting design and circadian dosimetry analyses should provide duration, phase and amplitude measures of 24 h exposure profiles. Exponential smoothing is used to derive suitable metrics from 24 h light measurements collected from private dwellings. A further application of these modified exposure time series as physiological models of the light drive is discussed. Unlike previous light drive models, the dose rate persists into periods of darkness following exposures. Comparisons to long duration exposure studies suggest this type of persistent light drive model could be incorporated into contemporary physiological models of the human circadian oscillator. © 2014 Crown copyright. Photochemistry and Photobiology © 2014 The American Society of Photobiology. This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland and Public Health England.
Enoki, Ryosuke; Kuroda, Shigeru; Ono, Daisuke; Hasan, Mazahir T; Ueda, Tetsuo; Honma, Sato; Honma, Ken-ichi
The circadian pacemaker in the hypothalamic suprachiasmatic nucleus (SCN) is a hierarchical multioscillator system in which neuronal networks play crucial roles in expressing coherent rhythms in physiology and behavior. However, our understanding of the neuronal network is still incomplete. Intracellular calcium mediates the input signals, such as phase-resetting stimuli, to the core molecular loop involving clock genes for circadian rhythm generation and the output signals from the loop to various cellular functions, including changes in neurotransmitter release. Using a unique large-scale calcium imaging method with genetically encoded calcium sensors, we visualized intracellular calcium from the entire surface of SCN slice in culture including the regions where autonomous clock gene expression was undetectable. We found circadian calcium rhythms at a single-cell level in the SCN, which were topologically specific with a larger amplitude and more delayed phase in the ventral region than the dorsal. The robustness of the rhythm was reduced but persisted even after blocking the neuronal firing with tetrodotoxin (TTX). Notably, TTX dissociated the circadian calcium rhythms between the dorsal and ventral SCN. In contrast, a blocker of gap junctions, carbenoxolone, had only a minor effect on the calcium rhythms at both the single-cell and network levels. These results reveal the topological specificity of the circadian calcium rhythm in the SCN and the presence of coupled regional pacemakers in the dorsal and ventral regions. Neuronal firings are not necessary for the persistence of the calcium rhythms but indispensable for the hierarchical organization of rhythmicity in the SCN.
Abraham, Ute; Schlichting, Julia Katharina; Kramer, Achim; Herzel, Hanspeter
Body temperature rhythms synchronize circadian oscillations in different tissues, depending on the degree of cellular coupling: the responsiveness to temperature is higher when single circadian oscillators are uncoupled. So far, the role of coupling in temperature responsiveness has only been studied in organotypic tissue slices of the central circadian pacemaker, because it has been assumed that peripheral target organs behave like uncoupled multicellular oscillators. Since recent studies indicate that some peripheral tissues may exhibit cellular coupling as well, we asked whether peripheral network dynamics also influence temperature responsiveness. Using a novel technique for long-term, high-resolution bioluminescence imaging of primary cultured cells, exposed to repeated temperature cycles, we were able to quantitatively measure period, phase, and amplitude of central (suprachiasmatic nuclei neuron dispersals) and peripheral (mouse ear fibroblasts) single cell oscillations in response to temperature. Employing temperature cycles of different lengths, and different cell densities, we found that some circadian characteristics appear cell-autonomous, e.g. period responses, while others seem to depend on the quality/degree of cellular communication, e.g. phase relationships, robustness of the oscillation, and amplitude. Overall, our findings indicate a strong dependence on the cell's ability for intercellular communication, which is not only true for neuronal pacemakers, but, importantly, also for cells in peripheral tissues. Hence, they stress the importance of comparative studies that evaluate the degree of coupling in a given tissue, before it may be used effectively as a target for meaningful circadian manipulation.
Bessa, Zoélia Camila Moura; Melo, Paula Rocha De; Gonçalves, Bruno S B; Azevedo, Carolina V M De
In marmosets, social synchrony between circadian profiles of activity is stronger in animals that cohabit in a family. The activity of three breeding pairs was recorded by actiwatches to investigate the mechanisms involved in the synchrony between the circadian activity profiles during cohabitation in marmoset reproductive pairs. The dyads were submitted to LD 12:12 (21 days) and LL: 1) cohabitation (24 days), 2) removal of the cage mate (20 days), 3) reintroduction of the mate into the cage of the 1 st situation (30 days) and 4) removal of the cage mate (7 days). Next, they were rejoined and maintained in LD 12:12 (11 days). In conditions involving cohabitation of pair, the general and maximum correlation indexes between circadian profiles were higher in cage mates compared to animals of the same or different sex with which they maintain only acoustic and olfactive contact. This strong synchrony between rhythms was accompanied by a stable phase relationship at the activity onset and offset, with identical circadian periods between mates. When the pairs were separated, there was a break in stability in the phase relationships between activity profiles with different circadian periods and a greater phase angle difference between rhythms of cage mates. During separation, two females and one male progressively anticipated the activity onset and offset in a phase similar to that in previous conditions, expressing entrainment to the mate. During the first reintroduction, two pairs exhibited signs of masking in rhythm. Although modulation in the rhythm of some animals has been observed through acoustic cues from animals outside the colony, we suggest that cohabitation favors strong synchrony between the circadian activity profiles of marmoset reproductive pairs involving synchronization by entrainment and masking. Further studies in the absence of external social cues are necessary to clarify the role of these mechanisms on social synchronization in marmosets.
Fernandez, Fabian; Nyhuis, Casandra C; Anand, Payal; Demara, Bianca I; Ruby, Norman F; Spanò, Goffredina; Clark, Caron; Edgin, Jamie O
To evaluate sleep consolidation and circadian activity rhythms in infants and toddlers with Down syndrome (DS) under light and socially entrained conditions within a familiar setting. Given previous human and animal data suggesting intact circadian regulation of melatonin across the day and night, it was hypothesized that behavioral indices of circadian rhythmicity would likewise be intact in the sample with DS. A cross-sectional study of 66 infants and young children with DS, aged 5-67 months, and 43 typically developing age-matched controls. Sleep and measures of circadian robustness or timing were quantified using continuous in-home actigraphy recordings performed over seven days. Circadian robustness was quantified via time series analysis of rest-activity patterns. Phase markers of circadian timing were calculated alongside these values. Sleep efficiency was also estimated based on the actigraphy recordings. This study provided further evidence that general sleep quality is poor in infants and toddlers with DS, a population that has sleep apnea prevalence as high as 50% during the preschool years. Despite poor sleep quality, circadian rhythm and phase were preserved in children with DS and displayed similar developmental trajectories in cross-sectional comparisons with a typically developing (TD) cohort. In line with past work, lower sleep efficiency scores were quantified in the group with DS relative to TD children. Infants born with DS exhibited the worst sleep fragmentation; however, in both groups, sleep efficiency and consolidation increased across age. Three circadian phase markers showed that 35% of the recruitment sample with DS was phase-advanced to an earlier morning schedule, suggesting significant within-group variability in the timing of their daily activity rhythms. Circadian rhythms of wake and sleep are robust in children born with DS. The present results suggest that sleep fragmentation and any resultant cognitive deficits are likely not
Ayres, Fabio J.; Rangayyan, Rangaraj M.
Objective One of the commonly missed signs of breast cancer is architectural distortion. We have developed techniques for the detection of architectural distortion in mammograms, based on the analysis of oriented texture through the application of Gabor filters and a linear phase portrait model. In this paper, we propose constraining the shape of the general phase portrait model as a means to reduce the false-positive rate in the detection of architectural distortion. Material and methods The methods were tested with one set of 19 cases of architectural distortion and 41 normal mammograms, and with another set of 37 cases of architectural distortion. Results Sensitivity rates of 84% with 4.5 false positives per image and 81% with 10 false positives per image were obtained for the two sets of images. Conclusion The adoption of a constrained phase portrait model with a symmetric matrix and the incorporation of its condition number in the analysis resulted in a reduction in the false-positive rate in the detection of architectural distortion. The proposed techniques, dedicated for the detection and localization of architectural distortion, should lead to efficient detection of early signs of breast cancer. (orig.)
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
National Aeronautics and Space Administration — Lynntech proposes a novel spacecraft position estimation method that leverages existing star trackers on board of a vehicle in an interplanetary trajectory for...
Nigel I Wood
Full Text Available The R6/2 transgenic mouse model of Huntington's disease (HD shows a disintegration of circadian rhythms that can be delayed by pharmacological and non-pharmacological means. Since the molecular machinery underlying the circadian clocks is intact, albeit progressively dysfunctional, we wondered if light phase shifts could modulate the deterioration in daily rhythms in R6/2 mice. Mice were subjected to four x 4 hour advances in light onset. R6/2 mice adapted to phase advances, although angles of entrainment increased with age. A second cohort was subjected to a jet-lag paradigm (6 hour delay or advance in light onset, then reversal after 2 weeks. R6/2 mice adapted to the original shift, but could not adjust accurately to the reversal. Interestingly, phase shifts ameliorated the circadian rhythm breakdown seen in R6/2 mice under normal LD conditions. Our previous finding that the circadian period (tau of 16 week old R6/2 mice shortens to approximately 23 hours may explain how they adapt to phase advances and maintain regular circadian rhythms. We tested this using a 23 hour period light/dark cycle. R6/2 mice entrained to this cycle, but onsets of activity continued to advance, and circadian rhythms still disintegrated. Therefore, the beneficial effects of phase-shifting are not due solely to the light cycle being closer to the tau of the mice. Our data show that R6/2 mice can adapt to changes in the LD schedule, even beyond the age when their circadian rhythms would normally disintegrate. Nevertheless, they show abnormal responses to changes in light cycles. These might be caused by a shortened tau, impaired photic re-synchronization, impaired light detection and/or reduced masking by evening light. If similar abnormalities are present in HD patients, they may suffer exaggerated jet-lag. Since the underlying molecular clock mechanism remains intact, light may be a useful treatment for circadian dysfunction in HD.
Thurley, Kevin; Herbst, Christopher; Wesener, Felix; Koller, Barbara; Wallach, Thomas; Maier, Bert; Kramer, Achim
Circadian rhythms govern multiple aspects of animal metabolism. Transcriptome-, proteome- and metabolome-wide measurements have revealed widespread circadian rhythms in metabolism governed by a cellular genetic oscillator, the circadian core clock. However, it remains unclear if and under which conditions transcriptional rhythms cause rhythms in particular metabolites and metabolic fluxes. Here, we analyzed the circadian orchestration of metabolic pathways by direct measurement of enzyme activities, analysis of transcriptome data, and developing a theoretical method called circadian response analysis. Contrary to a common assumption, we found that pronounced rhythms in metabolic pathways are often favored by separation rather than alignment in the times of peak activity of key enzymes. This property holds true for a set of metabolic pathway motifs (e.g., linear chains and branching points) and also under the conditions of fast kinetics typical for metabolic reactions. By circadian response analysis of pathway motifs, we determined exact timing separation constraints on rhythmic enzyme activities that allow for substantial rhythms in pathway flux and metabolite concentrations. Direct measurements of circadian enzyme activities in mouse skeletal muscle confirmed that such timing separation occurs in vivo. PMID:28159888
Nakao, Reiko; Yamamoto, Saori; Horikawa, Kazumasa; Yasumoto, Yuki; Nikawa, Takeshi; Mukai, Chiaki; Oishi, Katsutaka
The central circadian clock in the suprachiasmatic nucleus of the hypothalamus synchronizes peripheral clocks through neural and humoral signals in most mammalian tissues. Here, we analyzed the effects of unilateral sciatic denervation on the expression of circadian clock- and clock-controlled genes in the gastrocnemius muscles of mice twice per day on days 0, 3, 7, 9, 11 and 14 after denervation and six times on each of days 7 and 28 after denervation to assess the regulation mechanism of the circadian clock in skeletal muscle. Sciatic denervation did not affect systemic circadian rhythms since core body temperature (Day 7), corticosterone secretion (Days 7 and 28), and hepatic clock gene expression remained intact (Days 7 and 28). Expression levels of most circadian clock-related genes such as Arntl, Per1, Rora, Nr1d1 and Dbp were reduced in accordance with the extent of muscle atrophy, although circadian Per2 expression was significantly augmented (Day 28). Cosinor analysis revealed that the circadian expression of Arntl (Days 7 and 28) and Dbp (Day 28) was phase advanced in denervated muscle. The mRNA expression of Clock was significantly increased in denervated muscle on Day 3 when the severe atrophy was absent, and it was not affected by atrophic progression for 28 days. Sciatic denervation did not affect the expression of these genes in the contralateral muscle (Days 7 and 28), suggesting that humoral changes were not involved in denervation-induced muscle clock disruption. We then analyzed genome-wide gene expression using microarrays to determine the effects of disrupting the molecular clock in muscle on circadian rhythms at Day 7. Among 478 circadian genes, 313 lost rhythmicity in the denervated muscles. These denervation-sensitive genes included the lipid metabolism-related genes, Nrip1, Bbs1, Ptgis, Acot1, Scd2, Hpgd, Insig1, Dhcr24, Ldlr and Mboat1. Our findings revealed that sciatic denervation disrupts the circadian expression of clock and clock
Full Text Available Rhythms in female reproduction are critical to insure that timing of ovulation coincides with oocyte maturation and optimal sexual arousal. This fine tuning of female reproduction involves both the estradiol feedback as an indicator of oocyte maturation, and the master circadian clock of the suprachiasmatic nuclei as an indicator of the time of the day. Herein we are providing an overview of the state of knowledge regarding the differential inhibitory and stimulatory effects of estradiol at different stages of the reproductive axis, and the mechanisms through which the two main neurotransmitters of the suprachiasmatic nucleus, arginine vasopressin and vasoactive intestinal peptide, convey daily time cues to the reproductive axis. In addition we will report the most recent findings on the putative functions of peripheral clocks located throughout the reproductive axis (kisspeptin neurons, GnRH neurons, gonadotropic cells, the ovary and the uterus. This review will point to the critical position of the kisspeptin neurons of the anteroventral periventricular nucleus, which integrate both the stimulatory estradiol signal, and the daily arginine vasopressinergic signal, while displaying a circadian clock. Finally, given the critical role of the light/dark cycle in the synchronization of female reproduction, we will discuss the impact of circadian disruptions observed during shift work conditions on female reproductive performance and fertility in both animal model and humans.
Connolly, M.J.; Liekhus, K.J.
In the conditional no-migration determination (NMD) for the test phase of the Waste Isolation Pilot Plant (WIPP), the US Environmental Protection Agency (EPA) imposed certain conditions on the US Department of Energy (DOE) regarding gas phase volatile organic compound (VOC) concentrations in the void space of transuranic (TRU) waste containers. Specifically, the EPA required the DOE to ensure that each waste container has no layer of confinement that contains flammable mixtures of gases or mixtures of gases that could become flammable when mixed with air. The EPA also required that sampling of the headspace of waste containers outside inner layers of confinement be representative of the entire void space of the container. The EPA stated that all layers of confinement in a container would have to be sampled until DOE can demonstrate to the EPA that sampling of all layers is either unnecessary or can be safely reduced. A test program was conducted at the Idaho National Engineering and Environmental Laboratory (INEEL) to demonstrate that the gas phase VOC concentration in the void space of each layer of confinement in vented drums can be estimated from measured drum headspace using a theoretical transport model and that sampling of each layer of confinement is unnecessary. This report summarizes the studies performed in the INEEL test program and extends them for the purpose of developing a methodology for determining gas phase VOC concentrations in both vented and unvented TRU waste containers. The methodology specifies conditions under which waste drum headspace gases can be said to be representative of drum gases as a whole and describes a method for predicting drum concentrations in situations where the headspace concentration is not representative. The methodology addresses the approach for determining the drum VOC gas content for two purposes: operational period drum handling and operational period no-migration calculations
Lubinski, Alexander J; Page, Terry L
The cockroach, Leucophaea maderae, can be trained in an associative olfactory memory task by either classical or operant conditioning. When trained by classical conditioning, memory formation is regulated by a circadian clock, but once the memory is formed, it can be recalled at any circadian time. In contrast, when trained via operant conditioning, animals can learn the task at any circadian phase, but the ability to recall the long-term memory is tied to the phase of training. The optic lobes of the cockroach contain a circadian clock that drives circadian rhythms of locomotor activity, mating behavior, sensitivity of the compound eye to light, and the sensitivity of olfactory receptors in the antennae. To evaluate the role of the optic lobes in regulating learning and memory processes, the authors examined the effects of surgical ablation of the optic lobes on memory formation in classical conditioning and memory recall following operant conditioning. The effect of optic lobe ablation was to "rescue" the deficit in memory acquisition at a time the animals normally cannot learn and "rescue" the animal's ability to recall a memory formed by operant conditioning at a phase where memory was not normally expressed. The results suggested that the optic lobe pacemaker regulates these processes through inhibition at "inappropriate" times of day. As a pharmacological test of this hypothesis, the authors showed that injections of fipronil, an antagonist of GABA and glutamate-activated chloride channels, had the same effects as optic lobe ablation on memory formation and recall. The data suggest that the optic lobes contain the circadian clock(s) that regulate learning and memory processes via inhibition of neural processes in the brain. © 2015 The Author(s).
Rodriguez-Zas, Sandra L; Southey, Bruce R; Shemesh, Yair; Rubin, Elad B; Cohen, Mira; Robinson, Gene E; Bloch, Guy
Honey bee workers care for ("nurse") the brood around the clock without circadian rhythmicity, but then they forage outside with strong circadian rhythms and a consolidated nightly rest. This chronobiological plasticity is associated with variation in the expression of the canonical "clock genes" that regulate the circadian clock: nurse bees show no brain rhythms of expression, while foragers do. These results suggest that the circadian system is organized differently in nurses and foragers. Nurses switch to activity with circadian rhythms shortly after being removed from the hive, suggesting that at least some clock cells in their brain continue to measure time while in the hive. We performed a microarray genome-wide survey to determine general patterns of brain gene expression in nurses and foragers sampled around the clock. We found 160 and 541 transcripts that exhibited significant sinusoidal oscillations in nurses and foragers, respectively, with peaks of expression distributed throughout the day in both task groups. Consistent with earlier studies, transcripts of genes involved in circadian rhythms, including Clockwork Orange that has not been studied before in bees, oscillated in foragers but not in nurses. The oscillating transcripts also were enriched for genes involved in the visual system, "development" and "response to stimuli" (foragers), "muscle contraction" and "microfilament motor gene expression" (nurses), and "generation of precursor metabolites" and "energy" (both). Transcripts of genes encoding P450 enzymes oscillated in both nurses and foragers but with a different phase. This study identified new putative clock-controlled genes in the honey bee and suggests that some brain functions show circadian rhythmicity even in nurse bees that are active around the clock.
Rodriguez-Zas, Sandra L.; Southey, Bruce R.; Shemesh, Yair; Rubin, Elad B.; Cohen, Mira; Robinson, Gene E.; Bloch, Guy
Honey bee workers care for ("nurse") the brood around the clock without circadian rhythmicity, but then they forage outside with strong circadian rhythms and a consolidated nightly rest. This chronobiological plasticity is associated with variation in the expression of the canonical “clock genes” that regulate the circadian clock: nurse bees show no brain rhythms of expression, while foragers do. These results suggest that the circadian system is organized differently in nurses and foragers. Nurses switch to activity with circadian rhythms shortly after removed from the hive suggesting that at least some clock cells in their brain continue to measure time while in the hive. We performed a microarray genome-wide survey to determine general patterns of brain gene expression in nurses and foragers sampled around the clock. We found 160 and 541 transcripts that exhibited significant sinusoidal oscillations in nurses and foragers, respectively, with peaks of expression distributed throughout the day in both task groups. Consistent with earlier studies, transcripts of genes involved in circadian rhythms, including Clockwork Orange that has not been studied before in bees, oscillated in foragers but not in nurses. The oscillating transcripts also were enriched for genes involved in the visual system, “development” and “response to stimuli” (foragers), “muscle contraction” and “microfilament motor gene expression” (nurses), and “generation of precursor metabolites” and “energy” (both). Transcripts of genes encoding P450 enzymes oscillated in both nurses and foragers but with a different phase. This study identified new putative clock-controlled genes in the honey bee and suggests that some brain functions show circadian rhythmicity even in nurse bees that are active around the clock. PMID:22306970
Marston Oliver J
Full Text Available Temporal control of brain and behavioral states emerges as a consequence of the interaction between circadian and homeostatic neural circuits. This interaction permits the daily rhythm of sleep and wake, regulated in parallel by circadian cues originating from the suprachiasmatic nuclei (SCN and arousal-promoting signals arising from the orexin-containing neurons in the tuberal hypothalamus (TH. Intriguingly, the SCN circadian clock can be reset by arousal-promoting stimuli while activation of orexin/hypocretin neurons is believed to be under circadian control, suggesting the existence of a reciprocal relationship. Unfortunately, since orexin neurons are themselves activated by locomotor promoting cues, it is unclear how these two systems interact to regulate behavioral rhythms. Here mice were placed in conditions of constant light, which suppressed locomotor activity, but also revealed a highly pronounced circadian pattern in orexin neuronal activation. Significantly, activation of orexin neurons in the medial and lateral TH occurred prior to the onset of sustained wheel-running activity. Moreover, exposure to a 6 h dark pulse during the subjective day, a stimulus that promotes arousal and phase advances behavioral rhythms, activated neurons in the medial and lateral TH including those containing orexin. Concurrently, this stimulus suppressed SCN activity while activating cells in the median raphe. In contrast, dark pulse exposure during the subjective night did not reset SCN-controlled behavioral rhythms and caused a transient suppression of neuronal activation in the TH. Collectively these results demonstrate, for the first time, pronounced circadian control of orexin neuron activation and implicate recruitment of orexin cells in dark pulse resetting of the SCN circadian clock.
Pittendrigh, Colin S.; Daan, Serge
1. In the first part of the paper, the model of non-parametric entrainment of circadian pacemakers is tested for the case of nocturnal rodents. The model makes use of the available data on freerunning period (τ) in constant darkness and on phase response curves (PRC) for short light pulses. It is
van Someren, E.J.W.; Raymann, RJEM; Scherder, E.J.A.; Daanen, H.A.M.; Swaab, D.F.
At older ages, the circadian rhythm of body temperature shows a decreased amplitude, an advanced phase, and decreased stability. The present review evaluates to what extent these changes may result from age-related deficiencies at several levels of the thermoregulatory system, including
van Someren, Eus J. W.; Raymann, Roy J. E. M.; Scherder, Erik J. A.; Daanen, Hein A. M.; Swaab, Dick F.
At older ages, the circadian rhythm of body temperature shows a decreased amplitude, an advanced phase, and decreased stability. The present review evaluates to what extent these changes may result from age-related deficiencies at several levels of the thermoregulatory system, including
Refinetti, R; Susalka, S J
We recorded body temperature and locomotor activity of Tokay geckos (Gekko gecko) with free access to a heat source under a 14:10 light-dark cycle and in constant darkness. Under the light-dark cycle, the lizards selected higher temperatures during the light phase, when locomotor activity was less intense. Rhythmicity in temperature selection was transiently disrupted but later resumed when the animals were placed in constant darkness. These results demonstrate the existence of a circadian rhythm of temperature selection in nocturnal ectotherms and extend previous findings of a temporal mismatch between the rhythms of locomotor activity and temperature selection in nocturnal rodents.
Bartlett, Delwyn J; Biggs, Sarah N; Armstrong, Stuart M
Delayed sleep phase disorder (DSPD) - a circadian rhythm sleep disorder - is most commonly seen in adolescents. The differential diagnosis between DSPD and conventional psychophysiological insomnia is important for correct therapeutic intervention. Adolescent DSPD sleep duration is commonly 9 hours or more. Depression may be comorbid with DSPD. DSPD has a negative impact on adolescent academic performance. DSPD treatments include bright light therapy, chronotherapeutic regimens, and administration of melatonin as a chronobiotic (as distinct from a soporific). Attention to non-photic and extrinsic factors including healthy sleep parameters is also important to enable better sleep and mood outcomes in adolescents.
Chapman, D. K.; Brown, A. H.; Dahl, A. O.
Plant circadian rhythms of leaf movement in seedlings of the pepper plant (Capsicum annuum L., var. Yolo Wonder) were observed at different g-levels by means of a centrifuge. Except for the chronically imposed g-force all environmental conditions to which the plants were exposed were held constant. The circadian period, rate of change of amplitude of successive oscillations, symmetry of the cycles, and phase of the rhythm all were found not to be significantly correlated with the magnitude of the sustained g-force.
Le Glou, Eric; Seugnet, Laurent; Shaw, Paul J; Preat, Thomas; Goguel, Valérie
Several lines of evidence indicate that sleep plays a critical role in learning and memory. The aim of this study was to evaluate anesthesia resistant memory following sleep deprivation in Drosophila. Four to 16 h after aversive olfactory training, flies were sleep deprived for 4 h. Memory was assessed 24 h after training. Training, sleep deprivation, and memory tests were performed at different times during the day to evaluate the importance of the time of day for memory formation. The role of circadian rhythms was further evaluated using circadian clock mutants. Memory was disrupted when flies were exposed to 4 h of sleep deprivation during the consolidation phase. Interestingly, normal memory was observed following sleep deprivation when the memory test was performed during the 2 h preceding lights-off, a period characterized by maximum wake in flies. We also show that anesthesia resistant memory was less sensitive to sleep deprivation in flies with disrupted circadian rhythms. Our results indicate that anesthesia resistant memory, a consolidated memory less costly than long-term memory, is sensitive to sleep deprivation. In addition, we provide evidence that circadian factors influence memory vulnerability to sleep deprivation and memory retrieval. Taken together, the data show that memories weakened by sleep deprivation can be retrieved if the animals are tested at the optimal circadian time.
Casey J Guenthner
Full Text Available BACKGROUND: Hepatocytes, the parenchymal cells of the liver, express core clock genes, such as Period2 and Cryptochrome2, which are involved in the transcriptional/translational feedback loop of the circadian clock. Whether or not the liver is capable of sustaining rhythms independent of a central pacemaker is controversial. Whether and how circadian information may be shared among cells in the liver in order to sustain oscillations is currently unknown. RESULTS: In this study we isolated primary hepatocytes from transgenic Per2(Luc mice and used bioluminescence as a read-out of the state of the circadian clock. Hepatocytes cultured in a collagen gel sandwich configuration exhibited persistent circadian rhythms for several weeks. The amplitude of the rhythms damped, but medium changes consistently reset the phase and amplitude of the cultures. Cry2(-/- Per2(Luc cells oscillated robustly and expressed a longer period. Co-culturing with wildtype cells did not significantly shorten the period, indicating that coupling among hepatocytes is insufficient to synchronize cells with significantly differing periods. However, spatial patterns revealed by cellular imaging of wildtype cultures provided evidence of weak local coupling among the hepatocytes. CONCLUSIONS: Our results with primary hepatocyte cultures demonstrate that cultured hepatocytes are weakly coupled. While this coupling is not sufficient to sustain global synchrony, it does increase local synchrony, which may stabilize the circadian rhythms of peripheral oscillators, such as the liver, against noise in the entraining signals.
Tong Jian; Edmunds, L.N.
It has been known in recent years that living cells can exhibit circadian rhythms in totally different physiological processes. Intracellular messengers were demonstrated to mediate the entrained pathways linking rhythmic components between circadian clock and its output signalling. Levels of cyclic AMP and cyclic GMP in synchronized cells, and activities of the two key enzymes (AC and PDE) responsible for the cyclic AMP metabolism were measured by applying the isotopic techniques. Bimodal circadian oscillations of the messenger levels and the enzyme activities were disclosed in LD: 12, 12 cycle and constant darkness, as well as in the dividing and non-dividing cultures of the Euglena ZC mutant. Interference experiments with the enzyme activator and inhibitor such as forskolin, 8-Br-cGMP and LY 83583, and analysis of the cell division cycle (CDC) and coupling messengers suggested that the peak pulse of cyclic AMP, circadian oscillation of the AC-cAMP-PDE system and phase-dependent regulation by cyclic GMP might be important coupling factors in downstream mediation between the circadian clock and the CDC. (7 figs.)
Full Text Available Hypercholesterolemia is a well-known risk factor for a wide range of diseases in developed countries. Here, we report that mice lacking functional LDLR (low density lipoprotein receptor, an animal model of human familial hypercholesterolemia, show circadian abnormalities. In free running behavioral experiments in constant darkness, these mice showed a prolonged active phase and distinctly bimodal rhythms. Even when the circadian rhythms were entrained by light and dark cycles, these mice showed a significant attenuation of behavioral onset intensity at the start of the dark period. Further, we hypothesized that the combination of hypercholesterolemia and circadian abnormalities may affect cardiovascular disease progression. To examine this possibility, we generated LDLR-deficient mice with impaired circadian rhythms by simultaneously introducing a mutation into Period2, a core clock gene, and found that these mice showed a significant enlargement of artery plaque area with an increase in inflammatory cytokine IL-6 levels. These results suggest that circadian dysfunction may be associated with the development or progression of cardiovascular diseases.
Full Text Available The rotation of the earth on its axis creates the environment of a 24 h solar day, which organisms on earth have used to their evolutionary advantage by integrating this timing information into their genetic make-up in the form of a circadian clock. This intrinsic molecular clock is pivotal for maintenance of synchronized homeostasis between the individual organism and the external environment to allow coordinated rhythmic physiological and behavioral function. Aryl hydrocarbon receptor (AhR is a master regulator of dioxin-mediated toxic effects, and is, therefore, critical in maintaining adaptive responses through regulating the expression of phase I/II drug metabolism enzymes. AhR expression is robustly rhythmic, and physiological cross-talk between AhR signaling and circadian rhythms has been established. Increasing evidence raises a compelling argument that disruption of endogenous circadian rhythms contributes to the development of disease, including sleep disorders, metabolic disorders and cancers. Similarly, exposure to environmental pollutants through air, water and food, is increasingly cited as contributory to these same problems. Thus, a better understanding of interactions between AhR signaling and the circadian clock regulatory network can provide critical new insights into environmentally regulated disease processes. This review highlights recent advances in the understanding of the reciprocal interactions between dioxin-mediated AhR signaling and the circadian clock including how these pathways relate to health and disease, with emphasis on the control of metabolic function.
Full Text Available In conventional position sensorless permanent magnet (PM machine drives, the rotor position is obtained from the phase-locked loop (PLL with the regulation of spatial signal in estimated back electromotive force (EMF voltages. Due to the sinusoidal distribution of back-EMF voltages, a small-signal approximation is assumed in the PLL in order to estimate the position. That is, the estimated position is almost equal to the actual position per sample instant. However, at high speed when the ratio of sampling frequency, fsample, over the rotor operating frequency, fe, is low, this approximation might not be valid during the speed and load transient. To overcome this limitation, a position estimation is proposed specifically for the high-speed operation of a PM machine drive. A discrete-time EMF voltage estimator is developed to obtain the machine spatial signal. In addition, an arctangent calculation is cascaded to the PLL in order to remove this small-signal approximation for better sensorless drive performance. By using the discrete-time EMF estimation and modified PLL, the drive is able to maintain the speed closed-loop at 36 krpm with only 4.2 sampling points per electrical cycle on a PM machine, according to experimental results.
Matsumura, Ritsuko; Okamoto, Akihiko; Node, Koichi; Akashi, Makoto
The circadian clock is driven by transcriptional oscillation of clock genes in almost all body cells. To investigate the effect of cell type-specific intracellular environment on the circadian machinery, we examined gene expression profiles in five peripheral tissues. As expected, the phase relationship between expression rhythms of nine clock genes was similar in all tissues examined. We also compared relative expression levels of clock genes among tissues, and unexpectedly found that quantitative variation remained within an approximately three-fold range, which was substantially smaller than that of metabolic housekeeping genes. Interestingly, circadian gene expression was little affected even when fibroblasts were cultured with different concentrations of serum. Together, these findings support a hypothesis that expression levels of clock genes are quantitatively compensated for the intracellular environment, such as redox potential and metabolite composition. However, more comprehensive studies are required to reach definitive conclusions.
Ostrowska, Z.; Zwirska-Korczala, K.; Marek, B.; Buntner, B.
Circadian variations of serum melatonin and testosterone in sexually mature male Wistar rats after a one-week starvation were examined using, the radioimmunoassay RIA method at 2-h intervals under 12:12 h light-dark cycle. The population mean cosinor analysis justified the existence of a significant circadian rhythm of melatonin and testosterone in starved rats, whereas their mean 24-h concentration was lower. Both melatonin and testosterone circadian rhythms were disturbed with phase shifts from 1.58 to 16.59 h and from 18.00 to 3.49 h, respectively. A significant correlation between the melatonin and testosterone concentrations during day/night cycle was observed. (author). 38 refs, 4 figs, 1 tab
Boyko, Yuliya; Jennum, Poul; Toft, Palle
, medication, as well as the critical illness itself have been reported as important sleep disturbing factors. Secretion of sleep hormone, melatonin, expressing circadian rhythmicity was found abolished or phase delayed in critically ill patients. Various interventions have been tested in several studies...... aiming to improve sleep quality and circadian rhythm in the ICU. The results of these studies were inconclusive due to using the sleep assessment methods other than PSG or the absence of a reliable sleep scoring tool for the analysis of the PSG findings in this patient population. Development of a valid......Sleep and circadian rhythm are reported to be severely abnormal in critically ill patients. Disturbed sleep can lead to the development of delirium and, as a result, can be associated with prolonged stay in the intensive care unit (ICU) and increased mortality. The standard criterion method...
Merrow, M; Boesl, C; Ricken, J; Messerschmitt, M; Goedel, M; Roenneberg, T
Neurospora crassa has been systematically investigated for circadian entrainment behavior. Many aspects of synchronization can be investigated in this simple, cellular system, ranging from systematic entrainment and drivenness to masking. Clock gene expression during entrainment and entrainment
Two compounds that target components of the circadian clock killed several types of cancer cells in the lab and slowed the growth of brain cancer in mice without harming healthy cells, as this Cancer Currents post reports.
.... These 'biological clocks' are important to human physiology. For example, psychiatric and medical studies have shown that circadian rhythmicity is involved in some forms of depressive illness, 'jet lag', drug tolerance/efficacy, memory, and insomnia...
Mattis, Joanna; Sehgal, Amita
Sleep-wake cycles are known to be disrupted in people with neurodegenerative disorders. These findings are now supported by data from animal models for some of these disorders, raising the question of whether the disrupted sleep/circadian regulation contributes to the loss of neural function. As circadian rhythms and sleep consolidation also break down with normal aging, changes in these may be part of what makes aging a risk factor for disorders like Alzheimer's disease (AD). Mechanisms underlying the connection between circadian/sleep dysregulation and neurodegeneration remain unclear, but several recent studies provide interesting possibilities. While mechanistic analysis is under way, it is worth considering treatment of circadian/sleep disruption as a means to alleviate symptoms of neurodegenerative disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.
National Aeronautics and Space Administration — We developed and refined our current mathematical model of circadian rhythms to incorporate melatonin as a marker rhythm. We used an existing physiologically based...
Angelousi, Anna; Nasiri-Ansari, Narjes; Spilioti, Eliana; Mantzou, Emilia; Kalotyxou, Vasiliki; Chrousos, George; Kaltsas, Gregory; Kassi, Eva
Circadian timing system is a highly conserved, ubiquitous molecular "clock" which creates internal circadian rhythmicity. Dysregulation of clock genes expression is associated with various diseases including immune dysregulation. In this study we investigated the circadian pattern of Clock-related genes in patients with polyglandular autoimmune syndrome type III (PAS type III). Nineteen patients diagnosed with PAS type III and 12 healthy controls were enrolled. mRNA and protein expression of Clock-related genes (CLOCK, BMAL1, ROR and Per-1,-2,-3), as well as the GR-a and the GILZ genes were determined by real-time quantitative PCR and western blot analysis from blood samples drawn at 8 pm and 8am. Serum cortisol and TSH, as well as plasma ACTH, were measured by chemiluminescence. There were no statistical significant differences in the metabolic profile, cortisol, ACTH and TSH levels between patients and controls. Patients with PAS type III expressed higher transcript levels of CLOCK, BMAL1 and Per-1 in the evening than in the morning (p = 0.03, p = 0.029, p = 0.013, respectively), while the ratios (R pm/am ) of GR-a, CLOCK, BMAL1, and Per-3 mRNA levels were statistically different between patients and controls. Cortisol circadian variation (F pm/am ) was positively correlated with GILZ mRNA circadian pattern (R pm/am ) in the patient group and with the GR-a mRNA (R pm/am ) in the control group. Our findings suggest that there is an aberrant circadian rhythm of Clock-related genes in patients with PAS type III. The disruption of the expression of 4 circadian Clock-related genes could indicate a possible association with the pathogenesis of the disease.
Curie, Thomas; Mongrain, Valérie; Dorsaz, Stéphane; Mang, Géraldine M.; Emmenegger, Yann; Franken, Paul
Study Objectives: Besides their well-established role in circadian rhythms, our findings that the forebrain expression of the clock-genes Per2 and Dbp increases and decreases, respectively, in relation to time spent awake suggest they also play a role in the homeostatic aspect of sleep regulation. Here, we determined whether time of day modulates the effects of elevated sleep pressure on clock-gene expression. Time of day effects were assessed also for recognized electrophysiological (EEG delta power) and molecular (Homer1a) markers of sleep homeostasis. Design: EEG and qPCR data were obtained for baseline and recovery from 6-h sleep deprivation starting at ZT0, -6, -12, or -18. Setting: Mouse sleep laboratory. Participants: Male mice. Interventions: Sleep deprivation. Results: The sleep-deprivation induced changes in Per2 and Dbp expression importantly varied with time of day, such that Per2 could even decrease during sleep deprivations occurring at the decreasing phase in baseline. Dbp showed similar, albeit opposite dynamics. These unexpected results could be reliably predicted assuming that these transcripts behave according to a driven damped harmonic oscillator. As expected, the sleep-wake distribution accounted for a large degree of the changes in EEG delta power and Homer1a. Nevertheless, the sleep deprivation-induced increase in delta power varied also with time of day with higher than expected levels when recovery sleep started at dark onset. Conclusions: Per2 and delta power are widely used as exclusive state variables of the circadian and homeostatic process, respectively. Our findings demonstrate a considerable cross-talk between these two processes. As Per2 in the brain responds to both sleep loss and time of day, this molecule is well positioned to keep track of and to anticipate homeostatic sleep need. Citation: Curie T; Mongrain V; Dorsaz S; Mang GM; Emmenegger Y; Franken P. Homeostatic and circadian contribution to EEG and molecular state
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
Yamashita, Shuhei; Uehara, Tomoe; Matsuo, Minako; Kikuchi, Yo; Numano, Rika
The biochemical, physiological and behavioral processes are under the control of internal clocks with the period of approximately 24 hr, circadian rhythms. The expression of clock gene Period1 (Per1) oscillates autonomously in cells and is induced immediately after a light pulse. Per1 is an indispensable member of the central clock system to maintain the autonomous oscillator and synchronize environmental light cycle. Per1 expression could be detected by Per1∷luc and Per1∷GFP plasmid DNA in which firefly luciferase and Green Fluorescence Protein were rhythmically expressed under the control of the mouse Per1 promoter in order to monitor mammalian circadian rhythms. Membrane protein, MELANOPSIN is activated by blue light in the morning on the retina and lead to signals transduction to induce Per1 expression and to reset the phase of circadian rhythms. In this report Per1 induction was measured by reporter signal assay in Per1∷luc and Per1∷GFP fibroblast cell at the input process of circadian rhythms. To the result all process to reset the rhythms by Melanopsin is completed in single cell like in the retina projected to the central clock in the brain. Moreover, the phase of circadian rhythm in Per1∷luc cells is synchronized by photo-activated Melanopsin, because the definite peak of luciferase activity in one dish was found one day after light illumination. That is an available means that physiological circadian rhythms could be real-time monitor as calculable reporter (bioluminescent and fluorescent) chronological signal in both single and groups of cells.
Full Text Available Economic experiments reveal that humans value cooperation and fairness. Punishing unfair behavior is therefore common, and according to the theory of strong reciprocity, it is also directly related to rewarding cooperative behavior. However, empirical data fail to confirm that positive and negative reciprocity are correlated. Inspired by this disagreement, we determine whether the combined application of reward and punishment is evolutionarily advantageous. We study a spatial public goods game, where in addition to the three elementary strategies of defection, rewarding, and punishment, a fourth strategy that combines the latter two competes for space. We find rich dynamical behavior that gives rise to intricate phase diagrams where continuous and discontinuous phase transitions occur in succession. Indirect territorial competition, spontaneous emergence of cyclic dominance, as well as divergent fluctuations of oscillations that terminate in an absorbing phase are observed. Yet, despite the high complexity of solutions, the combined strategy can survive only in very narrow and unrealistic parameter regions. Elementary strategies, either in pure or mixed phases, are much more common and likely to prevail. Our results highlight the importance of patterns and structure in human cooperation, which should be considered in future experiments.
Full Text Available In neuronal population signals, including the electroencephalogram (EEG and electrocorticogram (ECoG, the low-frequency component (LFC is particularly informative about motor behavior and can be used for decoding movement parameters for brain-machine interface (BMI applications. An idea previously expressed, but as of yet not quantitatively tested, is that it is the LFC phase that is the main source of decodable information. To test this issue, we analyzed human ECoG recorded during a game-like, one-dimensional, continuous motor task with a novel decoding method suitable for unfolding magnitude and phase explicitly into a complex-valued, time-frequency signal representation, enabling quantification of the decodable information within the temporal, spatial and frequency domains and allowing disambiguation of the phase contribution from that of the spectral magnitude. The decoding accuracy based only on phase information was substantially (at least 2 fold and significantly higher than that based only on magnitudes for position, velocity and acceleration. The frequency profile of movement-related information in the ECoG data matched well with the frequency profile expected when assuming a close time-domain correlate of movement velocity in the ECoG, e.g., a (noisy copy of hand velocity. No such match was observed with the frequency profiles expected when assuming a copy of either hand position or acceleration. There was also no indication of additional magnitude-based mechanisms encoding movement information in the LFC range. Thus, our study contributes to elucidating the nature of the informative low-frequency component of motor cortical population activity and may hence contribute to improve decoding strategies and BMI performance.
Reijmers, L.G.J.E.; Leus, I.E.; Burbach, J.P.H.; Spruijt, B.M.; Ree, van J.M.
Disruption of circadian rhythm can impair long-term passive avoidance memory of rats and mice. The present study investigated whether disruption of circadian rhythm can also impair social memory of male rats. Social memory was assessed using the social discrimination test, in which a short-term
Brainard, Jason; Gobel, Merit; Bartels, Karsten; Scott, Benjamin; Koeppen, Michael; Eckle, Tobias
The rotation of the earth and associated alternating cycles of light and dark--the basis of our circadian rhythms--are fundamental to human biology and culture. However, it was not until 1971 that researchers first began to describe the molecular mechanisms for the circadian system. During the past few years, groundbreaking research has revealed a multitude of circadian genes affecting a variety of clinical diseases, including diabetes, obesity, sepsis, cardiac ischemia, and sudden cardiac death. Anesthesiologists, in the operating room and intensive care units, manage these diseases on a daily basis as they significantly affect patient outcomes. Intriguingly, sedatives, anesthetics, and the intensive care unit environment have all been shown to disrupt the circadian system in patients. In the current review, we will discuss how newly acquired knowledge of circadian rhythms could lead to changes in clinical practice and new therapeutic concepts. © The Author(s) 2014.
Voogel, A. J.; Stok, W. J.; Pretorius, P. J.; van Montfrans, G. A.; Langewouters, G. J.; Karemaker, J. M.
Head-down tilted bedrest is a ground-based microgravity simulation model. Since in this position the influence of chief external determinants of circadian blood pressure variation, i.e. activity and posture, are reduced, it may reveal endogenous oscillatory factors. The effects of 42 days of 6
Keith, Dove; Finlay, Liam; Butler, Judy; Gómez, Luis; Smith, Eric; Moreau, Régis; Hagen, Tory
Highlights: • 24 month old rats were supplemented with 0.2% lipoic acid in the diet for 2 weeks. • Lipoic acid shifts phase of core circadian clock proteins. • Lipoic acid corrects age-induced desynchronized lipid metabolism rhythms. - Abstract: It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) β without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks
Keith, Dove; Finlay, Liam; Butler, Judy [Linus Pauling Institute, Oregon State University (United States); Gómez, Luis; Smith, Eric [Linus Pauling Institute, Oregon State University (United States); Biochemistry Biophysics Department, Oregon State University (United States); Moreau, Régis [Linus Pauling Institute, Oregon State University (United States); Hagen, Tory, E-mail: Tory.Hagen@oregonstate.edu [Linus Pauling Institute, Oregon State University (United States); Biochemistry Biophysics Department, Oregon State University (United States)
Highlights: • 24 month old rats were supplemented with 0.2% lipoic acid in the diet for 2 weeks. • Lipoic acid shifts phase of core circadian clock proteins. • Lipoic acid corrects age-induced desynchronized lipid metabolism rhythms. - Abstract: It is well established that lipid metabolism is controlled, in part, by circadian clocks. However, circadian clocks lose temporal precision with age and correlates with elevated incidence in dyslipidemia and metabolic syndrome in older adults. Because our lab has shown that lipoic acid (LA) improves lipid homeostasis in aged animals, we hypothesized that LA affects the circadian clock to achieve these results. We fed 24 month old male F344 rats a diet supplemented with 0.2% (w/w) LA for 2 weeks prior to sacrifice and quantified hepatic circadian clock protein levels and clock-controlled lipid metabolic enzymes. LA treatment caused a significant phase-shift in the expression patterns of the circadian clock proteins Period (Per) 2, Brain and Muscle Arnt-Like1 (BMAL1), and Reverse Erythroblastosis virus (Rev-erb) β without altering the amplitude of protein levels during the light phase of the day. LA also significantly altered the oscillatory patterns of clock-controlled proteins associated with lipid metabolism. The level of peroxisome proliferator-activated receptor (PPAR) α was significantly increased and acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) were both significantly reduced, suggesting that the LA-supplemented aged animals are in a catabolic state. We conclude that LA remediates some of the dyslipidemic processes associated with advanced age, and this mechanism may be at least partially through entrainment of circadian clocks.
Wyatt, J. K.; Ritz-De Cecco, A.; Czeisler, C. A.; Dijk, D. J.
The interaction of homeostatic and circadian processes in the regulation of waking neurobehavioral functions and sleep was studied in six healthy young subjects. Subjects were scheduled to 15-24 repetitions of a 20-h rest/activity cycle, resulting in desynchrony between the sleep-wake cycle and the circadian rhythms of body temperature and melatonin. 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. These measures exhibited their circadian nadir at or shortly after the temperature minimum, which in turn was shortly after the melatonin maximum. Neurobehavioral measures showed impairment toward the end of the 13-h 20-min scheduled wake episodes. This wake-dependent deterioration of neurobehavioral functions can be offset by the circadian drive for wakefulness, which peaks in the latter half of the habitual waking day during entrainment. The data demonstrate the exquisite sensitivity of many neurobehavioral functions to circadian phase and the accumulation of homeostatic drive for sleep.
Monk, T. H.; Buysse, D. J.; Reynolds, C. F. 3rd; Berga, S. L.; Jarrett, D. B.; Begley, A. E.; Kupfer, D. J.
This study explored the relationship between circadian performance rhythms and rhythms in rectal temperature, plasma cortisol, plasma melatonin, subjective alertness and well-being. Seventeen healthy young adults were studied under 36 h of 'unmasking' conditions (constant wakeful bedrest, temporal isolation, homogenized 'meals') during which rectal temperatures were measured every minute, and plasma cortisol and plasma melatonin measured every 20 min. Hourly subjective ratings of global vigour (alertness) and affect (well-being) were obtained followed by one of two performance batteries. On odd-numbered hours performance (speed and accuracy) of serial search, verbal reasoning and manual dexterity tasks was assessed. On even-numbered hours, performance (% hits, response speed) was measured at a 25-30 min visual vigilance task. Performance of all tasks (except search accuracy) showed a significant time of day variation usually with a nocturnal trough close to the trough in rectal temperature. Performance rhythms appeared not to reliably differ with working memory load. Within subjects, predominantly positive correlations emerged between good performance and higher temperatures and better subjective alertness; predominantly negative correlations between good performance and higher plasma levels of cortisol and melatonin. Temperature and cortisol rhythms correlated with slightly more performance measures (5/7) than did melatonin rhythms (4/7). Global vigour correlated about as well with performance (5/7) as did temperature, and considerably better than global affect (1/7). In conclusion: (1) between-task heterogeneity in circadian performance rhythms appeared to be absent when the sleep/wake cycle was suspended; (2) temperature (positively), cortisol and melatonin (negatively) appeared equally good as circadian correlates of performance, and (3) subjective alertness correlated with performance rhythms as well as (but not better than) body temperature, suggesting that
Full Text Available 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 peripheral tissues. However, it is still difficult to investigate the molecular oscillator in primary culture cells. Results In this study, we used a novel Tol2 transposon based Dbp promoter or Bmal1 promoter driven luciferase reporter vector system to detect and analyze the intrinsic molecular oscillator in primary culture cells (mouse embryonic fibroblasts, fetal bovine heart endothelial cells and rat astrocytes. The results showed circadian molecular oscillations in all examined primary culture cells. Moreover, the phase relationship between Dbp promoter driven and Bmal1 promoter driven molecular rhythms were almost anti-phase, which suggested that these reporters appropriately read-out the intrinsic cellular circadian clock. Conclusions Our results indicate that gene transfer strategy using the Tol2 transposon system of a useful and safe non-viral vector is a powerful tool for investigating circadian rhythms in peripheral tissues.
Fábio Rizental Coutinho
Full Text Available Ultrasonic measurement techniques for velocity estimation are currently widely used in fluid flow studies and applications. An accurate determination of interfacial position in gas-liquid two-phase flows is still an open problem. The quality of this information directly reflects on the accuracy of void fraction measurement, and it provides a means of discriminating velocity information of both phases. The algorithm known as Velocity Matched Spectrum (VM Spectrum is a velocity estimator that stands out from other methods by returning a spectrum of velocities for each interrogated volume sample. Interface detection of free-rising bubbles in quiescent liquid presents some difficulties for interface detection due to abrupt changes in interface inclination. In this work a method based on velocity spectrum curve shape is used to generate a spatial-temporal mapping, which, after spatial filtering, yields an accurate contour of the air-water interface. It is shown that the proposed technique yields a RMS error between 1.71 and 3.39 and a probability of detection failure and false detection between 0.89% and 11.9% in determining the spatial-temporal gas-liquid interface position in the flow of free rising bubbles in stagnant liquid. This result is valid for both free path and with transducer emitting through a metallic plate or a Plexiglas pipe.
Coutinho, Fábio Rizental; Ofuchi, César Yutaka; de Arruda, Lúcia Valéria Ramos; Neves, Flávio; Morales, Rigoberto E M
Ultrasonic measurement techniques for velocity estimation are currently widely used in fluid flow studies and applications. An accurate determination of interfacial position in gas-liquid two-phase flows is still an open problem. The quality of this information directly reflects on the accuracy of void fraction measurement, and it provides a means of discriminating velocity information of both phases. The algorithm known as Velocity Matched Spectrum (VM Spectrum) is a velocity estimator that stands out from other methods by returning a spectrum of velocities for each interrogated volume sample. Interface detection of free-rising bubbles in quiescent liquid presents some difficulties for interface detection due to abrupt changes in interface inclination. In this work a method based on velocity spectrum curve shape is used to generate a spatial-temporal mapping, which, after spatial filtering, yields an accurate contour of the air-water interface. It is shown that the proposed technique yields a RMS error between 1.71 and 3.39 and a probability of detection failure and false detection between 0.89% and 11.9% in determining the spatial-temporal gas-liquid interface position in the flow of free rising bubbles in stagnant liquid. This result is valid for both free path and with transducer emitting through a metallic plate or a Plexiglas pipe.
Oishi, Katsutaka; Uchida, Daisuke; Ohkura, Naoki; Doi, Ryosuke; Ishida, Norio; Kadota, Koji; Horie, Shuichi
Metabolic disorders such as diabetes and obesity are considered risk factors for cardiovascular diseases by increasing levels of blood plasminogen activator inhibitor-1 (PAI-1). Ketogenic diets (KDs) have been used as an approach to weight loss in both obese and nonobese individuals. We examined circadian changes in plasma PAI-1 and its mRNA expression levels in tissues from mice fed with a KD (KD mice), to evaluate its effects on fibrinolytic functions. Two weeks on the kDa increased plasma levels of free fatty acids and ketones accompanied by hypoglycemia in mice. Plasma PAI-1 concentrations were extremely elevated in accordance with mRNA expression levels in the heart and liver, but not in the kidneys of KD mice. Circadian expression of PAI-1 mRNA was phase-advanced for 4.7, 7.9, and 7.8 hours in the heart, kidney, and adipose tissues, respectively, as well as that of circadian genes mPer2 and DBP in KD mice, suggesting that peripheral clocks were phase-advanced by ketosis despite feeding ad libitum under a periodic light-dark cycle. The circadian clock that regulates behavioral activity rhythms was also phase-advanced, and its free-running period was significantly shortened in KD mice. Our findings suggest that ketogenic status increases hypofibrinolytic risk by inducing abnormal circadian expression of PAI-1.
Trenkwalder, C; Hening, W A; Walters, A S; Campbell, S S; Rahman, K; Chokroverty, S
The symptoms of restless legs syndrome (RLS) worsen while patients are sitting or lying and also worsen at night. The current study was designed to determine if the periodic limb movements (PLMs) and sensory symptoms of RLS are modulated by an independent circadian factor. We recorded sleeping and waking PLMs and waking sensory symptoms in eight volunteers with RLS for 3 successive nights and days, starting with a polysomnographic recording of 2 nights, followed by a third night of sleep deprivation and the day after sleep deprivation. This study showed that both the PLMs and sensory symptoms were worst at night with a maximum for both between midnight and 1:00 AM and a minimum between 9:00 and 11:00 AM. Sleep and drowsiness had a tendency to worsen PLMs and sensory symptoms after the night of sleep deprivation. Circadian temperature curves were normal in all four patients with adequate data collection. The highest PLM counts occurred on the falling phase of the circadian temperature curve whereas the lowest PLM counts occurred on the rising phase of the curve. We conclude that the PLM and sensory symptoms in RLS are influenced by a circadian rhythm, and that the "worsening at night" criterion of the RLS Definition Criteria is, at least in part, distinct from the "worsening while lying or sitting" criterion.
Noguchi, Takako; Leise, Tanya L; Kingsbury, Nathaniel J; Diemer, Tanja; Wang, Lexie L; Henson, Michael A; Welsh, David K
Circadian rhythms of mammalian physiology and behavior are coordinated by the suprachiasmatic nucleus (SCN) in the hypothalamus. Within SCN neurons, various aspects of cell physiology exhibit circadian oscillations, including circadian clock gene expression, levels of intracellular Ca 2+ ([Ca 2+ ] i ), and neuronal firing rate. [Ca 2+ ] i oscillates in SCN neurons even in the absence of neuronal firing. To determine the causal relationship between circadian clock gene expression and [Ca 2+ ] i rhythms in the SCN, as well as the SCN neuronal network dependence of [Ca 2+ ] i rhythms, we introduced GCaMP3, a genetically encoded fluorescent Ca 2+ indicator, into SCN neurons from PER2::LUC knock-in reporter mice. Then, PER2 and [Ca 2+ ] i were imaged in SCN dispersed and organotypic slice cultures. In dispersed cells, PER2 and [Ca 2+ ] i both exhibited cell autonomous circadian rhythms, but [Ca 2+ ] i rhythms were typically weaker than PER2 rhythms. This result matches the predictions of a detailed mathematical model in which clock gene rhythms drive [Ca 2+ ] i rhythms. As predicted by the model, PER2 and [Ca 2+ ] i rhythms were both stronger in SCN slices than in dispersed cells and were weakened by blocking neuronal firing in slices but not in dispersed cells. The phase relationship between [Ca 2+ ] i and PER2 rhythms was more variable in cells within slices than in dispersed cells. Both PER2 and [Ca 2+ ] i rhythms were abolished in SCN cells deficient in the essential clock gene Bmal1 . These results suggest that the circadian rhythm of [Ca 2+ ] i in SCN neurons is cell autonomous and dependent on clock gene rhythms, but reinforced and modulated by a synchronized SCN neuronal network.
Dimitri eDe Bundel
Full Text Available The circadian clock comprises a set of genes involved in cell-autonomous transcriptional feedback loops that orchestrate the expression of a range of downstream genes, driving circadian patterns of behavior. Cognitive dysfunction, mood disorders, anxiety disorders and substance abuse disorders have been associated with disruptions in circadian rhythm and circadian clock genes, but the causal relationship of these associations is still poorly understood. In the present study, we investigate the effect of genetic disruption of the circadian clock, through deletion of both paralogs of the core gene cryptochrome (Cry1 and Cry2. Mice lacking Cry1 and Cry2 (Cry1-/-Cry2-/- displayed attenuated dark phase and novelty-induced locomotor activity. Moreover, they showed impaired recognition memory but intact fear memory. Depression-related behaviors in the forced swim test or sucrose preference tests were unaffected but Cry1-/-Cry2-/- mice displayed increased anxiety in the open field and elevated plus maze tests. Finally, hyperlocomotion and striatal phosphorylation of extracellular signal-regulated kinase (ERK induced by a single cocaine administration are strongly reduced in Cry1-/-Cry2-/- mice. Interestingly, only some behavioral measures were affected in mice lacking either Cry1 or Cry2. Notably, recognition memory was impaired in both Cry1-/-Cry2+/+ and Cry1+/+Cry2-/- mice. Moreover, we further observed elevated anxiety in Cry1-/-Cry2+/+ and Cry1+/+Cry2-/- mice. Our data indicate that beyond their role in the control of circadian rhythm, cryptochrome genes have a direct influence in cognitive function, anxiety-related behaviors and sensitivity to psychostimulant drugs.
Meyer-Kovac, Judit; Kolbe, Isa; Ehrhardt, Lea; Leliavski, Alexei; Husse, Jana; Salinas, Gabriela; Lingner, Thomas; Tsang, Anthony H; Barclay, Johanna L; Oster, Henrik
Circadian Clock gene mutant mice show dampened 24-h feeding rhythms and an increased sensitivity to high-fat diet (HFD) feeding. Restricting HFD access to the dark phase counteracts its obesogenic effect in wild-type mice. The extent to which altered feeding rhythms are causative for the obesogenic phenotype of Clock mutant mice, however, remains unknown. Metabolic parameters of wild-type (WT) and Clock Δ19 mutant mice (MT) were investigated under ad libitum and nighttime restricted HFD feeding. Liver circadian clock function was partially rescued by hydrodynamic tail vein delivery of WT- Clock DNA vectors in mutant mice and transcriptional, metabolic, endocrine and behavioral rhythms studied. Nighttime-restricted feeding restored food intake, but not body weight regulation in MT mice under HFD, suggesting Clock -dependent metabolic dysregulation downstream of circadian appetite control. Liver-directed Clock gene therapy partially restored liver circadian oscillator function and transcriptome regulation without affecting centrally controlled circadian behaviors. Under HFD, MT mice with partially restored liver clock function (MT-LR) showed normalized body weight gain, rescued 24-h food intake rhythms, and WT-like energy expenditure. This was associated with decreased nighttime leptin and daytime ghrelin levels, reduced hepatic lipid accumulation, and improved glucose tolerance. Transcriptome analysis revealed that hepatic Clock rescue in MT mice affected a range of metabolic pathways. Liver Clock gene therapy improves resistance against HFD-induced metabolic impairments in mice with circadian clock disruption. Restoring or stabilizing liver clock function might be a promising target for therapeutic interventions in obesity and metabolic disorders.
Full Text Available Several aspects of behavior and physiology, such as sleep and wakefulness, blood pressure, body temperature, and hormone secretion exhibit daily oscillations known as circadian rhythms. These circadian rhythms are orchestrated by an intrinsic biological clock in the suprachiasmatic nuclei (SCN of the hypothalamus which is adjusted to the daily environmental cycles of day and night by the process of photoentrainment. In mammals, the neuronal signal for photoentrainment arises from a small subset of intrinsically photosensitive retinal ganglion cells (ipRGCs that send a direct projection to the SCN. ipRGCs also mediate other non-image-forming (NIF visual responses such as negative masking of locomotor activity by light, and the pupillary light reflex (PLR via co-release of neurotransmitters glutamate and pituitary adenylate cyclase-activating peptide (PACAP from their synaptic terminals. The relative contribution of each neurotransmitter system for the circadian photoentrainment and other NIF visual responses is still unresolved. We investigated the role of glutamatergic neurotransmission for circadian photoentrainment and NIF behaviors by selective ablation of ipRGC glutamatergic synaptic transmission in mice. Mutant mice displayed delayed re-entrainment to a 6 h phase shift (advance or delay in the light cycle and incomplete photoentrainment in a symmetrical skeleton photoperiod regimen (1 h light pulses between 11 h dark periods. Circadian rhythmicity in constant darkness also was reduced in some mutant mice. Other NIF responses such as the PLR and negative masking responses to light were also partially attenuated. Overall, these results suggest that glutamate from ipRGCs drives circadian photoentrainment and negative masking responses to light.
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
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
Liu, Y.; Li, S.-M.; Liggio, J.
The mixed-phase relative rates approach for determining aerosol particle organic heterogeneous reaction kinetics is often performed utilizing mass spectral tracers as a proxy for particle-phase reactant concentration. However, this approach may be influenced by signal contamination from oxidation products during the experiment. In the current study, the mixed-phase relative rates technique has been improved by combining a positive matrix factor (PMF) analysis with electron ionization aerosol mass spectrometry (unit-mass resolution), thereby removing the influence of m / z fragments from reaction products on the reactant signals. To demonstrate the advantages of this approach, the heterogeneous reaction between OH radicals and citric acid (CA) was investigated using a photochemical flow tube coupled to a compact time-of-flight aerosol mass spectrometer (C-ToF-AMS). The measured heterogeneous rate constant (k2) of citric acid toward OH was (3.31 ± 0.29) × 10-12 cm3 molecule-1 s-1 at 298 K and (30 ± 3)% relative humidity (RH) and was several times greater than the results utilizing individual m / z fragments. This phenomenon was further evaluated for particulate-phase organophosphates (triphenyl phosphate (TPhP), tris-1,3-dichloro-2-propyl phosphate (TDCPP) and tris-2-ethylhexyl phosphate (TEHP)), leading to k2 values significantly larger than previously reported. The results suggest that heterogeneous kinetics can be significantly underestimated when the structure of the products is highly similar to the reactant and when a non-molecular tracer is measured with a unit-mass resolution aerosol mass spectrometer. The results also suggest that the heterogeneous lifetime of organic aerosol in models can be overestimated due to underestimated OH uptake coefficients. Finally, a comparison of reported rate constants implies that the heterogeneous oxidation of aerosols will be dependent upon a number of factors related to the reaction system, and that a single rate
Liu, Y.; Li, S.-M.; Liggio, J.
The mixed-phase relative rate approach for determining aerosol particle organic component heterogeneous reaction kinetics and OH uptake coefficients to particles is often performed utilizing mass spectral tracers as a proxy for particle phase reactant concentration. However, this approach may be influenced by signal contaminations from oxidation products during the experiment. In the current study, the mixed-phase relative rates technique has been improved by combining a Positive Matrix Factor (PMF) analysis with electron ionization Aerosol Mass Spectrometry, thereby removing the influence of m / z fragments from reaction products on the reactant signals. To demonstrate the advantages of this approach, the heterogeneous reaction between OH radicals and citric acid (CA) was investigated using a photochemical flow tube coupled to a compact time-of-flight aerosol mass spectrometer (C-ToF-AMS). The measured heterogeneous rate constant (k2) of citric acid toward OH was (3.31 ± 0.29) × 10-12 cm3 molecule-1 s-1 at 298 K and (30 ± 3)% RH and was ∼7.7 times greater than previously reported results utilizing individual m / z fragments. This phenomenon was further confirmed for particulate-phase organophosphates (TPhP, TDCPP, and TEHP), leading to k2 values significantly larger than previously reported. The results suggest that heterogeneous kinetics can be significantly underestimated when a non-molecular ion peak is used as the tracer. Finally, the results suggest that the heterogeneous lifetime of organic aerosol in models can be overestimated due to underestimated OH uptake coefficients, and that it may be necessary to revisit the heterogeneous kinetic data of organic aerosol components which were derived in the context of the relative rates technique.
Most aspects of mammalian function display circadian rhythms driven by an endogenous clock. The circadian clock is operated by genes and comprises a central clock in the brain that responds to environmental cues and controls subordinate clocks in peripheral tissues via circadian output pathways. The...
Spoelstra, K.; Wikelski, Martin; Daan, Serge; Loudon, Andrew; Hau, Michaela
Circadian rhythms with an endogenous period close or equal to the natural light-dark cycle are considered evolutionarily adaptive (‘circadian resonance hypothesis’). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under natural
Spoelstra, Kamiel; Wikelski, Martin; Daan, Serge; Loudon, Andrew S I; Hau, Michaela
Circadian rhythms with an endogenous period close to or equal to the natural light-dark cycle are considered evolutionarily adaptive ("circadian resonance hypothesis"). Despite remarkable insight into the molecular mechanisms driving circadian cycles, this hypothesis has not been tested under
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.
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
Full Text Available The fan activity rhythm of Sabella spallanzanii (Gmelin, 1791 and its entrainment capability to light were studied. Animals were tested under constant darkness (DD followed by two consecutive 24 h light-darkness regimes: a first 11 h light period (LD and a second 9 h light period, with its phase inverted (DL. An infrared analogical video-camera took shots each 30 s. A number of pictures with open fan were counted every 15 min. In DD a weak free-running periodicity in the circadian range was found, thus reinforcing the matching of the 24 h period under study in both photoperiod regimes. A nocturnal activity was characterised with a consistent anticipation to lightOFF (i.e. entrainment. Moreover, this phase of entrainment differed between DL and LD. The presence of endogenous activity rhythm with a variable phase angle of entrainment is a distinctive feature of circadian pacemakers.
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.
Scheer, Frank A J L; Shea, Thomas J; Hilton, Michael F; Shea, Steven A
Sleep inertia is the impaired cognitive performance immediately upon awakening, which decays over tens of minutes. This phenomenon has relevance to people who need to make important decisions soon after awakening, such as on-call emergency workers. Such awakenings can occur at varied times of day or night, so the objective of the study was to determine whether or not the magnitude of sleep inertia varies according to the phase of the endogenous circadian cycle. Twelve adults (mean, 24 years; 7 men) with no medical disorders other than mild asthma were studied. Following 2 baseline days and nights, subjects underwent a forced desynchrony protocol composed of seven 28-h sleep/wake cycles, while maintaining a sleep/wakefulness ratio of 1:2 throughout. Subjects were awakened by a standardized auditory stimulus 3 times each sleep period for sleep inertia assessments. The magnitude of sleep inertia was quantified as the change in cognitive performance (number of correct additions in a 2-min serial addition test) across the first 20 min of wakefulness. Circadian phase was estimated from core body temperature (fitted temperature minimum assigned 0 degrees ). Data were segregated according to: (1) circadian phase (60 degrees bins); (2) sleep stage; and (3) 3rd of the night after which awakenings occurred (i.e., tertiary 1, 2, or 3). To control for any effect of sleep stage, the circadian rhythm of sleep inertia was initially assessed following awakenings from Stage 2 (62% of awakening occurred from this stage; n = 110). This revealed a significant circadian rhythm in the sleep inertia of cognitive performance (p = 0.007), which was 3.6 times larger during the biological night (circadian bin 300 degrees , approximately 2300-0300 h in these subjects) than during the biological day (bin 180 degrees , approximately 1500-1900 h). The circadian rhythm in sleep inertia was still present when awakenings from all sleep stages were included (p = 0.004), and this rhythm could not be
Ho Mien, Ivan; Chua, Eric Chern-Pin; Lau, Pauline; Tan, Luuan-Chin; Lee, Ivan Tian-Guang; Yeo, Sing-Chen; Tan, Sara Shuhui; Gooley, Joshua J
Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21-28 yr) lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm(-2) s(-1)), intermittent red light (1 min on/off), or bright white light (2,500 lux) near the onset of nocturnal melatonin secretion (n = 8 in each group). Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69), with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light.
Ivan Ho Mien
Full Text Available Exposure to light is a major determinant of sleep timing and hormonal rhythms. The role of retinal cones in regulating circadian physiology remains unclear, however, as most studies have used light exposures that also activate the photopigment melanopsin. Here, we tested the hypothesis that exposure to alternating red light and darkness can enhance circadian resetting responses in humans by repeatedly activating cone photoreceptors. In a between-subjects study, healthy volunteers (n = 24, 21-28 yr lived individually in a laboratory for 6 consecutive days. Circadian rhythms of melatonin, cortisol, body temperature, and heart rate were assessed before and after exposure to 6 h of continuous red light (631 nm, 13 log photons cm(-2 s(-1, intermittent red light (1 min on/off, or bright white light (2,500 lux near the onset of nocturnal melatonin secretion (n = 8 in each group. Melatonin suppression and pupillary constriction were also assessed during light exposure. We found that circadian resetting responses were similar for exposure to continuous versus intermittent red light (P = 0.69, with an average phase delay shift of almost an hour. Surprisingly, 2 subjects who were exposed to red light exhibited circadian responses similar in magnitude to those who were exposed to bright white light. Red light also elicited prolonged pupillary constriction, but did not suppress melatonin levels. These findings suggest that, for red light stimuli outside the range of sensitivity for melanopsin, cone photoreceptors can mediate circadian phase resetting of physiologic rhythms in some individuals. Our results also show that sensitivity thresholds differ across non-visual light responses, suggesting that cones may contribute differentially to circadian resetting, melatonin suppression, and the pupillary light reflex during exposure to continuous light.
Full Text Available Life on earth has adapted to the day-night cycle by evolution of internal, so-called circadian clocks that adjust behavior and physiology to the recurring changes in environmental conditions. In mammals, a master pacemaker located in the suprachiasmatic nucleus (SCN of the hypothalamus receives environmental light information and synchronizes peripheral tissues and central non-SCN clocks to geophysical time. Regulatory systems such as the hypothalamus-pituitary-adrenal (HPA axis and the autonomic nervous system (ANS, both being important for the regulation of stress responses, receive strong circadian input. In this review, we summarize the interaction of circadian and stress systems and the resulting physiological and pathophysiological consequences. Finally, we critically discuss the relevance of rodent stress studies for humans, addressing complications of translational approaches and offering strategies to optimize animal studies from a chronobiological perspective.
Cui, Peng; Zhong, Tingyan; Wang, Zhuo; Wang, Tao; Zhao, Hongyu; Liu, Chenglin; Lu, Hui
Circadian genes express periodically in an approximate 24-h period and the identification and study of these genes can provide deep understanding of the circadian control which plays significant roles in human health. Although many circadian gene identification algorithms have been developed, large numbers of false positives and low coverage are still major problems in this field. In this study we constructed a novel computational framework for circadian gene identification using deep neural networks (DNN) - a deep learning algorithm which can represent the raw form of data patterns without imposing assumptions on the expression distribution. Firstly, we transformed time-course gene expression data into categorical-state data to denote the changing trend of gene expression. Two distinct expression patterns emerged after clustering of the state data for circadian genes from our manually created learning dataset. DNN was then applied to discriminate the aperiodic genes and the two subtypes of periodic genes. In order to assess the performance of DNN, four commonly used machine learning methods including k-nearest neighbors, logistic regression, naïve Bayes, and support vector machines were used for comparison. The results show that the DNN model achieves the best balanced precision and recall. Next, we conducted large scale circadian gene detection using the trained DNN model for the remaining transcription profiles. Comparing with JTK_CYCLE and a study performed by Möller-Levet et al. (doi: https://doi.org/10.1073/pnas.1217154110), we identified 1132 novel periodic genes. Through the functional analysis of these novel circadian genes, we found that the GTPase superfamily exhibits distinct circadian expression patterns and may provide a molecular switch of circadian control of the functioning of the immune system in human blood. Our study provides novel insights into both the circadian gene identification field and the study of complex circadian-driven biological
Momma, Tomoyuki; Okayama, Hirokazu; Saitou, Masaru; Sugeno, Hidekazu; Yoshimoto, Nobuhiro; Takebayashi, Yuji; Ohki, Shinji; Takenoshita, Seiichi
Circadian rhythms are fundamental biological systems in most organisms. Epidemiological and animal studies have demonstrated that disruption of circadian rhythms is linked to tumor progression and mammalian tumorigenesis. However, the clinical significance of in situ clock gene expression in precancerous and cancerous colorectal lesions remains unknown. The present study aimed to investigate mRNA transcript levels of circadian clock genes within human colorectal cancer and adenoma tissue sections. Using in situ hybridization, the expression of key clock genes, including period circadian protein homolog ( Per ) 1 and 2, cryptochrome 1 ( Cry1 ), circadian locomoter output cycles protein kaput ( Clock ), brain and muscle ARNT-like protein 1 ( Bmal1 ) and casein kinase 1ε ( CK1 ε) were retrospectively examined in 51 cases of colorectal carcinoma and 10 cases of adenoma. The expression of clock genes was almost undetectable in the majority of adenomas, whereas positive expression of clock genes was observed in 27-47% of carcinomas. Notably, positive Per1 , Per2 and Clock staining in colorectal carcinomas were each significantly associated with a larger tumor size (P=0.012, P=0.011 and P=0.009, respectively). Tumors with positive Per2 and Clock expression tended to exhibit deeper depth of invasion and were generally more advanced than tumors that did not express these genes (P=0.052 and P=0.064, respectively). However, no statistically significant association was observed between clock gene expression and clinicopathological variables, including histopathological differentiation, lymph node metastasis, depth of invasion or disease stage, although Per2 -positive tumors tended to be associated with poorer overall survival (P=0.060). The results of the current study suggest that dysregulated expression of clock genes may be important in human colorectal tumorigenesis.
Full Text Available Abstract Background Fluorescent and bioluminescent time-lapse microscopy approaches have been successfully used to investigate molecular mechanisms underlying the mammalian circadian oscillator at the single cell level. However, most of the available software and common methods based on intensity-threshold segmentation and frame-to-frame tracking are not applicable in these experiments. This is due to cell movement and dramatic changes in the fluorescent/bioluminescent reporter protein during the circadian cycle, with the lowest expression level very close to the background intensity. At present, the standard approach to analyze data sets obtained from time lapse microscopy is either manual tracking or application of generic image-processing software/dedicated tracking software. To our knowledge, these existing software solutions for manual and automatic tracking have strong limitations in tracking individual cells if their plane shifts. Results In an attempt to improve existing methodology of time-lapse tracking of a large number of moving cells, we have developed a semi-automatic software package. It extracts the trajectory of the cells by tracking theirs displacements, makes the delineation of cell nucleus or whole cell, and finally yields measurements of various features, like reporter protein expression level or cell displacement. As an example, we present here single cell circadian pattern and motility analysis of NIH3T3 mouse fibroblasts expressing a fluorescent circadian reporter protein. Using Circadian Gene Express plugin, we performed fast and nonbiased analysis of large fluorescent time lapse microscopy datasets. Conclusions Our software solution, Circadian Gene Express (CGE, is easy to use and allows precise and semi-automatic tracking of moving cells over longer period of time. In spite of significant circadian variations in protein expression with extremely low expression levels at the valley phase, CGE allows accurate and
Disis, Mary L
.... This proposal outlines a Phase II clinical trial designed to estimate survival in Stage IV HER2 positive breast cancer patients with no evidence of disease and receiving trastuzumab and a HER2 ICD peptide based vaccine...
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.
Arendt, Josephine; Middleton, Benita
Living for extended periods in Antarctica exposes base personnel to extremes of daylength (photoperiod) and temperature. At the British Antarctic Survey base of Halley, 75°S, the sun does not rise for 110 d in the winter and does not set for 100 d in summer. Photoperiod is the major time cue governing the timing of seasonal events such as reproduction in many species. The neuroendocrine signal providing photoperiodic information to body physiology is the duration of melatonin secretion which reflects the length of the night: longer in the short days of winter and shorter in summer. Light of sufficient intensity and spectral composition serves to suppress production of melatonin and to set the circadian timing and the duration of the rhythm. In humans early observations suggested that bright (>2000 lux) white light was needed to suppress melatonin completely. Shortly thereafter winter depression (Seasonal Affective Disorder or SAD) was described, and its successful treatment by an artificial summer photoperiod of bright white light, sufficient to shorten melatonin production. At Halley dim artificial light intensity during winter was measured, until 2003, at a maximum of approximately 500 lux in winter. Thus a strong seasonal and circadian time cue was absent. It seemed likely that winter depression would be common in the extended period of winter darkness and could be treated with an artificial summer photoperiod. These observations, and predictions, inspired a long series of studies regarding human seasonal and circadian status, and the effects of light treatment, in a small overwintering, isolated community, living in the same conditions for many months at Halley. We found little evidence of SAD, or change in duration of melatonin production with season. However the timing of the melatonin rhythm itself, and/or that of its metabolite 6-sulphatoxymelatonin (aMT6s), was used as a primary marker of seasonal, circadian and treatment changes. A substantial phase
Santiago A Plano
Full Text Available The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN and is synchronized by several environmental stimuli, mainly the light-dark (LD cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2. The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC, cGMP and its related protein kinase (PKG. Pharmacological manipulation of cGMP by phosphodiesterase (PDE inhibition (e.g., sildenafil increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions.
Gøtze, Jens Peter; Georg, Birgitte; Jørgensen, Henrik L
Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) have important local functions within the myocardium, where they protect against accelerated fibrosis. As circadian expression of cardiac natriuretic peptides could be of importance in local cardiac protection against disease, we...... OFF. Eight animals (4 males and 4 females) were included at each time point. Another 48 animals were killed during the second cycle of dark/dark (designated Circadian Time or CT: CT 4, CT 8, CT 12, CT 16, CT 20, and CT 24). The cellular contents of the clock genes Per1 and Bmal1 as well as ANP, BNP......, and their common receptor (NPR-A) were determined using RT-PCR. Per1 and Bmal1 mRNA contents oscillated in antiphase in both atrial and ventricular regions, where Bmal1 mRNA peaked 12h out of phase relative to Per1 mRNA. ANP and NPR-A atrial mRNA contents revealed borderline significant diurnal changes, whereas...
Mészáros, Krisztina; Pruess, Linda; Szabó, Attila J.
intervals on embryonic day 20 and at postnatal weeks 1, 4, and 12. Canonical clock gene (Clock, Bmal1, Rev-erbα, Cry1, Cry2, Per1, Per2) and kidney-specific clock-controlled gene (αENaC, SGK1, NHE3, AVPR2) expression was profiled by RT-PCR. To investigate the role of nutritional cues, the feeding pattern...... 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....... During the nursing period, oscillations are entrained by nutritional cues. The coupling of the circadian expression of tubular regulators of fluid and electrolyte excretion to the feeding-entrained clockwork may be important to maintain homeostasis during this critical period....
Leise, Tanya L
The challenging problems presented by noisy biological oscillators have led to the development of a great variety of methods for accurately estimating rhythmic parameters such as period and amplitude. This chapter focuses on wavelet-based methods, which can be quite effective for assessing how rhythms change over time, particularly if time series are at least a week in length. These methods can offer alternative views to complement more traditional methods of evaluating behavioral records. The analytic wavelet transform can estimate the instantaneous period and amplitude, as well as the phase of the rhythm at each time point, while the discrete wavelet transform can extract the circadian component of activity and measure the relative strength of that circadian component compared to those in other frequency bands. Wavelet transforms do not require the removal of noise or trend, and can, in fact, be effective at removing noise and trend from oscillatory time series. The Fourier periodogram and spectrogram are reviewed, followed by descriptions of the analytic and discrete wavelet transforms. Examples illustrate application of each method and their prior use in chronobiology is surveyed. Issues such as edge effects, frequency leakage, and implications of the uncertainty principle are also addressed. © 2015 Elsevier Inc. All rights reserved.
Full Text Available Leon Lack, Michelle Bailey, Nicole Lovato, Helen WrightSchool of Psychology, Flinders University, Adelaide, South Australia, AustraliaAbstract: Evening chronotypes typically have sleep patterns timed 2–3 hours later than morning chronotypes. Ambulatory studies have suggested that differences in the timing of underlying circadian rhythms as a cause of the sleep period differences. However, differences in endogenous circadian rhythms are best explored in laboratory protocols such as the constant routine. We used a 27-hour modified constant routine to measure the endogenous core temperature and melatonin circadian rhythms as well as subjective and objective sleepiness from hourly 15-minute sleep opportunities. Ten (8f morning type individuals were compared with 12 (8f evening types. All were young, healthy, good sleepers. The typical sleep onset, arising times, circadian phase markers for temperature and melatonin and objective sleepiness were all 2–3 hours later for the evening types than morning types. However, consistent with past studies the differences for the subjective sleepiness rhythms were much greater (5–9 hours. Therefore, the present study supports the important role of subjective alertness/sleepiness in determining the sleep period differences between morning and evening types and the possible vulnerability of evening types to delayed sleep phase disorder.Keywords: chronotype, constant routine, circadian rhythms, sleep propensity, subjective sleepiness
Kvaslerud, T.; Hansen, M.V.; Rosenberg, J.
concerning post-operative circadian disturbances. We also present the literature concerning circadian variation in post-operative morbidity and mortality. PubMed and the Cochrane database were searched for papers using a combination of 'circadian,' 'surgery,' 'post-operative,' 'mortality' and 'morbidity....... There is a peak incidence of myocardial ischemia, fatal thromboembolism and sudden unexpected death in the morning hours. A circadian variation exists in post-operative morbidity and mortality. The observed circadian variation in post-operative morbidity and mortality may warrant a chronopharmacological approach...
Dodd, Antony N; Salathia, Neeraj; Hall, Anthony; Kévei, Eva; Tóth, Réka; Nagy, Ferenc; Hibberd, Julian M; Millar, Andrew J; Webb, Alex A R
Circadian clocks are believed to confer an advantage to plants, but the nature of that advantage has been unknown. We show that a substantial photosynthetic advantage is conferred by correct matching of the circadian clock period with that of the external light-dark cycle. In wild type and in long- and short-circadian period mutants of Arabidopsis thaliana, plants with a clock period matched to the environment contain more chlorophyll, fix more carbon, grow faster, and survive better than plants with circadian periods differing from their environment. This explains why plants gain advantage from circadian control.
Full Text Available Regulators of G protein signaling (RGS are a multi-functional protein family, which functions in part as GTPase-activating proteins (GAPs of G protein α-subunits to terminate G protein signaling. Previous studies have demonstrated that the Rgs16 transcripts exhibit robust circadian rhythms both in the suprachiasmatic nucleus (SCN, the master circadian light-entrainable oscillator (LEO of the hypothalamus, and in the liver. To investigate the role of RGS16 in the circadian clock in vivo, we generated two independent transgenic mouse lines using lentiviral vectors expressing short hairpin RNA (shRNA targeting the Rgs16 mRNA. The knockdown mice demonstrated significantly shorter free-running period of locomotor activity rhythms and reduced total activity as compared to the wild-type siblings. In addition, when feeding was restricted during the daytime, food-entrainable oscillator (FEO-driven elevated food-anticipatory activity (FAA observed prior to the scheduled feeding time was significantly attenuated in the knockdown mice. Whereas the restricted feeding phase-advanced the rhythmic expression of the Per2 clock gene in liver and thalamus in the wild-type animals, the above phase shift was not observed in the knockdown mice. This is the first in vivo demonstration that a common regulator of G protein signaling is involved in the two separate, but interactive circadian timing systems, LEO and FEO. The present study also suggests that liver and/or thalamus regulate the food-entrained circadian behavior through G protein-mediated signal transduction pathway(s.
Czeisler, C. A.; Dumont, M.; Duffy, J. F.; Steinberg, J. D.; Richardson, G. S.; Brown, E. N.; Sanchez, R.; Rios, C. D.; Ronda, J. M.
Many elderly people complain of disturbed sleep patterns but there is not evidence that the need to sleep decreases with age; it seems rather that the timing and consolidation of sleep change. We tried to find out whether there is a concurrent change in the output of the circadian pacemaker with age. The phase and amplitude of the pacemaker's output were assessed by continuous measurement of the core body temperature during 40 h of sustained wakefulness under constant behavioural and environmental conditions. 27 young men (18-31 years) were compared with 21 older people (65-85 years; 11 men, 10 women); all were healthy and without sleep complaints. The mean amplitude of the endogenous circadian temperature oscillation (ECA) was 40% greater in young men than in the older group. Older men had a lower mean temperature ECA than older women. The minimum of the endogenous phase of the circadian temperature oscillation (ECP) occurred 1 h 52 min earlier in the older than in the young group. Customary bedtimes and waketimes were also earlier in the older group, as was their daily alertness peak. There was a close correlation between habitual waketime and temperature ECP in young men, which may lose precision with age, especially among women. These findings provide evidence for systematic age-related changes in the output of the human circadian pacemaker. We suggest that these changes may underlie the common complaints of sleep disturbance among elderly people. These changes could reflect the observed age-related deterioration of the hypothalamic nuclei that drive mammalian circadian rhythms.
Hung, Guang-Uei; Huang, Jin-Long; Lin, Wan-Yu; Tsai, Shih-Chung; Wang, Kuo-Yang; Chen, Shih-Ann; Lloyd, Michael S.; Chen, Ji
The use of SPECT phase analysis to optimize left-ventricular (LV) lead positions for cardiac resynchronization therapy (CRT) was performed at baseline, but CRT works as simultaneous right ventricular (RV) and LV pacing. The aim of this study was to assess the impact of RV apical (RVA) pacing on optimal LV lead positions measured by SPECT phase analysis. This study prospectively enrolled 46 patients. Two SPECT myocardial perfusion scans were acquired under sinus rhythm with complete left bundle branch block and RVA pacing, respectively, following a single injection of 99m Tc-sestamibi. LV dyssynchrony parameters and optimal LV lead positions were measured by the phase analysis technique and then compared between the two scans. The LV dyssynchrony parameters were significantly larger with RVA pacing than with sinus rhythm (p ∝0.01). In 39 of the 46 patients, the optimal LV lead positions were the same between RVA pacing and sinus rhythm (kappa = 0.861). In 6 of the remaining 7 patients, the optimal LV lead positions were along the same radial direction, but RVA pacing shifted the optimal LV lead positions toward the base. The optimal LV lead positions measured by SPECT phase analysis were consistent, no matter whether the SPECT images were acquired under sinus rhythm or RVA pacing. In some patients, RVA pacing shifted the optimal LV lead positions toward the base. This study supports the use of baseline SPECT myocardial perfusion imaging to optimize LV lead positions to increase CRT efficacy. (orig.)
Pendergast, Julie S; Branecky, Katrina L; Huang, Roya; Niswender, Kevin D; Yamazaki, Shin
Consumption of high-fat diet acutely alters the daily rhythm of eating behavior and circadian organization (the phase relationship between oscillators in central and peripheral tissues) in mice. Voluntary wheel-running activity counteracts the obesogenic effects of high-fat diet and also modulates circadian rhythms in mice. In this study, we sought to determine whether voluntary wheel-running activity could prevent the proximate effects of high-fat diet consumption on circadian organization and behavioral rhythms in mice. Mice were housed with locked or freely rotating running wheels and fed chow or high-fat diet for 1 week and rhythms of locomotor activity, eating behavior, and molecular timekeeping (PERIOD2::LUCIFERASE luminescence rhythms) in ex vivo tissues were measured. Wheel-running activity delayed the phase of the liver rhythm by 4 h in both chow- and high-fat diet-fed mice. The delayed liver phase was specific to wheel-running activity since an enriched environment without the running wheel did not alter the phase of the liver rhythm. In addition, wheel-running activity modulated the effect of high-fat diet consumption on the daily rhythm of eating behavior. While high-fat diet consumption caused eating events to be more evenly dispersed across the 24 h-day in both locked-wheel and wheel-running mice, the effect of high-fat diet was much less pronounced in wheel-running mice. Together these data demonstrate that wheel-running activity is a salient factor that modulates liver phase and eating behavior rhythms in both chow- and high-fat-diet fed mice. Wheel-running activity in mice is both a source of exercise and a self-motivating, rewarding behavior. Understanding the putative reward-related mechanisms whereby wheel-running activity alters circadian rhythms could have implications for human obesity since palatable food and exercise may modulate similar reward circuits.
Full Text Available Life is controlled by multiple rhythms. Although the interaction of the daily (circadian clock with environmental stimuli, such as light, is well documented, its relationship to endogenous clocks with other periods is little understood. We establish that the marine worm Platynereis dumerilii possesses endogenous circadian and circalunar (monthly clocks and characterize their interactions. The RNAs of likely core circadian oscillator genes localize to a distinct nucleus of the worm’s forebrain. The worm’s forebrain also harbors a circalunar clock entrained by nocturnal light. This monthly clock regulates maturation and persists even when circadian clock oscillations are disrupted by the inhibition of casein kinase 1δ/ε. Both circadian and circalunar clocks converge on the regulation of transcript levels. Furthermore, the circalunar clock changes the period and power of circadian behavior, although the period length of the daily transcriptional oscillations remains unaltered. We conclude that a second endogenous noncircadian clock can influence circadian clock function.
Claudia Patricia Álvarez Barón
Full Text Available Neurospora crassa is a widely studied model of circadian rhythmicity. In this fungus, metabolism is controlled by multiple factors which include development, medium characteristics and the circadian clock. The study of the circadian control of metabolism in this fungus could be masked by the use of restrictive media that inhibit growth and development. In this report, the presence of a circadian rhythm in the activity of the enzyme Succinate Dehydrogenase in Neurospora crassa is demonstrated. Rhythmic and arrhythmic Neurospora strains were grown in complete medium without conidiation restriction. A circadian change in the enzymatic activity was found with high values in hours corresponding to the night and a low level during the day. This finding highlights the importance of deeper studies in the circadian control of metabolism in this fungus, given the existence of multiple pathways of regulation of metabolic enzymes and a circadian clock control at the transcriptional and post-transcriptional levels.
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.
Moreira, Jeverson; Geoffroy, Pierre Alexis
Bipolar disorder (BD) is a severe and common psychiatric disorder. BD pathogenesis, clinical manifestations and relapses are associated with numerous circadian rhythm abnormalities. Lithium (Li) is the first-line treatment in BD, and its therapeutic action has been related to its ability to alter circadian rhythms. We systematically searched the PubMed database until January 2016, aiming to critically examine published studies investigating direct and indirect effects of Li on circadian rhythms. The results, from the 95 retained studies, indicated that Li: acts directly on the molecular clocks; delays the phase of sleep-wakefulness rhythms and the peak elevation of diurnal cycle body temperature; reduces the amplitude and shortens the duration of activity rhythms and lengthens free-running rhythms. Chronic Li treatment stabilizes free-running activity rhythms, by improving day-to-day rhythmicity of the activity, with effects that appear to be dose related. Pharmacogenetics demonstrate several associations of Li's response with circadian genes (NR1D1, GSK3β, CRY1, ARNTL, TIM, PER2). Finally, Li acts on the retinal-hypothalamic pineal pathway, influencing light sensitivity and melatonin secretion. Li is a highly investigated chronobiologic agent, and although its chronobiological effects are not completely understood, it seems highly likely that they constitute an inherent component of its therapeutic action in the treatment of mood disorders.
Full Text Available The formation of fear memories is a powerful and highly evolutionary conserved mechanism that serves the behavioral adaptation to environmental threats. Accordingly, classical fear conditioning paradigms have been employed to investigate fundamental molecular processes of memory formation. Evidence suggests that a circadian regulation mechanism allows for a timestamping of such fear memories and controlling memory salience during both their acquisition and their modification after retrieval. These mechanisms include an expression of molecular clocks in neurons of the amygdala, hippocampus, and medial prefrontal cortex and their tight interaction with the intracellular signaling pathways that mediate neural plasticity and information storage. The cellular activities are coordinated across different brain regions and neural circuits through the release of glucocorticoids and neuromodulators such as acetylcholine, which integrate circadian and memory-related activation. Disturbance of this interplay by circadian phase shifts or traumatic experience appears to be an important factor in the development of stress-related psychopathology, considering these circadian components are of critical importance for optimizing therapeutic approaches to these disorders.
Kim, Hyunbae; Zheng, Ze; Walker, Paul D; Kapatos, Gregory; Zhang, Kezhong
Cyclic AMP-responsive element binding protein, hepatocyte specific (CREBH), is a liver-enriched, endoplasmic reticulum-tethered transcription factor known to regulate the hepatic acute-phase response and lipid homeostasis. In this study, we demonstrate that CREBH functions as a circadian transcriptional regulator that plays major roles in maintaining glucose homeostasis. The proteolytic cleavage and posttranslational acetylation modification of CREBH are regulated by the circadian clock. Functionally, CREBH is required in order to maintain circadian homeostasis of hepatic glycogen storage and blood glucose levels. CREBH regulates the rhythmic expression of the genes encoding the rate-limiting enzymes for glycogenolysis and gluconeogenesis, including liver glycogen phosphorylase (PYGL), phosphoenolpyruvate carboxykinase 1 (PCK1), and the glucose-6-phosphatase catalytic subunit (G6PC). CREBH interacts with peroxisome proliferator-activated receptor α (PPARα) to synergize its transcriptional activities in hepatic gluconeogenesis. The acetylation of CREBH at lysine residue 294 controls CREBH-PPARα interaction and synergy in regulating hepatic glucose metabolism in mice. CREBH deficiency leads to reduced blood glucose levels but increases hepatic glycogen levels during the daytime or upon fasting. In summary, our studies revealed that CREBH functions as a key metabolic regulator that controls glucose homeostasis across the circadian cycle or under metabolic stress. Copyright © 2017 American Society for Microbiology.
Xiao, Bo; Cui, Li-Qiang; Ding, Cheng; Wang, Han
The aim of this study was to investigate lithium and 2,4-dichlorophenol (2,4-DCP)-induced circadian rhythm disorder and their genome-wide effects in zebrafish. Zebrafish larvae were exposed to 250 ppm LiCl (n = 40) or 20 ppm 2,4-DCP. RNA was subsequently extracted and determined quantitatively. The mRNA levels of circadian clock-related genes, including clock1a, bmal1b, per2, and per1b, were determined. Microarray datasets were generated and the differentially expressed genes (DEGs) were identified. The mRNA levels of some upregulated and downregulated DEGs were examined by quantitative real-time polymerase chain reaction (RT-PCR). Finally, gene ontology (GO) enrichment analysis was applied to determine the roles of the DEGs. The mRNA expression levels of circadian rhythm-related genes in the daily cycle were significantly affected after incubation of zebrafish with LiCl and 2,4-DCP. Many genes were differentially expressed during the light phase (97 h) and RT-PCR validation tests revealed that the expression patterns of DEGs were in accordance with those obtained by microarray analysis. GO functional enrichment analysis showed that the DEGs in LiCl- and 2,4-DCP-treated groups were associated with signal transduction and development. Collectively, our findings indicate that LiCl and 2,4-DCP could affect signal transduction pathways and immune response, thereby inducing circadian rhythm disorder.
Felipo, Vicente; Piedrafita, Blanca; Barios, Juan A; Agustí, Ana; Ahabrach, Hanan; Romero-Vives, María; Barrio, Luis C; Rey, Beatriz; Gaztelu, Jose M; Llansola, Marta
Patients with liver cirrhosis show disturbances in sleep and in its circadian rhythms which are an early sign of minimal hepatic encephalopathy (MHE). The mechanisms of these disturbances are poorly understood. Rats with porta-caval shunt (PCS), a model of MHE, show sleep disturbances reproducing those of cirrhotic patients. The aims of this work were to characterize the alterations in circadian rhythms in PCS rats and analyze the underlying mechanisms. To reach these aims, we analyzed in control and PCS rats: (a) daily rhythms of spontaneous and rewarding activity and of temperature, (b) timing of the onset of activity following turning-off the light, (c) synchronization to light after a phase advance and (d) the molecular mechanisms contributing to these alterations in circadian rhythms. PCS rats show altered circadian rhythms of spontaneous and rewarding activities (wheel running). PCS rats show more rest bouts during the active phase, more errors in the onset of motor activity and need less time to re-synchronize after a phase advance than control rats. Circadian rhythm of body temperature is also slightly altered in PCS rats. The internal period length (tau) of circadian rhythm of motor activity is longer in PCS rats. We analyzed some mechanisms by which hypothalamus modulate circadian rhythms. PCS rats show increased content of cGMP in hypothalamus while the activity of cGMP-dependent protein kinase was reduced by 41% compared to control rats. Altered cGMP-PKG pathway in hypothalamus would contribute to altered circadian rhythms and synchronization to light.
Full Text Available Introduction. The aim of the study was to examine the effect of circadian rhythm on dynamic balance performance and to determine the role of physical activity level, body temperature, chronotype, and gender in this possible effect. Material and
Rath, Martin Fredensborg; Rohde, Kristian; Fahrenkrug, Jan
in the rat neocortex. Among these, Per1, Per2, Per3, Cry1, Bmal1, Nr1d1 and Dbp were found to exhibit daily rhythms. The amplitude of circadian oscillation in neocortical clock gene expression was damped and the peak delayed as compared with the SCN. Lesions of the SCN revealed that rhythmic clock gene...
Mahmoud, Karim D.; Lennon, Ryan J.; Ting, Henry H.; Rihal, Charanjit S.; Holmes, David R.
Objectives We sought to determine the circadian, weekly, and seasonal variation of coronary stent thrombosis. Background Other adverse cardiovascular events such as acute myocardial infarction are known to have higher incidences during the early morning hours, Mondays, and winter months. Methods The
Stenvers, Dirk Jan; Jonkers, Cora F.; Fliers, Eric; Bisschop, Peter H. L. T.; Kalsbeek, Andries
Life on earth has evolved under the daily rhythm of light and dark. Consequently, most creatures experience a daily rhythm in food availability. In this review, we first introduce the mammalian circadian timing system, consisting of a central clock in the suprachiasmatic nucleus (SCN) and peripheral
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-tuned the b...
located in the third ventricle of the hypothalamus by two independent groups: F. K. Stephan and Irvin ... levels of biological organization, and we have tried to represent this aspect of our discipline in this special ... nature of circadian rhythm research, because at the core of all these studies lies a genetic architecture which.
Jasper, Isabelle; Gordijn, Marijke; Haeussler, Andreas; Hermsdoerfer, Joachim
The aim of the present study was to analyze the circadian rhythmicity in handwriting kinematics and legibility and to compare the performance between Dutch and German writers. Two subject groups underwent a 40 h sleep deprivation protocol under Constant Routine conditions either in Groningen (10
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 ...
Boivin, D. B.; Czeisler, C. A.
The present study was designed to investigate whether a weak photic stimulus can reset the endogenous circadian rhythms of plasma melatonin and plasma cortisol in human subjects. A stimulus consisting of three cycles of 5 h exposures to ordinary room light (approximately 180 lux), centered 1.5 h after the endogenous temperature nadir, significantly phase-advanced the plasma melatonin rhythm in eight healthy young men compared with the phase delays observed in eight control subjects who underwent the same protocol but were exposed to darkness (p melatonin and plasma cortisol maintained stable temporal relationships with the endogenous core body temperature cycle, consistent with the conclusion that exposure to ordinary indoor room light had shifted a master circadian pacemaker.
St Hilaire, Melissa A; Lockley, Steven W
Totally blind individuals are highly likely to suffer from Non-24-Hour Sleep-Wake Disorder due to a failure of light to reset the circadian pacemaker in the suprachiasmatic nuclei. In this outpatient case series, we investigated whether daily caffeine administration could entrain the circadian pacemaker in non-entrained blind patients to alleviate symptoms of non-24-hour sleep-wake disorder. Three totally blind males (63.0 ± 7.5 years old) were studied at home over ~4 months. Urinary 6-sulphatoxymelatonin (aMT6s) rhythms were measured for 48 h every 1-2 weeks. Participants completed daily sleep-wake logs, and rated their alertness and mood using nine-point scales every ~2-4 h while awake on urine sampling days. Caffeine capsules (150 mg per os) were self-administered daily at 10 a.m. for approximately one circadian beat cycle based on each participant's endogenous circadian period τ and compared to placebo (n = 2) or no treatment (n = 1) in a single-masked manner. Non-24-h aMT6s rhythms were confirmed in all three participants (τ range = 24.32-24.57 h). Daily administration of 150 mg caffeine did not entrain the circadian clock. Caffeine treatment significantly improved daytime alertness at adverse circadian phases (p caffeine was able to improve daytime alertness acutely and may therefore provide temporary symptomatic relief, the inability of caffeine to correct the underlying circadian disorder means that an entraining agent is required to treat Non-24-Hour Sleep-Wake Disorder in the blind appropriately. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
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
Patton, Danica F; Mistlberger, Ralph E
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 (SCN) is directly entrained by daily light-dark (LD) 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 system.
Mallis, M M; DeRoshia, C W
Maintaining optimal alertness and neurobehavioral functioning during space operations is critical to enable the National Aeronautics and Space Administration's (NASA's) vision "to extend humanity's reach to the Moon, Mars and beyond" to become a reality. Field data have demonstrated that sleep times and performance of crewmembers can be compromised by extended duty days, irregular work schedules, high workload, and varying environmental factors. This paper documents evidence of significant sleep loss and disruption of circadian rhythms in astronauts and associated performance decrements during several space missions, which demonstrates the need to develop effective countermeasures. Both sleep and circadian disruptions have been identified in the Behavioral Health and Performance (BH&P) area and the Advanced Human Support Technology (AHST) area of NASA's Bioastronautics Critical Path Roadmap. Such disruptions could have serious consequences on the effectiveness, health, and safety of astronaut crews, thus reducing the safety margin and increasing the chances of an accident or incident. These decrements oftentimes can be difficult to detect and counter effectively in restrictive operational environments. NASA is focusing research on the development of optimal sleep/wake schedules and countermeasure timing and application to help mitigate the cumulative effects of sleep and circadian disruption and enhance operational performance. Investing research in humans is one of NASA's building blocks that will allow for both short- and long-duration space missions and help NASA in developing approaches to manage and overcome the human limitations of space travel. In addition to reviewing the current state of knowledge concerning sleep and circadian disruptions during space operations, this paper provides an overview of NASA's broad research goals. Also, NASA-funded research, designed to evaluate the relationships between sleep quality, circadian rhythm stability, and
Pittendrigh, Colin S.; Daan, Serge
1. This paper is an attempt to integrate in a general model the major findings reported earlier in this series on: lability and history dependence of circadian period, τ; dependence of τ and α on light intensity as described in Aschoffs Rule; the interrelationships between τ and phase response
Kumar Jha, Pawan; Bouâouda, Hanan; Gourmelen, Sylviane; Dumont, Stephanie; Fuchs, Fanny; Goumon, Yannick; Bourgin, Patrice; Kalsbeek, A.; Challet, Etienne
Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light-dark cycle. However, non-photic factors, such as behavioural arousal and metabolic cues, can also phase-shift the master clock in the suprachiasmatic nuclei (SCN) and/or reduce the synchronizing
Jha, Pawan Kumar; Bouâouda, Hanan; Gourmelen, Sylviane; Dumont, Stephanie; Fuchs, Fanny; Goumon, Yannick; Bourgin, Patrice; Kalsbeek, Andries; Challet, Etienne
Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light/dark cycle. However, nonphotic factors, such as behavioral arousal and metabolic cues, can also phase shift the master clock in the suprachiasmatic nuclei (SCNs) and/or reduce the synchronizing
Full Text Available Crustacean hyperglycemic hormone (CHH synthesizing cells in the optic lobe, one of the pacemakers of the circadian system, have been shown to be present in crayfish. However, the presence of CHH in the central brain, another putative pacemaker of the multi-oscillatory circadian system, of this decapod and its circadian transcription in the optic lobe and brain have yet to be explored. Therefore, using qualitative and quantitative PCR, we isolated and cloned a CHH mRNA fragment from two putative pacemakers of the multi-oscillatory circadian system of Procambarus clarkii, the optic lobe and the central brain. This CHH transcript synchronized to daily light-dark cycles and oscillated under dark, constant conditions demonstrating statistically significant daily and circadian rhythms in both structures. Furthermore, to investigate the presence of the peptide in the central brain of this decapod, we used immunohistochemical methods. Confocal microscopy revealed the presence of CHH-IR in fibers and cells of the protocerebral and tritocerebal clusters and neuropiles, particularly in some neurons located in clusters 6, 14, 15 and 17. The presence of CHH positive neurons in structures of P. clarkii where clock proteins have been reported suggests a relationship between the circadian clockwork and CHH. This work provides new insights into the circadian regulation of CHH, a pleiotropic hormone that regulates many physiological processes such as glucose metabolism and osmoregulatory responses to stress.
Nelson-Mora, Janikua; Prieto-Sagredo, Julio; Loredo-Ranjel, Rosaura; Fanjul-Moles, María Luisa
Crustacean hyperglycemic hormone (CHH) synthesizing cells in the optic lobe, one of the pacemakers of the circadian system, have been shown to be present in crayfish. However, the presence of CHH in the central brain, another putative pacemaker of the multi-oscillatory circadian system, of this decapod and its circadian transcription in the optic lobe and brain have yet to be explored. Therefore, using qualitative and quantitative PCR, we isolated and cloned a CHH mRNA fragment from two putative pacemakers of the multi-oscillatory circadian system of Procambarus clarkii, the optic lobe and the central brain. This CHH transcript synchronized to daily light-dark cycles and oscillated under dark, constant conditions demonstrating statistically significant daily and circadian rhythms in both structures. Furthermore, to investigate the presence of the peptide in the central brain of this decapod, we used immunohistochemical methods. Confocal microscopy revealed the presence of CHH-IR in fibers and cells of the protocerebral and tritocerebal clusters and neuropiles, particularly in some neurons located in clusters 6, 14, 15 and 17. The presence of CHH positive neurons in structures of P. clarkii where clock proteins have been reported suggests a relationship between the circadian clockwork and CHH. This work provides new insights into the circadian regulation of CHH, a pleiotropic hormone that regulates many physiological processes such as glucose metabolism and osmoregulatory responses to stress.
DeAngelo, Daniel J; Stock, Wendy; Stein, Anthony S; Shustov, Andrei; Liedtke, Michaela; Schiffer, Charles A; Vandendries, Erik; Liau, Katherine; Ananthakrishnan, Revathi; Boni, Joseph; Laird, A Douglas; Fostvedt, Luke; Kantarjian, Hagop M; Advani, Anjali S
This study evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of inotuzumab ozogamicin (InO) for CD22-positive relapsed/refractory acute lymphoblastic leukemia. In phase 1, patients received InO 1.2 (n = 3), 1.6 (n = 12), or 1.8 (n = 9) mg/m 2 per cycle on days 1, 8, and 15 over a 28-day cycle (≤6 cycles). The recommended phase 2 dose (RP2D) was confirmed (expansion cohort; n = 13); safety and activity of InO were assessed in patients receiving the RP2D in phase 2 (n = 35) and in all treated patients (n = 72). The RP2D was 1.8 mg/m 2 per cycle (0.8 mg/m 2 on day 1; 0.5 mg/m 2 on days 8 and 15), with reduction to 1.6 mg/m 2 per cycle after complete remission (CR) or CR with incomplete marrow recovery (CRi). Treatment-related toxicities were primarily cytopenias. Four patients experienced treatment-related venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS; 1 fatal). Two VOD/SOS events occurred during treatment without intervening transplant; of 24 patients proceeding to poststudy transplant, 2 experienced VOD/SOS after transplant. Forty-nine (68%) patients had CR/CRi, with 41 (84%) achieving minimal residual disease (MRD) negativity. Median progression-free survival was 3.9 (95% confidence interval, 2.9-5.4) months; median overall survival was 7.4 (5.7-9.2) months for all treated patients, with median 23.7 (range, 6.8-29.8) months of follow-up for all treated patients alive at data cutoff. Achievement of MRD negativity was associated with higher InO exposure. InO was well tolerated and demonstrated high single-agent activity and MRD-negativity rates. This trial was registered at www.clinicaltrials.gov as #NCT01363297.
Kristin L. Kopperud
Full Text Available Many ecologically and economically important marine fish species worldwide spend portions of their lives in coastal regions that are increasingly inundated by artificial light at night. However, while extensive research illustrates the harmful effects of inappropriate light exposure on biological timing in humans, rodents and birds, comparable studies on marine fish are virtually nonexistent. This study aimed to assess the effects of light on biological clock function in the marine fish retina using the Atlantic tarpon (Megalops atlanticus as a model. Using anti-opsin immunofluorescence, we observed robust rhythms of photoreceptor outer segment position (retinomotor movement over the course of the daily light–dark cycle: cone outer segments were contracted toward the inner retina and rods were elongated during the day; the opposite occurred at night. Phase shifting the daily light–dark cycle caused a corresponding shift of retinomotor movement timing, and cone retinomotor movement persisted in constant darkness, indicating control by a circadian clock. Constant light abolished retinomotor movements of both photoreceptor types. Thus, abnormally-timed light exposure may disrupt normal M. atlanticus clock function and harm vision, which in turn may affect prey capture and predator avoidance. These results should help inform efforts to mitigate the effects of coastal light pollution on organisms in marine ecosystems.
Chellappa, Sarah L; Morris, Christopher J; Scheer, Frank A J L
Shift work increases the risk for human errors, such that drowsiness due to shift work has contributed to major industrial disasters, including Space Shuttle Challenger, Chernobyl and Alaska Oil Spill disasters, with extraordinary socio-economical costs. Overnight operations pose a challenge because our circadian biology inhibits cognitive performance at night. Yet how the circadian system modulates cognition over multiple days under realistic shift work conditions remains to be established. Importantly, because task-specific cognitive brain regions show different 24-h circadian dynamics, we hypothesize that circadian misalignment impacts cognition task-dependently. Using a biologically-driven paradigm mimicking night shift work, with a randomized, cross-over design, we show that misalignment between the circadian pacemaker and behavioral/environmental cycles increases cognitive vulnerability on sustained attention, cognitive throughput, information processing and visual-motor performance over multiple days, compared to circadian alignment (day shifts). Circadian misalignment effects are task-dependent: while they acutely impair sustained attention with recovery after 3-days, they progressively hinder daily learning. Individuals felt sleepier during circadian misalignment, but they did not rate their performance as worse. Furthermore, circadian misalignment effects on sustained attention depended on prior sleep history. Collectively, daily circadian misalignment may provide an important biological framework for developing countermeasures against adverse cognitive effects in shift workers.
Caponio, Francesco; Squeo, Giacomo; Brunetti, Lucio; Pasqualone, Antonella; Summo, Carmine; Paradiso, Vito M; Catalano, Pasquale; Bianchi, Biagio
Nowadays, olive oil extraction is basically achieved by means of two-phase decanters, which allow a reduction of water consumption and the leaching of phenolic compounds. Despite this, most of the working settings derive from studies carried out on three-phase decanters. Hence, the aim of the present study was to assess the influence of two-phase decanter feed pipe position (FP) on the extraction efficiency and chemical-sensory characteristics of virgin olive oil. Three different positions were considered: at 825 mm (FP1), 610 mm (FP2) and 520 mm (FP3) from the outlet of the oily phase. Position FP3 allowed the highest oil recovery (up to 10%), the lowest percentage of oil in the olive pomace and, in general, a regular trend in terms of oil extraction efficiency. However, the oily must that came out of the decanter was not completely clean in terms of residual content of solid sediment and water. The feeding position partially affected the profile of antioxidant compounds. In two-phase decanters, loading the olive paste close to the outlet of the oily phase is recommended to increase the extraction efficiency without jeopardizing the chemical-sensory characteristics of virgin olive oil. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.
Soliman, A; Safigholi, H [Sunnybrook Research Institute, Toronto, ON (Canada); Sunnybrook Health Sciences Center, Toronto, ON (Canada); Nosrati, R [Sunnybrook Health Sciences Center, Toronto, ON (Canada); Ryerson University, Toronto, ON (Canada); Owrangi, A; Morton, G [Sunnybrook Health Sciences Center, Toronto, ON (Canada); University of Toronto, Toronto, ON (Canada); Song, W [Sunnybrook Research Institute, Toronto, ON (Canada); Sunnybrook Health Sciences Center, Toronto, ON (Canada); Ryerson University, Toronto, ON (Canada); University of Toronto, Toronto, ON (Canada)
Purpose: To propose a new method that provides a positive contrast visualization of the prostate brachytherapy seeds using the phase information from MR images. Additionally, the feasibility of using the processed phase information to distinguish seeds from calcifications is explored. Methods: A gel phantom was constructed using 2% agar dissolved in 1 L of distilled water. Contrast agents were added to adjust the relaxation times. Four iodine-125 (Eckert & Ziegler SML86999) dummy seeds were placed at different orientations with respect to the main magnetic field (B0). Calcifications were obtained from a sheep femur cortical bone due to its close similarity to human bone tissue composition. Five samples of calcifications were shaped into different dimensions with lengths ranging between 1.2 – 6.1 mm.MR imaging was performed on a 3T Philips Achieva using an 8-channel head coil. Eight images were acquired at eight echo-times using a multi-gradient echo sequence. Spatial resolution was 0.7 × 0.7 × 2 mm, TR/TE/dTE = 20.0/2.3/2.3 ms and BW = 541 Hz/pixel. Complex images were acquired and fed into a two-step processing pipeline: the first includes phase unwrapping and background phase removal using Laplacian operator (Wei et al. 2013). The second step applies a specific phase mask on the resulting tissue phase from the first step to provide the desired positive contrast of the seeds and to, potentially, differentiate them from the calcifications. Results: The phase-processing was performed in less than 30 seconds. The proposed method has successfully resulted in a positive contrast of the brachytherapy seeds. Additionally, the final processed phase image showed difference between the appearance of seeds and calcifications. However, the shape of the seeds was slightly distorted compared to the original dimensions. Conclusion: It is feasible to provide a positive contrast of the seeds from MR images using Laplacian operator-based phase processing.
Mortola, Jacopo P
This article reviews human and animal studies about the circadian patterns of physiological variables involved with the respiratory function. Some measures reflecting the mechanical properties of the lungs, such as functional residual capacity, forced expiratory volumes and airway resistance, change periodically with the time of the day. Also resting pulmonary ventilation (V(E)), tidal volume, and breathing rate follow circadian patterns. In humans, these patterns occur independently of the daily changes in activity, whereas, to some extent, they are linked to changes in the state of arousal. Differently, in some rodents, the circadian oscillations of the breathing pattern occur independently of the daily rhythms of either activity or state of arousal. Recent measurements of the breathing pattern for unlimited periods of time in undisturbed animals have indicated that the circadian changes occur in close temporal phase with those of oxygen consumption, carbon dioxide production, and body temperature. However, none of these variables can fully explain the circadian pattern of breathing, the origin of which remains unclear. Both in humans and in rats the V(E) responses to hypercapnia or hypoxia differ at various times of the day. In rats, the daily differences in V(E) responses are buffered by changes in metabolic rate, such that, unlike humans, the hyperventilation (defined as the increase in ventilation-metabolism ratio) remains constant throughout the 24 h. The presence of a biological clock is a major advantage in the adaptation to the environment, although it forces some variables to deviate periodically from their mean value. In humans, these deviations become apparent in conditions of hypoxia. Hence, a daily time-window exists in which the respiratory system is less capable of responding to challenges, a factor which may contribute to the findings that some cardio-respiratory symptoms and diseases peak at particular times of the day.
Baba, Kenkichi; Davidson, Alec J; Tosini, Gianluca
Previous studies have reported the presence of a circadian rhythm in PERIOD2::LUCIFERASE (PER2::LUC) bioluminescence in mouse photoreceptors, retina, RPE, and cornea. Melatonin (MLT) modulates many physiological functions in the eye and it is believed to be one of the key circadian signals within the eye. The aim of the present study was to investigate the regulation of the PER2::LUC circadian rhythm in mouse cornea and to determine the role played by MLT. Corneas were obtained from PER2::LUC mice and cultured to measure bioluminescence rhythmicity in isolated tissue using a Lumicycle or CCD camera. To determine the time-dependent resetting of the corneal circadian clocks in response to MLT or IIK7 (a melatonin type 2 receptor, MT2, agonist) was added to the cultured corneas at different times of the day. We also defined the location of the MT2 receptor within different corneal layers using immunohistochemistry. A long-lasting bioluminescence rhythm was recorded from cultured PER2::LUC cornea and PER2::LUC signal was localized to the corneal epithelium and endothelium. MLT administration in the early night delayed the cornea rhythm, whereas administration of MLT at late night to early morning advanced the cornea rhythm. Treatment with IIK7 mimicked the MLT phase-shifting effect. Consistent with these results, MT2 immunoreactivity was localized to the corneal epithelium and endothelium. Our work demonstrates that MLT entrains the PER2::LUC bioluminescence rhythm in the cornea. Our data indicate that the cornea may represent a model to study the molecular mechanisms by which MLT affects the circadian clock.
Hevia, Montserrat A; Canessa, Paulo; Müller-Esparza, Hanna; Larrondo, Luis F
The circadian clock of the plant model Arabidopsis thaliana modulates defense mechanisms impacting plant-pathogen interactions. Nevertheless, the effect of clock regulation on pathogenic traits has not been explored in detail. Moreover, molecular description of clocks in pathogenic fungi--or fungi in general other than the model ascomycete Neurospora crassa--has been neglected, leaving this type of question largely unaddressed. We sought to characterize, therefore, the circadian system of the plant pathogen Botrytis cinerea to assess if such oscillatory machinery can modulate its virulence potential. Herein, we show the existence of a functional clock in B. cinerea, which shares similar components and circuitry with the Neurospora circadian system, although we found that its core negative clock element FREQUENCY (BcFRQ1) serves additional roles, suggesting extracircadian functions for this protein. We observe that the lesions produced by this necrotrophic fungus on Arabidopsis leaves are smaller when the interaction between these two organisms occurs at dawn. Remarkably, this effect does not depend solely on the plant clock, but instead largely relies on the pathogen circadian system. Genetic disruption of the B. cinerea oscillator by mutation, overexpression of BcFRQ1, or by suppression of its rhythmicity by constant light, abrogates circadian regulation of fungal virulence. By conducting experiments with out-of-phase light:dark cycles, we confirm that indeed, it is the fungal clock that plays the main role in defining the outcome of the Arabidopsis-Botrytis interaction, providing to our knowledge the first evidence of a microbial clock modulating pathogenic traits at specific times of the day.
Santiago A. Plano
Full Text Available Daily interactions between the hypothalamic circadian clock at the suprachiasmatic nucleus (SCN and peripheral circadian oscillators regulate physiology and metabolism to set temporal variations in homeostatic regulation. Phase coherence of these circadian oscillators is achieved by the entrainment of the SCN to the environmental 24-h light:dark (LD cycle, coupled through downstream neural, neuroendocrine, and autonomic outputs. The SCN coordinate activity and feeding rhythms, thus setting the timing of food intake, energy expenditure, thermogenesis, and active and basal metabolism. In this work, we will discuss evidences exploring the impact of different photic entrainment conditions on energy metabolism. The steady-state interaction between the LD cycle and the SCN is essential for health and wellbeing, as its chronic misalignment disrupts the circadian organization at different levels. For instance, in nocturnal rodents, non-24 h protocols (i.e., LD cycles of different durations, or chronic jet-lag simulations might generate forced desynchronization of oscillators from the behavioral to the metabolic level. Even seemingly subtle photic manipulations, as the exposure to a “dim light” scotophase, might lead to similar alterations. The daily amount of light integrated by the clock (i.e., the photophase duration strongly regulates energy metabolism in photoperiodic species. Removing LD cycles under either constant light or darkness, which are routine protocols in chronobiology, can also affect metabolism, and the same happens with disrupted LD cycles (like shiftwork of jetlag and artificial light at night in humans. A profound knowledge of the photic and metabolic inputs to the clock, as well as its endocrine and autonomic outputs to peripheral oscillators driving energy metabolism, will help us to understand and alleviate circadian health alterations including cardiometabolic diseases, diabetes, and obesity.
Lane, Jacqueline M; Chang, Anne-Marie; Bjonnes, Andrew C; Aeschbach, Daniel; Anderson, Clare; Cade, Brian E; Cain, Sean W; Czeisler, Charles A; Gharib, Sina A; Gooley, Joshua J; Gottlieb, Daniel J; Grant, Struan F A; Klerman, Elizabeth B; Lauderdale, Diane S; Lockley, Steven W; Munch, Miriam; Patel, Sanjay; Punjabi, Naresh M; Rajaratnam, Shanthakumar M W; Rueger, Melanie; St Hilaire, Melissa A; Santhi, Nayantara; Scheuermaier, Karin; Van Reen, Eliza; Zee, Phyllis C; Shea, Steven A; Duffy, Jeanne F; Buxton, Orfeu M; Redline, Susan; Scheer, Frank A J L; Saxena, Richa
The risk of type 2 diabetes (T2D) is increased by abnormalities in sleep quantity and quality, circadian alignment, and melatonin regulation. A common genetic variant in a receptor for the circadian-regulated hormone melatonin (MTNR1B) is associated with increased fasting blood glucose and risk of T2D, but whether sleep or circadian disruption mediates this risk is unknown. We aimed to test if MTNR1B diabetes risk variant rs10830963 associates with measures of sleep or circadian physiology in intensive in-laboratory protocols (n = 58-96) or cross-sectional studies with sleep quantity and quality and timing measures from self-report (n = 4,307-10,332), actigraphy (n = 1,513), or polysomnography (n = 3,021). In the in-laboratory studies, we found a significant association with a substantially longer duration of elevated melatonin levels (41 min) and delayed circadian phase of dim-light melatonin offset (1.37 h), partially mediated through delayed offset of melatonin synthesis. Furthermore, increased T2D risk in MTNR1B risk allele carriers was more pronounced in early risers versus late risers as determined by 7 days of actigraphy. Our results provide the surprising insight that the MTNR1B risk allele influences dynamics of melatonin secretion, generating a novel hypothesis that the MTNR1B risk allele may extend the duration of endogenous melatonin production later into the morning and that early waking may magnify the diabetes risk conferred by the risk allele. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
Czeisler, C. A.; Klerman, E. B.
Daily oscillations characterize the release of nearly every hormone. The circadian pacemaker, located in the suprachiasmatic nucleus of the hypothalamus, generates circadian, approximately 24-hour rhythms in many physiologic functions. However, the observed hormonal oscillations do not simply reflect the output of this internal clock. Instead, daily hormonal profiles are the product of a complex interaction between the output of the circadian pacemaker, periodic changes in behavior, light exposure, neuroendocrine feedback mechanisms, gender, age, and the timing of sleep and wakefulness. The interaction of these factors can affect hormonal secretory pulse frequency and amplitude, with each endocrine system differentially affected by these factors. This chapter examines recent advances in understanding the effects on endocrine rhythms of a number of these factors. Sleep exerts a profound effect on endocrine secretion. Sleep is a dynamic process that is characterized by periodic changes in electrophysiologic activity. These electrophysiologic changes, which are used to mark the state and depth of sleep, are associated with periodic, short-term variations in hormonal levels. The secretion of hormones such as renin and human growth hormone are strongly influenced by sleep or wake state, while melatonin and cortisol levels are relatively unaffected by sleep or wake state. In addition, sleep is associated with changes in posture, behavior, and light exposure, each of which is known to affect endocrine secretion. Furthermore, the tight concordance of habitual sleep and wake times with certain circadian phases has made it difficult to distinguish sleep and circadian effects on these hormones. Specific protocols, designed to extract circadian and sleep information semi-independently, have been developed and have yielded important insights into the effects of these regulatory processes. These results may help to account for changes in endocrine rhythms observed in circadian
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
Full Text Available Experimental evidence indicates that during pre-visual stages of development in mammals, circadian regulation is still not under the control of the light-entrainable hypothalamic pacemaker, raising the possibility that the circadian rhythmicity that occurs during postnatal development is under the control of peripheral oscillators, such as the main olfactory bulb (MOB. We evaluated the outcome of olfactory bulbectomy on the temporal pattern of core body temperature and gross locomotor activity in newborn rabbits. From postnatal day 1 (P1, pups were randomly assigned to one of the following conditions: intact pups (INT, intact pups fed by enteral gavage (INT+ENT, sham operated pups (SHAM, pups with unilateral lesions of the olfactory bulb (OBx-UNI, and pups with bilateral lesions of the olfactory bulb (OBx-BI. At the beginning of the experiment, from P1-8, the animals in all groups were fed at 11:00, from P9-13 the feeding schedule was delayed 6 h (17:00, and finally, from P14-15 the animals were subjected to fasting conditions. The rabbit pups of the INT, INT+ENT, SHAM and OBx-UNI groups exhibited a clear circadian rhythmicity in body temperature and locomotor activity, with a conspicuous anticipatory rise hours prior to the nursing or feeding schedule, which persisted even during fasting conditions. In addition, phase delays in the nursing or feeding schedule induced a clear phase shift in both parameters. In contrast, the OBx-BI group exhibited atypical rhythmicity in both parameters under entrained conditions that altered the anticipatory component, as well as deficient phase control of both rhythms. The present results demonstrate that the expression of circadian rhythmicity at behavioral and physiological levels during early stages of rabbit development largely depends on the integrity of the main olfactory bulb.
Nováková, Marta; Nevsímalová, Sona; Príhodová, Iva; Sládek, Martin; Sumová, Alena
Smith-Magenis syndrome (SMS) is associated with sleep disturbances and disrupted melatonin production. The study aimed to ascertain whether the sleep and melatonin production anomalies in SMS patients may be due to an alteration of the molecular mechanism of the circadian clock. Five SMS patients (3-17 yr old) and five healthy age-matched control subjects were involved in the study. Saliva and buccal scrub samples were collected every 4 h during a 24-h period. Daily profiles of melatonin were determined in saliva using a direct double-antibody radioimmunoassay. Daily profiles of clock gene mRNA levels (Per1, Per2, and Rev-erbα) were determined in buccal scrub samples by RT-PCR. In controls, melatonin levels were elevated during the nighttime and very low during the daytime. Daily profiles of clock genes, Per1, Per2, and Rev-erbα, mRNA levels in buccal mucosa exhibited significant and mutually synchronized circadian variations (Per1 and Rev-erbα: P < 0.001; Per2: P < 0.05); the mRNA levels were elevated during the daytime and decreased during the nighttime. In SMS patients, melatonin profiles were significantly altered compared with controls, being phase reversed, phase advanced, depressed, or abolished. Only Per1 and Rev-erbα mRNA profiles exhibited significant circadian rhythms (P < 0.05); the Per2 expression exhibited high variability, and the profile was out of phase with the other clock genes. Our findings suggest that the anomalies in melatonin profiles of SMS patients might be due to a disturbance of the molecular circadian clockwork.
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....../night variations in gene expression in the circadian system as well as in the whole brain and peripheral tissues have, during the last decade, been performed. However, studies of circadian changes in the proteome have been less investigated. In this survey, the anatomy and function of the circadian......-generating system in mammals is described, and recent proteomic studies that investigate day/night changes in the retina, SCN, and pineal gland are reviewed. Further circadian changes controlled by the SCN in gene and protein expression in the liver are discussed....
Geyfman, Mikhail; Kumar, Vivek; Liu, Qiang; Ruiz, Rolando; Gordon, William; Espitia, Francisco; Cam, Eric; Millar, Sarah E.; Smyth, Padhraic; Ihler, Alexander; Takahashi, Joseph S.; Andersen, Bogi
The role of the circadian clock in skin and the identity of genes participating in its chronobiology remain largely unknown, leading us to define the circadian transcriptome of mouse skin at two different stages of the hair cycle, telogen and anagen. The circadian transcriptomes of telogen and anagen skin are largely distinct, with the former dominated by genes involved in cell proliferation and metabolism. The expression of many metabolic genes is antiphasic to cell cycle-related genes, the former peaking during the day and the latter at night. Consistently, accumulation of reactive oxygen species, a byproduct of oxidative phosphorylation, and S-phase are antiphasic to each other in telogen skin. Furthermore, the circadian variation in S-phase is controlled by BMAL1 intrinsic to keratinocytes, because keratinocyte-specific deletion of Bmal1 obliterates time-of-day–dependent synchronicity of cell division in the epidermis leading to a constitutively elevated cell proliferation. In agreement with higher cellular susceptibility to UV-induced DNA damage during S-phase, we found that mice are most sensitive to UVB-induced DNA damage in the epidermis at night. Because in the human epidermis maximum numbers of keratinocytes go through S-phase in the late afternoon, we speculate that in humans the circadian clock imposes regulation of epidermal cell proliferation so that skin is at a particularly vulnerable stage during times of maximum UV exposure, thus contributing to the high incidence of human skin cancers. PMID:22753467
Brager, Allison J; Stowie, Adam C; Prosser, Rebecca A; Glass, J David
Cocaine is a potent disruptor of photic and non-photic pathways for circadian entrainment of the master circadian clock of the suprachiasmatic nucleus (SCN). These actions of cocaine likely involve its modulation of molecular (clock gene) components for SCN clock timekeeping. At present, however, the physiological basis of such an interaction is unclear. To address this question, we compared photic and non-photic phase-resetting responses between wild-type (WT) and Per2 mutant mice expressing nonfunctional PER2 protein to systemic and intra-SCN cocaine administrations. In the systemic trials, cocaine was administered i.p. (20 mg/kg) either at midday or prior to a light pulse in the early night to assess its non-photic and photic behavioral phase-resetting actions, respectively. In the intra-SCN trial, cocaine was administered by reverse microdialysis at midday to determine if the SCN is a direct target for its non-photic phase-resetting action. Non-photic phase-advancing responses to i.p. cocaine at midday were significantly (∼3.5-fold) greater in Per2 mutants than WTs. However, the phase-advancing action of intra-SCN cocaine perfusion at midday did not differ between genotypes. In the light pulse trial, Per2 mutants exhibited larger photic phase-delays than did WTs, and the attenuating action of cocaine on this response was proportionately larger than in WTs. These data indicate that the Per2 clock gene is a potent modulator of cocaine's actions in the circadian system. With regard to non-photic phase-resetting, the SCN is confirmed as a direct target of cocaine action; however, Per2 modulation of this effect likely occurs outside of the SCN. Copyright © 2013 Elsevier B.V. All rights reserved.
Ihara NL (in press) The tau mutation destabilizes the circadian system of golden hamste,’s Fifth Sapporo Symposium on Biological Rhythms Hokkaido...Shimomura K and Ihara NL (in press) The tau mutation destabilizes the circadian system of golden hamsters Fifth Sapporo Symposium oh Biological Rhythms...Switzerland, April 5 University of Pisa, Dipartimento di Scienze del Comportamento Animale e dell’Uomo, invited lecture: "Circadian Organization in the
Connolly, J.J.; Moore-Ede, M.C.
Nuclear power plants must operate 24 h, 7 days a week. For the most part, shift schedules currently in use at nuclear power plants have been designed to meet operational needs without considering the biological clocks of the human operators. The development of schedules that also take circadian principles into account is a positive step that can be taken to improve plant safety by optimizing operator alertness. These schedules reduce the probability of human errors especially during backshifts. In addition, training programs that teach round-the-clock workers how to deal with the problems of shiftwork can help to optimize performance and alertness. These programs teach shiftworkers the underlying causes of the sleep problems associated with shiftwork and also provide coping strategies for improving sleep and dealing with the transition between shifts. When these training programs are coupled with an improved schedule, the problems associated with working round-the-clock can be significantly reduced
Fathallah-Shaykh, Hassan M; Bona, Jerry L; Kadener, Sebastian
Eukaryotic circadian clocks include interconnected positive and negative feedback loops. The clock-cycle dimer (CLK-CYC) and its homolog, CLK-BMAL1, are key transcriptional activators of central components of the Drosophila and mammalian circadian networks, respectively. In Drosophila, negative loops include period-timeless and vrille; positive loops include par domain protein 1. Clockwork orange (CWO) is a recently discovered negative transcription factor with unusual effects on period, timeless, vrille, and par domain protein 1. To understand the actions of this protein, we introduced a new system of ordinary differential equations to model regulatory networks. The model is faithful in the sense that it replicates biological observations. CWO loop actions elevate CLK-CYC; the transcription of direct targets responds by integrating opposing signals from CWO and CLK-CYC. Loop regulation and integration of opposite transcriptional signals appear to be central mechanisms as they also explain paradoxical effects of period gain-of-function and null mutations.
Masera, R G; Carignola, R; Staurenghi, A H; Sartori, M L; Lazzero, A; Griot, G; Angeli, A
Natural Killer (NK) cells are a lymphocyte subset actively involved in cytotoxicity against tumor-transformed and virus-infected cells; they are a reliable model for the study of neuroendocrine-immune interactions. In previous works we demonstrated that in healthy subjects NK activity of peripheral blood mononuclear cells (PBMC) and susceptibility to endogenous modifiers display statistically validated circadian rhythms. In rheumatoid arthritis (RA) and in other autoimmune rheumatic diseases abnormalities of the circadian rhythm of serum cortisol and altered levels of NK cell activity have been reported. We evaluated the circadian pattern of NK cell activity in 7 hospitalized patients with autoimmune rheumatic diseases (4 RA, 1 scleroderma, 2 mixed connective tissue disease). Temporal variations of in vitro responses to either positive recombinant (immune interferon, r IFN-gamma IFN-gamma: 650 IU/ml; recombinant interleukin-2, r IL-2 IL-2: 100 IU/ml) or negative (cortisol: 10(-6) M) modifiers were also studied. Blood was drawn at 4h intervals for 24 h, starting at 0800. PBMC preparations were immediately separated and incubated for 20h in the presence or absence of modifiers. NK activity was assessed with a direct non-radiometric 4h cytolytic assay, using K 562 cells as targets. Significant circadian variations of spontaneous NK activity were documented only in women with RA, with a peak in the evening hours and a minimum in the night or in the early morning (p < 0.05, PR 51.5%, phi 1829). Population-mean cosinor analysis did not yield detection of significant circadian variations of in vitro responsiveness to modifiers.(ABSTRACT TRUNCATED AT 250 WORDS)
Djeddi, Djamal; Cantin, Danny; Samson, Nathalie; Tian, Hao; Praud, Jean-Paul
It is presently recommended that oral feeding be started in premature infants as soon as possible, often at an age at which nasal continuous positive airway pressure (nCPAP) is still required for ventilatory support. Our previous data showed that application of nCPAP up to 10 cmH2O in full-term lambs had no deleterious effect on cardiorespiratory safety, feeding efficiency, or on nutritive swallowing-breathing coordination. Besides fear of swallowing-breathing coordination disturbances, esophageal motility disruption by nCPAP could be a reason to delay oral feeding. To our knowledge, no study has focused on the effects of nCPAP on esophageal motility in the neonatal period. The aim of the present study was therefore to further assess the effects of nCPAP on oral feeding by assessing its effects on the esophageal phase of nutritive swallowing (nutritive esophagodeglutition). Six full-term lambs, ages 2 to 3 days, underwent esophageal multichannel intraluminal impedance-pH monitoring. Lambs were bottle-fed under 2 randomized conditions, namely spontaneous breathing and nCPAP 6 cmH(2)O. Beyond confirmation of unaltered feeding efficiency, analysis of multiple variables measured by impedance monitoring revealed that nCPAP 6 does not alter nutritive esophagodeglutition in any way (nCPAP vs spontaneous breathing, P > 0.1 for all variables). offering further support to neonatologists pleading for initiation of oral feeding in infants still on nCPAP, the present results set the foundations for similar clinical studies in preterm human infants to confirm the absence of effects of nCPAP on nutritive swallowing.
Larsen, Bjørn Strøier; Kumarathurai, Preman; Nielsen, Olav W
AIMS: The aim of the study was to assess a possible circadian variation of premature atrial contractions (PACs) in a community-based population and to determine if the daily variation could be used to assess a more vulnerable period of PACs in predicting later incidence of atrial fibrillation (AF...... subgroups were studied based on a cut-off point of ≥720 PACs/day termed frequent PACs (n = 66) and not frequent PACs with ... variation in heart rate. After adjusting for relevant risk factors, the risk of AF was equal in all time intervals throughout the day. CONCLUSION: Premature atrial contractions showed a circadian variation in subjects with frequent PACs. No specific time interval of the day was more predictive of AF than...
Brooke H Miller
Full Text Available Over the past two decades, it has become clear just how much of our physiology is under the control of the suprachiasmatic nucleus (SCN and the cell-intrinsic molecular clock that ticks with a periodicity of approximately 24 hours. The SCN prepares our digestive system for meals, our adrenal axis for the stress of waking up in the morning, and the genes expressed in our muscles when we prepare to exercise, Long before molecular studies of genes such as Clock, Bmal1, and the Per homologs were possible, it was obvious that female reproductive function was under strict circadian control at every level of the hypothalamic-pituitary-gonadal (HPG axis, and in the establishment and successful maintenance of pregnancy. This review highlights our current understanding of the role that the SCN plays in regulating female reproductive physiology, with a special emphasis on the advances made possible through the use of circadian mutant mice.
Thun, Eirunn; Bjorvatn, Bjørn; Flo, Elisabeth; Harris, Anette; Pallesen, Ståle
Sleep deprivation and time of day are both known to influence performance. A growing body of research has focused on how sleep and circadian rhythms impact athletic performance. This review provides a systematic overview of this research. We searched three different databases for articles on these issues and inspected relevant reference lists. In all, 113 articles met our inclusion criteria. The most robust result is that athletic performance seems to be best in the evening around the time when the core body temperature typically is at its peak. Sleep deprivation was negatively associated with performance whereas sleep extension seems to improve performance. The effects of desynchronization of circadian rhythms depend on the local time at which performance occurs. The review includes a discussion of differences regarding types of skills involved as well as methodological issues. Copyright © 2014 Elsevier Ltd. All rights reserved.
Full Text Available There are a few rhythms of our daily lives that we are under the influence. One of them is characterized by predictable changes over a 24-hour timescale called circadian clock. This cellular clock is coordinated by the suprachiasmatic nucleus in the anterior hypothalamus. The clock consist of an autoregulatory transcription-translation feedback loop compose of four genes/proteins; BMAL1, Clock, Cyrptochrome, and Period. BMAL 1 and Clock are transcriptional factors and Period and Cyrptochrome are their targets. Period and Cyrptochrome dimerize in the cytoplasm to enter the nucleus where they inhibit Clock/BMAL activity.It has been demonstrate that circadian clock plays an important role cellular proliferation, DNA damage and repair mechanisms, checkpoints, apoptosis and cancer.
Scherrer, Vsevolod; Roberts, Richard; Preckel, Franzis
Meta-analyses suggest that morning-oriented students obtain better school grades than evening-oriented students. This finding has generally been found for students in high school using self-report data for the assessment of circadian preference. Two studies (N = 2718/192) investigated whether these findings generalize across samples (i.e. elementary school-aged students) and methods (i.e. parent reports). These studies also explored whether the relation between circadian preference and school achievement could be explained within an expectancy-value framework. To this end, the Lark-Owl Chronotype Indicator (LOCI) was modified to obtain parents' evaluations of their children's circadian preference, while students completed a battery of assessments designed to explore the test-criterion evidence. Structural equation modeling and correlational analyses revealed: (1) morning and evening orientation were two separable factors of children's circadian preference; (2) correlations with behavioral (e.g. sleep and eating times) and psychological (e.g. cognitive ability) data supported the test-criterion validity of both factors; (3) morning orientation was positively related to school achievement and (4) consistent with an expectancy-value framework this relation was mediated by children's academic self-concept (ASC). These findings have important research and policy implications for considering circadian preference in the schooling of elementary students.
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.
Sumová, Alena; Bendová, Zdeňka; Sládek, Martin; El-Hennamy, Rehab; Matějů, Kristýna; Polidarová, Lenka; Sosniyenko, Serhiy; Illnerová, Helena
Roč. 57, Suppl.3 (2008), S139-S148 ISSN 0862-8408 R&D Projects: GA ČR GA309/08/0503; GA AV ČR(CZ) IAA500110605; GA MŠk(CZ) LC554 Grant - others:EC(XE) LSH-2004-115-4-018741 Institutional research plan: CEZ:AV0Z50110509 Keywords : circadian clock * ontogenesis * suprachiasmatic nucleus Subject RIV: FH - Neurology Impact factor: 1.653, year: 2008
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.
Thurley, Kevin; Herbst, Christopher; Wesener, Felix; Koller, Barbara; Wallach, Thomas; Maier, Bert; Kramer, Achim; Westermark, Pål O
Circadian (24-h) rhythms influence the behavior and physiology of many organisms. These rhythms are generated at the gene expression level, causing the waxing and waning of protein abundances. Metabolic enzymes are affected, but the principles for the propagation of enzyme rhythmicity to cellular metabolism as quantified by fluxes through metabolic pathways and metabolite concentrations are not understood. We used the mathematics of chemical kinetics to systematically investigate how rhythms ...
Full Text Available During our daily activities, we experience variations in our cognitive performance, which is often accompanied by cravings for small rewards, such as consuming coffee or chocolate. This indicates that the time of day, cognitive performance and reward may be related to one another. This review will summarize data that describes the influence of the circadian clock on addiction and mood-related behavior and put the data into perspective in relation to memory processes.
...: test the hypothesis that multiple nightly bouts of exercise will induce significant delays in the endogenous circadian rhythms of core body temperature, plasma melatonin, reaction time, alertness...
Full Text Available The circadian clock is a transcriptional network that functions to regulate the expression of genes important in the anticipation of changes in cellular and organ function. Recent studies have revealed that the recognition of pathogens and subsequent initiation of inflammatory responses are strongly regulated by a macrophage-intrinsic circadian clock. We hypothesized that the circadian pattern of gene expression might be influenced by inflammatory stimuli and that loss of circadian function in immune cells can promote pro-inflammatory behavior. To investigate circadian rhythms in inflammatory cells, peritoneal macrophages were isolated from mPer2luciferase transgenic mice and circadian oscillations were studied in response to stimuli. Using Cosinor analysis, we found that LPS significantly altered the circadian period in peritoneal macrophages from mPer2luciferase mice while qPCR data suggested that the pattern of expression of the core circadian gene (Bmal1 was disrupted. Inhibition of TLR4 offered protection from the LPS-induced impairment in rhythm, suggesting a role for toll-like receptor signaling. To explore the mechanisms involved, we inhibited LPS-stimulated NO and superoxide. Inhibition of NO synthesis with L-NAME had no effect on circadian rhythms. In contrast, inhibition of superoxide with Tempol or PEG-SOD ameliorated the LPS-induced changes in circadian periodicity. In gain of function experiments, we found that overexpression of NOX5, a source of ROS, could significantly disrupt circadian function in a circadian reporter cell line (U2OS whereas iNOS overexpression, a source of NO, was ineffective. To assess whether alteration of circadian rhythms influences macrophage function, peritoneal macrophages were isolated from Bmal1-KO and Per-TKO mice. Compared to WT macrophages, macrophages from circadian knockout mice exhibited altered balance between NO and ROS release, increased uptake of oxLDL and increased adhesion and migration
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.
Videnovic, Aleksandar; Golombek, Diego
Impaired sleep and alertness, initially recognized by James Parkinson in his famous monograph "An Essay on the Shaking Palsy" in 1817, is one of the most common and disabling nonmotor symptoms of Parkinson's disease (PD). It is only recently, however, that sleep disturbances in PD have received the attention of medical and research community. Dopamine, the major neurotransmitter implicated in the pathogenesis of PD, plays a pivotal role in the regulation of sleep and circadian homeostasis. Sleep dysfunction affects up to 90% of patients with PD, and may precede the onset of the disease by decades. Sleep dysfunction in PD may be categorized into disturbances of overnight sleep and daytime alertness. Etiology of impaired sleep and alertness in PD is multifactorial. Co-existent primary sleep disorders, medication side effects, overnight re-emergence of motor symptoms, and primary neurodegeneration itself, are main causes of sleep disruption and excessive daytime sleepiness among patients with PD. Increasing body of evidence suggests that the circadian system becomes dysregulated in PD, which may lead to poor sleep and alertness. Treatment options are limited and frequently associated with unwanted side effects. Further studies that will examine pathophysiology of sleep dysfunction in PD, and focus on novel treatment approaches are therefore very much needed. In this article we review the role of dopamine in regulation of sleep and alertness and discuss main sleep and circadian disturbances associated with PD. Copyright © 2012 Elsevier Inc. All rights reserved.
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.
Escobar, Carolina; Salgado, Roberto; Rodriguez, Katia; Blancas Vázquez, Aurea Susana; Angeles-Castellanos, Manuel; Buijs, Ruud M
Food is a potent time signal for the circadian system and has shown to entrain and override temporal signals transmitted by the biological clock, the suprachiasmatic nucleus, which adjusts mainly to the daily light/dark (LD) alternation. Organisms mostly ingest food in their active period and this permits a correct coordination between the LD and the food elicited time signals with the circadian system. Under conditions when feeding opportunities are shifted to the usual resting/sleep phase, the potent entraining force of food, shifts circadian fluctuations in several tissues, organs, and brain structures toward meal time, resulting a desynchrony within the body and between the organism and the external LD cycle. The daily scheduled access to a palatable snack exerts similar changes specifically to brain areas involved in motivation and reward responses. This review describes the phenomenology of food entrainment and entrainment by a palatable snack. It suggests how scheduled feeding can lead to food addiction and how shifted feeding schedules toward the sleep phase can result in altered ingestive behavior, obesity and disturbed metabolic responses. Copyright © 2011 Elsevier Inc. All rights reserved.
Dang, Fabin; Sun, Xiujie; Ma, Xiang; Wu, Rong; Zhang, Deyi; Chen, Yaqiong; Xu, Qian; Wu, Yuting; Liu, Yi
Although food availability is a potent synchronizer of the peripheral circadian clock in mammals, the underlying mechanisms are unclear. Here, we show that hepatic Bmal1, a core transcription activator of the molecular clock, is post-transcriptionally regulated by signals from insulin, an important hormone that is temporally controlled by feeding. Insulin promotes postprandial Akt-mediated Ser42-phosphorylation of Bmal1 to induce its dissociation from DNA, interaction with 14-3-3 protein and subsequently nuclear exclusion, which results in the suppression of Bmal1 transcriptional activity. Inverted feeding cycles not only shift the phase of daily insulin oscillation, but also elevate the amplitude due to food overconsumption. This enhanced and reversed insulin signalling initiates the reset of clock gene rhythms by altering Bmal1 nuclear accumulation in mouse liver. These results reveal the molecular mechanism of insulin signalling in regulating peripheral circadian rhythms. PMID:27576939
Van der Heijden, Kristiaan B; Smits, Marcel G; Van Someren, Eus J W; Gunning, W Boudewijn
To investigate whether ADHD-related sleep-onset insomnia (SOI) is a circadian rhythm disorder, we compared actigraphic sleep estimates, the circadian rest-activity rhythm, and dim light melatonin onset (DLMO) in ADHD children having chronic idiopathic SOI with that in ADHD children without sleep problems. Participants were 87 psychotropic-medication-naïve children, aged 6 to 12 yrs, with rigorously diagnosed ADHD and SOI (ADHD-SOI) and 33 children with ADHD without SOI (ADHD-noSOI) referred from community mental health institutions and pediatric departments of non-academic hospitals in The Netherlands. Measurements were 1 wk, 24 h actigraphy recordings and salivary DLMO. The mean (+/-SD) sleep onset time was 21:38 +/- 0:54 h in ADHD-SOI, which was significantly (p insomnia show a delayed sleep phase and delayed DLMO, compared with ADHD children without SOI.
Sun, Qinfei; Guerrero, Josep M.; Jing, Tianjun
An active islanding detection method based on Frequency-Locked Loop (FLL) for constant power controlled inverter in single-phase microgrid is proposed. This method generates a phase shift comparing the instantaneous frequency obtained from FLL unit with the nominal frequency to modify the reference...
Full Text Available Rest activity pattern was studied in wild-captured males of Octodon degus (n=9, Octodon bridgesi (n=3, and Spalacopus cyanus (n=6 (Rodentia: Octodontidae. Ten-minute resolution actograms were constructed from data obtained by an automated acquisition system. After two months of habituation to a stable light-dark schedule, recordings were performed in isolation chambers under a 12: 12 Light Dark schedule. A free-running period (constant darkness was recorded for O. bridgesi and S. cyanus. O. degus displayed a crepuscular pattern of rest activity rhythm. Entrained O. bridgesi and S. cyanus displayed nocturnal preference, with rest anticipating light phase and without crepuscular activity bouts. Under constant darkness, active phase occurred at subjective night in O. bridgesi and S. cyanus. Wild-captured O. bridgesi and S. cyanus possess a circadian driven nocturnal preference, while wild O. degus displays a crepuscular profile. Diurnal active phase preference of wild S. cyanus colonies observed in the field could not be explained solely by photic entrainment, since social and/or masking processes appear to be operative. The genus Octodon includes species with diverse chronotypes. We propose that crepuscular diurnal pattern observed in O. degus is a recent acquisition among the octodontid lineage