Main Clock Research Articles

Adaptive coupling between neurons widens the entrainment range of the suprachiasmatic nucleus.

In many realistic systems, such as neural networks in the brain, the coupling strength between neurons is not fixed, but adaptively adjusts according to their activities. The suprachiasmatic nucleus (SCN), as the main clock in the mammalian brain, has been found to be a plastic neural network, and the coupling strength between neurons is highly dynamical. An important function of the SCN is entrainment, reflecting the ability of the SCN to synchronize with the external light-dark cycle. The entrainment ability is reflected by the entrainment range, which is a period range for the external light-dark cycle to which the SCN can entrain. In this article, we investigated whether the entrainment range of the SCN is affected by the adaptive coupling. We use a modified Kuramoto model with external light-dark cycle. We found that when the light sensitivity is larger than the fixed coupling strength (the coupling strength without adaptive rules), adaptive coupling can widen the entrainment range. Our findings help to understand the impact of the adaptive coupling between oscillatorty neurons on the collective behavior of the SCN, and provides a possible explanation for the plasticity of coupling in the master clock network.

The Effect of Melatonin on Metabolism and the Sleep-Wake Cycle

The aim of this study was to investigate the influence of melatonin on metabolism and the implementation of the sleep-wake cycle. Methodology. Publications for this review were collected from PubMed, MedLine, and Google Scholar databases. Results. Melatonin is the main hormone that communicates the main circadian clock, located in the suprachiasmatic nucleus of the hypothalamus, and the peripheral biological clock located in brain cells and other organs. Melatonin production is related to day and night cycles, with peak production of the hormone occurring at night. Considering the pathophysiological mechanisms triggered by melatonin deficiency, the question reasonably arises about the possibilities of treating metabolic disorders (including type 2 diabetes), cardiovascular pathology and sleep disorders with melatonin preparations. Domestic and foreign publications provide reports of the clinically successful use of such drugs to improve sleep quality, increase sensitivity to glucose, lower blood pressure, reduce myocardial ischemia, and improve anthropometric parameters. All this makes melatonin a promising drug for managing cardiovascular risks against the background of metabolic disorders.

Circadian desynchrony and glucose metabolism.

The circadian timing system controls glucose metabolism in a time-of-day dependent manner. In mammals, the circadian timing system consists of the main central clock in the bilateral suprachiasmatic nucleus (SCN) of the anterior hypothalamus and subordinate clocks in peripheral tissues. The oscillations produced by these different clocks with a period of approximately 24-h are generated by the transcriptional-translational feedback loops of a set of core clock genes. Glucose homeostasis is one of the daily rhythms controlled by this circadian timing system. The central pacemaker in the SCN controls glucose homeostasis through its neural projections to hypothalamic hubs that are in control of feeding behavior and energy metabolism. Using hormones such as adrenal glucocorticoids and melatonin and the autonomic nervous system, the SCN modulates critical processes such as glucose production and insulin sensitivity. Peripheral clocks in tissues, such as the liver, muscle, and adipose tissue serve to enhance and sustain these SCN signals. In the optimal situation all these clocks are synchronized and aligned with behavior and the environmental light/dark cycle. A negative impact on glucose metabolism becomes apparent when the internal timing system becomes disturbed, also known as circadian desynchrony or circadian misalignment. Circadian desynchrony may occur at several levels, as the mistiming of light exposure or sleep will especially affect the central clock, whereas mistiming of food intake or physical activity will especially involve the peripheral clocks. In this review, we will summarize the literature investigating the impact of circadian desynchrony on glucose metabolism and how it may result in the development of insulin resistance. In addition, we will discuss potential strategies aimed at reinstating circadian synchrony to improve insulin sensitivity and contribute to the prevention of type 2 diabetes.

Research on FPGA-based dual-channel time synchronization system

As geological exploration progresses in depth and scope, the distance between transmitting and receiving systems also increases. Consequently, the synchronization of time between the two becomes an increasingly critical issue. In response, this paper presents a proposed design for a time synchronization system that is suitable for use between transmitting and receiving equipment. The system uses GPS as the main clock source. The information within the GPS system will be encoded and decoded using the FPGA. This allows us to obtain both UTC time and the time of the IRIG-B code format, enabling compatibility with the various system interfaces. Our experiments have confirmed that the system has a time error at the microsecond level, and the precision satisfies the design requirements. This verifies the validity and reliability of the system.

Current state of knowledge on the centrifugal visual system (including the pinealo-to-retinal connection) in mammals and its hypothesized role in circadian rhythms

The ubiquity of circadian rhythms in living organisms has generally been accepted by researchers over the last century. Indeed, morphology and molecular biology of the circadian clock were described during the last fifty years. This main biological clock is located in the suprachiasmatic nucleus of the hypothalamus. This nucleus is connected with the retina by the retinohypothalamic tract. This way, light regulates the functioning of the biological clock and biological rhythms such as the sleep-wake cycle and other cyclic functions by releasing melatonin from the pineal body (PB) into the general circulation. Melatonin reaches the retina via the bloodstream as humoral feedback. More than a hundred years ago a reverse neuronal connection between the central nervous system and the retina was hypothesized. This so-called centrifugal visual or retinopetal system has been explored in detail in birds, but less information is available in mammals. In this work, the morphology and physiology of mammalian centrifugal visual pathways are reviewed. It is generally accepted that the centrifugal (retinopetal) fibers terminate mainly on the amacrine cells of the retina. Histaminergic fibers terminate on dopaminergic amacrine cells. Serotoninergic synapses were identified on ganglion cells. In addition, serotoninergic fibers were also associated with photoreceptor terminals. Luteinizing hormone releasing hormone fibers have been observed in birds, but not in mammalian retinas. In summary, based on the data available in the literature, it seems that the retinopetal system has a mandatory role in lower vertebrates, but a modulatory role in mammals. There is currently no adequate way to eliminate the centrifugal visual system that would better explain its true function.

Sub-50 fs temporal resolution in an FEL-optical laser pump-probe experiment at FLASH2.

High temporal resolution is essential for ultra-fast pump-probe experiments. Arrival time jitter and drift measurements, as well as their control, become critical especially when combining XUV or X-ray free-electron lasers (FELs) with optical lasers due to the large scale of such facilities and their distinct pulse generation processes. This paper presents the application of a laser pulse arrival time monitor that actively corrects the arrival time of an optical laser relative to the FEL's main optical clock. Combined with post-analysis single pulse jitter correction this new approach improves the temporal resolution for pump-probe experiments significantly. Benchmark measurements on photo-ionization of xenon atoms performed at FLASH beamline FL26, demonstrate a sub-50 fs FWHM overall temporal resolution.

A High Performance Reconfigurable Hardware Architecture for Lightweight Convolutional Neural Network

Since the lightweight convolutional neural network EfficientNet was proposed by Google in 2019, the series of models have quickly become very popular due to their superior performance with a small number of parameters. However, the existing convolutional neural network hardware accelerators for EfficientNet still have much room to improve the performance of the depthwise convolution, squeeze-and-excitation module and nonlinear activation functions. In this paper, we first design a reconfigurable register array and computational kernel to accelerate the depthwise convolution. Next, we propose a vector unit to implement the nonlinear activation functions and the scale operation. An exchangeable-sequence dual-computational kernel architecture is proposed to improve the performance and the utilization. In addition, the memory architectures are designed to complete the hardware accelerator for the above computing architecture. Finally, in order to evaluate the performance of the hardware accelerator, the accelerator is implemented based on Xilinx XCVU37P. The results show that the proposed accelerator can work at the main system clock frequency of 300 MHz with the DSP kernel at 600 MHz. The performance of EfficientNet-B3 in our architecture can reach 69.50 FPS and 255.22 GOPS. Compared with the latest EfficientNet-B3 accelerator, which uses the same FPGA development board, the accelerator proposed in this paper can achieve a 1.28-fold improvement of single-core performance and 1.38-fold improvement of performance of each DSP.

ArduSiPM technology: Compact and light All-in-one detectors for space application

ArduSiPM technology integrates System on Chip (SoC) innovation and Silicon photomultiplier (SiPM) detector improvements into a new generation of all-in-one scintillation detectors, developed by INFN Rome since 2014. To minimize reliance on pre-built Commercial off-the-shelf (COTS) components, we utilize the peripherals and CPU of the SoC for edge computing tasks and various functions, such as Counters, Analog-to-Digital Converters (ADCs), Digital-to-Analog Converters (DACs), Pulse-Width modulation (PWM), and digital input/output interfaces. Our compact electronic system eliminates the need for external data acquisition systems and ASICs, while also enabling the CPU to perform edge computing functions. The detector, capable of measuring the rate, arrival time (with a resolution of 7 ns correlated to the SoC main clock), and number of photons arriving on the SiPM, is ideal for radiation monitoring and highly sensitive photon detection. The INFN MICRO experiment explores circuits and engineering solutions for developing detectors for diverse fields such as Transient Luminous Events, analytical chemistry, and nano/picosatellites. Our ultimate goal is to integrate the detector into the onboard computer of a satellite, akin to navigation instruments and attitude control systems, with future improvements in SoC technology easily leveraged thanks to our approach’s independence from the specific SoC.

Reciprocal Interactions between Circadian Clocks, Food Intake, and Energy Metabolism.

Like other biological functions, food intake and energy metabolism display daily rhythms controlled by the circadian timing system that comprises a main circadian clock and numerous secondary clocks in the brain and peripheral tissues. Each secondary circadian clock delivers local temporal cues based on intracellular transcriptional and translational feedback loops that are tightly interconnected to intracellular nutrient-sensing pathways. Genetic impairment of molecular clocks and alteration in the rhythmic synchronizing cues, such as ambient light at night or mistimed meals, lead to circadian disruption that, in turn, negatively impacts metabolic health. Not all circadian clocks are sensitive to the same synchronizing signals. The master clock in the suprachiasmatic nuclei of the hypothalamus is mostly synchronized by ambient light and, to a lesser extent, by behavioral cues coupled to arousal and exercise. Secondary clocks are generally phase-shifted by timed metabolic cues associated with feeding, exercise, and changes in temperature. Furthermore, both the master and secondary clocks are modulated by calorie restriction and high-fat feeding. Taking into account the regularity of daily meals, the duration of eating periods, chronotype, and sex, chrononutritional strategies may be useful for improving the robustness of daily rhythmicity and maintaining or even restoring the appropriate energy balance.

Endogenous carbon monoxide (CO) as a modulating factor of molecular biological clock in the hypothalamic structures involved in light transmission in pig and wild boar hybrid during long and short day season.

Mature males of a wild boar-pig crossbreed, during the long and short day season, were used for the study which demonstrates that the chemical light carrier CO regulates the expression of biological clock genes in the hypothalamus via humoral pathways. Autologous blood with experimentally elevated concentrations of endogenous CO (using lamps with white light-emitting diodes) was infused into the ophthalmic venous sinus via the right dorsal nasal vein. Molecular biology methods: qPCR and Western Blot were used to determine the expression of genes and biological clock proteins. The results showed that elevated endogenous CO levels, through blood irradiation, induces changes in genes expression involved in the functioning of the main biological clock located in suprachiasmatic nuclei. Changes in the expression of the transcription factors Bmal1, Clock and Npas2 have a similar pattern in both structures, where a very large decrease in gene expression was shown after exposure to elevated endogenous CO levels. The changes in the gene expression of PER 1-2, CRY 1-2, and REV-ERB α-β and ROR β are not the same for both POA and DH hypothalamic structures, indicating that both structures respond differently to the humoral signal received. The results indicate that CO is a chemical light molecule whose production in an organism depends on the amount of light. An adequate amount of light is an essential factor for the proper functioning of the main biological clock.

Single nucleotide polymorphisms (SNPs) in circadian genes: Impact on gene function and phenotype.

Circadian rhythm is an endogenous timing system that allows an organism to anticipate and adapt to daily changes and regulate various physiological variables such as the sleep-wake cycle. This rhythm is governed by a molecular circadian clock mechanism, generated by a transcriptional and translational feedback loop (TTFL) mechanism. In mammals, TTFL is determined by the interaction of four main clock proteins: BMAL1, CLOCK, Cryptochromes (CRY), and Periods (PER). BMAL1 and CLOCK form dimers and initiate the transcription of clock-controlled genes (CCG) by binding an E-box element with the promotor genes. Among CCGs, PERs and CRYs accumulate in the cytosol and translocate into the nucleus, where they interact with the BMAL1/CLOCK dimer and inhibit its activity. Several epidemiological and genetic studies have revealed that circadian rhythm disruption causes various types of disease. In this chapter, we summarize the effect of core clock gene SNPs on circadian rhythm and diseases in humans.

Influence of DNA-Polymorphisms in Selected Circadian Clock Genes on Clock Gene Expression in Subjects from the General Population and Their Association with Sleep Duration.

Background and Objectives: Circadian rhythms have an important implication in numerous physiological and metabolic processes, including the sleep/wake cycle. Inter-individual differences in factors associated with circadian system may be due to gene differences in gene expression. Although several studies have analyzed the association between DNA polymorphisms and circadian variables, the influence on gene expression has been poorly analyzed. Our goal was to analyze the association of genetic variations in the clock genes and the gene expression level. Materials and Methods: We carried out a cross-sectional study of 102 adults (50.9% women). RNA and DNA were isolated from blood and single-nucleotide polymorphisms (SNPs), and the main circadian clock genes were determined. Gene expression of CLOCK, PER1, and VRK2 genes was measured by Reverse-transcription polymerase chain reaction (RT-PCR). The association between the DNA-SNPs and gene expression was analyzed at the gene level. In addition, a polygenic risk score (PRS), including all the significant SNPs related to gene expression, was created for each gene. Multivariable model analysis was performed. Results: Sex-specific differences were detected in PER1 expression, with these being higher in women (p = 0.034). No significant differences were detected in clock genes expression and lifestyle variables. We observed a significant association between the ARNTL-rs7924734, ARNTL-rs10832027, VRK2- rs2678902 SNPs, and CLOCK gene expression; the PER3-rs228642 and PER3-rs10127838 were related to PER1 expression, and the ARNTL-rs10832027, ARNTL-rs11022778, and MNTR1B-rs10830963 were associated with VRK2 gene expression (p < 0.05). The specific PRS created was significantly associated with each of the gene expressions analyzed (p < 0.001). Finally, sleep duration was associated with PER3-rs238666 (p = 0.008) and CLOCK-rs4580704 (p = 0.023). Conclusion: We detected significant associations between DNA-SNPs in the clock genes and their gene expression level in leukocytes and observed some differences in gene expression per sex. Moreover, we reported for the first time an association between clock gene polymorphisms and CLOCK, PER1, and VRK2 gene expression. These findings need further investigation.

The Role of Glia Clocks in the Regulation of Sleep in Drosophila melanogaster.

In Drosophila melanogaster, the pacemaker located in the brain plays the main role in maintaining circadian rhythms; however, peripheral oscillators including glial cells, are also crucial components of the circadian network. In the present study, we investigated an impact of oscillators located in astrocyte-like glia, the chiasm giant glia of the optic lobe, epithelial and subperineurial glia on sleep of Drosophila males. We described that oscillators located in astrocyte-like glia and chiasm giant glia are necessary to maintain daily changes in clock neurons arborizations, while those located in epithelial glia regulate amplitude of these changes. Finally, we showed that communication between glia and neurons through tripartite synapses formed by epithelial glia and, in effect, neurotransmission regulation plays important role in wake-promoting during the day.SIGNIFICANCE STATEMENT Circadian clock or pacemaker regulates many aspects of animals' physiology and behavior. The pacemaker is located in the brain and is composed of neurons. However, there are also additional oscillators, called peripheral clocks, which synchronize the main clock. Despite the critical role of glia in the clock machinery, little is known which type of glia houses peripheral oscillators and how they affect neuronal clocks. This study using Drosophila shows that oscillators in specific glia types maintain awakeness during the day by regulating the daily plasticity of clock neurons.

A Charge-Sharing IIR Filter With Linear Interpolation and High Stopband Rejection

This article introduces a new discrete-time (DT) charge-sharing (CS) low-pass filter (LPF) that achieves high-order filtering and improves its stopband rejection while maintaining a reasonable duty cycle of the main clock at 20%. It proposes two key innovations: 1) a linear interpolation of the sampling capacitor and 2) a charge re-circulation of the history capacitors for deep stopband rejection. Fabricated in 28-nm CMOS, the proposed IIR LPF demonstrates a 1–9.9-MHz bandwidth (BW) programmability and achieves a record-high 120-dB stopband rejection at 100 MHz while consuming merely 0.92 mW. The in/out-of-band IIP3 is +17.7 dBm/+26.6 dBm, and the input-referred noise is 3.5 nV/ <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\sqrt {\mathrm{ Hz}}$ </tex-math></inline-formula> .

Dorsal clock networks drive temperature preference rhythms in Drosophila.

SUMMARYAnimals display a body temperature rhythm (BTR). Little is known about the mechanisms by which a rhythmic pattern of BTR is regulated and how body temperature is set at different times of the day. As small ectotherms, Drosophila exhibit a daily temperature preference rhythm (TPR), which generates BTR. Here, we demonstrate dorsal clock networks that play essential roles in TPR. Dorsal neurons 2 (DN2s) are the main clock for TPR. We find that DN2s and posterior DN1s (DN1ps) contact and the extent of contacts increases during the day and that the silencing of DN2s or DN1ps leads to a lower temperature preference. The data suggest that temporal control of the microcircuit from DN2s to DN1ps contributes to TPR regulation. We also identify anterior DN1s (DN1as) as another important clock for TPR. Thus, we show that the DN networks predominantly control TPR and determine both a rhythmic pattern and preferred temperatures.

HERMES-Core—A 1.59-TOPS/mm2 PCM on 14-nm CMOS In-Memory Compute Core Using 300-ps/LSB Linearized CCO-Based ADCs

We present a 256 <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\times$ </tex-math></inline-formula> 256 in-memory compute (IMC) core designed and fabricated in 14-nm CMOS technology with backend-integrated multi-level phase change memory (PCM). It comprises 256 linearized current-controlled oscillator (CCO)-based A/D converters (ADCs) at a compact 4- <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> pitch and a local digital processing unit (LDPU) performing affine scaling and ReLU operations. A frequency-linearization technique for CCO is introduced, which increases the maximum CCO frequency beyond 3 GHz, while ensuring accurate on-chip matrix–vector multiplications (MVMs). Moreover, the design and functionality of the digital ADC calibration procedure is described in detail and the MVM accuracy is quantified. Finally, the measured classification accuracies of deep learning (DL) inference applications on the MNIST and CIFAR-10 datasets, when two IMC cores are employed, are presented. For a performance density of 1.59 TOPS/mm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</sup> , a measured energy efficiency of 10.5 TOPS/W, at a main clock frequency of 1 GHz, is achieved.

Computational Technologies for the Wearable Sports Training System Based on Sensor Acquisition

Aiming at the problems of long time-consuming and low precision in traditional training system, a wearable sports training system based on data mining is proposed and designed. According to the overall structure of the system, the hardware and software of the system are designed respectively. The hardware part is mainly composed of attitude measurement unit, power supply unit, main control unit, clock circuit, and reset circuit. The software part introduces the data mining method of mining sports training information data. The experimental results show that the system designed in this study effectively shortens the time-consuming time, improves the accuracy, and has certain advantages.

Possible protective effects of the Bmal1 gene and melatonin on the prognosis of apical periodontitis

Apical periodontitis (AP) is defined as inflammation of the tissues surrounding the root apex and presents many challenges for successful endodontic treatment. The presence of microorganisms and other irritants in the root canal system, as well as the host defence mechanism, play a crucial role in the development of AP. Although the root canal procedure is commonly recommended as a standard first-line treatment with a high success rate, a successful outcome cannot always be guaranteed in cases of AP. Another important factor to consider is the integrity of the immune system is essential for defence against infectious microorganisms and their by-products. The functional modulation of the immune system by various methods, such as therapeutic, nutritional, and prophylactic approaches, continues to be an important focus of attention. However, the influence of these mechanisms on AP has not yet been fully understood. The main circadian clock controls most of the metabolic and pathophysiological processes in the human body. The brain and muscle Arnt-like protein-1 (Bmal1), one of the circadian clock genes, regulates the cellular events of the immune system in oral tissues. Additionally, melatonin controls the expression of the Bmal1 clock gene by activating the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signalling pathway. Therefore, this hypothetical study set out to assess whether the melatonin hormone might significantly reduce the severity of AP by creating differences in the cellular responses of the immune system through the Bmal1 clock gene. In light of this brief review, it is determined that both the Bmal1 clock gene and melatonin should be considered in the treatment process and prognosis of AP.

Identification of TIMELESS and RORA as key clock molecules of non-small cell lung cancer and the comprehensive analysis

BackgroundThe incidence rate of non-small cell lung cancer (NSCLC) has been increasing worldwide, and the correlation of circadian rhythm disruption with a raised risk of cancer and worse prognosis has been shown by accumulating evidences recently. On the other hand, drug resistance and the impact of tumor heterogeneity have been inevitable in NSCLC therapy. These both lead to an urgent need to identify more useful prognostic and predictive markers for NSCLC diagnosis and treatment, especially on the aspect of circadian clock genes.MethodsThe expression of the main clock genes in cancer was probed with TIMER and Oncomine databases. The prognostic value of key clock genes was probed systematically with the Kaplan–Meier estimate and Cox regression on samples from TCGA database. RT-qPCR was performed on patient tissue samples to further validate the results from databases. The functional enrichment analysis was performed using the “ClusterProfiler” R package, and the correlation of key clock genes with tumor mutation burden, immune checkpoint, and immune infiltration levels were also assessed using multiple algorithms including TIDE, TIMER2.0, and XCELL.ResultsTIMELESS was significantly upregulated in lung tissue of clinical lung cancer patients as well as TCGA and Oncomine databases, while RORA was downregulated. Multivariate Cox regression analysis indicated that TIMELESS (P = 0.004, HR = 1.21 [1.06, 1.38]) and RORA (P = 0.047, HR = 0.868 [0.755, 0.998]) has a significant correlation with overall survival in NSCLC. Genes related to TIMELESS were enriched in the cell cycle and immune system, and the function of RORA was mainly focused on oncogenic signaling pathways or glycosylation and protein activation. Also, TIMELESS was positively correlated with tumor mutation burden while RORA was negatively correlated with it. TIMELESS and RORA were also significantly correlated with immune checkpoint and immune infiltration levels in NSCLC. Additionally, TIMELESS showed a significant positive relationship with lipid metabolism.ConclusionsTIMELESS and RORA were identified as key clock genes in NSCLC, and were independent prognostic factors for overall survival in NSCLC. The function of them were assessed in many aspects, indicating the strong potential of the two genes to serve as biomarkers for NSCLC progression and prognosis.

A 2.44μs row conversion time 12-bit high-speed differential single-slope ADC with TDC applied to CMOS image sensor

To improve the quantization speed of single-slope (SS) analog-to-digital converter (ADC), a cross-coupling input technique is proposed, which can automatically select the direction of input coupling according to the signal polarity. The proposed SS ADC is implemented and simulated through 110 nm process. The main clock frequency is 125 MHz. The simulation results show that the row conversion time of SS ADC is 2.44 μs, the resolution is 500 ps, and the power consumption is 129–198 μW. It is proved that these techniques can greatly improve the speed of quantization while ensuring power consumption and accuracy.