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Background: Hypertension (HTN) is a medical condition characterized by persistent systolic and diastolic blood pressures of ≥ 140 mmHg and ≥ 90 mmHg, respectively. With more than 1200 million adult patients aged 30–79 years worldwide according to the latest WHO data, HTN is a major health risk factor; more importantly, 46% of patients are unaware of this condition. Essential hypertension (EH), also known as primary hypertension, is the predominant subtype and has a complex etiology that involves both genetic and non-genetic factors. Majority of living organisms are influenced by the light and dark cycle of a day and respond to these changes through an intricate clock referred to as the "biological clock" or "circadian rhythm". The connection between circadian rhythm and blood pressure is well established, with many studies supporting the role of circadian rhythm gene mutation(s)/polymorphism(s) in EH. To date, no such data are available from any Indian population. Methods: This case‒control study was conducted on 405 EH patients and 505 healthy controls belonging to the Jammu region of North India after an informed consent was obtained from the participants. A total of three single nucleotide variants, two in the CLOCK gene (rs1801260 and rs34789226) and one in the BMAL1/ARNTL gene (rs6486121), were selected for genotyping. Genotyping was performed via the RFLP technique, and the applicable statistical analyses were performed via the SPSS and SNPStats programs. Results: Logistic regression analysis revealed a statistically significant association of both CLOCK gene variants rs1801260 (T > C 3'UTR) and rs34789226 (C > T Exon 9) and a nonsignificant association of the BMAL1/ARNTL intronic variant rs6486121 (C > T) with EH. The 3'UTR variant showed a statistically significant association under the codominant (p < 0.0001), dominant (p < 0.0001), and recessive (p = 0.0004) models. In contrast, the exon 9 variant showed a statistically significant negative association under the codominant (p = 0.003) and dominant (p = 0.015) models only. The rs6486121/rs1801260 and rs1801260/rs34789226/rs6486121 haplotypes showed significant differences in their distribution between cases and controls (p < 0.0001). Certain genotypes and haplotypes were found more common in hypertensive males than females. Conclusion: This is a first report linking circadian rhythm gene polymorphisms with EH in any Indian population. The statistically significant association of the CLOCK gene 3'UTR and exon 9 polymorphisms with EH, highlight the potential role of this gene and probably other genes of the circadian pathway in the etiology of EH in the study population. Additionally, our study also revealed that certain genotypes are making males more susceptible to EH. [ABSTRACT FROM AUTHOR]

The physiological role and the molecular architecture of the circadian clock in fully developed organisms are well established. Yet, we have a limited understanding of the function of the clock during ontogenesis. We have used a null mutant (per0) of the clock gene period (per) in Drosophila melanogaster to ask whether PER may play a role during normal brain development. In third-instar larvae, we have observed that the absence of functional per results in increased genotoxic stress compared to wild-type controls. We have detected increased double-strand DNA breaks in the central nervous system and chromosome aberrations in dividing neuronal precursor cells. We have demonstrated that reactive oxygen species (ROS) are causal to the genotoxic effect and that expression of PER in glia is necessary and sufficient to suppress such a phenotype. Finally, we have shown that the absence of PER may result in less condensed chromatin, which contributes to DNA damage. [ABSTRACT FROM AUTHOR]

Circadian rhythms are generated by the master pacemaker suprachiasmatic nucleus (SCN) in concert with local clocks throughout the body. Although many brain regions exhibit cycling clock gene expression, the identity of a discrete extra-SCN brain oscillator that produces rhythmic behavior has remained elusive. Here, we show that an extra-SCN oscillator in the lateral amygdala (LA) is defined by expression of the clock-output molecule mWAKE/ANKFN1. mWAKE is enriched in the anterior/dorsal LA (adLA), and, strikingly, selective disruption of clock function or excitatory signaling in adLAmWAKE neurons abolishes Period2 (PER2) rhythms throughout the LA. mWAKE levels rise at night and promote rhythmic excitability of adLAmWAKE neurons by upregulating Ca2+-activated K+ channel activity specifically at night. adLAmWAKE neurons coordinate rhythmic sensory perception and anxiety in a clock-dependent and WAKE-dependent manner. Together, these data reveal the cellular identity of an extra-SCN brain oscillator and suggest a multi-level hierarchical system organizing molecular and behavioral rhythms. [Display omitted] • mWAKE labels a local circadian oscillator in the lateral amygdala (LA) • mWAKE generates rhythmic excitability by upregulating K Ca current at night • LAmWAKE neurons organize molecular rhythms throughout the LA • Distinct LAmWAKE outputs coordinate daily cycling of touch perception and anxiety The identity and function of local brain oscillators remain poorly understood. Liu et al. use mWAKE as a genetic entrée to uncover a local clock mechanism in the lateral amygdala that coordinates sensory perception and internal state in a time-dependent manner. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy is a common neurological disorder that is often associated with drug resistance. The current approach to treating patients with drug resistance involves surgery, which does not guarantee complete recovery. Currently, new antiepileptic drugs are being developed that target signaling cascades involved in epileptogenesis. The development of such drugs requires knowledge of the basic mechanisms of epilepsy pathogenesis. The aim of this work was to investigate the dynamics of changes in proteins involved in the regulation of apoptosis, circadian rhythms and antioxidant response in the temporal cortex of the brain during prolonged kindling in the Krushinsky–Molodkina (KM) rat model of genetic audiogenic epilepsy. The dynamics of changes in proteins of interest—p53, CLOCK, Nrf2, p105—in the temporal cortex were studied (immunohistochemistry assay, Western blotting). It was found that control KM rats had lower levels of p53 than Wistar rats. In KM rats exposed to kindling for 21 days, p53 level was increased compared to KM controls. CLOCK levels appeared to be downregulated in the KM control group compared to the negative control and increased in the 21-day kindling KM group compared to the 7-day kindling KM group. No changes in the production of Nrf2 and p105 were detected. The data obtained suggest that the changes in the levels of the investigated proteins in control KM rats compared to Wistar rats are genetically determined. Induced epileptogenesis (kindling) for 21 days leads to activation of the p53-dependent apoptosis pathway and possible desynchronosis—alteration of circadian rhythms. The findings contribute to the study of temporal lobe epilepsy mechanisms and require further studies related to mitochondrial apoptosis and sleep-wake cycle shift in the pathogenesis of temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

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Seasonal daylength, or circadian photoperiod, is a pervasive environmental signal that profoundly influences physiology and behavior. In mammals, the central circadian clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus where it receives retinal input and synchronizes, or entrains, organismal physiology and behavior to the prevailing light cycle. The process of entrainment induces sustained plasticity in the SCN, but the molecular mechanisms underlying SCN plasticity are incompletely understood. Entrainment to different photoperiods persistently alters the timing, waveform, period, and light resetting properties of the SCN clock and its driven rhythms. To elucidate novel candidate genes for molecular mechanisms of photoperiod plasticity, we performed RNA sequencing on whole SCN dissected from mice raised in long (light:dark [LD] 16:8) and short (LD 8:16) photoperiods. Fewer rhythmic genes were detected in mice subjected to long photoperiod, and in general, the timing of gene expression rhythms was advanced 4-6 h. However, a few genes showed significant delays, including Gem. There were significant changes in the expression of the clock-associated gene Timeless and in SCN genes related to light responses, neuropeptides, gamma aminobutyric acid (GABA), ion channels, and serotonin. Particularly striking were differences in the expression of the neuropeptide signaling genes Prokr2 and Cck, as well as convergent regulation of the expression of 3 SCN light response genes, Dusp4, Rasd1, and Gem. Transcriptional modulation of Dusp4 and Rasd1 and phase regulation of Gem are compelling candidate molecular mechanisms for plasticity in the SCN light response through their modulation of the critical NMDAR-MAPK/ERK-CREB/CRE light signaling pathway in SCN neurons. Modulation of Prokr2 and Cck may critically support SCN neural network reconfiguration during photoperiodic entrainment. Our findings identify the SCN light response and neuropeptide signaling gene sets as rich substrates for elucidating novel mechanisms of photoperiod plasticity. Data are also available at http://circadianphotoperiodseq.com/, where users can view the expression and rhythmic properties of genes across these photoperiod conditions. [ABSTRACT FROM AUTHOR]

Circadian clocks are inherent to most organisms, including cryptozoic animals that seldom encounter direct light, and regulate their daily activity cycles. A conserved suite of clock genes underpins these rhythms. In this study, we explore the circadian behaviors of the red flour beetle Tribolium castaneum, a significant pest impacting stored grain globally. We report on how daily light and temperature cues synchronize distinct activity patterns in these beetles, characterized by reduced morning activity and increased evening activity, anticipating the respective environmental transitions. Although less robust, rhythmicity in locomotor activity is maintained in constant dark and constant light conditions. Notably, we observed more robust rhythmic behaviors in males than females with individual variation exceeding those previously reported for other insect species. RNA interference targeting the Clock gene weakened locomotor activity rhythms. Our findings demonstrate the existence of a circadian clock and of clock-controlled behaviors in T. castaneum. Furthermore, they highlight substantial individual differences in circadian activity, laying the groundwork for future research on the relevance of individual variation in circadian rhythms in an ecological and evolutionary context. [ABSTRACT FROM AUTHOR]

Atherosclerosis (AS) is a chronic inflammatory disease which gives rise to life-threatening complications like ischemic stroke. Rupture of carotid atherosclerotic plaque is the main cause of ischemic stroke. Emerging evidence has demonstrated that disturbed circadian rhythms could accelerate the progression of atherosclerosis by regulating endothelial function. Moreover, our previous study implicated the circadian gene circadian locomotor output cycles kaput (CLOCK) in the pathogenesis of unstable plaques. In this study, we explored the underlying mechanism that CLOCK mediates endothelial cell autophagy involved in the progression of AS. Circadian and autophagy gene expression was analyzed in the GSE41571 dataset and human carotid atherosclerotic plaque samples. Then we used ox-LDL to treat HUVECs, and analyzed CLOCK and autophagy gene in endothelial cells. Besides that, we comprehensively analyzed in vivo experiments to explore the function of CLOCK in autophagy and atherosclerosis using different staining including HE, MT and IF staining. In the dataset and patient samples, CLOCK expression and autophagy were decreased in the unstable plaque group compared with the stable group. Decreased Beclin1, ATG5, LC3, and CLOCK were also observed in HUVECs under oxidative stress condition which also enhances cell proliferation. In vivo, we also found decreasing level of CLOCK, Beclin1, LC3 and ATG5 in ApoE−/− mice compared with WT mice. Silencing of CLOCK in ApoE−/− mice may further aggravate atherosclerosis including decreased cap thickness and collagens. Our findings implicated that downregulation CLOCK would impair endothelial cell autophagy and accelerate atherosclerotic plaque, which provides a novel strategy for treatment of progression in AS. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Alterations in circadian rhythms increase the likelihood of developing type 2 diabetes and CVD. Circadian rhythms are controlled by several core clock genes, which are expressed in nearly every cell, including immune cells. Immune cells are key players in the pathophysiology of type 2 diabetes, and participate in the atherosclerotic process that underlies cardiovascular risk in these patients. The role of the core clock in the leukocytes of people with type 2 diabetes and the inflammatory process associated with it are unknown. We aimed to evaluate whether the molecular clock system is impaired in the leukocytes of type 2 diabetes patients and to explore the mechanism by which this alteration leads to an increased cardiovascular risk in this population. Methods: This is an observational cross-sectional study performed in 25 participants with type 2 diabetes and 28 healthy control participants. Clinical and biochemical parameters were obtained. Peripheral blood leukocytes were isolated using magnetic bead technology. RNA and protein lysates were obtained to assess clock-related gene transcript and protein levels using real-time PCR and western blot, respectively. Luminex XMAP technology was used to assess levels of inflammatory markers. Leukocyte–endothelial interaction assays were performed by perfusing participants' leukocytes or THP-1 cells (with/without CLK8) over a HUVEC monolayer in a parallel flow chamber using a dynamic adhesion system. Results: Participants with type 2 diabetes showed increased BMAL1 and NR1D1 mRNA levels and decreased protein levels of circadian locomotor output cycles kaput (CLOCK), cryptochrome 1 (CRY1), phosphorylated basic helix-loop-helix ARNT like 1 (p-BMAL1) and period circadian protein homologue 2 (PER2). Correlation studies revealed that these alterations in clock proteins were negatively associated with glucose, HbA1c, insulin and HOMA-IR levels and leukocyte cell counts. The leukocyte rolling velocity was reduced and rolling flux and adhesion were enhanced in individuals with type 2 diabetes compared with healthy participants. Interestingly, inhibition of CLOCK/BMAL1 activity in leukocytes using the CLOCK inhibitor CLK8 mimicked the effects of type 2 diabetes on leukocyte–endothelial interactions. Conclusions/interpretation: Our study demonstrates alterations in the molecular clock system in leukocytes of individuals with type 2 diabetes, manifested in increased mRNA levels and decreased protein levels of the core clock machinery. These alterations correlated with the impaired metabolic and proinflammatory profile of the participants with type 2 diabetes. Our findings support a causal role for decreased CLOCK/BMAL1 activity in the increased level of leukocyte–endothelial interactions. Overall, our data suggest that alterations in core clock proteins accelerate the inflammatory process, which may ultimately precipitate the onset of CVD in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Technological advances have led to a modern-day lighting and smartphone revolution, with artificial light exposure at night increasing to levels never before seen in the evolutionary history of living systems on Earth. Light as a pollutant, however, remains largely unrecognized, and the reproductive effects of light pollution are mostly if not entirely unconsidered. This is despite the reproductive system being intricately linked to metabolism and the circadian system, both of which can be disturbed even by low levels of light. Here, we aim to change this perspective by reviewing the physiological and pathophysiological mechanisms by which light exposure alters the intricate hormonal, metabolic and reproductive networks that are relevant to reproductive toxicology. Nascent human studies have recently identified the photoreceptors responsible for the light dose relationship with melatonin suppression and circadian re-entrainment, directly shown the association between the alignment of light-dark cycles with activity-rest cycles on metabolic health and provided proof-of-principle that properly timed blue light-enriched and blue light-depleted delivery can accelerate circadian re-entrainment. With these advances, there is now a need to consider testicular effects of light pollution. [ABSTRACT FROM AUTHOR]

A new transistor-less field-coupled nanocomputing (FCN) method for ultra-scale “nanochip” integration is called quantum-dot cellular automata (QCA). Electrostatic repulsion between electrons and the electron tunneling process in quantum dots is employed in QCA to depict digital circuitry. QCA technology is able to achieve higher clock speed, lower occupied chip area, and more energy efficiency than traditional complementary metal-oxide semiconductor (CMOS) technology. Irreversible majority gates are commonly utilized as the main building blocks in the development of QCA circuits. In order to create highly energy-efficient QCA circuits, some research has recently presented digital image processing design strategies that use majority gates as the primary building block. Image processing, which encompasses picture analysis, enhancement, and correction, is used to extract information from images and improve their quality. Among the primary methods for processing images are picture enhancement, restoration, compression, object recognition, and machine vision applications. However, morphological procedures such as dilation and erosion constitute the fundamental component of image processing and are widely applied in practical applications. In this study, QCA-optimized nanostructures are presented for applications in mathematical morphology, serving as erosion and dilation operators. The completed circuit comprises 33 cells and exhibits a temporal delay of approximately 0.75 during each clock cycle. A comparison with the best equivalent nano-architecture demonstrates a significant improvement in cell performance, scalability, and latency. [ABSTRACT FROM AUTHOR]

Obesity, a significant public health concern with high prevalence in both adults and children, is a complex disorder arising from the interaction of multiple genes and environmental factors. Advances in genome-wide association studies (GWAS) and sequencing technologies have identified numerous polygenic causes of obesity, particularly genes involved in hunger, satiety signals, adipocyte differentiation, and energy expenditure. This study investigates the relationship between six obesity-related genes (CLOCK, FTO, GHRL, LEP, LEPR, MC4R) and their impact on BMI, WC, HC, WHR, and emotional eating behavior in 220 Romanian adults. Emotional eating was assessed using the validated Emotional Eating Questionnaire (EEQ). Our analysis revealed significant variability in obesity-related phenotypes and emotional eating behaviors across different genotypes. Specifically, CLOCK/CC, FTO/AA, and LEP/AA genotypes were strongly associated with higher obesity metrics and emotional eating scores, while GHRL/TT and MC4R/CC were linked to increased BMI and WHR. The interplay between genetic predisposition and emotional eating behavior significantly influenced BMI and WHR, indicating a complex relationship between genetic and behavioral factors. This study, the first of its kind in Romania, provides a foundation for targeted interventions to prevent and reduce obesity and suggests potential strategies for gene expression modulation to mitigate the effects of emotional eating. Adopting a 'One Health' approach by creating an evidence base derived from both human and animal studies is crucial for understanding how to control obesity. [ABSTRACT FROM AUTHOR]

The Diederik cuckoo, Chrysococcyx caprius, is a small Afrotropical bird in the family Cuculidae. It is taxonomically related to 13 other species within the genus Chrysococcyx and is migratory in sub‐Saharan Africa. It has a unique breeding behaviour of being a brood parasite: Breeding pairs lay their eggs in the nests of a host species and hatchlings expel the eggs of the host species. The aim of the present study was to investigate diversity in two circadian clock genes, Clock and Adcyap1, to probe for a relationship between genetic polymorphisms and their role in circannual timing and habitat selection (phenology) in intra‐African migrants. DNA extracted from blood was used for the PCR amplification and sequencing of clock genes in 30 Diederik cuckoos. Three alleles were detected for Clock with similar genotypes between individuals from the Northern and Southern breeding ranges while 10 alleles were detected for Adcyap1, having shorter alleles in the North and longer alleles in the South. Population genetic analyses, including allele frequency and zygosity analysis, showed distinctly higher frequencies for the most abundant Clock allele, containing 10 polyglutamine repeats, as well as a high degree of homozygosity. In contrast, all individuals were heterozygous for Adcyap1 and alleles from both regions showed distinct differences in abundance. Comparisons between both clock genes and phenology found several phenotypic correlations. This included evidence of a relationship between the shorter alleles and habitat selection as well as a relationship between longer alleles and timing. In both instances, evidence is provided that these effects may be sex‐specific. Given that these genes drive some of the synchronicity between environments and the life cycles of birds, they provide valuable insight into the fitness of species facing global challenges including climate change, urbanisation and expanding agricultural practices. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal tumor with increasing incidence, presenting numerous clinical challenges. The histopathological examination of novel, unexplored biomarkers offers a promising avenue for research, with significant translational potential for improving patient outcomes. In this study, we evaluated the prognostic significance of ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian clock regulators (CLOCK, BMAL1, PER1, PER2), and KLOTHO in a retrospective cohort of 41 patients deceased by PDAC. Immunohistochemical techniques (IHC) and multiple statistical analyses (Kaplan–Meier curves, correlograms, and multinomial linear regression models) were performed. Our findings reveal that ferroptosis markers are directly associated with PDAC mortality, while circadian regulators and KLOTHO are inversely associated. Notably, TFRC emerged as the strongest risk marker associated with mortality (HR = 35.905), whereas CLOCK was identified as the most significant protective marker (HR = 0.01832). Correlation analyses indicate that ferroptosis markers are positively correlated with each other, as are circadian regulators, which also positively correlate with KLOTHO expression. In contrast, KLOTHO and circadian regulators exhibit inverse correlations with ferroptosis markers. Among the clinical variables examined, only the presence of chronic pathologies showed an association with the expression patterns of several proteins studied. These findings underscore the complexity of PDAC pathogenesis and highlight the need for further research into the specific molecular mechanisms driving disease progression. [ABSTRACT FROM AUTHOR]

Circadian rhythms are a ubiquitous feature throughout the organism. Accumulating evidence suggests that the dysfunction of circadian rhythms due to genetic mutations or environmental factors contributes to the genesis and progress of multiple diseases. The physiological homeostasis of the ocular surface, like any other tissue or organ, is also orchestrated by circadian rhythms. In this review, we summarize the molecular clocks and the expression of clock-controlled genes in the mammalian ocular surface. Based on the circadian expression of these genes, we conclude the diurnal oscillations of cellular biological activities in the mammalian ocular surface. Moreover, we evaluate the factors entraining circadian oscillators in the ocular surface. Finally, we further discuss the latest development of the close correlation between circadian rhythms and ocular health. Briefly, this review aimed to synthesize the previous studies to aid in understanding the importance of circadian rhythms in the ocular surface and the possible opportunities for circadian rhythm-based interventional strategies to restore the homeostasis of the ocular surface. [ABSTRACT FROM AUTHOR]

The involvement of the molecular clock in regulating cell physiological processes on a specific time scale is a recognized concept, yet its specific impact on optimizing androgen production in Leydig cells has been unclear. This study aimed to confirm the role of the REVERBA (NR1D1) gene in controlling the transcription of key genes related to Leydig cell steroid production. We investigated daily variations by collecting Leydig cells from rats at various times within a 24‐h period. Chromatin immunoprecipitation study showed a time‐dependent pattern for genes linked to steroid production (Nur77, Star, Cyp11a1, and Cyp17a1), which closely matched the 24‐h REVERBA levels in Leydig cells, peaking between zeitgeber time (ZT) 7–11. To understand the physiological significance of REVERBA's interaction with promoters of steroidogenesis‐related genes, Leydig cells from rats at two different times (ZT7 and ZT16; chosen based on REVERBA expression levels), were treated with either an agonist (GSK4112) or an antagonist (SR8278). The results revealed that the REVERBA agonist stimulated gene transcription, while the antagonist inhibited it, but only when REVERBA was sufficiently present, indicating a reliance on REVERBA's circadian fluctuation. Moreover, this REVERBA‐dependent stimulation had a clear impact on testosterone production in the culture medium, underscoring REVERBA's involvement in the circadian regulation of testosterone. This study indicates that REVERBA, in addition to being a core component of the cellular clock, plays a key role in regulating androgen production in Leydig cells by influencing the transcription of critical steroidogenesis‐related genes. [ABSTRACT FROM AUTHOR]

Background and objectivesAging clocks are computational models designed to measure biological age and aging rate based on age-related markers including epigenetic, proteomic, and immunomic changes, gut and skin microbiota, among others. In this narrative review, we aim to discuss the currently available aging clocks, ranging from epigenetic aging clocks to visual skin aging clocks.MethodsWe performed a literature search on PubMed/MEDLINE databases with keywords including: “aging clock,” “aging,” “biological age,” “chronological age,” “epigenetic,” “proteomic,” “microbiome,” “telomere,” “metabolic,” “inflammation,” “glycomic,” “lifestyle,” “nutrition,” “diet,” “exercise,” “psychosocial,” and “technology.”ResultsNotably, several CpG regions, plasma proteins, inflammatory and immune biomarkers, microbiome shifts, neuroimaging changes, and visual skin aging parameters demonstrated roles in aging and aging clock predictions. Further analysis on the most predictive CpGs and biomarkers is warranted. Limitations of aging clocks include technical noise which may be corrected with additional statistical techniques, and the diversity and applicability of samples utilized.ConclusionAging clocks have significant therapeutic potential to better understand aging and the influence of chronic inflammation and diseases in an expanding older population.

In high-frequency electronics, optimizing RF oscillators performance is essential, especially as applications reach into wide frequency bands. This article describes proposed clock generators for UWB sensor systems based on oscillators with dielectric resonator (DRO). Evaluation boards with different sizes of microstrip conductors were developed and tested, based on which new versions of boards were created. Improvements were made to integrate the DRO into a shielded box to ensure minimal external interference. The final designs demonstrated stable operation with low phase noise λ (1 MHz) = -108.805 dBc at fc = 21.732 GHz, sufficient power (3.65 dBm) and low power consumption(56 mW).

The densification of the vehicle fleet leads to numerous challenges in road safety management. Wireless Sensor Networks (WSN) helps to manage vehicle-vehicle-infrastructure interactivity, in particular to predict dangers and avoid accidents, detect and penalize traffic violations. This requires a massive deployment of communicating nodes embedded in vehicles and in road infrastructure. The reliability of the systems built on these nodes lies in the accuracy of the ranging. In order to improve the factors that impact accuracy, various ranging protocols have been developed, but their implementations most often involve the use of expensive and specialized transceivers, which incorporate a dedicated IEEE 802.15.4a ranging layer. Our approach implements the basic and advanced functions integrated into low-cost transceivers and microcontrollers. As result, in two or three links according to the case, our protocol performs simultaneously the ranging and the data exchange, against a specific ranging session with a minimum of three exchanges for the other protocols. Moreover, each node knows the ranging data and has its clock frequency adapted to the controlled process. So, we meet the challenges of large-scale low-cost node deployment, while ensuring high reliability and performance of ranging.

Abstract 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.

With the rapid development of technologies such as autonomous driving and robotic navigation, the demand for accurate and reliable positioning results with BDS has increased. The current status and future development of BDS high precision services are reviewed. The operational PPP-B2b of BDS-3 achieves positioning accuracy at decimeter-level within 14 min and has the drawbacks in regional coverage and long convergence time compared with the international counterparts, such as CLAS of QZSS and HAS of Galileo. A development frame for multi-layer BDS high-precision services is proposed by considering its construction cost, compatibility of user terminal, operating maintenance burden, and service level. The global high-precision service with the improved orbit and clock accuracy enhanced with the inter-satellite link is taken as the most fundamental layer. By incorporating inter-satellite link observations, the orbit errors URE and clock errors are significantly reduced to approximately 0.05 m and 0.16 ns, respectively, which will expand PPP service to global. Based on this, the regional PPP-AR and PPP-RTK services with improved convergence performance are taken as the second layer. With PPP-AR, the convergence time drops to 10 min. With PPP-RTK, the convergence time would be further shortened to less than 3 min. The LEO enhanced PPP service is taken as the third layer which overcomes both drawbacks of the long convergence time of the inter-satellite link enhanced service (the first layer) and the regional coverage of the PPP-AR/PPP-RTK services (the second layer). The simulation results show that by introducing a LEO constellation of 288 satellites, the LEO enhanced PPP can achieve positioning accuracy better than 5 cm within approximately 1 min. In addition, the integration of LEO constellation and PPP-RTK is further proposed to enable instantaneous convergence. The implementation challenges are also presented. [ABSTRACT FROM AUTHOR]

Resveratrol is a polyphenol known to have metabolic as well as circadian effects. However, there is little information regarding the metabolic and circadian effect of resveratrol on muscle cells. We sought to investigate the metabolic impact of resveratrol throughout the circadian cycle to clarify the associated signaling pathways. C2C12 myotubes were incubated with resveratrol in the presence of increasing concentrations of glucose, and metabolic and clock proteins were measured for 24 h. Resveratrol led to SIRT1, AMPK and PP2A activation. Myotubes treated with increasing glucose concentrations showed higher activation of the mTOR signaling pathway. However, resveratrol did not activate the mTOR signaling pathway, except for P70S6K and S6. In accordance with the reduced mTOR activity, resveratrol led to advanced circadian rhythms and reduced levels of pBMAL1 and CRY1. Resveratrol increased myogenin expression and advanced its rhythms. In conclusion, resveratrol activates the SIRT1-AMPK-PP2A axis, advances circadian rhythms and induces muscle development. [ABSTRACT FROM AUTHOR]

Activity patterns tend to be highly stereotyped and critical for executing many different behaviors including foraging, social interactions, and predator avoidance. Differences in the circadian timing of locomotor activity and rest periods can facilitate habitat partitioning and the exploitation of novel niches. As a consequence, closely related species often display highly divergent activity patterns, suggesting that shifts from diurnal to nocturnal behavior, or vice versa, are critical for survival. In Africa's Lake Malawi alone, there are over 500 species of cichlids, which inhabit diverse environments and exhibit extensive phenotypic variation. We have previously identified a substantial range in activity patterns across adult Lake Malawi cichlid species, from strongly diurnal to strongly nocturnal. In many species, including fishes, ecological pressures differ dramatically across life-history stages, raising the possibility that activity patterns may change over ontogeny. To determine if rest-activity patterns change across life stages, we compared the locomotor patterns of six Lake Malawi cichlid species. While total rest and activity did not change between early juvenile and adult stages, rest-activity patterns did, with juveniles displaying distinct activity rhythms that are more robust than adults. One distinct difference between juveniles and adults is the emergence of complex social behavior. To determine whether social context is required for activity rhythms, we next measured locomotor behavior in group-housed adult fish. We found that when normal social interactions were allowed, locomotor activity patterns were restored, supporting the notion that social interactions promote circadian regulation of activity in adult fish. These findings reveal a previously unidentified link between developmental stage and social interactions in the circadian timing of cichlid activity. [ABSTRACT FROM AUTHOR]

In high-frequency electronics, optimizing RF oscillators performance is essential, especially as applications reach into wide frequency bands. This article describes proposed clock generators for UWB sensor systems based on oscillators with dielectric resonator (DRO). Evaluation boards with different sizes of microstrip conductors were developed and tested, based on which new versions of boards were created. Improvements were made to integrate the DRO into a shielded box to ensure minimal external interference. The final designs demonstrated stable operation with low phase noise λ (1 MHz) = -108.805 dBc at fc = 21.732 GHz, sufficient power (3.65 dBm) and low power consumption(56 mW). [ABSTRACT FROM AUTHOR]

The research is concerned with dealing with the history of the calendar and time calculation in the Islamic Maghreb, through the use of the Mnjanah instrument. The research begins by studying quick glimpses of the tools of ancient civilizations, and how they were transferred to the Greater Islamic Maghreb, then we study the most important names of the machines through various sources and references, and we discuss the Eastern and Maghriban machines, and the way they work, as their driving energy varies from one clock machine to another, as some of them move through water or air or that move through sand and even through mercury. From there, we discuss the Andalusian Mnjanahs, their most prominent types, and their most important and famous makers, and then we move on to the temporal Mnjanahs of the far Maghreb in the Zayani and Hafsid eras. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Circadian oscillations have been reported in major renal functions such as renal blood flow, glomerular filtration rate, and urinary excretion. These oscillations can be explained, in part, by the rhythmic variations in renal transporter expressions. However, given that a multitude of renal transporters are regulated by the circadian clock, and that the functions of some of these transporters are coupled, the underlying mechanisms that link variations in transporter expression to the observed changes in kidney function have yet to be fully elucidated. To better understand the impact of the circadian clock on renal solute and water transport, we have developed a computational model of the epithelial transport of the rat kidney that represents the observed rhythmic variations in glomerular filtration rate (GFR) and in the activities of Na+/H+ exchanger 3, sodium-gLucose cotransporter 1, epithelial Na+ channels, pendrin, and renal outer-medullary K+ channels. The model predicts the rhythmic oscillations in GFR and key renal transporter activities give rise to a significant shift in transport loads among different nephron segments. Together, these oscillations yield 3-4-fold daily fluctuations in urine output and urinary electrolyte excretion rates. [ABSTRACT FROM AUTHOR]

Sleep genetics is an intriguing, as yet less understood, understudied, emerging area of biological and medical discipline. A generalist may not be aware of the current status of the field given the variety of journals that have published studies on the genetics of sleep and the circadian clock over the years. For researchers venturing into this fascinating area, this review thus includes fundamental features of circadian rhythm and genetic variables impacting sleep–wake cycles. Sleep/wake pathway medication exposure and susceptibility are influenced by genetic variations, and the responsiveness of sleep-related medicines is influenced by several functional polymorphisms. This review highlights the features of the circadian timing system and then a genetic perspective on wakefulness and sleep, as well as the relationship between sleep genetics and sleep disorders. Neurotransmission genes, as well as circadian and sleep/wake receptors, exhibit functional variability. Experiments on animals and humans have shown that these genetic variants impact clock systems, signaling pathways, nature, amount, duration, type, intensity, quality, and quantity of sleep. In this regard, the overview covers research on sleep genetics, the genomic properties of several popular model species used in sleep studies, homologs of mammalian genes, sleep disorders, and related genes. In addition, the study includes a brief discussion of sleep, narcolepsy, and restless legs syndrome from the viewpoint of a model organism. It is suggested that the understanding of genetic clues on sleep function and sleep disorders may, in future, result in an evidence-based, personalized treatment of sleep disorders. [ABSTRACT FROM AUTHOR]

Clock gene disruption has been reported in inflammatory and autoimmune diseases. Specifically, it has been shown that clock gene expression is down-regulated in intestinal tissue and peripheral blood mononuclear cells of patients with inflammatory bowel disease (IBD). We aimed to determine the systemic expression of the circadian clock genes in newly diagnosed untreated, young patients with celiac disease (CeD). We prospectively enrolled patients younger than 20 years old who underwent diagnostic endoscopic procedures either for CeD diagnosis or due to other gastrointestinal complaints, at the pediatric and adult gastroenterology units, the Tel Aviv Sourasky Medical Center from 8/2016–8/2022. Demographic data, anthropometric parameters, and endoscopic macroscopic and microscopic findings were obtained. Blood samples were obtained to determine tissue transglutaminase (tTG) and core clock gene (CLOCK , BMAL1 , PER1 , PER2 , CRY1 , CRY2) expression in white blood cells (WBC). Thirty individuals were analyzed (18 with newly diagnosed CeD and 12 controls). Expression of the clock genes CLOCK , BMAL1 , CRY2 , PER1 and PER2 was significantly reduced in CeD patients compared to controls, while CRY1 did not differ between the groups. In conclusion, newly diagnosed, untreated, young patients with CeD have reduced clock gene expression in WBC compared to controls. These results suggest that, in CeD, the inflammatory response is associated with systemic disruption of clock gene expression, as is manifested in other inflammatory and autoimmune diseases. NCT03662646. • Clock gene disruption is seen in inflammatory and autoimmune diseases. • Newly diagnosed patients with celiac disease have reduced clock gene expression. • Celiac disease patients had reduced expression of CLOCK , BMAL1 , CRY2 , PER1 , PER2. • Inflammation in celiac disease is associated with clock gene disruption. [ABSTRACT FROM AUTHOR]

Obesity and overweight are common and complex conditions influenced by multiple genetic and environmental factors. Several genetic variants located in the genes involved in clock systems and fat taste perception can affect metabolic health. In particular, the polymorphisms in CLOCK and BMAL1 genes were reported to be significantly related to cardiovascular disease, metabolic syndrome, sleep reduction, and evening preference. Moreover, genetic variants in the CD36 gene have been shown to be involved in lipid metabolism, regulation of fat intake, and body weight regulation. The aim of this study is to evaluate, for the first time, the association between variants in some candidate genes (namely, BMAL1 rs7950226 (G>A), CLOCK rs1801260 (A>G), CLOCK rs4864548 (G>A), CLOCK rs3736544 (G>A), CD36 rs1984112 (A>G), CD36 rs1761667 (G>A)) and overweight/obesity (OB) in pregnant women. A total of 163 normal-weight (NW) and 128 OB participants were included. A significant correlation was observed between A-allele in CLOCK rs4864548 and an increased risk of obesity (OR: 1.97; 95% CI 1.22–3.10, p = 0.005). In addition, we found that subjects carrying the haplotype of rs1801260-A, rs4864548-A, and rs3736544-G are likely to be overweight or obese (OR 1.47, 95% CI 1.03–2.09, p = 0.030), compared with those with other haplotypes. Moreover, a significant relation was observed between third-trimester lipid parameters and genetic variants—namely, CD36 rs1984112, CD36 rs1761667, BMAL1 rs7950226, and CLOCK rs1801260. A multivariate logistic regression model revealed that CLOCK rs4864548 A-allele carriage was a strong risk factor for obesity (OR 2.05, 95% CI 1.07–3.93, p = 0.029); on the other hand, greater adherence to Mediterranean diet (OR 0.80, 95% CI 0.65–0.98, p = 0.038) and higher HDL levels (OR 0.96, 95% CI 0.94–0.99, p = 0.021) were related to a reduced risk of obesity. Interestingly, an association between maternal CLOCK rs4864548 and neonatal birthweight was detected (p = 0.025). These data suggest a potential role of the polymorphisms in clock systems and in fat taste perception in both susceptibility to overweight/obesity and influencing the related metabolic traits in pregnant women. [ABSTRACT FROM AUTHOR]

Purpose: Interventions performed within the first hour after trauma increase survival rates. Literature showed that measuring times can optimize the trauma resuscitation process as time awareness potentially reduces acute care time. This study examined the effect of a digital clock placement on trauma resuscitation times in an academic level-1 trauma center. Methods: A prospective observational pre–post cohort analysis was conducted for six months before and after implementing a visible clock in the trauma resuscitation room, indicating the time passed since starting the in-hospital resuscitation process. Trauma patients (age ≥ 16) presented during weekdays between 9.00 AM and 9.00 PM were included. Time until diagnostics (X-Ray, FAST, or CT scan), time until therapeutic intervention, and total resuscitation time were measured manually with a stopwatch by a researcher in the trauma resuscitation room. Patient characteristics and information regarding trauma- and injury type were collected. Times before and after clock implementation were compared. Results: In total, 100 patients were included, 50 patients in each cohort. The median total resuscitation time (including CT scan) was 40.3 min (IQR 23.3) in the cohort without a clock compared to 44.3 (IQR 26.1) minutes in the cohort with a clock. The mean time until the first diagnostic and until the CT scan was 8.3 min (SD 3.1) and 25.5 min (SD 7.1) without a clock compared to 8.6 min (SD 6.5) and 26.6 min (SD 11.5) with a clock. Severely injured patients (Injury Severity Score (ISS) ≥ 16) showed a median resuscitation time in the cohort without a clock (n = 9) of 54.6 min (IQR 50.5) compared to 46.0 min (IQR 21.6) in the cohort with a clock (n = 8). Conclusion: This study found no significant reduction in trauma resuscitation time after clock placement. Nonetheless, the data represent a heterogeneous population, not excluding specific patient categories for whom literature has shown that a short time is essential, such as severely injured patients, might benefit from the presence of a trauma clock. Future research is recommended into resuscitation times of specific patient categories and practices to investigate time awareness. [ABSTRACT FROM AUTHOR]

Technological advances have led to a modern-day lighting and smartphone revolution, with artificial light exposure at night increasing to levels never before seen in the evolutionary history of living systems on Earth. Light as a pollutant, however, remains largely unrecognized, and the reproductive effects of light pollution are mostly if not entirely unconsidered. This is despite the reproductive system being intricately linked to metabolism and the circadian system, both of which can be disturbed even by low levels of light. Here, we aim to change this perspective by reviewing the physiological and pathophysiological mechanisms by which light exposure alters the intricate hormonal, metabolic and reproductive networks that are relevant to reproductive toxicology. Nascent human studies have recently identified the photoreceptors responsible for the light dose relationship with melatonin suppression and circadian re-entrainment, directly shown the association between the alignment of light-dark cycles with activity-rest cycles on metabolic health and provided proof-of-principle that properly timed blue light-enriched and blue light-depleted delivery can accelerate circadian re-entrainment. With these advances, there is now a need to consider testicular effects of light pollution.

Abstract The Diederik cuckoo, Chrysococcyx caprius, is a small Afrotropical bird in the family Cuculidae. It is taxonomically related to 13 other species within the genus Chrysococcyx and is migratory in sub‐Saharan Africa. It has a unique breeding behaviour of being a brood parasite: Breeding pairs lay their eggs in the nests of a host species and hatchlings expel the eggs of the host species. The aim of the present study was to investigate diversity in two circadian clock genes, Clock and Adcyap1, to probe for a relationship between genetic polymorphisms and their role in circannual timing and habitat selection (phenology) in intra‐African migrants. DNA extracted from blood was used for the PCR amplification and sequencing of clock genes in 30 Diederik cuckoos. Three alleles were detected for Clock with similar genotypes between individuals from the Northern and Southern breeding ranges while 10 alleles were detected for Adcyap1, having shorter alleles in the North and longer alleles in the South. Population genetic analyses, including allele frequency and zygosity analysis, showed distinctly higher frequencies for the most abundant Clock allele, containing 10 polyglutamine repeats, as well as a high degree of homozygosity. In contrast, all individuals were heterozygous for Adcyap1 and alleles from both regions showed distinct differences in abundance. Comparisons between both clock genes and phenology found several phenotypic correlations. This included evidence of a relationship between the shorter alleles and habitat selection as well as a relationship between longer alleles and timing. In both instances, evidence is provided that these effects may be sex‐specific. Given that these genes drive some of the synchronicity between environments and the life cycles of birds, they provide valuable insight into the fitness of species facing global challenges including climate change, urbanisation and expanding agricultural practices.

The physiological role and the molecular architecture of the circadian clock in fully developed organisms are well established. Yet, we have a limited understanding of the function of the clock during ontogenesis. We have used a null mutant (per0) of the clock gene period (per) in Drosophila melanogaster to ask whether PER may play a role during normal brain development. In third-instar larvae, we have observed that the absence of functional per results in increased genotoxic stress compared to wild-type controls. We have detected increased double-strand DNA breaks in the central nervous system and chromosome aberrations in dividing neuronal precursor cells. We have demonstrated that reactive oxygen species (ROS) are causal to the genotoxic effect and that expression of PER in glia is necessary and sufficient to suppress such a phenotype. Finally, we have shown that the absence of PER may result in less condensed chromatin, which contributes to DNA damage.

Circadian clocks are universally used to coordinate biological processes with the Earth's 24-h solar day and are critical for the health and environmental success of an organism. Circadian rhythms in eukaryotes are driven by a cell-intrinsic transcription-translation feedback loop that controls daily oscillations in gene expression which regulate diverse physiological functions. Substantial evidence now exists demonstrating that immune activation and inflammatory responses during infection are under circadian control, however, the cellular mechanisms responsible for this are not well understood. The zebrafish (Danio rerio) is a powerful model organism to study vertebrate circadian biology and immune function. Zebrafish contain homologs of mammalian circadian clock genes which, to our current knowledge, function similarly to impart timekeeping ability. Consistent with studies in mammalian models, several studies in fish have now demonstrated a bidirectional relationship between the circadian clock and inflammation: the circadian clock regulates immune activity, and inflammation can alter circadian rhythms. This review summarizes our current understanding of the molecular mechanisms of the zebrafish clock and the bi-directional relationship between the circadian clock and inflammation in fish.

Biological clocks are evolved time-keeping systems by which organisms rhythmically coordinate physiology within the body, and align it with rhythms in their environment. Clocks are highly sensitive to light and are at the interface of several major endocrine pathways. Worryingly, exposure to artificial-light-at-night (ALAN) is rapidly increasing in ever more extensive parts of the world, with likely impact on wild organisms mediated by endocrine–circadian pathways. In this overview, we first give a broad-brush introduction to biological rhythms. Then, we outline interactions between the avian clock, endocrine pathways, and environmental and internal modifiers. The main focus of this review is on the circadian hormone, melatonin. We summarize information from avian field and laboratory studies on melatonin and its relationships with behaviour and physiology, including often neglected developmental aspects. When exposed to ALAN, birds are highly vulnerable to disruption of behavioural rhythms and of physiological systems under rhythmic control. Several studies suggest that melatonin is likely a key mediator for a broad range of effects. We encourage further observational and experimental studies of ALAN impact on melatonin, across the full functional range of this versatile signalling molecule, as well as on other candidate compounds at the endocrine–circadian interface. This article is part of the theme issue 'Endocrine responses to environmental variation: conceptual approaches and recent developments'. [ABSTRACT FROM AUTHOR]

Background and Aims: Sleep is predicted as a key modulator of cognition, but the underlying mechanisms are poorly understood. In this study, we investigated the effects of melatonin on chronic rapid eye movement sleep deprivation (CRSD)‐induced cognitive impairment and circadian dysfunction in rat models. Methods: Thirty‐six Sprague‐Dawley male rats were divided into three groups: CRSD with saline treatment, CRSD with chronic melatonin injection (20 mg/kg/day), and non‐sleep‐deprived control. The cognitive behavioral tests as well as the expression of clocks and HDAC3 were evaluated in all groups. Results: CRSD significantly reduced recognition index in novel object location, increased escape latency and distance traveling in Morris water maze while melatonin treatment attenuated CRSD‐induced hippocampal‐dependent spatial learning and memory deficits. Furthermore, the mRNAs of brain and muscle aryl hydrocarbon receptor nuclear translocator‐like 1(Bmal1) and circadian locomotor output cycles kaput (Clock) were globally down‐regulated by CRSD with constant intrinsic oscillation in both hippocampus and peripheral blood. The protein levels of hippocampal Bmal1, Clock, and HDAC3 were also remarkably down‐regulated following CRSD. Melatonin treatment reversed CRSD‐induced alterations of Bmal1/Clock and HDAC3 on both mRNA levels and protein levels. Conclusions: Our data indicate that melatonin treatment attenuates CRSD‐induced cognitive impairment via regulating HDAC3‐Bmal1/Clock interaction. These findings explore a broader understanding of the relationship between sleep and cognition and provide a potential new therapeutic target for cognitive impairment. [ABSTRACT FROM AUTHOR]

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Time is an extremely important element in the field of GNSS positioning. In precise positioning with a single-centimetre accuracy, satellite clock corrections are used. In this article, the longest available data set of satellite clock corrections of four GNSS systems from 2014 to 2021 was analysed. This study covers the determination of the quality (outliers number and magnitude), availability, stability, and determination of the specificity and nature of the clock correction for each satellite system. One problem with the two newest satellite systems (Galileo and BeiDou) is the lack of availability of satellite signals in the early years of the analysis. These data were available only in the later years of the period covered by the analysis, as most of the satellites have only been in orbit since 2018–2019. Interestingly, the percentage of outlying observations was highest in Galileo and lowest in BeiDou. Phase and frequency plots showed a significant number of outlying observations. On the other hand, after eliminating outlying observations, each system showed a characteristic graph waveform. The most consistent and stable satellite clock corrections are provided by the GPS and GLONASS systems. The main problems discussed in this paper are the determination of the number and magnitude of outliers in clock products of four GNSS systems (GPS, GLONASS, Galileo, Beidou) and the study on the long-term stability of GNSS clocks analysis, which covers the years 2014–2021. [ABSTRACT FROM AUTHOR]

In children, teenagers, and young adults, environmental factors and genetic modifications have contributed to the development of obesity. There is a close relationship between obesity and circadian rhythm. To understand the role of CLOCK and BMAL1 in obesity, we analyzed the methylation status of CLOCK and BMAL1 in obese and control subjects. In this paper, we analyzed the methylation status of the CLOCK and BMAL1 genes by using MS-HRM in a total of 55 obese and 54 control subjects. In our study, we demonstrated that the level of fasting glucose and the level of HDL-cholesterol were associated with CLOCK methylation in obesity. We also showed a significant association between BMAL1 gene methylation and waist and hip circumference in obese subjects. This is the first study that shows the methylation of BMAL1 is associated with the obese phenotype. However, we could not show a direct association between CLOCK methylation and the obese phenotype. In this paper, a novel epigenetic interaction between circadian clock genes and obesity was demonstrated. [ABSTRACT FROM AUTHOR]

In 1736/37, Joseph-Nicolas Delisle and Jean Jacques Dortous de Mairan communicated about the clocks that would enable the astronomers of the Saint Petersburg observatory to make highly exact observations. Delisle, who was in charge of the Saint Petersburg observatory, demanded old-fashioned clocks in the manner of Huygens. Mairan, well-versed in astronomy himself, recommended equation clocks. The article uses these seemingly inappropriate preferences to discuss eighteenth-century notions of accuracy and precision in clocks. It analyses the multiple factors that influenced expectations regarding the performance of timekeeping instruments, and draws attention to handling and monitoring practices. The latter reflected the individual user's purposes and experience, but also affected the clocks' going. Furthermore, the article presents the result of a statistical analysis, which serves to evaluate the historical performance of the Saint Petersburg observatory clocks and provides a foil against which Delisle's judgement of them is examined. [ABSTRACT FROM AUTHOR]

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Summary: Epilepsy is a brain disorder affecting up to 1 in 26 individuals. Despite its clinical importance, the molecular mechanisms of epileptogenesis are still far from clarified. Our previous study showed that disruption of Clock in excitatory neurons alters cortical circuits and leads to generation of focal epilepsy. In this study, a GAD-Cre;Clockflox/flox mouse line with conditional Clock gene knockout in inhibitory neurons was established. We observed that seizure latency was prolonged, the severity and mortality of pilocarpine-induced seizure were significantly reduced, and memory was improved in GAD-Cre;Clockflox/flox mice. We hypothesize that mice with CLOCK knockout in inhibitory neurons have increased threshold for seizure, opposite from mice with CLOCK knockout in excitatory neurons. Further investigation showed Clock knockout in inhibitory neurons upregulated the basal protein level of ARC, a synaptic plasticity-associated immediate-early gene product, likely through the BDNF-ERK pathway. Altered basal levels of ARC may play an important role in epileptogenesis after Clock deletion in inhibitory neurons. Although sEPSCs and intrinsic properties of layer 5 pyramidal neurons in the somatosensory cortex exhibit no changes, the spine density increased in apical dendrite of pyramidal neurons in CLOCK knockout group. Our results suggest an underlying mechanism by which the circadian protein CLOCK in inhibitory neurons participates in neuronal activity and regulates the predisposition to epilepsy.

This article is devoted to the creative work of the nonconformist artist Borukh (Boris Arckadyevich Shteinberg, 1938–2003). His legacy has hardly been studied, and the information about him is mainly found in catalogs, memoirs of friends and colleagues, and exhibition explications. Meanwhile, the work of this artist is a highlight of Russian underground art. Borukh was a multi-talented master: a writer, painter and graphic artist, author of collages and assemblages. The emphasis in the article is on the artist’s original metal works. They represent an important chapter in his creative biography, standing out both against the background of the late Soviet and Russian art and in a wider context. Having a creative relationship with the works of such masters of object art as, for example, Cornell, Arman, and Cesar, Borukh’s metals illustrate the commonality of searches in the art of the second half of the 20th century.

Day-boundary discontinuity (DBD) is an effect present in precise GNSS satellite orbit and clock products originating from the method used for orbit and clock determination. The non-Gaussian measurement noise and data processing in 24 h batches are responsible for DBDs. In the case of the clock product, DBD is a time jump in the boundary epochs of two adjacent batches of processed data and its magnitude might reach a couple of ns. This article presents the four GNSS (Global Navigation Satellite System) systems DBD analysis in terms of change over an 8 year period. For each of 118 satellites available in this period, the yearly value of DBD was subject to analysis including standard deviation and frequency of outliers. Results show that the smallest DBDs appear in the GPS system, the biggest – for the BeiDou space segment. Moreover, the phenomenon of changes in DBDs over time is clearly seen at the beginning of the analysed period when the magnitude and number of the DBDs were larger than for current, newest clock products

Pancreatic ductal adenocarcinoma (PDAC) is an extremely lethal tumor with increasing incidence, presenting numerous clinical challenges. The histopathological examination of novel, unexplored biomarkers offers a promising avenue for research, with significant translational potential for improving patient outcomes. In this study, we evaluated the prognostic significance of ferroptosis markers (TFRC, ALOX-5, ACSL-4, and GPX-4), circadian clock regulators (CLOCK, BMAL1, PER1, PER2), and KLOTHO in a retrospective cohort of 41 patients deceased by PDAC. Immunohistochemical techniques (IHC) and multiple statistical analyses (Kaplan–Meier curves, correlograms, and multinomial linear regression models) were performed. Our findings reveal that ferroptosis markers are directly associated with PDAC mortality, while circadian regulators and KLOTHO are inversely associated. Notably, TFRC emerged as the strongest risk marker associated with mortality (HR = 35.905), whereas CLOCK was identified as the most significant protective marker (HR = 0.01832). Correlation analyses indicate that ferroptosis markers are positively correlated with each other, as are circadian regulators, which also positively correlate with KLOTHO expression. In contrast, KLOTHO and circadian regulators exhibit inverse correlations with ferroptosis markers. Among the clinical variables examined, only the presence of chronic pathologies showed an association with the expression patterns of several proteins studied. These findings underscore the complexity of PDAC pathogenesis and highlight the need for further research into the specific molecular mechanisms driving disease progression.

Circadian rhythms are a ubiquitous feature throughout the organism. Accumulating evidence suggests that the dysfunction of circadian rhythms due to genetic mutations or environmental factors contributes to the genesis and progress of multiple diseases. The physiological homeostasis of the ocular surface, like any other tissue or organ, is also orchestrated by circadian rhythms. In this review, we summarize the molecular clocks and the expression of clock-controlled genes in the mammalian ocular surface. Based on the circadian expression of these genes, we conclude the diurnal oscillations of cellular biological activities in the mammalian ocular surface. Moreover, we evaluate the factors entraining circadian oscillators in the ocular surface. Finally, we further discuss the latest development of the close correlation between circadian rhythms and ocular health. Briefly, this review aimed to synthesize the previous studies to aid in understanding the importance of circadian rhythms in the ocular surface and the possible opportunities for circadian rhythm-based interventional strategies to restore the homeostasis of the ocular surface.