Nobiletin, an activator of the pyruvate kinase isozyme M1/M2 protein, upregulated the glycolytic signalling pathway and alleviated depressive-like behaviour caused by artificial light exposure at night in zebrafish.

We established a zebrafish model of depression-like behaviour induced by exposure to artificial light at night (ALAN) and found that nobiletin (NOB) alleviated depression-like behaviour. Subsequently, based on the results of a 24-h free movement assay, clock gene expression and brain tissue transcriptome sequencing, the glycolysis signalling pathway was identified as a potential target through which NOB exerted antidepressant effects. Using the ALAN zebrafish model, we found that supplementation with exogenous L-lactic acid alleviated depressive-like behaviour. Molecular docking and molecular dynamics simulations revealed an inter-molecular interaction between NOB and the pyruvate kinase isozyme M1/M2 (PKM2) protein. We then used compound 3 k to construct a zebrafish model in which PKM2 was inhibited. Our analysis of this model suggested that NOB alleviated depression-like behaviour via inhibition of PKM2. In summary, NOB alleviated depressive-like behaviour induced by ALAN in zebrafish via targeting of PKM2 and activation of the glycolytic signalling pathway.

Novel assessment of CPAP adherence data reveals distinct diurnal patterns.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a prevalent condition effectively treated by continuous positive airway pressure (CPAP) therapy. CPAP adherence data, routinely gathered in clinical practice, include detailed information regarding both duration and timing of use. The purpose of the present study was to develop a systematic way to measure the diurnal pattern of CPAP adherence data and to see if distinct patterns exist in a clinical cohort. METHODS: Machine learning techniques were employed to analyze CPAP adherence data. A cohort of 200 unselected patients was assessed and a cluster analysis was subsequently performed. Application of this methodology to 17 patients with different visually noted patterns was carried out to further assess performance. RESULTS: Each 30-day period of CPAP use for each patient was characterized by four variables describing the time of day of initiation and discontinuation of CPAP use, as well as the consistency of use during those times. Further analysis identified six distinct clusters, reflecting different timing and adherence patterns. Specifically, clusters with relatively normal timing versus delayed timing were identified. Finally, application of this methodology showed generally good performance with limitations in the ability to characterize shift worker and non-24 rhythms. CONCLUSIONS: This study demonstrates a methodology for analysis of diurnal patterns from CPAP adherence data. Furthermore, distinct timing and adherence patterns are demonstrated. The potential impact of these patterns on the beneficial effects of CPAP requires elucidation.

Assessment of potential myopia risk factors, including chronotype, in Estonian adolescents: a cross-sectional study.

BACKGROUND: Myopia is a growing healthcare concern worldwide. Increasing evidence suggests that sleep and circadian rhythms may be associated with myopia. Furthermore, the risk factors of myopia have not been studied in the Estonian population to date. This study aimed to evaluate chronotype, lifestyle factors, and parental myopia in relation to myopia in Estonian secondary school students. METHODS: Grade 10 students from three secondary schools in Tallinn, each with distinct focuses: one science-oriented, one arts-oriented, and one sports-oriented, were invited to participate. They underwent a comprehensive ocular examination, including cycloplegic autorefraction and ocular biometry. Chronotype was evaluated with the Morningness - Eveningness Questionnaire. Participants reported parental myopia and replied to a set of questions, separately for schooldays and free days, to indicate the amount of time they spent outdoors, doing near work and intermediate distance activities. Myopia was defined as cycloplegic SER ≤ - 0.50 D. Logistic regression analysis was performed to assess the association of the studied factors with myopia. RESULTS: A total of 123 students (57% female) participated in the study, with a mean age of 16.71 years (standard deviation 0.41). In a multivariable regression model, having two myopic parents was associated with higher odds of myopia (OR 3.78, 95% CI 1.15 - 12.42). We found no association between myopia and chronotype. Notably, time spent outdoors and doing near work or intermediate distance work did not affect the likelihood of having myopia. We observed that students attending the sports-oriented school had lower odds of myopia than those attending the science-oriented school (OR 0.12, 95% CI 0.03-0.51). CONCLUSION: Chronotype was not associated with myopia in our study sample. Consistent with previous reports, we identified parental myopia as a myopia risk factor. Interestingly, there was no association between myopia and time spent outdoors or near work. However, the odds of myopia varied depending on the school attended by the participants, which may reflect the educational load or lifestyle of participants in earlier childhood.

An evaluation of sleep quality and nutritional status in nurses with different chronotypes.

This study was conducted to investigate the effect of shift work on the sleep quality and nutritional status of nurses with different chronotypes. The study was designed to include 21 people from each chronotype and was completed with 60 participants. The participants were asked to record their food consumption during three different types of shifts they worked over a period of three days. We found that the Pittsburgh Sleep Quality Index (PSQI) score of the evening types was higher than that of the morning types (p < 0.05). The evening types had significantly higher weight, BMI, waist circumference, hip circumference, waist-to-height ratio and neck circumference measurements than the morning types (p < 0.05). The daily energy, fat and SFA intakes of the morning types were significantly higher for those working 16:00-08:00 and 08:00-08:00 compared to those working 08:00-16:00 (p < 0.05). The highest carbohydrate intake was between 08:00-08:00. The amount of carbohydrate, energy and SFA consumed by the intermediate types between 08:00 and 08:00 was significantly higher than that consumed between 08:00 and 16:00. Chronotype and shift hours should also be taken into account when developing nutrition plans for participants who work shifts.

Evolution of light-dependent functions of GIGANTEA.

GIGANTEA is a multifaceted plant-specific protein that originated in a streptophyte ancestor. The current known functions of GI include circadian clock control, light signalling, flowering time regulation, stomata response, chloroplast biogenesis, accumulation of anthocyanin, chlorophyll, and starch, phytohormone signalling, senescence and response to drought, salt, and oxidative stress. Six decades since its discovery, no functional domains have been defined, and its mechanism of action is still not well-characterised. In this review, we explore the functional evolution of GI to distinguish between ancestral and more recently acquired roles. GI integrated itself into various existing signalling pathways of the circadian clock, blue light, photoperiod, and osmotic and oxidative stress response. It also evolved parallelly to acquire new functions for chloroplast accumulation, red light signalling and anthocyanin production. In this review, we have encapsulated the known mechanisms of various biological functions of GI. Additionally, this manuscript will throw light on the evolution of GI in plant lineage.

Acetylsalicylic acid dosed at bedtime vs. dosed in the morning for circadian rhythm of blood pressure- a systematic review and meta-analysis.

Introduction: Cardiovascular disease (CVD) is a leading global cause of morbidity and mortality, with high systolic blood pressure (SBP) identified as a major risk factor. Aspirin (Acetylsalicylic acid-ASA) has been considered for CVD prevention, prompting questions about its optimal use in primary and secondary prevention and the ideal dosing time to maximize its impact on circadian blood pressure rhythms. Previous research suggests a potential benefit of bedtime aspirin dosing in reducing blood pressure, attributed to its effects on the renin-angiotensin-aldosterone system and nitric oxide production. This systematic review and meta-analysis aim to further explore the circadian effects of aspirin on blood pressure, focusing on the timing of administration. Methods: Adhering to PRISMA guidelines, a comprehensive search of PubMed, Cochrane Library, and clinicaltrials.gov was conducted. Randomized controlled trials (RCTs) involving patients aged >18 with cardiovascular history and hypertension were included. The primary objective was to assess the impact of bedtime-dosed and morning-dosed aspirin on systolic and diastolic blood pressure. Low-dose aspirin was administered for primary or secondary prevention. The Cochrane Risk of Bias tool evaluated study quality. Meta-analyses were conducted using RevMan 5.3, with mean deviations and 95% confidence intervals employed for outcomes. Results: Initial searches yielded 1,181 articles, with six studies meeting the inclusion criteria. These RCTs involved 1,470 patients, with 1,086 completing follow-up. Bedtime aspirin dosing demonstrated a significant reduction in both systolic and diastolic blood pressure compared to morning dosing (p < 0.05). Meta-analysis results for systolic blood pressure revealed a weighted mean difference of approximately 3.65 mmHg in favour of bedtime dosing, with low heterogeneity (I 2 = 0%). For diastolic blood pressure, the weighted mean difference was 1.92, again favouring bedtime dosing, with 3% heterogeneity. Conclusion: This meta-analysis, involving over 1,300 cardiovascular/hypertensive patients, supports the effectiveness of bedtime aspirin in reducing systolic and diastolic blood pressure compared to morning dosing. The results align with previous findings but distinguish themselves by incorporating a more diverse patient population and addressing moderate heterogeneity. While the study's outcomes are promising, further research, including larger sample sizes and longer durations, is warranted for comprehensive clinical implementation. As the study exclusively focused on aspirin timing, future investigations should explore sustained blood pressure effects in patients with clinical indications for aspirin alongside other hypertensive medications.

Sleep and diurnal alternative polyadenylation sites associated with human APA-linked brain disorders.

Disruption of sleep and circadian rhythms are a comorbid feature of many pathologies, and can negatively influence many health conditions, including neurodegenerative disease, metabolic illness, cancer, and various neurological disorders. Genetic association studies linking sleep and circadian disturbances with disease susceptibility have mainly focused on changes in gene expression due to mutations, such as single-nucleotide polymorphisms. The interaction between sleep and/or circadian rhythms with the use of Alternative Polyadenylation (APA) has been largely undescribed, particularly in the context of other disorders. APA generates transcript isoforms by utilizing various polyadenylation sites (PASs) from the same gene affecting its mRNA translation, stability, localization, and subsequent function. Here we identified unique APAs expressed in rat brain over time-of-day, immediately following sleep deprivation, and the subsequent recovery period. From these data, we performed a secondary analysis of these sleep- or time-of-day associated PASs with recently described APA-linked human brain disorder susceptibility genes.

Circadian rhythm and daytime variation do not affect intraoperative bacterial sternal contamination and postoperative wound infections following cardiac surgery.

Studies have documented various effects of circadian rhythm and daytime variations on the cardiovascular and immune system as well as wound healing. From June to December 2016, n = 367 cardiac surgery patients were enrolled. Microbiological swabs from the mediastinum and subcutaneous wound were taken before sternal closure. Patients were assigned to groups based on operation start: morning (n = 219) or afternoon (n = 135). Bacterial contamination and wound infections were studied in relation to circadian rhythm and daytime variation. We did not observe any difference in mortality (morning: 3.7%, afternoon: 3.0%, p > 0.99) and major adverse events (morning: 8.2%, afternoon: 5.9%, p = 0.53). In 27.7% of the morning group, at least one positive intraoperative swab was observed, similar to the afternoon group (25.6%, p = 0.71). The incidence of positive presternal swabs was 15.6% in the morning compared to 9.1% in the afternoon (p = 0.18). About 90% of the germs detected were part of the natural skin flora (e.g., Cutibacterium acnes and Staphylococcus epidermidis). The incidence of sternal wound infections was 7.3% (morning) and 3.0% (afternoon) (p = 0.18). We did not find differences in the incidence of intraoperative bacterial sternal contamination, nor postoperative infections, between patients who underwent cardiac surgery in the morning or afternoon.

Melatonin's role in the timing of sleep onset is conserved in nocturnal mice.

Melatonin supplementation strengthens non-restorative sleep rhythms and its temporal alignment in both humans and night-active rodents. Of note, although the sleep cycle is reversed in day-active and night-active (nocturnal) mammals, both, produce melatonin at night under the control of the circadian clock. The effects of exogenous melatonin on sleep and sleepiness are relatively clear, but its endogenous role in sleep, particularly, in timing sleep onset (SO), remains poorly understood. We show in nocturnal mice that the increases in mid-nighttime sleep episodes, and the mid-nighttime decline in activity, are coupled to nighttime melatonin signaling. Furthermore, we show that endogenous melatonin modulates SO by reducing the threshold for wake-to-sleep transitioning. Such link between melatonin and SO timing may explain phenomena such as increased sleep propensity in circadian rhythm sleep disorders and chronic insomnia in patients with severely reduced nocturnal melatonin levels. Our findings demonstrate that melatonin's role in sleep is evolutionarily conserved, effectively challenging the argument that melatonin cannot play a major role in sleep regulation in nocturnal mammals, where the main activity phase coincides with high melatonin levels.

A one-day journey to the suburbs: circadian clock in the Drosophila visual system.

Living organisms, which are constantly exposed to cyclical variations in their environment, need a high degree of plasticity in their visual system to respond to daily and seasonal fluctuations in lighting conditions. In Drosophila melanogaster, the visual system is a complex tissue comprising different photoreception structures that exhibit daily rhythms in gene expression, cell morphology, and synaptic plasticity, regulated by both the central and peripheral clocks. In this review, we briefly summarize the structure of the circadian clock and the visual system in Drosophila and comprehensively describe circadian oscillations in visual structures, from molecules to behaviors, which are fundamental for the fine-tuning of visual sensitivity. We also compare some features of the rhythmicity in the visual system with that of the central pacemaker and hypothesize about the differences in the regulatory signals and mechanisms that control these two clocks.

The Relationship between Sleep and Physical Activity by Age, Race, and Gender.

Cardiometabolic diseases remain the leading cause of death in the United States. Lifestyle factors contribute the majority of risk for these diseases. Although diet and exercise have been the primary focus of research on modifiable behaviors to target for interventions to prevent cardiometabolic disease, recent evidence suggests that sleep also plays an important role. Indeed, the updated American Heart Association campaign includes sleep as one of its "Essential Eight". This review details the reciprocally reinforcing positive relationship between sleep and daytime physical activity behaviors and explores how this relationship differs based on age, gender and race. For example, interventions to improve moderate intensity physical activity may be particularly beneficial to women, older adults, and Black Americans, who are at increased risk for sleep disturbances. Communicating to Americans the importance of managing their time to meet current physical activity and sleep recommendations is a challenge given that there are so many competing behaviors consuming large amounts of time (e.g., social media, gaming), but is critical given the importance of these behaviors for cardiometabolic health.

Evidence for a role of human blood-borne factors in mediating age-associated changes in molecular circadian rhythms.

Aging is associated with a number of physiologic changes including perturbed circadian rhythms; however, mechanisms by which rhythms are altered remain unknown. To test the idea that circulating factors mediate age-dependent changes in peripheral rhythms, we compared the ability of human serum from young and old individuals to synchronize circadian rhythms in culture. We collected blood from apparently healthy young (age 25-30) and old (age 70-76) individuals at 14:00 and used the serum to synchronize cultured fibroblasts. We found that young and old sera are equally competent at initiating robust ~24 hr oscillations of a luciferase reporter driven by clock gene promoter. However, cyclic gene expression is affected, such that young and old sera promote cycling of different sets of genes. Genes that lose rhythmicity with old serum entrainment are associated with oxidative phosphorylation and Alzheimer's Disease as identified by STRING and IPA analyses. Conversely, the expression of cycling genes associated with cholesterol biosynthesis increased in the cells entrained with old serum. Genes involved in the cell cycle and transcription/translation remain rhythmic in both conditions. We did not observe a global difference in the distribution of phase between groups, but found that peak expression of several clock-controlled genes (PER3, NR1D1, NR1D2, CRY1, CRY2, and TEF) lagged in the cells synchronized ex vivo with old serum. Taken together, these findings demonstrate that age-dependent blood-borne factors affect circadian rhythms in peripheral cells and have the potential to impact health and disease via maintaining or disrupting rhythms respectively.

Ellagic Acid Protects against Alcohol-Related Liver Disease by Modulating the Hepatic Circadian Rhythm Signaling through the Gut Microbiota-NPAS2 Axis.

Alcohol-related liver disease (ALD) encompasses a spectrum of hepatic disorders resulting from alcohol abuse, which constitutes the predominant etiology of morbidity and mortality associated with hepatic pathologies globally. Excessive alcohol consumption disrupts the integrity of the intestinal barrier and perturbs the balance of gut microbiota, thereby facilitating the progression of ALD. Ellagic acid (EA) has been extensively reported to be an effective intervention for alleviating liver symptoms. However, the target molecules of EA in improving ALD and its underlying mechanism remain elusive. First, our study indicates that EA ameliorated ALD through the hepatic circadian rhythm signaling by up-regulating neuronal PAS domain protein 2 (NPAS2). Furthermore, analysis of the intestinal microbiome showed that EA significantly enhanced the abundance of beneficial bacteria, which was positively correlated with NPAS2 expression and negatively correlated with liver injury. Finally, antibiotic treatment and fecal microbiota transplantation (FMT) experiments established a causal relationship between the reshaped microbiota and NPAS2 in the amelioration of ALD. In summary, our study demonstrates novel evidence that EA attenuated ALD by modulating the hepatic circadian rhythm signaling pathway via the gut microbiota-NPAS2 axis, providing valuable insights for EA and microbiome-targeted interventions against ALD.

The Change Rate of the Fbxl21 Gene and the Amino Acid Composition of Its Protein Correlate with the Species-Specific Lifespan in Placental Mammals.

This article proposes a methodology for establishing a relationship between the change rate of a given gene (relative to a given taxon) together with the amino acid composition of the proteins encoded by this gene and the traits of the species containing this gene. The methodology is illustrated based on the mammalian genes responsible for regulating the circadian rhythms that underlie a number of human disorders, particularly those associated with aging. The methods used are statistical and bioinformatic ones. A systematic search for orthologues, pseudogenes, and gene losses was performed using our previously developed methods. It is demonstrated that the least conserved Fbxl21 gene in the Euarchontoglires superorder exhibits a statistically significant connection of genomic characteristics (the median of dN/dS for a gene relative to all the other orthologous genes of a taxon, as well as the preference or avoidance of certain amino acids in its protein) with species-specific lifespan and body weight. In contrast, no such connection is observed for Fbxl21 in the Laurasiatheria superorder. This study goes beyond the protein-coding genes, since the accumulation of amino acid substitutions in the course of evolution leads to pseudogenization and even gene loss, although the relationship between the genomic characteristics and the species traits is still preserved. The proposed methodology is illustrated using the examples of circadian rhythm genes and proteins in placental mammals, e.g., longevity is connected with the rate of Fbxl21 gene change, pseudogenization or gene loss, and specific amino acid substitutions (e.g., asparagine at the 19th position of the CRY-binding domain) in the protein encoded by this gene.

Work Around the Clock: How Work Hours Induce Social Jetlag and Sleep Deficiency.

A growing body of evidence has placed an increasing emphasis on how sleep affects health. Not only does insufficient sleep make one subjectively feel worse, but is associated with chronic diseases that are considered epidemics in industrialized nations. This is partly caused by the growing need for prolonged work and social schedules, exemplified by shift work, late-night weekends, and early morning work/school start times (social jetlag). Here, we consider fundamental relationships between the circadian clock and biologic processes and discuss how common practices, such as shift work and social jetlag, contribute to sleep disruption, circadian misalignment, and adverse health outcomes.

Sleep Deficiency in the Elderly.

With aging, there are normative changes to sleep physiology and circadian rhythmicity that may predispose older adults to sleep deficiency, whereas many health-related and psychosocial/behavioral factors may precipitate sleep deficiency. In this article, we describe age-related changes to sleep and describe how the health-related and psychosocial/behavioral factors typical of aging may converge in older adults to increase the risk for sleep deficiency. Next, we review the consequences of sleep deficiency in older adults, focusing specifically on important age-related outcomes, including mortality, cognition, depression, and physical function. Finally, we review treatments for sleep deficiency, highlighting safe and effective nonpharmacologic interventions.

Adding Insult to Injury: Sleep Deficiency in Hospitalized Patients.

Sleep deficiency is a common problem in the hospital setting. Contributing factors include preexisting medical conditions, illness severity, the hospital environment, and treatment-related effects. Hospitalized patients are particularly vulnerable to the negative health effects of sleep deficiency that impact multiple organ systems. Objective sleep measurement is difficult to achieve in the hospital setting, posing a barrier to linking improvements in hospital outcomes with sleep promotion protocols. Key next steps in hospital sleep promotion include improvement in sleep measurement techniques and harmonization of study protocols and outcomes to strengthen existing evidence and facilitate data interpretation across studies.

Glaucoma-inducing retinal ganglion cell degeneration alters diurnal rhythm of key molecular components of the central clock and locomotor activity in mice.

Glaucoma is a chronic optic neuropathy characterized by the progressive degeneration of retinal ganglion cells (RGC). These cells play a crucial role in transmitting visual and non-visual information to brain regions, including the suprachiasmatic nucleus (SCN), responsible for synchronizing biological rhythms. To understand how glaucoma affects circadian rhythm synchronization, we investigated potential changes in the molecular clock machinery in the SCN. We found that the progressive increase in intraocular pressure (IOP) negatively correlated with spontaneous locomotor activity (SLA). Transcriptome analysis revealed significant alterations in the SCN of glaucomatous mice, including downregulation of genes associated with circadian rhythms. In fact, we showed a loss of diurnal oscillation in the expression of vasoactive intestinal peptide (Vip), its receptor (Vipr2), and period 1 (Per1) in the SCN of glaucomatous mice. These findings were supported by the 7-h phase shift in the peak expression of arginine vasopressin (Avp) in the SCN of mice with glaucoma. Despite maintaining a 24-h period under both light/dark (LD) and constant dark (DD) conditions, glaucomatous mice exhibited altered SLA rhythms, characterized by decreased amplitude. Taken altogether, our findings provide evidence of how glaucoma affects the regulation of the central circadian clock and its consequence on the regulation of circadian rhythms.

Crosstalk between the circatidal and circadian clocks mediates behavioral adaptation to tidal patterns.

The ability to anticipate tides is critical for a wide range of marine organisms, but this task is complicated by the diversity of tidal patterns on Earth. Previous findings suggest that organisms whose geographic range spans multiple types of tidal cycles can produce distinct patterns of rhythmic behavior that correspond to the tidal cycles they experience. How this behavioral plasticity is achieved, however, is unclear. Here, we show that Parhyale hawaiensis adapts its rhythmic behavior to various naturally occurring tidal regimens through the plastic contribution of its circatidal and circadian clocks. After entrainment to a tidal cycle that deviated only mildly from a regular 12.4 h tidal cycle, animals exhibited strong circatidal rhythms. By contrast, following entrainment to more irregularly spaced tides or to tides that occurred every 24.8 h, a significant fraction of animals instead synchronized to the light/dark (LD) cycle and exhibited circadian behavior, while others showed rhythmic behavior with both circatidal and circadian traits. We also show that the circatidal clock, while able to entrain to various naturally occurring tidal patterns, does not entrain to an unnatural one. We propose that Parhyale hawaiensis's ecological success around the world relies in part on the plastic interactions between the circatidal and circadian clocks, which shape its rhythmic behavior appropriately according to tidal patterns.

State of the Science: The Transdiagnostic Intervention for Sleep and Circadian Dysfunction.

The transdiagnostic intervention for sleep and circadian dysfunction (TranS-C) was developed to provide one protocol that treats a range of sleep and circadian problems across a range of mental disorders. The focus of TranS-C includes, and goes beyond, categorically defined sleep and circadian disorders to facilitate healthy sleep along empirically derived "sleep health" dimensions. In this State of the Science review, we highlight key advantages of a transdiagnostic approach to sleep and circadian problems, including (a) the potential to better understand and treat comorbidity between various sleep and circadian problems and mental disorders, as well as the potential to better understand and treat the heterogeneous sleep and circadian problems that are present within a specific mental disorder; (b) the opportunity to explore the hypothesis that sleep and circadian problems are an important transdiagnostic mechanism in the multifactorial maintenance of mental disorders; (c) the potential to transfer breakthroughs made across siloed areas of research and practice; (d) its suitability for dissemination into a broad range of settings, particularly lower resource settings; and (e) the opportunity to improve a range of important outcomes. We also explain the theoretical underpinnings of TranS-C, including the two-process model of sleep regulation and the Sleep Health Framework. TranS-C includes cognitive-behavioral therapy for insomnia (CBT-I) and we offer recommendations for when to use CBT-I versus TranS-C. The process for developing TranS-C is discussed along with outcome data, applications to underserved communities, and future directions for research.