In this paper, a low-power Injection-Locked Clock and Data Recovery (ILCDR) using 28nm FDSOI technology is presented. The back-gate auto-biasing of UTBB-FDSOI transistors allows us to create a QRO (Quadrature Ring Oscillator) reducing both size and power consumption. By injecting a digital signal into this circuit, we realize an Injection-Locked Oscillator (ILO) with low jitter. Thanks to the good performance of this oscillator, we propose a low power ILCDR with fast locking time and low jitter for burst-mode applications. The main novelty consists in the implementation of a complementary QRO based on back-gate control using FDSOI technology to realize a simple and efficient ILCDR circuit. With a Pseudo-Random Binary Sequence (PRBS7) at 868Mbps, the recovered clock jitter is 26.7ps (2.3%UIp-p) and the recovered data jitter is 11.9ps (1%UIp-p). With a 0.6V power supply, the power consumption is 318μW. The estimated Chip area is around 6600μm².

In the clock network design, the trade-off between power consumption and timing closure is an important and difficult issue. To achieve this target, a hybrid clock network architecture that combines both clock tree and clock mesh seems to be a promising solution. In this paper, we propose a novel clock mesh architecture – cross-mesh, with the average dispersion of the overall driving force, our methodology creates small non-zero skew clock trees. In addition, we integrate clock gating and register clustering techniques to further reduce dynamic power consumption. The proposed algorithms have four stages: cross-mesh planning, register clustering, mesh line connecting, and load balancing. Experimental results show that our methodology and algorithms get feasible solution effectively and improve both power consumption and clock skew simultaneously.

The circadian clock is an autonomous timekeeping system evolved by organisms to adapt to external changes, regulating a variety of important physiological and behavioral processes. Recent studies have shown that the sirtuin family of histone deacetylases is involved in regulating the expression of clock genes and plays an important role in maintaining the normal rhythm of clock gene expression and behavior. Moreover, sirtuins are regulated directly or indirectly by the circadian clock system. The mutual regulation between the circadian clock and sirtuins is likely involved in a variety of signal transduction and metabolism processes. In this review, we discuss the molecular mechanisms and research progress on the intertwined relationship between the circadian clock and sirtuins, highlighting sirtuins as molecular links between metabolic control and circadian rhythms and offering our perspectives on future developments in the field.

In light of advancing technology, the conventional clock network architecture has become inadequate for addressing the intricacies inherent in modern System-on-Chip (SoC) designs. While clock mesh topology offers resilience against On-Chip Variation (OCV) fluctuations, it still necessitates manual intervention. Therefore, substantial scope exists for methodological enhancements and the refinement of rapid analytical techniques. This paper introduces a novel clock mesh synthesis approach, underpinned by dynamic programming algorithms, that guarantees latency constraints. Our experimental findings demonstrate that our algorithm achieves an additional 26.6% reduction in power consumption compared to the baseline methodology. Furthermore, it substantially reduces runtime by an average of 78.0% when contrasted with traditional simulation methods. These results highlight the potential of our methodology for enhancing the efficiency and power management of clock mesh.

This review summarizes current understanding of the interaction between circadian rhythms of gene expression and epigenetic clocks characterized by the specific profile of DNA methylation in CpG-islands which mirror the chronological age of individual cells and the entire organism. Basic mechanisms of regulation for circadian genes CLOCK- BMAL1 as well as downstream clock-controlled genes (ССG) are also discussed here. It has been shown that circadian rhythms operate by finely tuned regulation of transcription and rely on various epigenetic mechanisms including activation of enhancers / suppressors, acetylation / deacetylation of histones and other proteins as well as DNA methylation. Overall, up to 20% of all genes expressed by the cell are subject to expression oscillations associated with circadian rhythms. Also included in the review is a brief list of genes involved in the regulation of circadian rhythms, along with genes important for metabolic control, aging, and oncogenesis. Knocking out some of them (for example, Sirt1) accelerates the aging process, while overexpression of Sirt1, on the contrary, protects against age-related changes. Circadian regulators control a number of genes that activate the cell cycle (Wee1, c-Myc, p20, p21, and Cyclin D1) and regulate histone modification and DNA methylation. Approaches for determining the epigenetic age from methylation profiles across CpG islands in individual cells are described. DNA methylation, which characterizes the function of the epigenetic clock, appears to link together such key biological processes as regeneration and functioning of stem cells, aging and malignant transformation. Finally, main features of adult stem cell aging in stem cell niches and current possibilities for modulating the epigenetic clock as part of antiaging therapy are discussed.

Satellite navigation spoofing is a major challenge in the field of satellite/inertial integrated navigation security. To effectively enhance the anti-spoofing capability of low-cost GNSS/MEMS-SINS integrated navigation system, this paper proposes a method integrating a dual-antenna global navigation satellite system (GNSS) and a micro-inertial measurement unit (MIMU) to determine the two-dimensional (2D) directions of spoofing signal sources. The proposed method evaluates whether the single-difference carrier-phase measurements conform to the corresponding directions given in ephemeris files, and employs the micro-inertial navigation technology to determine the 2D directions of the signal source. Based on a set of short-baseline dual-station measurements, the accuracy of the proposed method in determining the 2D azimuths of satellites in synchronous orbits is verified, and the deviation from the real value is evaluated. The experimental results show that the proposed method can effectively identify the spoofed satellite signals while providing high-precision direction information at three different distances: 100m, 10km, and 36000km.The two-dimensional angles errors do not exceed 0.2 rad, 0.05 rad, and 0.01 rad, respectively.

Neuronal PAS domain protein 2 (NPAS2) is a hemeprotein comprising a basic helix-loop-helix domain (bHLH) and two heme-binding sites, the PAS-A and PAS-B domains. This protein acts as a pyridine nucleotide-dependent and gas-responsive CO-dependent transcription factor and is encoded by a gene whose expression fluctuates with circadian rhythmicity. NPAS2 can heterodimerize with ARNTL in the activating limb of the transcriptional/translational feedback loop operating the circadian clock circuitry. NPAS2 can functionally substitute for the core transcription factor and histone/protein acetylase CLOCK in the molecular clockwork endowing central oscillators in the suprachiasmatic nuclei of hypothalamus as well as in peripheral oscillators in the cell of other body tissues, such as the liver and kidney.

The circadian clock is a 24-hour cycle within the body that regulates various factors, including sleep, body temperature, and hormone secretion. It allows the body to adjust to the light and dark cycle. Disruptions to the circadian rhythm are important risk factors for many diseases, including neurodegenerative illnesses. The central clock is controlled by the clock genes in the suprachiasmatic nucleus (SCN) of the brain, and one of the main functions of the circadian clock is to regulate lipid metabolism. There has been a lack of investigation on the circadian regulation of lipid metabolism-related apolipoprotein genes in the brain; thus, this study sought to summarize the rhythmic expression of clock genes and lipid metabolism-related apolipoprotein genes within the SCN of Mus musculus. Out of the 20 apolipoprotein genes that were studied by the published database, all 9 genes were highly expressed in the SCN. Most of the 6 genes showed rhythmic expression in the brain of mice, suggesting that the master clock might regulate them. The results, therefore, reveal a potential target for preventing and treating circadian disorders. We summarized most studies of lipid-related apolipoprotein genes within limited locations of the SCN and brain to further understand how disordered cerebral lipid metabolism causes multiple brain diseases and disorders. We reviewed recent studies, determined the unexplored questions, and identified a potential direction for further research.

The western flower thrips, Frankliniella occidentalis, is invasive and polyphagous. Its visual signal plays a crucial role in host location, suggesting that thrips has diurnal behavior. However, any diel rhythmicity of the thrips behavior is not yet well understood. This study analyzed the diurnal rhythmicity of the feeding and mating behaviors of thrips, and the patterns were explained in terms of diel rhythmicity by assessing the expression of genes associated with the circadian clock. Most feeding behaviors were observed during photophase in both larvae and adults. In mating behavior, which is mainly exhibited in 2~3 days-old young adults after emergence, most adults copulated at photophase. This diurnal pattern of the mating behavior was further supported by the analysis of a temporal calling behavior for mating, which was biased toward photophase. Four genes associated with the circadian clock were predicted in the F. occidentalis genome: period (PER), Timeless (TIM), Doubletime (DBT), and clock (CLK). All these genes exhibited a characteristic diel pattern in their gene expressions in a 24 h-period. The high expression peaks of these genes except for DBT were observed at photophase. To confirm the functional association of these genes with the feeding and mating behaviors, individual RNA interference specific to each gene was executed by feeding the gene-specific double-stranded RNA. Aside from DBT, suppression of these gene expressions resulted in significant deviations of the diel rhythms of the behaviors. These results suggest that the genetic components of the diel rhythmicity mediate the diurnal feeding and mating behaviors of F. occidentalis.

Gliomas are solid tumors of the Central Nervous System (CNS) that originated from different glial cells. The World Health Organization (WHO) classified these tumors into four groups (I-IV) with increasing malignancy. Glioblastoma (GBM) is the most common and aggressive type of brain tumor classified as a grade IV. GBM are resistant to conventional therapies with poor prognosis after diagnosis even when the Stupp protocol that combines surgery and radiochemotherapy is applied. Nowadays, few novel therapeutic strategies have been used to improve GBM treatment, looking for higher efficiency and lower side effects, but with relatively modest results. The circadian timing system temporally organizes the physiology and behavior of most organisms and daily regulates several cellular processes in organs, tissues, and even in individual cells, including tumor cells. The potentiality of the function of the circadian clock on cancer cells modulation as a new target for novel treatments with a chronobiological basis offers a different challenge that needs to be considered in further detail. The present review will discuss state of the art regarding GBM biology, the role of the circadian clock in tumor progression, and new chrono-chemotherapeutic strategies applied for GBM treatment.

Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risks of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like inflammation, oxidative stress, reduced mitochondrial capacity, and cell apoptosis contribute to this decline. Disruption of the circadian system with age may initiate these pathways in skeletal muscle, preceding the onset of sarcopenia. At present, there is no pharmacological treatment for sarcopenia, only resistance exercise and proper nutrition may delay its onset. Melatonin, derived from tryptophan, emerges as an exceptional candidate for treating sarcopenia due to its chronobiotic, antioxidant, and anti-inflammatory properties. Its impact on mitochondria, organelle where it is synthesized and crucial in aging skeletal muscle, further highlights its potential. In this review, we discuss the influence of clock genes in muscular aging, with special reference to peripheral clock genes in the skeletal muscle, as well as their relationship with melatonin, which is proposed as a potential therapy against sarcopenia.

The dengue virus (DENV) is an arbovirus belonging to the Flaviviridae family; the species comprises four antigenically distinct serotypes (DENV–1, DENV–2, DENV–3, and DENV–4), which are further subdivided into genotypes. The virus is transmitted to humans through mosquito bites, primarily from the Aedes spp. genus. Dengue is endemic in various parts of the world, including tropical and subtropical regions of Asia, Latin America, Africa, and Oceania. In Brazil, the state of Tocantins, located in north-central Brazil, has experienced a significant number of arboviral disease cases, particularly dengue. This study aimed to monitor DENV circulation within the state by conducting full genome sequencing of viral genomes recovered from 61 patients between June 2021 and July 2022. During this period, both DENV-1 and DENV-2 serotypes were identified. Our findings confirm the circulation of DENV serotypes 1 and 2 in Tocantins, affecting males and females equally, with younger age groups (4 to 43 years old) being the most susceptible. Phylogenetic analysis revealed that the circulating viruses belong to DENV–1 genotype V American and DENV–2 genotype III Southeast Asian/American. The Bayesian analysis of DENV-1 Genotype V sequenced here is closely related to genomes previously sequenced in the state of São Paulo. Regarding DENV-2 genotype III genomes, these are clustered in a distinct, well-supported subclade, along with previously reported isolates from the states of Goiás and São Paulo. In both cases, our results suggest that multiple introductions of these genotypes occurred in the Tocantins state. This observation highlights the significant impact of major population centers in Brazil on virus dispersion, including other Latin-American countries and the USA. In the SNP analysis, DENV-1 displayed 122 distinct missense mutations, while DENV-2 had 44, with significant mutations predominantly occurring in the envelope and NS5 proteins. The analyses performed here reveal the concomitant circulation of distinct DENV-1 and -2 genotypes in some Brazilian states, underscoring the dynamic evolution of the DENV and the ongoing significance of surveillance efforts in supporting public health policies.

The Munich ChronoType Questionnaire (MCTQ) has now been available for more than 15 years; its original publication has been cited 1,240 times (Google Scholar, May 2019); its online version, which was available until July 2017, has produced almost 300,000 entries from all over the world (MCTQ database). The MCTQ has gone through several versions, has been translated into 13 languages and has been validated against other more objective measures of daily timing in several independent studies. Besides being used as a method to correlate circadian features of human biology with other factors – ranging from health issues to geographical factors – the MCTQ gave rise to quantifying old wisdoms, like “teenagers are late” and has produced new concepts, like social jetlag. Some like the MCTQ’s simplicity and some view it critically; it is time to have a self-critical view on the MCTQ, to address some misunderstandings and give some definitions about MCTQ-derived chronotype and the concept of social jetlag.

In this paper, we revisit the q-states clock model for small systems. We present results for the thermodynamics of the q-states clock model from $q=2$ to $q=20$ for small square lattices $L \times L$, with L ranging from $L=3$ to $L=64$ with free-boundary conditions. Energy, specific heat, entropy and magnetization are measured. We found that the Berezinskii-Kosterlitz-Thouless (BKT)-like transition appears for $q>5$ regardless of lattice size, while the transition at $q=5$ is lost for $L<10$; for $q\leq 4$ the BKT transition is never present. We report the phase diagram in terms of $q$ showing the transition from the ferromagnetic (FM) to the paramagnetic (PM) phases at a critical temperature T$_1$ for small systems which turns into a transition from the FM to the BKT phase for larger systems, while a second phase transition between the BKT and the PM phases occurs at T$_2$. We also show that the magnetic phases are well characterized by the two dimensional (2D) distribution of the magnetization values. We make use of this opportunity to do an information theory analysis of the time series obtained from the Monte Carlo simulations. In particular, we calculate the phenomenological mutability and diversity functions. Diversity characterizes the phase transitions, but the phases are less detectable as $q$ increases. Free boundary conditions are used to better mimic the reality of small systems (far from any thermodynamic limit). The role of size is discussed.

REV-ERBα and its paralog, REV-ERBβ encoded by NR1D1 and NR1D2 genes, are key nuclear receptors that link the circadian timing system and metabolic homeostasis. Since heme is an endogenous ligand, REV-ERBs have been considered key components of the circadian molecular clock that can be pharmacologically targeted to treat various circadian rhythm-related diseases, such as cardiometabolic, inflammatory, and neuropsychiatric diseases, as well as cancer. REV-ERBs are believed to be functionally redundant and compensatory, although they often affect the expression of gene subsets in an isoform-specific manner. Therefore, this study aimed to identify the redundant and distinct roles of each isoform in controlling its target genes by comparing the transcriptome profiles of a panel of mutant U2OS human osteosarcoma cells in which either NR1D1 or NR1D2 was ablated. Indeed, our transcriptomic analyses revealed that most REV-ERB-regulated genes were controlled by redundant or even additive actions. However, the RNA expression profiles of each single mutant cell line also provided strong evidence for isoform-dependent actions. For example, REV-ERBα were more responsible for regulating the NF-κΒ signaling pathway, whereas a group of extracellular matrix components required REV-ERBβ to maintain their expression. We found that REV-ERBs have isoform-selective functions in the regulation of certain circadian output pathways, despite their overlapping roles in the circadian molecular clock. Thus, the development of isoform-selective REV-ERB modulators may help treat metabolic disturbances and certain types of cancer.

Sleep is an essential component of a healthy lifespan, influencing both physical and mental well-being along with good quality of life. Adequate sleep quality and quantity are associated with a host of health advantages, including enhanced immune function, learning and memory, emotional well-being, and cardiovascular health. Chronic sleep deprivation, or poor sleep quality, is associated with a variety of negative health outcomes, including an increased risk of obesity, diabetes, hypertension, depression, cancer, and even premature death. One compelling argument in favor of sleep as a predictor of a healthy lifespan is its effect on cellular repair and regeneration. During sleep, the body goes through important activities such as tissue repair, muscular growth, and memory consolidation. Sleep also helps the brain eliminate toxins and metabolic waste, which contributes to its optimal functioning. Without adequate sleep, these important processes are jeopardized, resulting in accelerated aging and greater susceptibility to chronic illnesses. Furthermore, sleep is essential for maintaining hormone balance, particularly those involved in appetite regulation and metabolism. Sleep disturbances can disrupt the regulation of these hormones, resulting in weight gain, metabolic diseases, and, ultimately, a shorter life span. Finally, prioritizing optimal sleep is pivotal for increasing longevity and general health. Emphasizing the importance of sleep hygiene and treating sleep-related dysfunctions should be part of the modern approach to extending healthy life.

This study introduces the MuhdoAge clock, a novel saliva-based epigenetic clock, designed to predict biological age with strong correlations in a healthy, disease-free cohort. Leveraging a comprehensive dataset from Muhdo Health, this research analyses saliva samples utilising the Illumina MethylationEPIC array. Through robust statistical methods, 237 significant CpG sites were identified that correlate with age-related methylation changes, exhibiting a coefficient of determination (R²) of 0.652 after outlier removal, with tiered algorithmic design improving this further to 0.726 in a new dataset that combined pathologic and healthy individuals (n=2682). Comparatively, the MuhdoAge clock was evaluated against other known epigenetic clocks, demonstrating high precision in predicting biological age within healthy individuals (R² = 0.878, n=1844), emphasising its potential utility in non-invasive, large-scale applications. The clock shows promise for integration into public health strategies for monitoring and potentially mitigating age-related decline, facilitated by its ease of use and accessibility through saliva sampling. Furthermore, this study highlights the impact of lifestyle and environmental factors on biological ageing, highlighting the importance of personalised health interventions. Future research is to focus on longitudinal studies to validate these findings and explore the mechanisms underlying epigenetic age acceleration.

We propose a method that enables precise determination of the number of atoms in a Dick-noise-free optical lattice clock, by effectively addressing quantum projection noise. Our approach relies on conducting stability measurements at three distinct parameter sets, allowing us to differentiate between quantum projection noise, photon shot noise, and technical noise. Importantly, our method enables accurate extraction of the atom number, even in the presence of photon shot noise and technical noise. To validate the effectiveness of our approach, we employ numerical simulations and optimize the modulation parameters to achieve the smallest uncertainty possible. The numerical simulations show the validity of our method and demonstrate a measurement uncertainty in the atom number that is below 4% across a wide range of atom numbers, provided that the standard deviation of atom number fluctuation is kept below 0.23 times the average atom number.

Huntington’s disease (HD) causes progressive movement disorders and cognitive deficits. Besides, sleep disturbances and emotional distress are prominent clinical signatures of HD. The experimental subjects and HD human brains display altered regenerative plasticity resulting from aberrant neurogenic and nonneurogenic areas. Sleep disorders, emotional disruption, and cognitive deficits have been linked to impaired cell cycle events of neural stem cells (NSC) in neurodegenerative disorders. In a physiological state, circadian clock gene pathways play important roles in the regulation of the proliferation and differentiation of NSC, whereas the irregular circadian clock pathway is attributed to impairment in the neurogenic process. The recent advancement of chemogenetic-based approaches represents a potential scientific tool to rectify the abnormal circadian clock which may aid in mitigating neurogenic failure in the brain. Notably, GABAergic vasoactive intestinal peptide (VIP)-expressing neurons in the brain plays a key role in the regulation of neuroplasticity and circadian rhythm. Thus, this conceptual review article addresses the potential link between sleep disorder and aberrant neurogenic events in HD and proposes chemogenetic kindling of vasoactive intestinal peptide (VIP) -expressing GABAergic neurons in the brain as a therapeutic strategy for reprogramming the clock gene pathways in mitigating the neurodegenerative failure in HD.

Achieving synchronization between the central and peripheral body clocks is essential for ensuring optimal metabolic function. Meal timing is an emerging field of research that investigates the influence of eating patterns on our circadian rhythm, metabolism, and overall health. This narrative review examines the relationship between meal timing, circadian rhythm, clock genes, circadian hormones, and metabolic function. It analyzes existing literature and experimental data to explore the connection between mealtime, circadian rhythms, and metabolic processes. The available evidence highlights the importance of aligning mealtime with the body’s natural rhythms to promote metabolic health and prevent metabolic disorders. Specifically, studies show that consuming meals later in the day is associated with a elevated prevalence of metabolic disorders, while early time-restricted eating, such as having an early breakfast and an earlier dinner, improves levels of glucose in the blood and substrate oxidation. Circadian hormones, including cortisol and melatonin, interact with mealtimes and play vital roles in regulating metabolic processes. Cortisol, aligned with dawn in diurnal mammals, activates energy reserves, stimulates appetite, influences clock gene expression, and synchronizes peripheral clocks. Consuming meals during periods of elevated melatonin levels, specifically during the circadian night, has been correlated with potential implications for glucose tolerance. Understanding the mechanisms of central and peripheral clock synchronization, including genetics, interactions with chronotype, sleep duration, and hormonal changes, provides valuable insights for optimizing dietary strategies and timing. This knowledge contributes to improved overall health and well-being by aligning mealtime with the body’s natural circadian rhythm.

Background and Objectives: Light therapy (LT) is used as an adjunctive treatment for sleep problems. This study evaluates the impact of LT on sleep quality and sleep-related parameters in patients with sleep disorders. Materials and Methods: We performed a pilot randomized, open-label clinical trial. Fourteen patients aged 20–60 years with sleep disorders for more than three months were randomized into the control and LT groups (1:1 ratio). The LT group was instructed to use a device that provides bright LT (6000 K, 380 lux, wavelength 480 nm) for at least 25 minutes before 09:00 am for two weeks. A self-reported questionnaire was used to evaluate circadian preference, mood, and sleep-related parameters. We analyzed serum cortisol levels and clock genes expression. Results: The Epworth Sleepiness Scale (ESS), insomnia severity index, and Pittsburgh Sleep Quality index were significantly improved within the LT group only after the two-week period. When comparing the two groups, only the change in ESS significant was significant (mean difference; control: -0.14 vs LT: -1.43, p=0.021) after adjusting for baseline characteristics. There were no significant differences in serum cortisol or clock genes expression. Conclusions: LT can improve daytime sleepiness in patients with sleep disorders; however, further well-designed studies are warranted to confirm its efficacy.

Using the projection evolution (PEv) approach, time can be included in the quantum mechanics as an observable. Having the time operator, it is possible to explore the temporal structure of various quantum events. In the present paper we discuss the possibility of constructing a quantum clock, which advances in time during its quantum evolution, in each step having some probability to localize itself on the time axis in the new position. We propose a working two-state model as the simplest example of such a clock.

Orbit and clock products are used in real-time GNSS precise point positioning without knowing their quality. This study develops a new approach to detect orbit and clock errors through comparing geometry-free and geometry-based wide-lane ambiguities in PPP model. The reparameterization and estimation procedures of the geometry-free and geometry-based ambiguities are described in detail. The effects of orbit and clock errors on ambiguities are given in analytical expressions. The numerical similarity and differences of geometry-free and geometry-based wide-lane ambiguities are analyzed using different orbit and clock products. Furthermore, two types of typical errors in orbit and clock are simulated and their effects on wide-lane ambiguities are numerically produced and analyzed. The contribution discloses that the geometry-free and geometry-based wide-lane ambiguities are equivalent in terms of their formal errors. Although they are very close in terms of their estimates when the used orbit and clock for geometry-based ambiguities are precise enough, they are not the same, in particular, in the case that the used orbit and clock, as a combination, contain significant errors. It is discovered that the discrepancies of geometry-free and geometry-based wide-lane ambiguities are coincided with the actual time-variant errors in the used orbit and clock at the line-of-sight direction. This provides a quality index for real-time users to detect the errors in real-time orbit and clock products, which potentially improves the accuracy of positioning.

The circadian clock regulates daily changes in behavioral, endocrine and metabolic activities in mammals. Circadian rhythms in cellular physiology are significantly affected by aging. In particular, we previously found that aging has profound impact on daily rhythms in mitochondrial functions, leading to increased oxidative stress. However, this is unlikely due to malfunction of molecular clocks in the suprachiasmatic nucleus or peripheral tissues, as robust clock oscillations are observed therein in old animals. Nonetheless, aging induces changes in gene expression levels and rhythms in various peripheral and probably central tissues. In this article, we review findings on the roles of the circadian clock and aging in regulating mitochondrial rhythms and redox homeostasis. Chronic sterile inflammation is implicated in mitochondrial dysfunction and increased oxidative stress during aging. In particular, upregulation of CD38 by inflammatory response can disturb mitochondrial functions in multiple ways.

Restricted feeding is well known to affect expression profiles of both clock and metabolic genes. However, it is unknown whether these changes in metabolic gene expression result from changes in the molecular clock or in feeding behavior. Here we eliminated the daily rhythm in feeding behavior by providing 6-meals evenly distributed over the light/dark-cycle. Animals on this 6-meals-a-day feeding schedule retained the normal day/night difference in physiological parameters including body temperature and locomotor activity. The daily rhythm in respiratory exchange ratio (RER), however, was significantly phase-shifted through increased utilization of carbohydrates during the light phase and increased lipid oxidation during the dark phase. This 6-meals-a-day feeding schedule did not have a major impact on the clock gene expression rhythms in the master clock but did have mild effects on peripheral clocks. By contrast, genes involved in glucose and lipid metabolism showed differential expression. Concluding, eliminating the daily rhythm in feeding behavior in rats does not affect the master clock and only mildly affects peripheral clocks, but disturbs metabolic rhythms in liver, skeletal muscle and brown adipose tissue in a tissue-dependent manner. Thereby a clear daily rhythm in feeding behavior strongly regulates timing of peripheral metabolism, separately from circadian clocks.

Beyond the usual ferromagnetic and paramagnetic phases present in spin systems, the usual q-state clock model, presents an intermediate vortex state when the number of possible orientations q for the system is equal to 5 or larger. Such vortex states give rise to the Berezinskii-Kosterlitz-Thouless (BKT) phase present up to the XY model in the limit q→∞. Based on information theory, we present here an analysis of the classical order parameters plus new short-range parameters defined here. Thus, we show that even using the first nearest neighbors spin-spin correlations only, it is possible to distinguish the two transitions presented by this system for q greater than or equal to 5. Moreover, the appearance at relatively low temperature and disappearance of the BKT phase at a rather fix higher temperature is univocally determined by the short-range interactions recognized by the information content of classical and new parameters.

An autonomous endogenous time-keeping is ubiquitous across many living organisms known as circadian clock when it has a period of about 24 hours. Interestingly, the fundamental design principle with a network of interconnected negative and positive feedback loops is conserved through evolution, although the molecular components differ. Filamentous fungus \textit{Neurospora crassa} is a well established chrono-genetics model organism to investigate the underlying mechanisms. The core negative feedback loop of the clock of \textit{Neurospora} is composed of the transcription activator White Collar Complex (WCC) (heterodimer of WC1 and WC2) and the inhibitory element called FFC complex which is made of FRQ (Frequency protein), FRH (Frequency interacting RNA Helicase) and CK1a (Casein kinase 1a). While exploring their temporal dynamics we investigate how limit cycle oscillations arise and how molecular switches support self-sustained rhythms. We develop a mathematical model of 10 variables with 26 parameters to understand the interactions and feedbacks among WC1 and FFC elements in nuclear and cytoplasmic compartments. We performed control and bifurcation analysis to show that our novel model produces robust oscillations with a wild-type period of 22.5 hrs. Our model reveals a switch between WC1 induced transcription and FFC assisted inactivation of WC1. Using the new model we also study possible mechanisms of glucose compensation. A fairly simple model with just 3 non-linearities helps to elucidate clock dynamics revealing a mechanism of rhythms production. The model can further be utilized to study entrainment and temperature compensation.

Patients with degenerative diseases refer to feeling more pain during the night. However, it is unknown whether spinal nociception can be circadian and how is it controlled. We investigated whether the paw withdrawal threshold (PWT) could exhibit physiological circadian behavior as well as the contribution of the dopaminergic A11 nucleus and the spinal dopamine (DA) receptors (DRs) on the circadian PWT and the spinal clock gene transcription. Results revealed that control rats present a circadian PWT. Injecting 6-hydroxidopamine (6-OHDA) into the dopaminergic A11 nucleus reduced DA tissue content in the lumbar spinal cord, abolished the circadian PWT, induced allodynia, and reduced Period 1 and 2 (Per1 and 2), retinoid-related orphan receptor α (Rorα), Cryptochrome 1 (Cry1), and brain and muscle aryl-hydrocarbon receptor nuclear translocator-like protein (Bmal) mRNA. Likewise, administration of D1-like and D2-like DR antagonists blunted circadian PWT, producing allodynia, and altered the clock genes mRNA. In contrast, administration of D1-like or D2-like DR agonists blocked 6-OHDA-induced allodynia. This study shows that the spinal cord has physiological circadian PWT, which is modulated by the descending dopaminergic A11 through differential activation of the spinal DRs. Also, A11 nuclei and spinal DRs can regulate the clock gene transcription, which can likely modulate the circadian PWT.

Clock Network Design (CDN) is a critical step while designing any Integrated-Circuits (ICs). It holds vital importance in the performance of entire circuit. Due to continuous scaling, 3D ICs stacked with TSV are gaining importance, with an objective to continue with the Moore's law. Through-Silicon-Via (TSV) provides the vertical interconnection between two die, which allows the electrical signal to flow through it. 3D ICs has many advantages over conventional 2D planar ICs like reduced power, area, cost, wire-length etc. The proposed work is mainly focused on power reduction and obstacle avoidance for 3D ICs. Various techniques have already been introduced for minimizing clock power within specified clock constraints of the 3D CND network. Proposed 3D Clock Tree Synthesis (CTS) is a combination of various algorithms with an objective to meet reduction in power as well as avoidance of obstacle or blockages while routing the clock signal from one sink to other sink. These blockages like RAM, ROM, PLL etc. are fixed during the placement process. The work is carried out mainly in three steps- first is Generation of 3D Clock tree avoiding the blockages, then Buffering and Embedding and finally validating the results by SPICE simulation. The experimental result shows that our CTS approach results in significant 9% reduction in power as compare to the existing work.

The most commonly used real-time augmentation services in China are International GNSS Service (IGS) real-time service, PPP-B2b service, and BeiDou Satellite-Based Augmentation System (BDSBAS) dual-frequency augmentation service. However, the research on the performance evaluation, comparison and application scope of these three products is still unknown and unrevealed. This article introduces methods for obtaining real-time augmentation information and real-time orbit and clock offset recovery. Based on real-time orbit and clock offset accuracy, positioning accuracy, and positioning availability, it systematically evaluates the performance of CNES, PPP-B2b, and BDSBAS augmentation information. The results indicate that the radial accuracy of CNES and PPP-B2b real-time orbit products is consistent, and the Root Mean Square (RMS) is better than 5 cm. CNES can achieve centimeter-level accuracy in both along-track and cross-track components, surpassing the decimeter-level accuracy of PPP-B2b. Both services demonstrate consistent accuracy in real-time clock offset, with PPP-B2b showing similar standard deviations (STD) of 0.16 ns for different satellites. However, for CNES, the STD of real-time clock offset varies for GPS, BDS-3 MEO, and BDS-3 IGSO satellites, with values of 0.10 ns, 0.19 ns, and 0.60 ns, respectively. The accuracy and availability of the two PPP services exhibit the same levels, with centimeter-level accuracy achieved after convergence and positioning availability exceeding 99%. Therefore, the difference between the two services in application areas depends on the acquisition of augmentation information. However, BDSBAS, which concentrates on code observations, demonstrates lower accuracy in real-time orbit and clock offset, positioning accuracy, and positioning availability compared to the other two services. Its primary application is in the aviation and maritime domains, where there is a greater need for service integrity, continuity, and reliability.

In Newtonian mechanics, time as well as space are perceived as absolute entities. In 2 Einstein’s special relativity, time is frame dependent. Time is also affected by gravitational field 3 and as the field varies in space, time also varies throughout space. In the present article, a 4 thermodynamic-based time is investigated. The entity is called "irreversibility", which is generated 5 when availability (also known as exergy) is destroyed. Since each thermodynamic system may 6 generate different amount of irreversibility, this quantity is system dependent. The time’s arrow is 7 automatically satisfied, since irreversibility generation always proceeds in one direction (toward 8 future). We have demonstrated that, like common time, irreversibility is frame dependent, and 9 affected by gravity in the similar manner as the common time. For this reason, we propose to 10 assign the entity irreversibility of the system as thermodynamic time. A possible application of the 11 thermodynamic time is an interpretation and managing of the aging of biological systems. The 12 metabolic efficiency is related to the irreversibility of the chemical processes and affect the aging of 13 the system. Our sensation of time-flow may be attributed to the flow of availability and destruction 14 of it through the living system. It is shown by other authors that entropy generation (equivalent to 15 irreversibility) is a parameter for the human life span. Since the thermodynamic time is based on a 16 concept of thermodynamics that is universal, further applications to other subjects, such as biological 17 clock, telomere, and cosmology are possible.

Circadian rhythms misalignment is associated with hypertension. The aim of the study was to evaluate the concentration of selected clock proteins- cryptochrome 1 (CRY1) and circadian locomotor output cycles kaput (CLOCK) and to determine their relationships with biochemical and anthropometric parameters and lifestyle elements (diet, physical activity, quality of sleep) in hypertensive patients. In 25 female with hypertension (HT) and 49 non-hypertensive women (NHT), the CRY1 and CLOCK concentrations, total antioxidant status (TAS), lipid profile and glycemia were conducted. Blood pressure and anthropometric measurements, nutritional, exercise and sleep analyses were performed. In HT the CRY1 level was 40.2% lower than in the NHT. No differences were noted in CLOCK concentration between groups. The study showed no relationship between CRY1 or CLOCK concentrations and glucose or lipids profile, amount of physical activity and sleep quality, although CRY1 was associated with some anthropometric parameters. There was a negative correlation between the CLOCK concentration and the amount of saturated fatty acids consumed (24h) in HT. That indicates the possible influence of the diet on the CLOCK level. In a detailed prognosis of the risk of hypertension, it is worth considering the measurement of the level of CRY1 in populations with abnormal anthropometric indices.

This study investigates whether a chronotherapeutic treatment of hepatocellular carcinoma (HCC) may improve treatment efficacy and mitigate side effects on healthy liver (HL). HCC was induced in Per2::luc mice which were irradiated at four time points of the day. Proliferation and DNA-double strand breaks were investigated in irradiated and non-irradiated organotypic slice culture (OSC) and ex vivo samples by detection of Ki67 and γ-H2AX. OSC proved useful to determine dose-dependent effects on proliferation and DNA damage but appeared unsuited to test the chronotherapeutic approach. Irradiation of ex vivo samples was most effective at the proliferation peaks in HCC at ZT02 (early inactivity phase) and ZT20 (late activity phase). Irradiation effects on HL were minimal at ZT20. Ex vivo samples revealed disruption in daily variation and down-regulation of all investigated clock genes except Per1 in non-irradiated HCC as compared with HL. Irradiation affected rhythmic clock gene expression in HL and HCC at all ZTs except at ZT20. Irradiation at ZT20 had no effect on total leukocyte numbers. Our results indicate ZT20 as the optimal time point for irradiation of HCC in mice. Translational studies are now needed to evaluate whether the late activity phase is the optimal time point for irradiation of HCC in man.

Abstract: The trend of fasting until noon (omission or delayed breakfast) is increasingly prevalent in modern society. This eating pattern triggers discordance between endogenous circadian clock rhythms and the feeding/fasting cycle and is associated with an increased incidence of obesity and T2D. Although the underlying mechanism of this association is not well understood, growing evidence suggests that fasting until noon, also known as an “extended postabsorptive state,” has the potential to cause a deleterious effect on clock gene expression and disrupted regulation of body weight, postprandial and overall glycemia, skeletal muscle protein synthesis, appetite and may also lead to lower energy expenditure. This manuscript overviews the clock gene-controlled glucose metabolism during the active and resting phases. The consequences of postponing until noon the transition from postabsorptive to fed state on glucose metabolism, weight control, and energy expenditure. Finally, we will discuss the metabolic advantage of shifting more energy, carbohydrates (CH), and proteins to the early hours of the day.

A method of accuracy error compensation for the time interval is examined, allowing to eliminate the dependence of accuracy error on the duration of measured intervals and minimising the influence of destabilising factors - ambient temperature changes and the initial deviation of the meter clock generator frequency from the nominal value. The compensation method is based on a calibration procedure that measures precise time intervals under conditions of changing ambient temperature. Then the dependence of the accuracy error on temperature for a particular meter is recorded. Based on these data, a correction table is compiled containing correction factors and temperature values at which these factors were determined. Under real measurement conditions, the correction factor corresponding to the current temperature is determined from the table for measured results correction. The table with correction factor values could be stored in the memory of the meter or processing computer. Experimental verification of the method showed that applying a correction for a meter with a standard XO class clock generator (certificated instability of ±50 ppm) can obtain an equivalent clock generator instability of ±0.15 ppm. The application of the method is efficient in cases where the use of high-end clocking to ensure the required measurement accuracy is not economically feasible.

Running at odds with the timing imposed by the circadian clock plays an important role in the process that leads to communicable and non communicable diseases. The primary objective of this study was to analyse whether early dinner eater children were at lower risks of acute respiratory infections than late dinner eater children, during the COVID-19 pandemic. Methods: This cross sectional study was conducted from July to December 2020 on children attending Majorcan emergency services. Clinical data collected included timing, symptoms, laboratory tests and imaging studies of current illness. Each diagnosis was validated by general paediatricians. Our survey on dinner time habits was carried out by using self-administered questionnaires. Results: A total of 669 children under age 18 were included in the study. The median of dinner time was 8:30 pm. Late dinner eaters accounted for a higher proportion of acute otitis media than early dinner eaters (7% vs 3%; P=0.028). Other infectious diseases were not associated with dinner time habits. Conclusions: We make a preliminary estimate of the link between late dinner habits and acute otitis media in children. However, no conclusions about causality can be established due to the observational design of the study.

It is often said in human society that it all starts from the mind, and this is true. The answer to the question “Why is it that pets require much fewer years to fully develop than humans?” could be headed to the Theory of Relativity and the perceived time according to the levels of instinct and rationality. It is perhaps no wonder that the French language translates the word “mind” as “l’esprit”, which also means “spirit” in the English language. Given that the Theory of Relativity applies to all physical matter, the theory applies to chemistry, biology and psychology as well. The level of instinct is proportional with the perceived speed of time and implicitly, to the speed of time itself for the whole organism, given that the nervous system coordinates all bodily functions. A pet may experience a few years as humans experience over a decade, making their perceived lifetime to be approximately equal to the human’s. The same applies to the perception of space and its components. This aspect would emphasise upon the fact that all life on Earth shows the same degree of value with regards to uniqueness. Nevertheless, the values represented by the hierarchy of competences among living organisms at the same time differs based on species. Honour of uniqueness and hierarchy of competences represent two scientific concepts that never overcross. As a result, there is no evidence to suggest that scientific facts as such constitute a form of contradiction to philosophical and religious ideas, given that religion refers to animals as companions of humans. With regards to the clock of the living organism; there are three kinds of clocks in a living organism: the emotional clock, the cognitive clock and the molecular clock. These three categories actually constitute the temporal layers of our dimension, so they are in a relationship of interdependence. When one has a feeling that time is slower or quicker, they are not fully experiencing that change in the time speed, but only partially. And one can profoundly experience the change of perceived time speed when they experience profound feelings, which sweep them away from reality. Complete, deep mental focus can bring about this profound change in perception, which will make the individual feel as if they are in a different form of reality. When one is more instinctive, the person in cause perceives time as slower and sees more opportunities within the same frame of time and space. When one experiences the “Fight or flight” mode, the person in the cause finds themselves to be in danger and has two options; to try to prevail over the danger or to flee it. Whilst experiencing such a mode, people are much more alert and therefore, time passes more slowly and the physical space dilates. When people are relaxed, however, time and space become smaller, and when they are in a deep state of resting, they become very small. And where there is a smaller dimension, there is a greater speed, just as the circulating air gains speed when it crosses narrow passages.

This present work explores the performance of a thermal-magnetic engine of Otto type, considering as a working substance an effective interacting spin model corresponding to the q− state clock model. We obtain all the thermodynamic quantities for the q = 2, 4, 6, 8 cases in a small lattice size (3×3 with free boundary conditions) by using the exact partition function calculated from the energies of all the accessible microstates of the system. The extension to bigger lattices was performed using the mean-field approximation. Our results indicate that the total work extraction of the cycle is highest for the q=4 case, while the performance for the Ising model (q=2) is the lowest of all cases studied. These results are strongly linked with the phase diagram of the working substance and the location of the cycle in the different magnetic phases present, where we find that the transition from a ferromagnetic to a paramagnetic phase extracts more work than one of the Berezinskii–Kosterlitz–Thouless to paramagnetic type. Additionally, as the size of the lattice increases, the extraction work is lower than smaller lattices for all values of q presented in this study.

GIGANTEA (GI) is a gene involved in multiple biological functions, which were analysed and are partially conserved in a series of mono- and dicotyledonous plant species. The identified biological functions include control over the circadian rhythm, light signalling, cold tolerance, hormone signalling and photoperiodic flowering. The latter function is a central role of GI, as it involves a multitude of pathways, both dependent and independent of the gene CONSTANS(CO) as well as on the basis of interaction with miRNA. The complexity of gene function of GI increases due to the existence of paralogs showing changes in genome structure as well as incidences of sub- and neofunctionalization. We present an updated report of the biological function of GI, integrating late insights into its role in floral initiation, flower development and flower volatile production.

Satellite clock bias (SCB) prediction is a crucial technology for satellite navigation systems, holding significant importance for Global Navigation Satellite System. This paper proposes a deep learning model for SCB prediction based on the fusion of the Beluga Whale Optimization (BWO), Convolutional Neural Network (CNN), Bidirectional Gated Recurrent Unit (BiGRU), and an attention mechanism. The CNN is utilized to extract the spatiotemporal characteristic information from the clock bias sequence, while the BiGRU fully extracts relevant features through forward and backward propagation. The introduction of an attention mechanism aims to preserve essential features within the clock bias sequence to enhance feature extraction by both CNN and BiGRU networks. Additionally, the BWO is employed to optimize parameter selection in order to improve model accuracy. Experimental verification demonstrates that for the BeiDou Navigation Satellite System's (BDS) hydrogen-maser atomic clocks, the predicted clock bias for 6 hours, 3 days, and 15 days are 0.078 ns, 0.475 ns, and 2.130 ns respectively - representing improvements of 31%, 45%, and 66% over CNN-BiGRU-Attention; 6%, 51%, and 56% over CNN-BiGRU; and 32%, 35%, and 73% over BiGRU, respectively.

The severity and outcome of coronavirus disease 2019 (COVID-19) largely depends on a patient’s age. Over 80% of hospitalizations are of those over 65 years of age with a 23-fold greater risk of death. In the clinic, COVID-19 patients most commonly present with fever, cough and dyspnea. Particularly in those over 65, it can progress to pneumonia, lung consolidation, cytokine release syndrome, endotheliitis, coagulopathy, multiple organ failure and death. Comorbidities such as cardiovascular disease, diabetes, obesity and hypertension increase the chances of fatal disease, but they alone do not explain the variability in COVID-19 symptoms. Here, we present the molecular differences between the young, middle-aged and elderly that may determine whether COVID-19 is a mild or life-threatening illness. We also discuss several biological age clocks that could be used in conjunction with genetic tests to identify both the mechanisms of the disease and individuals most at risk. Finally, based on these mechanisms, we discuss treatments that could increase survival in the elderly, not simply by inhibiting the virus, but by restoring patients’ ability to clear the infection.

In this paper, we will revisit the derivation of Heisenberg's uncertainty principle. We will see how the Heisenberg principle collapses at the Planck scale by introducing a minor modification. The beauty of our suggested modification is that it does not change the main equations in quantum mechanics; it only gives them a Planck scale limit where uncertainty collapses. We suspect that Einstein could have been right after all, when he stated, ``God does not throw dice." His now-famous saying was an expression of his skepticism towards the concept that quantum randomness could be the ruling force, even at the deepest levels of reality. Here we will explore the quantum realm with a fresh perspective, by re-deriving the Heisenberg principle in relation to the Planck scale. We will show how this idea also leads to an upper boundary on uncertainty, in addition to the lower boundary. These upper and lower boundaries are identical for the Planck mass particle; in fact, they are zero, and this highlights the truly unique nature of the Planck mass particle. Further, there may be a close connection between light and the Planck mass particle: In our model, the standard relativistic energy momentum relation also seems to apply to light, while in modern physics light generally stands outside the standard relativistic momentum energy relation. We will also suggest a new way to look at elementary particles, where mass and time are closely related, consistent with some of the recent work in experimental physics. Our model leads to a new time operator that does not appear to be in conflict with the Pauli objection. This indicates that both mass and momentum come in quanta, which are perfectly correlated to an internal Compton `clock' frequency in elementary particles.

In humans, age-associated degrading changes are observed in molecular and cellular processes underly the time-dependent decline in spatial navigation, time perception, cognitive and psy-chological abilities, and memory. Cross talk of biological, cognitive, and psychological clocks provides an integrative contribution to healthy and advanced aging. At the molecular level, ge-nome, proteome, and lipidome instability are widely recognized as the primary causal factors in aging. We narrow attention to the roles of protein aging linked to prevalent amino acids chirali-ty, enzymatic and spontaneous (non-enzymatic) post-translational modifications (PTMs SP), and non-equilibrium phase transitions. The homochirality of protein synthesis, resulting in the steady-state non-equilibrium condition of protein structure, makes them prone to multiple types of enzymatic and spontaneous PTMs, including racemization and isomerization. Spontaneous racemization leads to the loss of the balanced prevalent chirality. Advanced biological aging re-lated to irreversible PTMs SP has been associated with the nontrivial interplay between poor so-matic and mental health conditions. Through stress response systems (SRS), the environmental and psychological stressors contribute to the age-associated “collapse” of protein homochirality. The role of prevalent protein chirality and entropy of protein folding in biological aging is mainly overlooked. In a more generalized context, the time-dependent shift from enzymatic to the non-enzymatic transformation of biochirality might represent an important and yet un-der-appreciated hallmark of aging.

Time, traditionally viewed as a linear, non-dynamic parameter, is re-envisioned in this study as a Hyperdimensional concept. This paper conducts a cross-disciplinary examination, critically analysing the conceptualization of time in classical mechanics, quantum mechanics, and cosmology to propose a ground breaking reconceptualisation that extends beyond conventional frameworks. In classical mechanics, time is perceived as an absolute, continuously progressing backdrop, largely independent of events. Quantum mechanics treats time as a static parameter that does not influence quantum states but provides a framework for their evolution. In cosmology, time is considered a dimension that emerges from the Big Bang and serves as a measure for the universe's expansion, yet it does not interact with the structural dynamics of the cosmos. Challenging the transformative insights of Einstein’s relativity, which merges time with spatial dimensions under extreme conditions, we advocate for a perspective that views time as a Hyperdimensional and universal constant. This perspective posits that time, despite its unique and intrinsic properties, does not dynamically interact with or alter physical phenomena. Instead, it underpins our understanding of phenomena across different scales—from the minutiae of quantum states to the macroscopic dynamics of cosmology—without direct causation or change. A critical examination of time dilation and relativistic assumptions reveals significant discrepancies in traditional interpretations, particularly in how they are applied across different physical contexts. Our findings challenge the uniform applicability of time dilation, suggesting that observed phenomena often attributed to relativistic effects might better be explained through non-relativistic mechanisms such as phase shifts or changes in wavelength rather than temporal dilation. By synthesizing insights from various scientific domains, we advocate for a unified theory that recognizes time as a fundamental, universal dimension that is conceptual and non-interactive. Our goal is to bridge existing gaps between diverse scientific interpretations and promote a more integrated, profound understanding of time's autonomous and intrinsic nature.