Cnidarians are CLOCKing in.

Studies of the starlet sea anemone provide important insights into the early evolution of the circadian clock in animals.

Chronic circadian rhythm disorder induces heart failure with preserved ejection fraction-like phenotype through the Clock-sGC-cGMP-PKG1 signaling pathway.

Emerging evidence has documented that circadian rhythm disorders could be related to cardiovascular diseases. However, there is limited knowledge on the direct adverse effects of circadian misalignment on the heart. This study aimed to investigate the effect of chronic circadian rhythm disorder on heart homeostasis in a mouse model of consistent jetlag. The jetlag model was induced in mice by a serial 8-h phase advance of the light cycle using a light-controlled isolation box every 4 days for up to 3 months. Herein, we demonstrated for the first time that chronic circadian rhythm disorder established in the mouse jetlag model could lead to HFpEF-like phenotype such as cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction, following the attenuation of the Clock-sGC-cGMP-PKG1 signaling. In addition, clock gene knock down in cardiomyocytes induced hypertrophy via decreased sGC-cGMP-PKG signaling pathway. Furthermore, treatment with an sGC-activator riociguat directly attenuated the adverse effects of jetlag model-induced cardiac hypertrophy, cardiac fibrosis, and cardiac diastolic dysfunction. Our data suggest that circadian rhythm disruption could induce HFpEF-like phenotype through downregulation of the clock-sGC-cGMP-PKG1 signaling pathway. sGC could be one of the molecular targets against circadian rhythm disorder-related heart disease.

Time of day does not impact spinal serotonin levels in humans.

Spinal serotonin enables neuro-motor recovery (i.e., plasticity) in patients with debilitating paralysis. While there exists time of day fluctuations in serotonin-dependent spinal plasticity, it is unknown, in humans, whether this is due to dynamic changes in spinal serotonin levels or downstream signaling processes. The primary objective of this study was to determine if time of day variations in spinal serotonin levels exists in humans. To assess this, intrathecal drains were placed in seven adults with cerebrospinal fluid (CSF) collected at diurnal (05:00 to 07:00) and nocturnal (17:00 to 19:00) intervals. High performance liquid chromatography with mass spectrometry was used to quantify CSF serotonin levels with comparisons being made using univariate analysis. From the 7 adult patients, 21 distinct CSF samples were collected: 9 during the diurnal interval and 12 during nocturnal. Diurnal CSF samples demonstrated an average serotonin level of 216.6 ± $ \pm $ 67.7 nM. Nocturnal CSF samples demonstrated an average serotonin level of 206.7 ± $ \pm $ 75.8 nM. There was no significant difference between diurnal and nocturnal CSF serotonin levels (p = .762). Within this small cohort of spine healthy adults, there were no differences in diurnal versus nocturnal spinal serotonin levels. These observations exclude spinal serotonin levels as the etiology for time of day fluctuations in serotonin-dependent spinal plasticity expression.

Prediction of heart failure patients with distinct left ventricular ejection fraction levels using circadian ECG features and machine learning.

Heart failure (HF) encompasses a diverse clinical spectrum, including instances of transient HF or HF with recovered ejection fraction, alongside persistent cases. This dynamic condition exhibits a growing prevalence and entails substantial healthcare expenditures, with anticipated escalation in the future. It is essential to classify HF patients into three groups based on their ejection fraction: reduced (HFrEF), mid-range (HFmEF), and preserved (HFpEF), such as for diagnosis, risk assessment, treatment choice, and the ongoing monitoring of heart failure. Nevertheless, obtaining a definitive prediction poses challenges, requiring the reliance on echocardiography. On the contrary, an electrocardiogram (ECG) provides a straightforward, quick, continuous assessment of the patient's cardiac rhythm, serving as a cost-effective adjunct to echocardiography. In this research, we evaluate several machine learning (ML)-based classification models, such as K-nearest neighbors (KNN), neural networks (NN), support vector machines (SVM), and decision trees (TREE), to classify left ventricular ejection fraction (LVEF) for three categories of HF patients at hourly intervals, using 24-hour ECG recordings. Information from heterogeneous group of 303 heart failure patients, encompassing HFpEF, HFmEF, or HFrEF classes, was acquired from a multicenter dataset involving both American and Greek populations. Features extracted from ECG data were employed to train the aforementioned ML classification models, with the training occurring in one-hour intervals. To optimize the classification of LVEF levels in coronary artery disease (CAD) patients, a nested cross-validation approach was employed for hyperparameter tuning. HF patients were best classified using TREE and KNN models, with an overall accuracy of 91.2% and 90.9%, and average area under the curve of the receiver operating characteristics (AUROC) of 0.98, and 0.99, respectively. Furthermore, according to the experimental findings, the time periods of midnight-1 am, 8-9 am, and 10-11 pm were the ones that contributed to the highest classification accuracy. The results pave the way for creating an automated screening system tailored for patients with CAD, utilizing optimal measurement timings aligned with their circadian cycles.

Shift schedules and circadian preferences: the association with sleep and mood.

Object: We explored the circadian preferences of non-shift workers (non-SWs) and various types of shift workers (SWs), and the associations of these preferences with sleep and mood. Methods: In total, 4,561 SWs (2,419 women and 2,142 men aged 37.00 ± 9.80 years) and 2,093 non-SWs (1,094 women and 999 men aged 37.80 ± 9.73 years) completed an online survey. Of all SWs, 2,415 (1,079 women and 1,336 men aged 37.77 ± 9.96 years) reported regularly rotating or fixed schedules ("regular SWs"), and 2,146 (1,340 women and 806 men aged 36.12 ± 9.64 years) had irregular schedules ("irregular SWs"). Of the regular SWs, 2,040 had regularly rotating schedules, 212 had fixed evening schedules, and 163 had fixed night schedules. All participants completed the Morningness-Eveningness Questionnaire (MEQ) exploring circadian preferences, the short form of the Center for Epidemiological Studies-Depression Scale (CES-D) evaluating depression, the Insomnia Severity Index (ISI), and the Epworth Sleepiness Scale (ESS). Results: Compared to non-SWs, SWs had lower MEQ scores, i.e., more eveningness, after controlling for age, gender, income, occupation, and weekly work hours (F = 87.97, p < 0.001). Irregular SWs had lower MEQ scores than regular SWs (F = 50.89, p < 0.001). Among regular SWs, the MEQ scores of fixed evening and fixed night SWs were lower than those of regularly rotating SWs (F = 22.42, p < 0.001). An association between the MEQ and ESS scores was apparent in non-SWs (r = -0.85, p < 0.001) but not in SWs (r = 0.001, p = 0.92). Conclusion: SWs exhibited more eveningness than non-SWs; eveningness was particularly prominent in SWs with irregular or fixed evening/night shifts. Eveningness was associated with sleepiness only in non-SWs, but not in SWs.

Severe dawn phenomenon predicts long-term risk of all-cause mortality in patients with type 2 diabetes.

AIMS: The dawn phenomenon (DP) is an abnormal early morning blood glucose rise without nocturnal hypoglycaemia, which can be more easily and precisely assessed with continuous glucose monitoring (CGM). This prospective study aimed to explore the association between DP and the risk of all-cause mortality in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 5542 adult inpatients with type 2 diabetes in a single centre were analysed. The magnitude of DP (ΔG) was defined as the increment in the CGM-determined glucose value from nocturnal nadir (after 24:00) to prebreakfast. Participants were stratified into four groups by ΔG: ≤1.11, 1.12-3.33, 3.34-5.55, and >5.55 mmol/L. Cox proportional hazard regression models were used to evaluate the impact of DP on all-cause mortality risk. RESULTS: During a median follow-up of 9.4 years, 1083 deaths were identified. The restricted cubic spline revealed a nonlinear (p for nonlinearity = 0.002) relationship between ΔG and the risk of all-cause mortality. A multivariate-adjusted Cox regression model including glycated haemoglobin A1c (HbA1c) showed that ΔG > 5.55 mmol/L was associated with 30% (95% CI, 1.01-1.66) higher risk of all-cause mortality, as compared with ΔG 1.12-3.33 mmol/L. CONCLUSIONS: Higher ΔG is significantly related to an increased risk of all-cause mortality in type 2 diabetes, suggesting that severe DP should be given more attention as a part of glucose management to reduce the risk of long-term adverse outcomes.

Diurnal Variation in Choroidal Parameters Among Healthy Subjects Using Wide-Field Swept-Source Optical Coherence Tomography Angiography.

Purpose: The purpose of this study was to evaluate the diurnal variation in choroidal parameters in a wide field area among healthy subjects and to identify correlations between choroidal luminal area and stromal area and various systemic factors. Methods: In this cross-sectional study, 42 eyes from 21 healthy participants (mean age = 32.4 ± 8.8 years) were examined using wide-field swept-source optical coherence tomography angiography (WF SS-OCTA, 24 mm × 20 mm). Measurements of choroidal parameters, including choroidal volume (CV), choroidal thickness (CT), choroidal vessel volume (CVV), and choroidal stromal volume (CSV), were taken at 8:00, 12:00, 18:00, and 22:00. Systemic factors, such as blood pressure and heart rate, were concurrently monitored. Results: Our study observed significant diurnal variations in the mean total CV, CT, CVV, and CSV, with minimum measurements around 12:00 (P < 0.001) and peak values at 22:00 (P < 0.001). Furthermore, changes in CV in specific regions were more closely associated with fluctuations in CVV than CSV in the same regions. No significant diurnal variations were found in systolic (P = 0.137) or diastolic blood pressure (P = 0.236), whereas significant variations were observed in the heart rate (P = 0.001). Conclusions: Our study reveals diurnal variations in choroidal parameters and their associations, emphasizing that changes in choroidal volume relate more to the luminal than the stromal area in vessel-rich regions. This enhances our understanding of choroidal-related ocular diseases. Translational Relevance: Regions with higher choroidal vasculature observed greater choroidal volume changes.

Stress in autism (STREAM): A study protocol on the role of circadian activity, sleep quality and sensory reactivity.

Mental health issues are markedly increased in individuals with autism, making it the number one research priority by stakeholders. There is a crucial need to use personalized approaches to understand the underpinnings of mental illness in autism and consequently, to address individual needs. Based on the risk factors identified in typical mental research, we propose the following themes central to mental health issues in autism: sleep difficulties and stress. Indeed, the prevalence of manifold circadian disruptions and sleep difficulties in autism, alongside stress related to sensory overload, forms an integral part of autistic symptomatology. This proof-of-concept study protocol outlines an innovative, individualised approach towards investigating the interrelationships between stress indices, sleep and circadian activation patterns, and sensory sensitivity in autism. Embracing an individualized methodology, we aim to collect 14 days of data per participant from 20 individuals with autism diagnoses and 20 without. Participants' sleep will be monitored using wearable EEG headbands and a sleep diary. Diurnal tracking of heart rate and electrodermal activity through wearables will serve as proxies of stress. Those objective data will be synchronized with subjective experience traces collected throughout the day using the Temporal Experience Tracing (TET) method. TET facilitates the quantification of relevant aspects of individual experience states, such as stress or sensory sensitivities, by providing a continuous multidimensional description of subjective experiences. Capturing the dynamics of subjective experiences phase-locked to neural and physiological proxies both between and within individuals, this approach has the potential to contribute to our understanding of critical issues in autism, including sleep problems, sensory reactivity and stress. The planned strives to provide a pathway towards developing a more nuanced and individualized approach to addressing mental health in autism.

Short neuropeptide F in integrated insect physiology. / 昆虫生理中短神经肽Fçš„åŠŸèƒ½ç ”ç©¶è¿›å±•.

The short neuropeptide F (sNPF) family of peptides is a multifunctional group of neurohormones involved in the regulation of various physiological processes in insects. They have been found in a broad spectrum of species, but the number of isoforms in the precursor molecule varies from one to four. The receptor for sNPF (sNPFR), which belongs to the G protein-coupled receptor family, has been characterized in various insect orders and was shown to be an ortholog of the mammalian prolactin-releasing peptide receptor (PrPR). The sNPF signaling pathway interacts with other neurohormones such as insulin-like peptides, SIFamide, and pigment-dispersing factors (PDFs) to regulate various processes. The main physiological function of sNPF seems to be involved in the regulation of feeding, but the observed effects are species-specific. sNPF is also connected with the regulation of foraging behavior and the olfactory system. The influence of sNPF on feeding and thus energy metabolism may also indirectly affect other vital processes, such as reproduction and development. In addition, these neurohormones are involved in the regulation of locomotor activity and circadian rhythm in insects. This review summarizes the current state of knowledge about the sNPF system in insects.

Circadian Regulation of Bone Remodeling.

Adult bones are continuously remodeled by the balance between bone resorption by osteoclasts and subsequent bone formation by osteoblasts. Many studies have provided molecular evidence that bone remodeling is under the control of circadian rhythms. Circadian fluctuations have been reported in the serum and urine levels of bone turnover markers, such as digested collagen fragments and bone alkaline phosphatase. Additionally, the expressions of over a quarter of all transcripts in bones show circadian rhythmicity, including the genes encoding master transcription factors for osteoblastogenesis and osteoclastogenesis, osteogenic cytokines, and signaling pathway proteins. Serum levels of calcium, phosphate, parathyroid hormone, and calcitonin also display circadian rhythmicity. Finally, osteoblast- and osteoclast-specific knockout mice targeting the core circadian regulator gene Bmal1 show disrupted bone remodeling, although the results have not always been consistent. Despite these studies, however, establishing a direct link between circadian rhythms and bone remodeling in vivo remains a major challenge. It is nearly impossible to repeatedly collect bone materials from human subjects while following circadian changes. In addition, the differences in circadian gene regulation between diurnal humans and nocturnal mice, the main model organism, remain unclear. Filling the knowledge gap in the circadian regulation of bone remodeling could reveal novel regulatory mechanisms underlying many bone disorders including osteoporosis, genetic diseases, and fracture healing. This is also an important question for the basic understanding of how cell differentiation progresses under the influence of cyclically fluctuating environments.

The Association between Circadian Syndrome and Frailty in US adults: a cross-sectional study of NHANES Data from 2007 to 2018.

PURPOSE: Frailty and Circadian Syndrome (CircS) are prevalent among the elderly, yet the link between them remains underexplored. This study aims to examine the association between CircS and frailty, particularly focusing on the impact of various CircS components on frailty. MATERIALS AND METHODS: We conducted a cross-sectional analysis using data from the National Health and Nutrition Examination Survey (NHANES) spanning 2007 to 2018. The 49-item Frailty Index (FI) was employed to assess frailty. To understand the prevalence of CircS in relation to frailty, we applied three multivariate logistic regression models. Additionally, subgroup and interaction analyses were performed to investigate potential modifying factors. RESULTS: The study included 8,569 participants. In fully adjusted models, individuals with CircS showed a significantly higher risk of frailty compared to those without CircS (Odds Ratio [OR] = 2.18, 95% Confidence Interval [CI]: 1.91-2.49, p < 0.001). A trend of increasing frailty risk with greater CircS component was observed (trend test p < 0.001). Age (p = 0.01) and race (p = 0.02) interactions notably influenced this association, although the direction of effect was consistent across subgroups. Sensitivity analysis further confirmed the strength of this relationship. CONCLUSION: This study identifies a strong positive correlation between CircS and frailty in the elderly. The risk of frailty escalates with an increasing number of CircS components. These findings highlight the intricate interplay between circadian syndrome and frailty in older adults, offering valuable insights for developing targeted prevention and intervention strategies.

Crosstalk between circadian clocks and pathogen niche.

Circadian rhythms are intrinsic 24-hour oscillations found in nearly all life forms. They orchestrate key physiological and behavioral processes, allowing anticipation and response to daily environmental changes. These rhythms manifest across entire organisms, in various organs, and through intricate molecular feedback loops that govern cellular oscillations. Recent studies describe circadian regulation of pathogens, including parasites, bacteria, viruses, and fungi, some of which have their own circadian rhythms while others are influenced by the rhythmic environment of hosts. Pathogens target specific tissues and organs within the host to optimize their replication. Diverse cellular compositions and the interplay among various cell types create unique microenvironments in different tissues, and distinctive organs have unique circadian biology. Hence, residing pathogens are exposed to cyclic conditions, which can profoundly impact host-pathogen interactions. This review explores the influence of circadian rhythms and mammalian tissue-specific interactions on the dynamics of pathogen-host relationships. Overall, this demonstrates the intricate interplay between the body's internal timekeeping system and its susceptibility to pathogens, which has implications for the future of infectious disease research and treatment.

A subclass of evening cells promotes the switch from arousal to sleep at dusk.

Animals exhibit rhythmic patterns of behavior that are shaped by an internal circadian clock and the external environment. Although light intensity varies across the day, there are particularly robust differences at twilight (dawn/dusk). These periods are also associated with major changes in behavioral states, such as the transition from arousal to sleep. However, the neural mechanisms by which time and environmental conditions promote these behavioral transitions are poorly defined. Here, we show that the E1 subclass of Drosophila evening clock neurons promotes the transition from arousal to sleep at dusk. We first demonstrate that the cell-autonomous clocks of E2 neurons primarily drive and adjust the phase of evening anticipation, the canonical behavior associated with "evening" clock neurons. We next show that conditionally silencing E1 neurons causes a significant delay in sleep onset after dusk. However, rather than simply promoting sleep, activating E1 neurons produces time- and light-dependent effects on behavior. Activation of E1 neurons has no effect early in the day but then triggers arousal before dusk and induces sleep after dusk. Strikingly, these activation-induced phenotypes depend on the presence of light during the day. Despite their influence on behavior around dusk, in vivo voltage imaging of E1 neurons reveals that their spiking rate and pattern do not significantly change throughout the day. Moreover, E1-specific clock ablation has no effect on arousal or sleep. Thus, we suggest that, rather than specifying "evening" time, E1 neurons act, in concert with other rhythmic neurons, to promote behavioral transitions at dusk.

Circadian rhythm of cutaneous pruritus. / 皮肤瘙痒的昼夜节律.

One of the most common and significant symptoms for skin disorders is pruritus. Additionally, it serves as a significant catalyst for the exacerbation or reoccurrence of skin diseases. Pruritus seriously affects patients' physical and mental health, and even the quality of life. It brings a heavy burden to the patients, the families, even the whole society. The pathogenesis and regulation mechanisms for pruritus are complicated and have not yet been elucidated. Previous clinical studies have shown that itch worsens at night in scabies, chronic pruritus, atopic dermatitis, and psoriasis, suggesting that skin pruritus may change with circadian rhythm. Cortisol, melatonin, core temperature, cytokines, and prostaglandins are the main regulatory factors of the circadian rhythm of pruritus. Recent studies have shown that some CLOCK genes, such as BMAL1, CLOCK, PER, and CRY, play an important role in the regulation of the circadian rhythm of pruritus by regulating the Janus tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor kappa-B (NF-κB) signaling pathways. However, the mechanisms for circadian clock genes in regulation of circadian rhythm of pruritus have not been fully elucidated. Further studies on the mechanism of circadian clock genes in the regulation of circadian rhythm of pruritus will lay a foundation for elucidating the regulatory mechanisms for pruritus, and also provide new ideas for the control of pruritus and the alleviation of skin diseases.

Test-retest reliability and time-of-day variations of perfusion imaging at rest and during a vigilance task.

Arterial spin-labeled perfusion and blood oxygenation level-dependent functional MRI are indispensable tools for noninvasive human brain imaging in clinical and cognitive neuroscience, yet concerns persist regarding the reliability and reproducibility of functional MRI findings. The circadian rhythm is known to play a significant role in physiological and psychological responses, leading to variability in brain function at different times of the day. Despite this, test-retest reliability of brain function across different times of the day remains poorly understood. This study examined the test-retest reliability of six repeated cerebral blood flow measurements using arterial spin-labeled perfusion imaging both at resting-state and during the psychomotor vigilance test, as well as task-induced cerebral blood flow changes in a cohort of 38 healthy participants over a full day. The results demonstrated excellent test-retest reliability for absolute cerebral blood flow measurements at rest and during the psychomotor vigilance test throughout the day. However, task-induced cerebral blood flow changes exhibited poor reliability across various brain regions and networks. Furthermore, reliability declined over longer time intervals within the day, particularly during nighttime scans compared to daytime scans. These findings highlight the superior reliability of absolute cerebral blood flow compared to task-induced cerebral blood flow changes and emphasize the importance of controlling time-of-day effects to enhance the reliability and reproducibility of future brain imaging studies.

A mathematical model for the role of dopamine-D2 self-regulation in the production of ultradian rhythms.

Many self-motivated and goal-directed behaviours display highly flexible, approximately 4 hour ultradian (shorter than a day) oscillations. Despite lacking direct correspondence to physical cycles in the environment, these ultradian rhythms may be involved in optimizing functional interactions with the environment and reflect intrinsic neural dynamics. Current evidence supports a role of mesostriatal dopamine (DA) in the expression and propagation of ultradian rhythmicity, however, the biochemical processes underpinning these oscillations remain to be identified. Here, we use a mathematical model to investigate D2 autoreceptor-dependent DA self-regulation as the source of ultradian behavioural rhythms. DA concentration at the midbrain-striatal synapses is governed through a dual-negative feedback-loop structure, which naturally gives rise to rhythmicity. This model shows the propensity of striatal DA to produce an ultradian oscillation characterized by a flexible period that is highly sensitive to parameter variations. Circadian (approximately 24 hour) regulation consolidates the ultradian oscillations and alters their response to the phase-dependent, rapid-resetting effect of a transient excitatory stimulus. Within a circadian framework, the ultradian rhythm orchestrates behavioural activity and enhances responsiveness to an external stimulus. This suggests a role for the circadian-ultradian timekeeping hierarchy in governing organized behaviour and shaping daily experience through coordinating the motivation to engage in recurring, albeit not highly predictable events, such as social interactions.

Circadian dysfunction and cardio-metabolic disorders in humans.

The topic of human circadian rhythms is not only attracting the attention of clinical researchers from various fields but also sparking a growing public interest. The circadian system comprises the central clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral clocks in various tissues that are interconnected; together they coordinate many daily activities, including sleep and wakefulness, physical activity, food intake, glucose sensitivity and cardiovascular functions. Disruption of circadian regulation seems to be associated with metabolic disorders (particularly impaired glucose tolerance) and cardiovascular disease. Previous clinical trials revealed that disturbance of the circadian system, specifically due to shift work, is associated with an increased risk of type 2 diabetes mellitus. This review is intended to provide clinicians who wish to implement knowledge of circadian disruption in diagnosis and strategies to avoid cardio-metabolic disease with a general overview of this topic.

The use of prolonged-release melatonin in circadian medicine: a systematic review.

INTRODUCTION: Melatonin, a hormone produced by the pineal gland, regulates the sleep-wake cycle and is effective in restoring biological rhythms. Prolonged-release melatonin (PRM) is designed to mimic the natural physiological pattern of melatonin release. In circadian medicine, PRM can be used to treat sleep and circadian rhythm disorders, as well as numerous organic diseases associated with sleep disorders. EVIDENCE ACQUISITION: This systematic review analyzed 62 studies and adhered to the PRISMA guidelines, examining the effectiveness of PRM in organic pathologies and mental disorders. EVIDENCE SYNTHESIS: The main evidence concerns primary insomnia in subjects over the age of 55, showing significant improvements in sleep quality. In neurodevelopmental disorders, there is evidence of a positive impact on sleep quality and quality of life for patients and their caregivers. PRM shows efficacy in the treatment of sleep disorders in mood disorders, schizophrenia, and neurocognitive disorders, but requires further confirmation. The additional use of PRM is supported for the withdrawal of chronic benzodiazepine therapies. The tolerability and safety of PRM are excellent, with ample evidence supporting the absence of tolerance and dependence. CONCLUSIONS: Overall, PRM in circadian medicine is an effective chronopharmaceutical for restoring the sleep-wake rhythm in patients with insomnia disorder. This efficacy may also extend to sleep disorders associated with mood, neurodevelopmental and neurocognitive disorders, suggesting a further potential role in insomnia associated with various organic diseases.