Stability Of Circadian Rhythms Research Articles

Comparing Human-Smartphone Interactions and Actigraphy Measurements for Circadian Rhythm Stability and Adiposity: Algorithm Development and Validation Study.

This study aimed to investigate the relationships between adiposity and circadian rhythm and compare the measurement of circadian rhythm using both actigraphy and a smartphone app that tracks human-smartphone interactions. We hypothesized that the app-based measurement may provide more comprehensive information, including light-sensitive melatonin secretion and social rhythm, and have stronger correlations with adiposity indicators. We enrolled a total of 78 participants (mean age 41.5, SD 9.9 years; 46/78, 59% women) from both an obesity outpatient clinic and a workplace health promotion program. All participants (n=29 with obesity, n=16 overweight, and n=33 controls) were required to wear a wrist actigraphy device and install the Rhythm app for a minimum of 4 weeks, contributing to a total of 2182 person-days of data collection. The Rhythm app estimates sleep and circadian rhythm indicators by tracking human-smartphone interactions, which correspond to actigraphy. We examined the correlations between adiposity indices and sleep and circadian rhythm indicators, including sleep time, chronotype, and regularity of circadian rhythm, while controlling for physical activity level, age, and gender. Sleep onset and wake time measurements did not differ significantly between the app and actigraphy; however, wake after sleep onset was longer (13.5, SD 19.5 minutes) with the app, resulting in a longer actigraphy-measured total sleep time (TST) of 20.2 (SD 66.7) minutes. The obesity group had a significantly longer TST with both methods. App-measured circadian rhythm indicators were significantly lower than their actigraphy-measured counterparts. The obesity group had significantly lower interdaily stability (IS) than the control group with both methods. The multivariable-adjusted model revealed a negative correlation between BMI and app-measured IS (P=.007). Body fat percentage (BF%) and visceral adipose tissue area (VAT) showed significant correlations with both app-measured IS and actigraphy-measured IS. The app-measured midpoint of sleep showed a positive correlation with both BF% and VAT. Actigraphy-measured TST exhibited a positive correlation with BMI, VAT, and BF%, while no significant correlation was found between app-measured TST and either BMI, VAT, or BF%. Our findings suggest that IS is strongly correlated with various adiposity indicators. Further exploration of the role of circadian rhythm, particularly measured through human-smartphone interactions, in obesity prevention could be warranted.

Genomic investigation of duplication, functional conservation, and divergence in the LRR-RLK Family of Saccharum

BackgroundSugarcane (Saccharum spp.) holds exceptional global significance as a vital crop, serving as a primary source of sucrose, bioenergy, and various by-products. The optimization of sugarcane breeding by fine-tuning essential traits has become crucial for enhancing crop productivity and stress resilience. Leucine-rich repeat receptor-like kinases (LRR-RLK) genes present promising targets for this purpose, as they are involved in various aspects of plant development and defense processes.ResultsHere, we present a detailed overview of phylogeny and expression of 288 (495 alleles) and 312 (1365 alleles) LRR-RLK genes from two founding Saccharum species, respectively. Phylogenetic analysis categorized these genes into 15 subfamilies, revealing considerable expansion or reduction in certain LRR-type subfamilies. Compared to other plant species, both Saccharum species had more significant LRR-RLK genes. Examination of cis-acting elements demonstrated that SsLRR-RLK and SoLRR-RLK genes exhibited no significant difference in the types of elements included, primarily involved in four physiological processes. This suggests a broad conservation of LRR-RLK gene function during Saccharum evolution. Synteny analysis indicated that all LRR-RLK genes in both Saccharum species underwent gene duplication, primarily through whole-genome duplication (WGD) or segmental duplication. We identified 28 LRR-RLK genes exhibiting novel expression patterns in response to different tissues, gradient development leaves, and circadian rhythm in the two Saccharum species. Additionally, SoLRR-RLK104, SoLRR-RLK7, SoLRR-RLK113, and SsLRR-RLK134 were identified as candidate genes for sugarcane disease defense response regulators through transcriptome data analysis of two disease stresses. This suggests LRR-RLK genes of sugarcane involvement in regulating various biological processes, including leaf development, plant morphology, photosynthesis, maintenance of circadian rhythm stability, and defense against sugarcane diseases.ConclusionsThis investigation into gene duplication, functional conservation, and divergence of LRR-RLK genes in two founding Saccharum species lays the groundwork for a comprehensive genomic analysis of the entire LRR-RLK gene family in Saccharum. The results reveal LRR-RLK gene played a critical role in Saccharum adaptation to diverse conditions, offering valuable insights for targeted breeding and precise phenotypic adjustments.

Weak synchronization can alter circadian period length: implications for aging and disease conditions.

The synchronization of multiple oscillators serves as the central mechanism for maintaining stable circadian rhythms in physiology and behavior. Aging and disease can disrupt synchronization, leading to changes in the periodicity of circadian activities. While our understanding of the circadian clock under synchronization has advanced significantly, less is known about its behavior outside synchronization, which can also fall within a predictable domain. These states not only impact the stability of the rhythms but also modulate the period length. In C57BL/6 mice, aging, diseases, and removal of peripheral circadian oscillators often result in lengthened behavioral circadian periods. Here, we show that these changes can be explained by a surprisingly simple mathematical relationship: the frequency is the reciprocal of the period, and its distribution becomes skewed when the period distribution is symmetric. The synchronized frequency of a population in the skewed distribution and the macroscopic frequency of combined oscillators differ, accounting for some of the atypical circadian period outputs observed in networks without synchronization. Building on this finding, we investigate the dynamics of circadian outputs in the context of aging and disease, where synchronization is weakened.

Multi-omics analyses reveal the crosstalk between the circadian clock and the response to herbicide application in Oryza sativa.

Plants have evolved circadian clock systems that enable biological processes to occur in tandem with periodic changes in the environment. However, it is largely unknown whether crosstalk occurs between the circadian clock and the response to herbicide in rice. We identified 19 conserved rhythmic metabolites which were response to pesticide application and their metabolic abundance peaked mainly at ZT2 or ZT14-ZT18. We found a series of glyphosate, s-Metolachlor, fenclorim, metcamifen and GA3 response genes were expressed following stable circadian rhythms. In order to determine the patterns of their temporal expression, co-expression network analysis was done on 10,467 genes that were periodically expressed throughout a 24-hour period. Next, we identified 4,031 potential direct target genes of OsCCA1 in using DAP-seq data for OsCCA1. Of these, 339, 22, 53, 53 and 63 genes showed a response to glyphosate, s-Metolachlor, fenclorim, metcamifen and GA3 application, respectively. And they were mainly phased from dusk to midnight. Interestingly, we identified significant OsCCA1 binding peaks in the promoter regions of four herbicide resistance genes, including OsCYP81A12, OsCYP81E22, OsCYP76C2, and OsCYP76C4. Finally, we found that herbicide application could affects the expression of some of the central oscillator genes of the rice circadian clock. Here, we used multi-omics data to reveal the crosstalk between the circadian clock and herbicide response processes at the epigenomics, transcriptome, and metabolome levels in rice. This work will serve as a theoretical guide for identifying rhythmic herbicide targets, leading to the creation of new herbicides or the breeding of crops resistant to herbicides.

Effects of LED spectrum on circadian rhythmic expression of clock genes and Aanat2 in the brain of juvenile European seabass (Dicentrarchus labrax)

The circadian rhythm is a physiological phenomenon that occurs in various organisms with a cycle of about 24 hours. Light is one of the important environmental factors affecting biological rhythm. To clarify whether a shift in light spectrum can influence the circadian expression in fish brain, a total of 175 European seabasses [body weight: 32.5 ± 0.71) g; body length: (13.78 ± 0.35) cm] were exposed to white light (WL), red light (RL), yellow light (YL), green light (GL) or blue light (BL). After 50 days of exposure, circadian expressions of four core clock genes (Clock, Bmal1, Per2, Cry1) and Aanat2 gene in brain were examined. The results showed that the temporal expression patterns of positive clock gens (Clock and Bmal1) showed increases during the scotophase and decreases during the photophase, with peaks near the middle of the darkness. Clock gene expression showed a stable circadian rhythm (R2 = 0.578-0.824, P=0.000- 0.027) in all light groups while Bmal1 showed circadian rhythm in WL, GL and RL, not in BL and YL. Daily expression patterns of the negative clock genes oscillated in the opposite phase from the positive clock genes, showing increasing mRNA levels during the light, decreases during the dark, and peaks near the shift from night to day, except Per2 in RL and Cry1 in BL. Compared with WL, the acrophases of Clock and Bmal1 were delayed under all light treatments (BL: + 3.7h, +6.73h; RL: +2.4h,+1.35h; YL: + 4.94h, 2.00h; GL: +0.05, +0.16h). Cry1 showed advanced acrophase under all light treatments (BL: -10.74 h, GL: -3.81 h, RL: -3.93 h, YL: -7.56 h) but Per2 showed delayed acrophase in all light treatments (GL: +0.86 h, RL: +10.35 h, YL: +9.62 h), except in BL (-0.43 h). The acrophase of Aanat2 was advanced by all monochromatic light, the Aanat2 level was significantly increased in RL compared with other light treatment. Therefore, the results indicate that RL may regulate the expression of Aanat2 gene by affecting the expression of clock gene in fish brain. Spectrum can affect the biological clock system of fish, and unreasonable spectrum may disturb the rhythm of gene expression of biological clock of fish. Under the irradiation of light spectrum, some clock genes still maintain obvious circadian oscillation, while the rhythm of some clock genes is not obvious and may be destroyed. Our findings suggest a primary role of light spectrum information to the fish brain circadian system.

Active interventions of dynamic lighting on human circadian rhythm and sleep quality in confined spaces

People in closed spaces without daylight for a long time are prone to circadian rhythm desynchrony and sleep disorders. To explore the effects of different lighting patterns on circadian rhythm and sleep, 20 adults were confined in an underground lab by within-subject design for four consecutive weeks with one lighting pattern per week. The static lighting pattern (SLP) was used in the 1st week, then the circadian forward lighting pattern (FLP) in the 2nd and 4th weeks, and the backward lighting pattern (BLP) in the 3rd week. Their salivary melatonin, Karolinska Sleepiness Scale(KSS),core body temperature (CBT), Pittsburgh Sleep Quality Index (PSQI), sleep latency and the number of awakenings were measured. The results showed dim light melatonin onset (DLMO) was delayed by 0.62 h during the 1st week, indicating the backward tendency of circadian rhythm but without significance (p = 0.295). In the 2 nd week, the schedule was forced to bring forward by 2 h, assisted with FLP. The BLP in the 3rd week resulted in a significant delay of 1.87 h in DLMO(p = 0.002) and lower melatonin at bedtime (p = 0.001), with progressively longer sleep latency, lower sleepiness at night and CBT when waking up, and PSQI increased day by day, meaning the gradually deteriorated sleep. In the 4th week, DLMO was significantly shifted forward by 2.13 h (p = 0.003), melatonin at bedtime was higher (p = 0.000), and sleep quality gradually improved. Lighting interventions on KSS, CBT, PSQI and sleep latency showed day-by-day cumulative effects, and the dynamic lighting interventions can help maintain circadian rhythm stability in closed spaces and adapt to shift hours.

Desynchronosis: Types, Main Mechanisms, Role in the Pathogenesis of Epilepsy and Other Diseases: A Literature Review.

Circadian information is stored in mammalian tissues by an autonomous network of transcriptional feedback loops that have evolved to optimally regulate tissue-specific functions. Currently, stable circadian rhythms of the expression of clock genes (Bmal1/Per2/Cry1, etc.), hormones, and metabolic genes (Glut4/leptin, etc.) have been demonstrated. Desynchronoses are disorders of the body’s biorhythms, where the direction and degree of shift of various indicators of the oscillatory process are disturbed. Desynchronosis can be caused by natural conditions or man-made causes. The disruption of circadian rhythms is a risk factor for the appearance of physiological and behavioral disorders and the development of diseases, including epilepsy, and metabolic and oncological diseases. Evidence suggests that seizure activity in the epilepsy phenotype is associated with circadian dysfunction. Interactions between epilepsy and circadian rhythms may be mediated through melatonin, sleep–wake cycles, and clock genes. The correction of circadian dysfunction can lead to a decrease in seizure activity and vice versa. Currently, attempts are being made to pharmacologically correct desynchronosis and related psycho-emotional disorders, as well as combined somatic pathology. On the other hand, the normalization of the light regimen, the regulation of sleep–wake times, and phototherapy as additions to standard treatment can speed up the recovery of patients with various diseases.

Expression and Purification of Human Circadian Protein hRORγ for Structural and Functional Studies

The circadian rhythm is an internal biological clock composed of different autonomous oscillators that regulate many physiological activities such as the sleep wake cycle. Long term disruption of circadian rhythm can lead to sleep disorders, neurodegenerative disease, metabolic syndrome, and high risks of cancer. The mechanism of circadian rhythm is driven by interlocked time‐delayed feedback loops consisting of positive and negative transcriptional regulators. For instance, Retinoic Acid Receptor‐Related Orphan Receptors (RORs) are nuclear receptors to improve circadian rhythm stability and functionality. A naturally occurring flavonoid Nobiletin (NOB) was reported to enhance circadian amplitude due to its high affinity to human ROR gamma (hRORγ). The interaction between NOB and hRORγ has not been studied in detail which hinders the future application of NOB as a promising candidate of circadian interfering medicine to ameliorate related diseases. The goal of this project is to solve the atomic three‐dimensional structure of hRORγ/Nobiletin complex to understand their interaction. The hRORγ gene was cloned and expressed using E. coli BL21 cells. Expression protocols were optimized to produce large amounts of recombinant hRORγ which have been purified using affinity chromatography and size exclusion chromatography. Circular dichroism has been used to verify that the purified recombinant hRORγ is properly folded. High concentration homogenous recombinant hRORγ will be co‐crystalized with Nobiletin. The atomic structure of the complex will be determined using X‐ray crystallography. The resultant structural information will shed light on Nobiletin’s enhancement mechanism on circadian rhythm and build the foundation for future drug development.

CME: Light Therapy: Why, What, for Whom, How, and When (And a Postscript about Darkness).

Light therapy has become established as an evidence-based treatment for Seasonal Affective Disorder. Light impacts the timing and stability of circadian rhythms as expressed in sleep, mood, alertness, and cognition. Forty years of clinical trials and open treatment have led to guidelines for patient selection, using light alone or in combination with antidepressants (or lithium for bipolar depression). Mood and sleep disturbances can also respond to adjunct light therapy in a broader set of psychiatric, neurologic and medical illnesses. We specify criteria for choice of treatment devices: optimum dose (10,000 lux), spectrum (white light), exposure duration (30-60 minutes) and timing (early morning). Protocol adjustment requires continual monitoring with attention to rate of improvement and management of potential side effects.

Synergies of Multiple Zeitgebers Tune Entrainment.

Circadian rhythms are biological rhythms with a period close to 24h. They become entrained to the Earth's solar day via different periodic cues, so-called zeitgebers. The entrainment of circadian rhythms to a single zeitgeber was investigated in many mathematical clock models of different levels of complexity, ranging from the Poincaré oscillator and the Goodwin model to biologically more detailed models of multiple transcriptional translational feedback loops. However, circadian rhythms are exposed to multiple coexisting zeitgebers in nature. Therefore, we study synergistic effects of two coexisting zeitgebers on different components of the circadian clock. We investigate the induction of period genes by light together with modulations of nuclear receptor activities by drugs and metabolism. Our results show that the entrainment of a circadian rhythm to two coexisting zeitgebers depends strongly on the phase difference between the two zeitgebers. Synergistic interactions of zeitgebers can strengthen diurnal rhythms to reduce detrimental effects of shift-work and jet lag. Medical treatment strategies which aim for stable circadian rhythms should consider interactions of multiple zeitgebers.

Uncovering complexity details in actigraphy patterns to differentiate the depressed from the non-depressed

While the negative association between physical activity and depression has been well established, it is unclear what precise characteristics of physical activity patterns explain this association. Complexity measures may identify previously unexplored aspects of objectively measured activity patterns, such as the extent to which individuals show repetitive periods of physical activity and the diversity in durations of such repetitive activity patterns. We compared the complexity levels of actigraphy data gathered over 4 weeks (sim 40000 data points each) for every individual, from non-depressed (n=25) and depressed (n=21) groups using recurrence plots. Significantly lower levels of complexity were detected in the actigraphy data from the depressed group as compared to non-depressed controls, both in terms of lower mean durations of periods of recurrent physical activity and less diversity in the duration of these periods. Further, diagnosis of depression was not significantly associated with mean activity levels or measures of circadian rhythm stability, and predicted depression status better than these.

The effects of dynamic daylight-like light on the rhythm, cognition, and mood of irregular shift workers in closed environment

Shift workers are mostly suffered from the disruption of circadian rhythm and health problems. In this study, we designed proper light environment to maintain stable circadian rhythm, cognitive performance, and mood status of shift workers. We used five-channel light-emitting diodes to build up the dynamic daylight-like light environment. The illuminance, correlated color temperature, and circadian action factor of light were tunable in the ranges of 226 to 678 lx, 2680 to 7314 K, and 0.32 to 0.96 throughout the day (5:30 to 19:40). During the nighttime, these parameters maintained about 200 lx, 2700 K, and 0.32, respectively. In this light environment, three subjects had engaged in shift work for 38 consecutive days. We measured plasma melatonin, activity counts, continuous performance tests, and visual analogue scale on mood to assess the rhythm, cognitive performance, and mood of subjects. After 38-day shift work, the subjects’ peak melatonin concentration increased significantly. Their physiological and behavioral rhythms maintained stable. Their cognitive performance improved significantly after night work, compared with that before night work. Their mood status had no significant change during the 38-day shift work. These results indicated that the light environment was beneficial to maintain circadian rhythm, cognitive performance and mood status during long-term shift work in closed environment.

The role of circadian rhythm stability and amplitude in musculoskeletal disorder prevalence and work-family conflict.

AimThis study aimed to investigate the effect of circadian rhythm stability and amplitude on musculoskeletal disorder prevalence and work–family conflict among nurses.DesignThis cross‐sectional study was conducted on 386 nurses working in three hospitals, in Shahroud, Iran.MethodThe data were collected using the Circadian Rhythm Inventory, Nordic Musculoskeletal Disorders, and Carlson Work‐Family Conflict questionnaires.ResultsThe highest prevalence of musculoskeletal disorders was reported in the lower back (68.4%), upper back (65.5%) and shoulders (53.6%), respectively. No significant relation was found between circadian rhythm stability and amplitude, and musculoskeletal disorders prevalence. The nurses who could not overcome drowsiness reported more Work Interference with Family (WIF), Family Interference with Work (FIW) (time‐based) and FIW (strain‐based) compared to the nurses who overcame drowsiness. In addition, the appropriate nurses for shift work experienced less WIF, FIW (behavioural‐based) and WIF (strain‐based) compared to the nurses who could not work overtime or at night.

Patients with Subarachnoid Hemorrhage Exhibit Disturbed Expression Patterns of the Circadian Rhythm Gene Period-2.

Circadian rhythm gene expression in cerebral pacemaker regions is regulated by a transcriptional-translational feedback loop across the 24-h day-night cycle. In preclinical models of subarachnoid hemorrhage (SAH), cyclic gene expression is disrupted. Stabilization of circadian rhythm gene expression attenuates susceptibility to ischemic damage in both neuronal and myocardial tissues. In this clinical observational study, circadian rhythm gene Period-2 (Per2) mRNA expression levels were determined from blood leukocytes and cerebrospinal fluid (CSF) cells via real-time PCR on days 1, 7 and 14 after aneurysm rupture in 49 patients with spontaneous SAH. CSF Per2 expression was markedly suppressed immediately after SAH and remained suppressed over the course of two weeks of ICU treatment. Short-term mortality as well as occurrence of delirium was associated with greater extent of Per2 suppression on day 1 after SAH. Patients that developed delayed cerebral ischemia exhibited comparatively lower Per2 expression levels on day 7 after SAH, while presence of vasospasm remained unaffected. However, Per2 expression did not differ in patient groups with favourable or non-favourable functional neurological outcome (modified Rankin Scales 1–3 vs. 4–6). While our findings suggest a potential protective effect of stable circadian rhythm gene expression on the extent of ischemic damage, this effect was confined to the early disease course and was not reflected in patients’ functional neurological outcome.

CRYPTOCHROMES confer robustness, not rhythmicity, to circadian timekeeping.

Circadian rhythms are a pervasive property of mammalian cells, tissues and behaviour, ensuring physiological adaptation to solar time. Models of cellular timekeeping revolve around transcriptional feedback repression, whereby CLOCK and BMAL1 activate the expression of PERIOD (PER) and CRYPTOCHROME (CRY), which in turn repress CLOCK/BMAL1 activity. CRY proteins are therefore considered essential components of the cellular clock mechanism, supported by behavioural arrhythmicity of CRY‐deficient (CKO) mice under constant conditions. Challenging this interpretation, we find locomotor rhythms in adult CKO mice under specific environmental conditions and circadian rhythms in cellular PER2 levels when CRY is absent. CRY‐less oscillations are variable in their expression and have shorter periods than wild‐type controls. Importantly, we find classic circadian hallmarks such as temperature compensation and period determination by CK1δ/ε activity to be maintained. In the absence of CRY‐mediated feedback repression and rhythmic Per2 transcription, PER2 protein rhythms are sustained for several cycles, accompanied by circadian variation in protein stability. We suggest that, whereas circadian transcriptional feedback imparts robustness and functionality onto biological clocks, the core timekeeping mechanism is post‐translational.

Depression alters the circadian pattern of online activity

Human sleep/wake cycles follow a stable circadian rhythm associated with hormonal, emotional, and cognitive changes. Changes of this cycle are implicated in many mental health concerns. In fact, the bidirectional relation between major depressive disorder and sleep has been well-documented. Despite a clear link between sleep disturbances and subsequent disturbances in mood, it is difficult to determine from self-reported data which specific changes of the sleep/wake cycle play the most important role in this association. Here we observe marked changes of activity cycles in millions of twitter posts of 688 subjects who explicitly stated in unequivocal terms that they had received a (clinical) diagnosis of depression as compared to the activity cycles of a large control group (n = 8791). Rather than a phase-shift, as reported in other work, we find significant changes of activity levels in the evening and before dawn. Compared to the control group, depressed subjects were significantly more active from 7 PM to midnight and less active from 3 to 6 AM. Content analysis of tweets revealed a steady rise in rumination and emotional content from midnight to dawn among depressed individuals. These results suggest that diagnosis and treatment of depression may focus on modifying the timing of activity, reducing rumination, and decreasing social media use at specific hours of the day.

0214 The Relationship Between Work Stress and Sleep Quality in Shift Working Nurses: The Intermediate Effect of Circadian Rhythm Amplitude and Stability

Abstract Introduction Research suggests that work stress may be an important factor in poor sleep in shift working nurses. However, evidence is limited about the underlying mechanism. Circadian rhythm might be effective. The purpose of this study was to explore the relationship between work stress and sleep quality in shift working nurses and the mediation effect of circadian rhythm amplitude and stability respectively. Methods A total of 529 nurses working in shifts from seven hospitals were selected by convenient sampling in Shanghai, China. Participants were assessed with the Circadian Type Inventory (CTI), Chinese Nursing Stressor Scale (CNSS), Pittsburgh Sleep Quality Index (PSQI). The Amos24.0 software was applied to construct structural equation models with circadian rhythm amplitude (LV) and circadian rhythm stability (FR) as intermediate variables respectively. Results About 73.3% (388/529) of the nurses’ PSQI scores were above 5, indicating poor sleep quality. The correlations between work stress, circadian rhythm amplitude, circadian rhythm amplitude and sleep quality were all significant (all P<0.01).Sleep quality total score was positively correlated with work stress(γ=0.348) and circadian rhythm amplitude (γ=0.330). Work stress was positively correlated with circadian rhythm amplitude (γ=0.297,P<0.01). Sleep quality total score was negatively correlated circadian rhythm amplitude (γ=-0.204,P<0.01);Work stress was negatively correlated with circadian rhythm amplitude (γ= -0.284,P<0.01).Work stress showed significant indirect effects on sleep quality through the mediating effect of circadian rhythm amplitude (β=0.188,P<0.01) and circadian rhythm amplitude (β= 0.082,P<0.05). Conclusion It suggests that nurses working in shifts have poor sleep quality. Work stress and the amplitude and stability of circadian rhythm could affect sleep quality, and circadian rhythm amplitude and stability could mediate the relationship between work stress and sleep quality. Support The work was supported by Xinglin Young Talent Program of Shanghai University of Traditional Chinese Medicine(to Caiqin Wu) and The 12th Innovative activities of college students of Shanghai Traditional Chinese Medicine(2019SHUTCM094).

Expression and Purification of Human Circadian Protein hRORγ for Structural and Functional Studies

The circadian rhythm is an internal biological clock that runs in many living organisms. It regulates the sleep wake cycle among other physiological functions. Long term disruption of this internal clock can cause sleep disorders, metabolic diseases, and high risks of cancer. The circadian rhythm is controlled at molecular level by the transcriptional‐translational feedback loop (TTFL) that involve positive transcriptional activators CLOCK/BMAL1 and negative feedback suppressors PERs/CRYs. The Retinoic Acid Receptor‐Related Orphan Receptors (RORs) function as ligand‐dependent transcription factors which regulate BMAL1 production to improve circadian rhythm stability and robustness. It was shown that the naturally occurring flavonoid Nobiletin can bind to human ROR gamma (hRORγ) and increase its function through a yet unknown mechanism. Understanding the interaction between hRORγ and Nobiletin would provide insights in enhancing the circadian rhythm and ameliorating its related diseases. This project focuses on solving the three‐dimensional structure of hRORγ/Nobiletin complex to establish the mechanism of their interaction. The hRORγ gene was cloned and expressed using E. coli BL21 cells. Expression protocols were optimized to produce large amounts of hRORγ recombinant proteins. The soluble portion of expressed protein was purified using affinity chromatography and size exclusion chromatography, and the purified recombinant hRORγ is properly folded indicating from circular dichroism data. Once the required concentration is reached, the purified hRORγ will be co‐crystalized with Nobiletin. The crystals would be used for structural determination using X‐ray crystallography. The structural information will shed light on Nobiletin’s enhancement mechanism on circadian rhythm and provide guidance in related drug development.Support or Funding InformationResearch reported is supported by: National Research of General Medical Sciences of NIH under award number SC3GM109870. Researcher has used instruments sponsored by the BUILDing SCHOLARS program funded by the National Institute of General Medical Sciences of NIH under linked Award Numbers RL5GM118969, TL4GM118971, and UL1GM118970. Researcher is supported by Maximizing Access to Research Careers Grant # T34GM008048

The effect of work-related and socio-demographic factors on Work Ability Index (WAI) among Iranian workers.

The Work Ability Index (WAI) is a suitable and valid instrument, which provides a general view of workers' abilities and functional capacities. This study aimed to evaluate the effect of work-related and sociodemographic factors on work ability among employees of a company in Iran. This cross-sectional study was conducted on 167 employees. Work ability was measured by the Persian version of WAI. A questionnaire was also developed to assess work-related and sociodemographic factors. The data were analyzed using univariate analysis of variance (ANOVA), independent t-test, and Pearson's correlation. The mean (SD) score of WAI was 38.4 (6.4). WAI mean score (p < 0.05) was associated with age, gender, sleep quality, smoking, work schedule, the conflict between the work and individual, family, and social lives, work injuries, and job satisfaction. To improve the workers' work ability, interventional programs should be concentrated on changing work schedules, improving sleep quality, limiting work hours, and not scheduling sensitive individuals to night shifts, those whose circadian rhythm stability and circadian rhythm amplitude is rigid type and languid type, respectively.

Sleep-wake cycle impairment adding on the risk for COVID-19 severity in people with diabetes.

In the present article, we explore the risks of circadian disruptions and impact on the sleep-wake cycle of individuals with diabetes during COVID-19 pandemic. The association between the duration and quality of sleep and the stability of glucose levels is well-established. Therefore, during the pandemic with changes and limitations in the exposure to cyclic cues that entrain the circadian rhythms, such as light-dark and social interactions, we hypothesize that the power and stability of circadian rhythms decrease if measures are not taken to intentionally create a routine that includes zeitgebers. Knowing that sleep-wake cycle disruptions impair melatonin production, immune system response and glucose metabolism, and that individuals with diabetes are at higher risk for poor prognosis when infected by SARS-CoV-2 (especially if their blood glucose is out of target), we recommend monitoring and advising these individuals towards strategies to maintain adequate sleep quality and duration as part of their preventive and protective measures during the new pandemic routine.