Specific Times Of Day Research Articles

CNSC-29. CIRCADIAN SIGNALING IN GLIOBLASTOMA SYNCHRONIZES TUMOR DAILY RHYTHMS AND REGULATES TUMOR PROGRESSION

Abstract Glioblastoma (GBM) is the most common primary brain tumor in adults with a poor prognosis despite aggressive therapy. A recent, retrospective clinical study found that administering Temozolomide in the morning increased patient overall survival by 6 months compared to evening. Previous work has shown that murine and human models of GBM have cell-intrinsic circadian rhythms in expression of the core clock genes Bmal1 and Per2. This suggests that GBM has circadian rhythms that entrain to the hosts’ central clock. Understanding the mechanisms underlying circadian entrainment and tumor growth in GBM is essential to determine whether regulation of tumor biology and susceptibility to therapies varies with time of day. Here, we tested the hypothesis that daily host signaling regulates tumor growth and synchronizes circadian rhythms in GBM. We found that GBM cells transduced with luciferase reporters to record clock gene expression have intrinsic circadian rhythms, with Bmal1 peaking 8-12 h before Per2 in murine and human cell lines in vitro and in vivo. Further, intrinsic circadian rhythms in clock gene expression in GBM entrain to the host through glucocorticoid signaling, regardless of tumor type or host immune status. We found daily glucocorticoids (i.e., Dexamethasone) promoted or suppressed GBM growth depending on time of day of administration and on the clock gene, Bmal1. Blocking circadian signals, like VIP or glucocorticoids, dramatically slowed GBM growth and disease progression. Our results suggest that GBM tumors entrain to the circadian circuit of the brain and depend on clock-controlled cues like VIP and glucocorticoids to grow at specific times of day. This work may inform personalized circadian medicine to improve individual GBM patient outcomes.

Chorus Organization in a Neotropical Forest Cicada

In many species of animals, males aggregate in particular locations and produce calls to attract searching females for reproduction. One striking feature of such choruses is synchronization. On a scale of hours, choruses are often concentrated at particular times of day, such as dawn or dusk. On a scale of seconds, males may also synchronize the rhythm of their calls with one another. While synchronized calling at this scale suggests benefits acting at the collective level, competitive interactions between males to attract females can also lead to synchronized calling as an epiphenomenon. Why males in some species synchronize the rhythm of their calls is still debated, and more work is needed to understand the evolution of this behavior. I investigated chorus organization in the Emerald cicada (Zammara smaragdula), a Neotropical forest cicada in southern Belize, to explore these issues. Choruses in this species occurred at dawn and dusk and, occasionally, during daytime. There was no evidence for synchronization in the rhythm of calls among males, as bouts of collective calling occurred after quiet intervals of variable rather than fixed durations. The temporal aggregation of calls in this species thus probably emerged from competitive interactions among males to attract females. The degree of temporal overlap in the calls of males during a chorus varied as a function of chorus phase and time of day, suggesting flexibility in chorus organization, perhaps in relation to temporal variations in factors such as the number of calling cicadas, the number of predators present or ambient temperature during a chorus.

Differential regulation of sleep by blue, green, and red light in Drosophila melanogaster.

Exposure to blue-enriched light from electronic devices is an emergent disruptor of human sleep, especially at particular times of day. Further dissection of this phenomenon necessitates modeling in a tractable model organism. Thus, we investigated the effects of light color on sleep in Drosophila melanogaster. We measured sleep in red-eyed Canton-S (CS) and white-eyed w 1118 flies in baseline 12:12 light/dark conditions and experimental conditions with light-color (blue, red, or green) exposure for all 12 h of daylight or 3 h in the morning or evening. Blue light reduced daytime and nighttime sleep in CS but not in w 1118, potentially indicating a role for the compound eye in blue light's effects on fruit fly sleep. Red light, especially in the evening, reduced sleep during exposure in both strains. Green light had minimal effects on sleep in CS flies, but evening exposure reduced sleep in w 1118 flies, mimicking red light's effects. In conclusion, light's effects on sleep in D. melanogaster are dependent on wavelength and time-of-day. Future studies will aim to dissect these mechanisms genetically.

Variance in odds ratios for estimating the deterrent effect of darkness on cycling: Variation due to the choice of case and control hours.

Comparing the counts of cyclists travelling at specific times of day is one approach to measuring the impact of ambient light level. Here we investigate one source of variance in the magnitude of change seen in previous research-the choice of case and control hour. This was done through an analysis of cyclist flows using data from multiple automated cyclist counters in five cities (Arlington, Bergen, Berlin, Birmingham and Leeds) to determine the odds ratios (OR) for each combination of case and control hour. The results tend to reveal odds ratios above 1.0 indicating that cycling can be deterred by darkness. The odds ratios varied with the choice of case and control hour. For two cities (Birmingham and Leeds), the impact was small, with little difference in ORs between any case and control hour combination. For three cities the variance in ORs was larger. To represent the impact of darkness on cycling flows across the range of case and control hours we suggest the Mantel-Haenszel pooled odds ratio is used, in which the odds ratio for each combination of case and control hour is weighted by the total number of cyclists in that combination. This suggested a statistically significant (p<0.001) deterrent effect of darkness in all five cities.

Diazepam nasal spray administration is effective to control seizure clusters irrespective of time of day

IntroductionNeurologic circadian influences, including sleep/wake transitions, processes (e.g., hormonal variation), and behavioral patterns (e.g., consumption of food and oral medications), may affect seizure patterns. Specific circadian patterns of seizures have been reported depending on type, onset location, and severity; however, data on patterns for patients with seizure clusters and effectiveness of rescue therapy by time of day are limited.MethodsWe conducted post hoc analyses using patient diary data from the phase 3 safety study of diazepam nasal spray, which is indicated for acute treatment of seizure clusters in patients with epilepsy aged ≥6 years. Patients were administered age- and weight-based doses; second doses could be administered if needed to control a seizure cluster. We assessed clock timing of seizure-cluster onset along with second-dose use as a proxy for effectiveness. Treatment-emergent adverse events were recorded.ResultsSeizure-cluster onset was observed to be generally highest during mornings and late evenings and lowest in the early evening and middle of the night. Second-dose use was not consistently associated with a specific time of day. The safety profile was consistent with that expected from previous studies of diazepam nasal spray.ConclusionThese results suggest that diazepam nasal spray can be effectively administered at any time of day.

Circadian regulation of macromolecular complex turnover and proteome renewal

Although costly to maintain, protein homeostasis is indispensable for normal cellular function and long-term health. In mammalian cells and tissues, daily variation in global protein synthesis has been observed, but its utility and consequences for proteome integrity are not fully understood. Using several different pulse-labelling strategies, here we gain direct insight into the relationship between protein synthesis and abundance proteome-wide. We show that protein degradation varies in-phase with protein synthesis, facilitating rhythms in turnover rather than abundance. This results in daily consolidation of proteome renewal whilst minimising changes in composition. Coupled rhythms in synthesis and turnover are especially salient to the assembly of macromolecular protein complexes, particularly the ribosome, the most abundant species of complex in the cell. Daily turnover and proteasomal degradation rhythms render cells and mice more sensitive to proteotoxic stress at specific times of day, potentially contributing to daily rhythms in the efficacy of proteasomal inhibitors against cancer. Our findings suggest that circadian rhythms function to minimise the bioenergetic cost of protein homeostasis through temporal consolidation of protein turnover.

Characteristics of Cardiorespiratory Failure Preceding Seizure-Induced Mortality in SSKcnj16−/− Rats

Epilepsy is a common, chronic neurological condition characterized by repeated, uncontrolled seizures. These patients are at high risk for cardiorespiratory failure (CRF) and Sudden Unexpected Death in Epilepsy (SUDEP) — the mechanisms of which remain unknown. Most SUDEP events are unwitnessed at night suggesting a circadian influence on seizure-induced mortality. Here we studied cardiorespiratory (CR) function continuously (24/7) in a rat model of audiogenic seizures (SSKcnj16−/− rats) in which repeated seizures have been shown to cause progressive respiratory suppression and mortality. We hypothesized repeated seizures in SSKcnj16−/− rats also lead to 1) progressive dysfunction of post-ictal heart rate (HR) and blood pressure (BP) responses, and 2) cause death via cardiorespiratory failure most frequently when seizures occur after the onset of the inactive period (8am) or prior to the onset of the active phase (4pm). Age matched male and female SSKcnj16−/− rats were implanted with a carotid pressure telemeter and housed in a chronic monitoring plethysmograph with HD video to continuously measure breathing, BP, and HR. Audiogenic seizures (1/day (d) for up to 10d) were induced at a specific time of day and the physiologic data analyzed. Consistent with previous findings, repeated generalized tonic-clonic seizures (GTCSs) caused acute ictal/post-ictal apnea and transient respiratory rate suppression for ~5 minutes post-ictal which was exacerbated with additional seizures (n=6). In addition, GTCSs induced progressively greater transient post-ictal HR suppression and increased BP (n=3; p&lt;0.05 on days 8-10 compared to days 1-3). When seizures occurred at either 8am or 4pm, female SSKcnj16−/− rats had a 10% survival probability (18/20 died) and males had a 40% survival probability (12/20 died). These data combined with previous studies in which seizures were induced throughout the light period showed a higher percentage of deaths at specific times of day: &lt;10am (14%; n=81), 10am-2pm (3%; n=225), 2pm-7pm (8%; n=338). On average seizure-related mortality occurred 2-3 hours after seizures (20 of 30 events) and occurred throughout the 10-day protocol resulting from either moderate (score 2; 53%) or severe (score 3-4; 47%) seizures (Modified Racine Scale). Specific characteristics of death events (n=11-19) included transiently increased BP (+20mmHg) and tidal volume (+0.5 mL/100g; VT) but decreased HR (-50 beats/min), breathing frequency (-50 breaths/min; FB) and ventilation (-20 mL/min/100g; VE). These CR measures then returned to baseline until ~60 minutes post-seizure when there was a secondary decline in BP (-80 mmHg), elevated HR (+100 beats/min), and a concomitant progressive decline in VT and VE prior to terminal apnea/asystole. These data show acute progressive CR suppression with repeated seizures and seizure-induced CRF (tidal volume-mediated decreased ventilation and severe hypotension) leading to death, where time of day for seizure induction contributed to higher mortality rates. This model provides useful insight into the effects of seizures on CR function and understanding the mechanisms of SUDEP, with the ultimate goal of reducing the risk of SUDEP in patients with epilepsy. Supported by NIH HL122358 (MRH). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Association of largest meal timing and eating frequency with body mass index and obesity

Background and AimsThe circadian pattern of eating behaviors has garnered increasing interest as a strategy for obesity prevention and weight loss. It is believed that the benefits stem from aligning food intake with the body's natural daily rhythms. However, the existing body of evidence is limited in scale and scope and there has been insufficient evaluation of temporal eating behaviors, such as the specific time of day in which the highest calorie consumption occurs, meal frequency, and distribution. This research aims to explore the association between the timing of the largest meal of the day and eating frequency with Body Mass Index (BMI) and obesity. MethodsParticipants (n=2 050, 18-65y) were part of an exploratory cross-sectional and population-based research, with data collection in a virtual environment. Linear regression analyses and restricted cubic splines evaluated differences in BMI associated with independent eating variables [timing of the largest meal, number of meals/day (as continuous and categorical: ≤3 or >3/day), and each largest meal of the day (breakfast/lunch/dinner)]. Logistic regression models were fitted to assess Odds Ratios (OR) and 95% Confidence Intervals (CI) of obesity associated with the same independent variables. ResultsOur main findings were that the timing of the largest meal and reporting dinner as the largest meal were associated with higher values of BMI (respectively, 0.07Kg/m2 and 0.85Kg/m2,) and increased odds of obesity [respectively OR(95%CI):1.04(1.01,1.08), and OR(95%CI):1.67(1.18,2.38)]. Those who realized more than 3 meals/day presented lower values of BMI (-0.14Kg/m2) and 32% lower odds of having obesity [OR(95%CI):0.68(0.52,0.89)]. Reporting lunch as the largest meal also protected against obesity [OR(95%CI):0.71(0.54,0.93)]. These associations were statistically significant and independent of sex, age, marital status, education level, diet quality, sleep duration, and weekly frequency of physical exercise. ConclusionHaving the largest meal earlier in the day, concentrating the majority of caloric intake during lunch, and consuming more than three meals a day, may present a promising intervention for preventing and treating obesity/overweight.

Does darkness increase the risk of certain types of crime? A registered report protocol.

Evidence about the relationship between lighting and crime is mixed. Although a review of evidence found that improved road / street lighting was associated with reductions in crime, these reductions occurred in daylight as well as after dark, suggesting any effect was not due only to changes in visual conditions. One limitation of previous studies is that crime data are reported in aggregate and thus previous analyses were required to make simplifications concerning types of crimes or locations. We will overcome that by working with a UK police force to access records of individual crimes. We will use these data to determine whether the risk of crime at a specific time of day is greater after dark than during daylight. If no difference is found, this would suggest improvements to visual conditions after dark through lighting would have no effect. If however the risk of crime occurring after dark was greater than during daylight, quantifying this effect would provide a measure to assess the potential effectiveness of lighting in reducing crime risk after dark. We will use a case and control approach to analyse ten years of crime data. We will compare counts of crimes in 'case' hours, that are in daylight and darkness at different times of the year, and 'control' hours, that are in daylight throughout the year. From these counts we will calculate odds ratios as a measure of the effect of darkness on risk of crime, using these to answer three questions: 1) Is the risk of overall crime occurring greater after dark than during daylight? 2) Does the risk of crime occurring after dark vary depending on the category of crime? 3) Does the risk of crime occurring after dark vary depending on the geographical area?

Exercise training modifies skeletal muscle clock gene expression but not 24-hour rhythmicity in substrate metabolism of men with insulin resistance.

Twenty-four hour rhythmicity in whole-body substrate metabolism, skeletal muscle clock gene expression and mitochondrial respiration is compromised upon insulin resistance. With exercise training known to ameliorate insulin resistance, our objective was to test if exercise training can reinforce diurnal variation in whole-body and skeletal muscle metabolism in men with insulin resistance. In a single-arm longitudinal design, 10 overweight and obese men with insulin resistance performed 12weeks of high-intensity interval training recurrently in the afternoon (between 14.00 and 18.00h) and were tested pre- and post-exercise training, while staying in a metabolic research unit for 2days under free-living conditions with regular meals. On the seconddays, indirect calorimetry was performed at 08.00, 13.00, 18.00, 23.00 and 04.00h, muscle biopsies were taken from the vastus lateralis at 08.30, 13.30 and 23.30h, and blood was drawn at least bi-hourly over 24h. Participants did not lose body weight over 12weeks, but improved body composition and exercise capacity. Exercise training resulted in reduced 24-h plasma glucose levels, but did not modify free fatty acid and triacylglycerol levels. Diurnal variation of muscle clock gene expression was modified by exercise training with period genes showing an interaction (time × exercise) effect and reduced mRNA levels at 13.00h. Exercise training increased mitochondrial respiration without inducing diurnal variation. Twenty-four-hour substrate metabolism and energy expenditure remained unchanged. Future studies should investigate alternative exercise strategies or types of interventions (e.g. diet or drugs aiming at improving insulin sensitivity) for their capacity to reinforce diurnal variation in substrate metabolism and mitochondrial respiration. KEY POINTS: Insulin resistance is associated with blunted 24-h flexibility in whole-body substrate metabolism and skeletal muscle mitochondrial respiration, and disruptions in the skeletal muscle molecular circadian clock. We hypothesized that exercise training modifies 24-h rhythmicity in whole-body substrate metabolism and diurnal variation in skeletal muscle molecular clock and mitochondrial respiration in men with insulin resistance. We found that metabolic inflexibility over 24h persisted after exercise training, whereas mitochondrial respiration increased independent of time of day. Gene expression of Per1-3 and Rorα in skeletal muscle changed particularly close to the time of day at which exercise training was performed. These results provide the rationale to further investigate the differential metabolic impact of differently timed exercise to treat metabolic defects of insulin resistance that manifest at a particular time of day.

Early morning naps are correlated with incident Alzheimer’s Dementia in older adults

AbstractBackgroundPrevious findings suggest that frequent and longer naps during daytime are associated with elevated risks of Alzheimer’s dementia among older adults. This study aims to further examine whether naps during a particular time of a day are differentially linked to risk of Alzheimer’s dementia.MethodA total of 1,203 participants from the Rush Memory and Aging Project (mean age at actigraphy = 80.85±7.30 years; 77% female) wore accelerometers (Actical) for up to 14 (mean = 9.57±1.17) days and completed annual neurocognitive assessment for up to 17 (mean = 6.92±4.12) years. A validated algorithm was used to identify daytime naps between 9am and 7pm. We categorized participants into those who napped versus those who did not nap during each time period, i.e., morning (9‐11am), noon (11am‐1pm), early afternoon (1‐3pm), late afternoon (3‐5pm), and early evening (5‐7pm). We conducted Cox proportional hazards models to test whether napping at a specific time of day is correlated with incident Alzheimer’s dementia, adjusting for age, sex, education years, length of actigraphy recording, body mass index, intradaily variability of rest‐activity rhythms, and nighttime sleep duration.ResultAmong all participants, 357 developed Alzheimer’s dementia during follow‐up (mean time to incidents = 6.34±3.98 years). Compared to those who did not nap in the morning (9‐11am), participants who napped in the morning had 1.4‐fold (HR[95%CI] = 1.43 [1.07‐1.93], p = 0.01) risk for developing Alzheimer’s dementia. This association was attenuated after further adjusting for total nap duration and frequency (HR[95%CI] = 1.32[0.97‐1.79], p = 0.07). However, napping during other time periods was not associated with risk for Alzheimer’s dementia, after adjusting for the covariates (noon: HR[95%CI] = 1.26[0.94‐1.68], p = 0.12; early afternoon: HR[95%CI] = 1.22[0.81‐1.84], p = 0.33; late afternoon: HR[95%CI] = 1.22[0.81‐1.84], p = 0.34; early evening: HR[95%CI] = 0.84[0.62‐1.13], p = 0.24).ConclusionNapping in the morning may link to an increased risk of Alzheimer’s dementia in older adults. A potential explanation is that individuals who nap more in the morning are more likely to experience disturbances in sleep‐wake regulation. Future studies should investigate this underlying mechanism and test whether interventions to reduce morning naps or consolidate naps can benefit neurocognitive outcomes.

Donor circadian clock influences the long-term survival of heart transplantation by immunoregulation.

Circadian clocks play important role in immunoregulation. We aimed to investigate cardiac circadian clock specific pathways and compare cardiac grafts procured at different timing on survival after transplantation to explore novel criteria for donor selection. In primate heart, phase set enrichment analysis (PSEA) showed rhythmic transcripts were enriched in antigen processing and presentation during activation of circadian rhythm. Digital sorting of immune cell composition and single-sample gene set enrichment analysis (ssGSEA) in unused donor transcriptomes showed the pathway, positive regulation of circadian rhythm significantly correlates with allograft rejection and antigen presentation pathways as well as with increased compositions of matured dendritic cell, CD4+ T cell, and naive B cell. Single-centre retrospective cohort of 390 adult heart transplants between 1 January 2015 and 31 December 2020 was used to generate a propensity score matching (PSM) cohort. Survival curve differed significantly showing inferior long-term survival when donor hearts were procured at activation group (12 pm to 12 am) compared to repression group (12 am to 12 pm) (6-year survival: 64.2% vs. 75.8%, P = 0.0065). Activation group was also associated with significantly higher rates of in-hospital death, cardiopulmonary resuscitation, and usage of mechanical circulatory support after heart transplantation compared to repression group. Furthermore, tendency for post-transplant free of rejection rates was higher in repression group compared to activation group (acute rejection, Gehan-Breslow P = 0.11 and 0.04; chronic rejection, Log rank P = 0.077 and 0.15, in full and PSM cohorts, respectively). Adjusted Cox regression analysis showed that activation group was associated with 2.20 times increased hazard of death (hazard ratio: 2.20; 95% confidence interval: 1.23-3.95; P = 0.008) compared to repression group. Circadian immunity may represent donor-related risk factors for cardiac allograft rejection through activating genes related to antigen presentation pathway and immune cells oscillation at specific time of day. Molecular circadian clock should be considered during retrieval of cardiac allografts in order to maximize graft durability.

The Relationship between Sleep, Chronotype, and Dental Caries-A Narrative Review.

This article provides an overview of how sleep and circadian rhythm disturbances mutually influence the occurrence of dental caries and how it is possible to reduce the risk of circadian rhythm disturbances, sleep, and associated adverse effects. Dental caries is a global problem worldwide that contributes to sociological limitations. Numerous factors influence the occurrence of dental caries, from socioeconomic factors to cariogenic bacteria, dietary habits, and oral hygiene. However, sleep disorders and circadian rhythm disturbances represent a new approach in the fight against the increasing prevalence of dental caries worldwide. Bacteria in the oral cavity and the oral microbiome are mainly responsible for the development of caries, and saliva plays an important role in their regulation. The circadian rhythm regulates numerous physiological functions, including sleep and saliva production. Disturbances in sleep and circadian rhythms affect saliva production, which impacts the development of dental caries, as saliva is necessary for regulating and maintaining oral health, especially for controlling oral infections. A person's preference for a particular time of day depends on the circadian rhythm called chronotype. Individuals with an evening chronotype have a less healthy lifestyle that can lead to a higher caries risk than individuals with a morning chronotype. Because circadian rhythms are critical to maintaining sleep homeostasis and oral health, sleep disturbances can disrupt circadian rhythms and lead to a vicious cycle.

Intermittent fasting interventions to leverage metabolic and circadian mechanisms for cancer treatment and supportive care outcomes.

Intermittent fasting entails restricting food intake during specific times of day, days of the week, religious practice, or surrounding clinically important events. Herein, the metabolic and circadian rhythm mechanisms underlying the proposed benefits of intermittent fasting for the cancer population are described. We summarize epidemiological, preclinical, and clinical studies in cancer published between January 2020 and August 2022 and propose avenues for future research. An outstanding concern regarding the use of intermittent fasting among cancer patients is that fasting often results in caloric restriction, which can put patients already prone to malnutrition, cachexia, or sarcopenia at risk. Although clinical trials do not yet provide sufficient data to support the general use of intermittent fasting in clinical practice, this summary may be useful for patients, caregivers, and clinicians who are exploring intermittent fasting as part of their cancer journey for clinical outcomes and symptom management.

Diurnal Step Count Patterns in Progressive Multiple Sclerosis (P3-3.011)

<h3>Objective:</h3> Determine the relationship of diurnal step count patterns with disability in progressive multiple sclerosis (MS). <h3>Background:</h3> Worsening Expanded Disability Status Scale (EDSS) scores and longer Timed 25-Foot Walk (T25FW) times generally correspond to increased MS disability and correlate with lower daily physical activity. Patterns of diurnal physical activity and MS disability progression are understudied. <h3>Design/Methods:</h3> Participants (n=577) in the SPI2 study of MD1003 (high dose biotin) in progressive MS underwent EDSS and T25FW every three months with up to 27 months of follow up. A Fitbit flex (or flex2) continuously monitored step counts per minute. Recorded data was analyzed using the function-on-scalar regression technique where EDSS, T25FW and other patient demographics were used to predict per-patient diurnal step counts. <h3>Results:</h3> From 12pm to 8pm, EDSS (mean R2 = 0.36±0.02) outperformed T25FW (mean R2 = 0.26±0.02) in predicting mean diurnal step count curves per patient after adjusting for sex, age, and BMI. Including EDSS and T25FW increased mean R2 to 0.39±0.02. Men took 5.2% more steps than women from 12am to 7am on average, while women took 5.1% more steps than men from 10:30am to 1:30pm and 4.3% more from 7:30pm to 10pm on average (all p&lt;0.001). The impact of age was strongest from 3pm to 10pm, where each year of age corresponded to 0.44% fewer steps (p&lt;0.0001). From 10am to 11pm, every one-point increase in BMI translated to 1.3% fewer steps (p&lt;0.0001). Mean diurnal step count had midday troughs in summer, evening troughs in winter, and morning peaks in spring (all p&lt;0.001). <h3>Conclusions:</h3> The association between lower physical activity and disability metrics is not uniform throughout the day, and changes with the seasons. These results highlight the need for consistency in timing of clinical evaluation in research, and provide important insight into specific times of day that may be preferable for effective rehabilitation interventions. <b>Disclosure:</b> Mr. Navani has received personal compensation for serving as an employee of Datavant. Dr. Block has nothing to disclose. The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Atara. The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for EMD Serono. The institution of Dr. Cree has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. The institution of Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for TG Therapeutics. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Autobahn. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avotres. The institution of Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Gossamer Bio. Dr. Cree has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizon. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuron23. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Boston Pharma. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Hexal/Sandoz. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Siemens. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Therini. Dr. Cree has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunic AG. The institution of Dr. Cree has received research support from Genentech. Dr. Cree has received publishing royalties from a publication relating to health care. Prof. Abbasi-Asl has received research support from NIH. Prof. Abbasi-Asl has received research support from Weill Neurohub.

Modeling the Circadian Control of the Cell Cycle and Its Consequences for Cancer Chronotherapy.

The mammalian cell cycle is governed by a network of cyclin/Cdk complexes which signal the progression into the successive phases of the cell division cycle. Once coupled to the circadian clock, this network produces oscillations with a 24 h period such that the progression into each phase of the cell cycle is synchronized to the day-night cycle. Here, we use a computational model for the circadian clock control of the cell cycle to investigate the entrainment in a population of cells characterized by some variability in the kinetic parameters. Our numerical simulations showed that successful entrainment and synchronization are only possible with a sufficient circadian amplitude and an autonomous period close to 24 h. Cellular heterogeneity, however, introduces some variability in the entrainment phase of the cells. Many cancer cells have a disrupted clock or compromised clock control. In these conditions, the cell cycle runs independently of the circadian clock, leading to a lack of synchronization of cancer cells. When the coupling is weak, entrainment is largely impacted, but cells maintain a tendency to divide at specific times of day. These differential entrainment features between healthy and cancer cells can be exploited to optimize the timing of anti-cancer drug administration in order to minimize their toxicity and to maximize their efficacy. We then used our model to simulate such chronotherapeutic treatments and to predict the optimal timing for anti-cancer drugs targeting specific phases of the cell cycle. Although qualitative, the model highlights the need to better characterize cellular heterogeneity and synchronization in cell populations as well as their consequences for circadian entrainment in order to design successful chronopharmacological protocols.

COLD REGULATED GENE 27 and 28 Antagonize the Transcriptional Activity of the RVE8/LNK1/LNK2 Circadian Complex.

Many molecular and physiological processes in plants occur at a specific time of day. These daily rhythms are coordinated in part by the circadian clock, a timekeeper that uses daylength and temperature to maintain rhythms of approximately 24 hours in various clock-regulated phenotypes. The circadian MYB-like transcription factor REVEILLE 8 (RVE8) interacts with its transcriptional coactivators NIGHT LIGHT INDUCIBLE AND CLOCK REGULATED 1 (LNK1) and LNK2 to promote the expression of evening-phased clock genes and cold tolerance factors. While genetic approaches have commonly been used to discover connections within the clock and between clock elements and other pathways, here we used affinity purification coupled with mass spectrometry to identify time-of-day-specific protein interactors of the RVE8-LNK1/LNK2 complex in Arabidopsis (Arabidopsis thaliana). Among the interactors of RVE8/LNK1/LNK2 were COLD REGULATED GENE 27 (COR27) and COR28, which coprecipitated in an evening-specific manner. In addition to COR27 and COR28, we found an enrichment of temperature-related interactors that led us to establish a previously uncharacterized role for LNK1 and LNK2 in temperature entrainment of the clock. We established that RVE8, LNK1, and either COR27 or COR28 form a tripartite complex in yeast (Saccharomyces cerevisiae) and that the effect of this interaction in planta serves to antagonize transcriptional activation of RVE8 target genes, potentially through mediating RVE8 protein degradation in the evening. Together, these results illustrate how a proteomic approach can be used to identify time-of-day-specific protein interactions. Discovery of the RVE8-LNK-COR protein complex indicates a previously unknown regulatory mechanism for circadian and temperature signaling pathways.

Commemorating the Virgin Mary at Barking Abbey: Cambridge, University Library, Dd.12.56

AbstractThis article examines the unusual commemorative Office of the Virgin from Barking Abbey in a fifteenth-century book of hours, Cambridge, University Library, Dd.12.56 (hereafter Dd.12.56). As already evident in the Barking Ordinal, the nuns of this Abbey venerated Mary, one of their patron saints, with a weekly full three-nocturn, twelve-lesson Matins service. Dd.12.56, however, has only recently been linked to Barking Abbey and drawing on new material in this manuscript in correlation with others from the Abbey, I argue that the Barking nuns compiled a unique series of readings and responsories to honour Mary. The progression through the three nocturns of Matins articulates a Marian theology that intersects with the nuns’ self-understanding and I demonstrate that they carefully crafted the lesser hours to highlight specific times of day and to complement Marian hymns sung at Barking. The accepted belief that books of hours were for personal devotion obscures the possibility that such books reflect communal liturgical practices, potentially serving multiple purposes within a monastic setting. Although Dd.12.56 dates from the fifteenth century, it may testify to a much older liturgical practice, which originated in the twelfth century when the three-nocturn format was still prevalent in Benedictine use and before it was largely replaced by a two-nocturn format in the thirteenth century. Benedictine tradition offered individual monastic houses the opportunity to craft this service. Dd.12.56 stands as a new and important testimony to the rich and imaginative ways in which the Barking community created, collated and curated materials that they steeped in their minds and hearts.

Monitoring of Alarm Reactions of Red Deer (Cervus elaphus) in a Captive Population in Paneveggio Pale di San Martino Natural Park

The study analyzes red deer responses to disturbances during the day and different exposures to tourists, to establish the more appropriate times to carry out activities inside the Paneveggio deer enclosure. The alarm reactions of red deer were observed after presenting different types of visual stimuli inside and outside the fence, in order to answer some questions: Which stimuli produce the strongest reactions from the animals? Do animals differently react to stimuli presented outside and inside the fence? On which days and times are the animals more sensitive to disturbances? Are there different reactions between the males and females? The results suggest that the red deer adversely react to the disturbance at different degrees of intensity in relation to day, sex, tourist and where the stimuli are presented. It was observed that during the days with the highest tourist presence, the animals were particularly alarmed; discomfort accumulation produced the highest number of alarm reactions on Monday. For these reasons, it would be opportune to manage the pasture on Tuesday, Wednesday and Thursday, scheduled at specific times of day, preferably far from the estimated presence of tourists.

Time-of-day preferences for intercity air travel: Case - New Delhi, India

This paper investigates the preferred time slots of travelers flying from New Delhi to other major cities in India utilizing a revealed preference data. This paper presents the preferences for any one of the periods (Morning, Mid-Day, and Evening) as a binary choice model. Subsequently, the reasons for the choice of a particular time of day are explore and compared against the Morning time. The empirical models reveal that age, household income, the category of the route leading to the destination city, and trip purpose are some of the statistically relevant variables differentiating the preferences for any time slot against a specific one. In comparison, class of journey, gender, household income, and educational status are found to differentiate the choice among Morning, Mid-day, and Evening periods for the individuals who stated that they prefer to make the trip only during a specific period. The models imply that a respondent’s age is found to influence the choice of a specific time. In contrast, the gender of an individual and trip purpose significantly affected the choices among Morning, Mid-day, and Evening periods. Based on the transferability of choice models over time, the study interprets the findings in terms of plans and policies for airline operators and airport authorities. The operators could gain inputs to planning trip schedules and infrastructure facilities in response to socio-demographic changes.