cGMP-Phosphodiesterase Inhibition Enhances Photic Responses and Synchronization of the Biological Circadian Clock in Rodents

PubMed Central

Plano, Santiago A.; Agostino, Patricia V.; de la Iglesia, Horacio O.; Golombek, Diego A.

2012-01-01

The master circadian clock in mammals is located in the hypothalamic suprachiasmatic nuclei (SCN) and is synchronized by several environmental stimuli, mainly the light-dark (LD) cycle. Light pulses in the late subjective night induce phase advances in locomotor circadian rhythms and the expression of clock genes (such as Per1-2). The mechanism responsible for light-induced phase advances involves the activation of guanylyl cyclase (GC), cGMP and its related protein kinase (PKG). Pharmacological manipulation of cGMP by phosphodiesterase (PDE) inhibition (e.g., sildenafil) increases low-intensity light-induced circadian responses, which could reflect the ability of the cGMP-dependent pathway to directly affect the photic sensitivity of the master circadian clock within the SCN. Indeed, sildenafil is also able to increase the phase-shifting effect of saturating (1200 lux) light pulses leading to phase advances of about 9 hours, as well as in C57 a mouse strain that shows reduced phase advances. In addition, sildenafil was effective in both male and female hamsters, as well as after oral administration. Other PDE inhibitors (such as vardenafil and tadalafil) also increased light-induced phase advances of locomotor activity rhythms and accelerated reentrainment after a phase advance in the LD cycle. Pharmacological inhibition of the main downstream target of cGMP, PKG, blocked light-induced expression of Per1. Our results indicate that the cGMP-dependent pathway can directly modulate the light-induced expression of clock-genes within the SCN and the magnitude of light-induced phase advances of overt rhythms, and provide promising tools to design treatments for human circadian disruptions. PMID:22590651

Common View Time Transfer Using Worldwide GPS and DMA Monitor Stations

NASA Technical Reports Server (NTRS)

Reid, Wilson G.; McCaskill, Thomas B.; Oaks, Orville J.; Buisson, James A.; Warren, Hugh E.

1996-01-01

Analysis of the on-orbit Navstar clocks and the Global Positioning System (GPS) monitor station reference clocks is performed by the Naval Research Laboratory using both broadcast and postprocessed precise ephemerides. The precise ephemerides are produced by the Defense Mapping Agency (DMA) for each of the GPS space vehicles from pseudo-range measurements collected at five GPS and at five DMA monitor stations spaced around the world. Recently, DMA established an additional site co-located with the US Naval Observatory precise time site. The time reference for the new DMA site is the DoD Master Clock. Now, for the first time, it is possible to transfer time every 15 minutes via common view from the DoD Master Clock to the 11 GPS and DMA monitor stations. The estimated precision of a single common-view time transfer measurement taken over a 15-minute interval was between 1.4 and 2.7 nanoseconds. Using the measurements from all Navstar space vehicles in common view during the 15-minute interval, typically 3-7 space vehicles, improved the estimate of the precision to between 0.65 and 1.13 nanoseconds. The mean phase error obtained from closure of the time transfer around the world using the 11 monitor stations and the 25 space vehicle clocks over a period of 4 months had a magnitude of 31 picoseconds. Analysis of the low noise time transfer from the DoD Master Clock to each of the monitor stations yields not only the bias in the time of the reference clock, but also focuses attention on structure in the behaviour of the reference clock not previously seen. Furthermore, the time transfer provides a a uniformly sampled database of 15-minute measurements that make possible, for the first time, the direct and exhaustive computation of the frequency stability of the monitor station reference clocks. To lend perspective to the analysis, a summary is given of the discontinuities in phase and frequency that occurred in the reference clock at the Master Control Station during the period covered by the analysis.

Time Analyzer for Time Synchronization and Monitor of the Deep Space Network

NASA Technical Reports Server (NTRS)

Cole, Steven; Gonzalez, Jorge, Jr.; Calhoun, Malcolm; Tjoelker, Robert

2003-01-01

A software package has been developed to measure, monitor, and archive the performance of timing signals distributed in the NASA Deep Space Network. Timing signals are generated from a central master clock and distributed to over 100 users at distances up to 30 kilometers. The time offset due to internal distribution delays and time jitter with respect to the central master clock are critical for successful spacecraft navigation, radio science, and very long baseline interferometry (VLBI) applications. The instrument controller and operator interface software is written in LabView and runs on the Linux operating system. The software controls a commercial multiplexer to switch 120 separate timing signals to measure offset and jitter with a time-interval counter referenced to the master clock. The offset of each channel is displayed in histogram form, and "out of specification" alarms are sent to a central complex monitor and control system. At any time, the measurement cycle of 120 signals can be interrupted for diagnostic tests on an individual channel. The instrument also routinely monitors and archives the long-term stability of all frequency standards or any other 1-pps source compared against the master clock. All data is stored and made available for

Glial Cells in the Genesis and Regulation of Circadian Rhythms

PubMed Central

Chi-Castañeda, Donají; Ortega, Arturo

2018-01-01

Circadian rhythms are biological oscillations with a period of ~24 h. These rhythms are orchestrated by a circadian timekeeper in the suprachiasmatic nucleus of the hypothalamus, the circadian “master clock,” which exactly adjusts clock outputs to solar time via photic synchronization. At the molecular level, circadian rhythms are generated by the interaction of positive and negative feedback loops of transcriptional and translational processes of the so-called “clock genes.” A large number of clock genes encode numerous proteins that regulate their own transcription and that of other genes, collectively known as “clock-controlled genes.” In addition to the sleep/wake cycle, many cellular processes are regulated by circadian rhythms, including synaptic plasticity in which an exquisite interplay between neurons and glial cells takes place. In particular, there is compelling evidence suggesting that glial cells participate in and regulate synaptic plasticity in a circadian fashion, possibly representing the missing cellular and physiological link between circadian rhythms with learning and cognition processes. Here we review recent studies in support of this hypothesis, focusing on the interplay between glial cells, synaptic plasticity, and circadian rhythmogenesis. PMID:29483880

Molecular approaches towards the isolation of sleep-related genes.

PubMed

Schibler, U; Tafti, M

1999-06-01

Behavioural genetics is one of the most enticing fields in modern biology. Owing to straightforward and semiautomated techniques that can be used to measure locomotor activity, circadian rhythmicity is perhaps the best studied behaviour in animals. Thus, during the past decade, five essential circadian clock genes have been isolated in Drosophila, and homologous counterparts for all of these genes have also been found in mammals. As the sleep-wake cycle is under the control of the circadian clock, these circadian master genes are expected to influence sleeping behaviour. However, different vigilance states are regulated by additional mechanisms that also have a genetic basis. In this article we discuss molecular approaches that may prove useful in the search for sleep-related genes.

A Screening of UNF Targets Identifies Rnb, a Novel Regulator of Drosophila Circadian Rhythms.

PubMed

Kozlov, Anatoly; Jaumouillé, Edouard; Machado Almeida, Pedro; Koch, Rafael; Rodriguez, Joseph; Abruzzi, Katharine C; Nagoshi, Emi

2017-07-12

Behavioral circadian rhythms are controlled by multioscillator networks comprising functionally different subgroups of clock neurons. Studies have demonstrated that molecular clocks in the fruit fly Drosophila melanogaster are regulated differently in clock neuron subclasses to support their specific functions (Lee et al., 2016; Top et al., 2016). The nuclear receptor unfulfilled ( unf ) represents a regulatory node that provides the small ventral lateral neurons (s-LNvs) unique characteristics as the master pacemaker (Beuchle et al., 2012). We previously showed that UNF interacts with the s-LNv molecular clocks by regulating transcription of the core clock gene period ( per ) (Jaumouillé et al., 2015). To gain more insight into the mechanisms by which UNF contributes to the functioning of the circadian master pacemaker, we identified UNF target genes using chromatin immunoprecipitation. Our data demonstrate that a previously uncharacterized gene CG7837 , which we termed R and B ( Rnb ), acts downstream of UNF to regulate the function of the s-LNvs as the master circadian pacemaker. Mutations and LNv-targeted adult-restricted knockdown of Rnb impair locomotor rhythms. RNB localizes to the nucleus, and its loss-of-function blunts the molecular rhythms and output rhythms of the s-LNvs, particularly the circadian rhythms in PDF accumulation and axonal arbor remodeling. These results establish a second pathway by which UNF interacts with the molecular clocks in the s-LNvs and highlight the mechanistic differences in the molecular clockwork within the pacemaker circuit. SIGNIFICANCE STATEMENT Circadian behavior is generated by a pacemaker circuit comprising diverse classes of pacemaker neurons, each of which contains a molecular clock. In addition to the anatomical and functional diversity, recent studies have shown the mechanistic differences in the molecular clockwork among the pacemaker neurons in Drosophila Here, we identified the molecular characteristics distinguishing the s-LNvs, the master pacemaker of the locomotor rhythms, from other clock neuron subtypes. We demonstrated that a newly identified gene Rnb is an s-LNv-specific regulator of the molecular clock and essential for the generation of circadian locomotor behavior. Our results provide additional evidence to the emerging view that the differential regulation of the molecular clocks underlies the functional differences among the pacemaker neuron subgroups. Copyright © 2017 the authors 0270-6474/17/376673-13$15.00/0.

Regulation of circadian blood pressure: from mice to astronauts.

PubMed

Agarwal, Rajiv

2010-01-01

Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of blood pressure (BP) has been shown to be associated with greater target organ damage and with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP. The time-keeper in mammals resides centrally in the suprachiasmatic nucleus. Apart from this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice with the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon three major factors: physical activity, autonomic function, and sodium sensitivity. The integrated consideration of physical activity, autonomic function, and sodium sensitivity appears to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts.

Estimation of accuracy of time synchronization obtained by means of clock transportation

NASA Astrophysics Data System (ADS)

Zhang, Yuzhen; Ma, Dekang; Jin, Wenjing; Zhao, Gang; Huang, Peicheng

A portable clock experiment was carried out in October 1985 between Shanghai Observatory and Beijing Observatory using a small quartz clock made in Switzerland. The accuracy of time synchronization in 5 days is 70.18 microsec and the accuracy of determining the transmission time of short wave is satisfactory for reduction of the astronomical observations to the same master clock.

Segregation of Clock and Non-Clock Regulatory Functions of REV-ERB.

PubMed

Butler, Andrew A; Burris, Thomas P

2015-08-04

The molecular clock is a master controller of circadian cellular processes that affect growth, metabolic homeostasis, and behavior. A report in Science by Zhang et al. (2015) redefines our understanding of how Rev-erba acts as an internal feedback inhibitor that modulates activity of the core clock while simultaneously regulating tissue-specific metabolic processes. Copyright © 2015 Elsevier Inc. All rights reserved.

Navstar Global Positioning System (GPS) clock program: Present and future

NASA Technical Reports Server (NTRS)

Tennant, D. M.

1981-01-01

Global Positioning System (GPS) program status are discussed and plans for ensuring the long term continuation of the program are presented. Performance of GPS clocks is presented in terms of on orbit data as portrayed by GPS master control station kalman filter processing. The GPS Clock reliability program is reviewed in depth and future plans fo the overall clock program are published.

AN/TAC-1 demultiplexer circuit card assembly

NASA Astrophysics Data System (ADS)

Krueger, Paul J.

1989-01-01

This report describes the design, operation, and testing of the AN/TAC-1 demultiplexer subassembly. It demultiplexes the 6144 kb/s digital data stream received over fiber optic cable or tropo satellite support radio, and converts it into 2 digital groups and 16 digital channels. Timing recovery is accomplished by generating a 18432 kHz master clock synchronized to the incoming data. This master clock is divided modulo two to generate the proper group and loop timing.

A synchronous serial bus for multidimensional array acoustic logging tool

NASA Astrophysics Data System (ADS)

Men, Baiyong; Ju, Xiaodong; Lu, Junqiang; Qiao, Wenxiao

2016-12-01

In high-temperature and spatial borehole applications, a distributed structure is employed in a multidimensional array acoustic logging tool (MDALT) based on a phased array technique for electronic systems. However, new challenges, such as synchronous multichannel data acquisition, multinode real-time control and bulk data transmission in a limited interval, have emerged. To address these challenges, we developed a synchronous serial bus (SSB) in this study. SSB works in a half-duplex mode via a master-slave architecture. It also consists of a single master, several slaves, a differential clock line and a differential data line. The clock line is simplex, whereas the data line is half-duplex and synchronous to the clock line. A reliable communication between the master and the slaves with real-time adjustment of synchronisation is achieved by rationally designing the frame format and protocol of communication and by introducing a scramble code and a Hamming error-correcting code. The control logic of the master and the slaves is realized in field programmable gate array (FPGA) or complex programmable logic device (CPLD). The clock speed of SSB is 10 MHz, the effective data rate of the bulk data transmission is over 99%, and the synchronous errors amongst the slaves are less than 10 ns. Room-temperature test, high-temperature test (175 °C) and field test demonstrate that the proposed SSB is qualified for MDALT.

Emerging links between the biological clock and the DNA damage response.

PubMed

Collis, Spencer J; Boulton, Simon J

2007-08-01

For life forms to survive, they must adapt to their environmental conditions. One such factor that impacts on both prokaryotic and eukaryotic organisms is the light-dark cycle, a consequence of planetary rotation in relation to our sun. In mammals, the daily light cycle has affected the regulation of many cellular processes such as sleep-wake and calorific intake activities, hormone secretion, blood pressure and immune system responses. Such rhythmic behaviour is the consequence of circadian rhythm/biological clock (BC) systems which are controlled in a light stimulus-dependent manner by a master clock called the suprachiasmatic nucleus (SCN) situated within the anterior hypothalamus. Peripheral clocks located in other organs such as the liver and kidneys relay signals from the SCN, which ultimately leads to tightly controlled expression of several protein families that in turn act on a broad range of cellular functions. Work in lower organisms has demonstrated a link between aging processes and BC factors, and studies in both animal models and clinical trials have postulated a role for certain BC-associated proteins in tumourigenesis and cancer progression. Recent exciting data reported within the last year or so have now established a molecular link between specific BC proteins and factors that control the mammalian cell cycle and DNA damage checkpoints. This mini review will focus on these discoveries and emphasise how such BC proteins may be involved, through their interplay with cell cycle/DNA damage response pathways, in the development of human disease such as cancer.

Manipulating the circadian and sleep cycles to protect against metabolic disease.

PubMed

Nohara, Kazunari; Yoo, Seung-Hee; Chen, Zheng Jake

2015-01-01

Modernization of human society parallels an epidemic of metabolic disorders including obesity. Apart from excess caloric intake, a 24/7 lifestyle poses another important challenge to our metabolic health. Recent research under both laboratory and epidemiological settings has indicated that abnormal temporal organization of sleep and wakeful activities including food intake is a significant risk factor for metabolic disease. The circadian clock system is our intrinsic biological timer that regulates internal rhythms such as the sleep/wake cycle and also responses to external stimuli including light and food. Initially thought to be mainly involved in the timing of sleep, the clock, and/or clock genes may also play a role in sleep architecture and homeostasis. Importantly, an extensive body of evidence has firmly established a master regulatory role of the clock in energy balance. Together, a close relationship between well-timed circadian/sleep cycles and metabolic health is emerging. Exploiting this functional connection, an important holistic strategy toward curbing the epidemic of metabolic disorders (e.g., obesity) involves corrective measures on the circadian clock and sleep. In addition to behavioral and environmental interventions including meal timing and light control, pharmacological agents targeting sleep and circadian clocks promise convenient and effective applications. Recent studies, for example, have reported small molecules targeting specific clock components and displaying robust beneficial effects on sleep and metabolism. Furthermore, a group of clock-amplitude-enhancing small molecules (CEMs) identified via high-throughput chemical screens are of particular interest for future in vivo studies of their metabolic and sleep efficacies. Elucidating the functional relationship between clock, sleep, and metabolism will also have far-reaching implications for various chronic human diseases and aging.

Web-Based Time Synchronization - Naval Oceanography Portal

Science.gov Websites

section Advanced Search... Sections Home Time Earth Orientation Astronomy Meteorology Oceanography Ice You are here: Home › USNO › Precise Time › Display Clocks USNO Logo USNO Navigation Master Clock GPS Display Clocks TWSTT Telephone Time NTP Info Web-Based Time Synchronization Web time displays from the

The Navstar GPS master control station's Kalman filter experience

NASA Technical Reports Server (NTRS)

Scardera, Michael P.

1990-01-01

The Navstar Global Positioning System (GPS) is a highly accurate space based navigation system providing all weather, 24 hour a day service to both military and civilian users. The system provides a Gaussian position solution with four satellites, each providing its ephemeris and clock offset with respect to GPS time. The GPS Master Clock Station (MCS) is charged with tracking each Navstar spacecraft and precisely defining the ephemeris and clock parameters for upload into the vehicle's navigation message. Briefly described here are the Navstar system and the Kalman filter estimation process used by MCS to determine, predict, and ensure quality control for each of the satellite's ephemeris and clock states. Routine performance is shown. Kalman filter reaction and response is discussed for anomalous clock behavior and trajectory perturbations. Particular attention is given to MCS efforts to improve orbital adjust modeling. The satellite out of service time due to orbital maneuvering has been reduced in the past year from four days to under twelve hours. The planning, reference trajectory model, and Kalman filter management improvements are explained.

Circadian rhythm and menopause.

PubMed

Pines, A

2016-12-01

Circadian rhythm is an internal biological clock which initiates and monitors various physiological processes with a fixed time-related schedule. The master circadian pacemaker is located in the suprachiasmatic nucleus in the hypothalamus. The circadian clock undergoes significant changes throughout the life span, at both the physiological and molecular levels. This cyclical physiological process, which is very complex and multifactorial, may be associated with metabolic alterations, atherosclerosis, impaired cognition, mood disturbances and even development of cancer. Sex differences do exist, and the well-known sleep disturbances associated with menopause are a good example. Circadian rhythm was detected in the daily pattern of hot flushes, with a peak in the afternoons. Endogenous secretion of melatonin decreases with aging across genders, and, among women, menopause is associated with a significant reduction of melatonin levels, affecting sleep. Although it might seem that hot flushes and melatonin secretion are likely related, there are not enough data to support such a hypothesis.

Differentially Timed Extracellular Signals Synchronize Pacemaker Neuron Clocks

PubMed Central

Collins, Ben; Kaplan, Harris S.; Cavey, Matthieu; Lelito, Katherine R.; Bahle, Andrew H.; Zhu, Zhonghua; Macara, Ann Marie; Roman, Gregg; Shafer, Orie T.; Blau, Justin

2014-01-01

Synchronized neuronal activity is vital for complex processes like behavior. Circadian pacemaker neurons offer an unusual opportunity to study synchrony as their molecular clocks oscillate in phase over an extended timeframe (24 h). To identify where, when, and how synchronizing signals are perceived, we first studied the minimal clock neural circuit in Drosophila larvae, manipulating either the four master pacemaker neurons (LNvs) or two dorsal clock neurons (DN1s). Unexpectedly, we found that the PDF Receptor (PdfR) is required in both LNvs and DN1s to maintain synchronized LNv clocks. We also found that glutamate is a second synchronizing signal that is released from DN1s and perceived in LNvs via the metabotropic glutamate receptor (mGluRA). Because simultaneously reducing Pdfr and mGluRA expression in LNvs severely dampened Timeless clock protein oscillations, we conclude that the master pacemaker LNvs require extracellular signals to function normally. These two synchronizing signals are released at opposite times of day and drive cAMP oscillations in LNvs. Finally we found that PdfR and mGluRA also help synchronize Timeless oscillations in adult s-LNvs. We propose that differentially timed signals that drive cAMP oscillations and synchronize pacemaker neurons in circadian neural circuits will be conserved across species. PMID:25268747

MYC/MIZ1-dependent gene repression inversely coordinates the circadian clock with cell cycle and proliferation.

PubMed

Shostak, Anton; Ruppert, Bianca; Ha, Nati; Bruns, Philipp; Toprak, Umut H; Eils, Roland; Schlesner, Matthias; Diernfellner, Axel; Brunner, Michael

2016-06-24

The circadian clock and the cell cycle are major cellular systems that organize global physiology in temporal fashion. It seems conceivable that the potentially conflicting programs are coordinated. We show here that overexpression of MYC in U2OS cells attenuates the clock and conversely promotes cell proliferation while downregulation of MYC strengthens the clock and reduces proliferation. Inhibition of the circadian clock is crucially dependent on the formation of repressive complexes of MYC with MIZ1 and subsequent downregulation of the core clock genes BMAL1 (ARNTL), CLOCK and NPAS2. We show furthermore that BMAL1 expression levels correlate inversely with MYC levels in 102 human lymphomas. Our data suggest that MYC acts as a master coordinator that inversely modulates the impact of cell cycle and circadian clock on gene expression.

Clock and trigger distribution for CBM-TOF quality evaluation of RPC super module detector assemblies

NASA Astrophysics Data System (ADS)

Li, C.; Huang, X.; Cao, P.; Wang, J.; An, Q.

2018-03-01

RPC Super module (SM) detector assemblies are used for charged hadron identification in the Time-of-Flight (TOF) spectrometer at the Compressed Baryonic Matter (CBM) experiment. Each SM contains several multi-gap Resistive Plate Chambers (MRPCs) and provides up to 320 electronic channels in total for high-precision time measurements. Time resolution of the Time-to-Digital Converter (TDC) is required to be better than 20 ps. During mass production, the quality of each SM needs to be evaluated. In order to meet the requirements, the system clock signal as well as the trigger signal should be distributed precisely and synchronously to all electronics modules within the evaluation readout system. In this paper, a hierarchical clock and trigger distribution method is proposed for the quality evaluation of CBM-TOF SM detectors. In a first stage, the master clock and trigger module (CTM) allocated in a 6U PXI chassis distributes the clock and trigger signals to the slave CTM in the same chassis. In a second stage, the slave CTM transmits the clock and trigger signals to the TDC readout module (TRM) through one optical link. In a third stage, the TRM distributes the clock and trigger signals synchronously to 10 individual TDC boards. Laboratory test results show that the clock jitter at the third stage is less than 4 ps (RMS) and the trigger transmission latency from the master CTM to the TDC is about 272 ns with 11 ps (RMS) jitter. The overall performance complies well with the required specifications.

A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability

PubMed Central

Flourakis, Matthieu; Kula-Eversole, Elzbieta; Hutchison, Alan L.; Han, Tae Hee; Aranda, Kimberly; Moose, Devon L.; White, Kevin P.; Dinner, Aaron R.; Lear, Bridget C.; Ren, Dejian; Diekman, Casey O.; Raman, Indira M.; Allada, Ravi

2015-01-01

Summary Circadian clocks regulate membrane excitability in master pacemaker neurons to control daily rhythms of sleep and wake. Here we find that two distinctly timed electrical drives collaborate to impose rhythmicity on Drosophila clock neurons. In the morning, a voltage-independent sodium conductance via the NA/NALCN ion channel depolarizes these neurons. This current is driven by the rhythmic expression of NCA localization factor-1, linking the molecular clock to ion channel function. In the evening, basal potassium currents peak to silence clock neurons. Remarkably, daily antiphase cycles of sodium and potassium currents also drive mouse clock neuron rhythms. Thus, we reveal an evolutionarily ancient strategy for the neural mechanisms that govern daily sleep and wake. PMID:26276633

Assessment of GPS carrier-phase stability for time-transfer applications.

PubMed

Larson, K M; Levine, J; Nelson, L M; Parker, T E

2000-01-01

We have conducted global positioning system (GPS) carrier-phase time-transfer experiments between the master clock (MC) at the U.S. Naval Observatory (USNO) in Washington, DC and the alternate master clock (AMC) at Schriever Air Force Base near Colorado Springs, Colorado. These clocks are also monitored on an hourly basis with two-way satellite time-transfer (TWSTT) measurements. We compared the performance of the GPS carrier phase and TWSTT systems over a 236-d period. Because of power problems and data outages during the carrier-phase experiment, the longest continuous time span is 96 d. The data from this period show agreement with TWSTT within +/-1 ns, apart from an overall constant time offset (caused by unknown delays in the GPS hardware at both ends). For averaging times of a day, the carrier-phase and TWSTT systems have a frequency uncertainty of 2.5 and 5.5 parts in 10(15), respectively.

A synchronization technique for the on-board master clock of a regenerative TDMA satellite communications system

NASA Astrophysics Data System (ADS)

Pattini, F.; Porzio Giusto, P.

The design criteria and performance of the master clock (MCK) generator and the unique word (UW) detector are examined. A narrow band phase lock loop is used for the onboard MCK generator and it is implemented with an all-digital scheme that employs a D-type flip flop as the phase detector. The performance of the MCK generator is analyzed with a computer program which considers phase offset of the digital phase comparator. The characteristics and capabilities of the UW detector which provides strobe signals for the MCK generator and synchronization signals for the onboard switching matrix are described.

Scalable Multiprocessor for High-Speed Computing in Space

NASA Technical Reports Server (NTRS)

Lux, James; Lang, Minh; Nishimoto, Kouji; Clark, Douglas; Stosic, Dorothy; Bachmann, Alex; Wilkinson, William; Steffke, Richard

2004-01-01

A report discusses the continuing development of a scalable multiprocessor computing system for hard real-time applications aboard a spacecraft. "Hard realtime applications" signifies applications, like real-time radar signal processing, in which the data to be processed are generated at "hundreds" of pulses per second, each pulse "requiring" millions of arithmetic operations. In these applications, the digital processors must be tightly integrated with analog instrumentation (e.g., radar equipment), and data input/output must be synchronized with analog instrumentation, controlled to within fractions of a microsecond. The scalable multiprocessor is a cluster of identical commercial-off-the-shelf generic DSP (digital-signal-processing) computers plus generic interface circuits, including analog-to-digital converters, all controlled by software. The processors are computers interconnected by high-speed serial links. Performance can be increased by adding hardware modules and correspondingly modifying the software. Work is distributed among the processors in a parallel or pipeline fashion by means of a flexible master/slave control and timing scheme. Each processor operates under its own local clock; synchronization is achieved by broadcasting master time signals to all the processors, which compute offsets between the master clock and their local clocks.

Role of Chronobiology as a Transdisciplinary Field of Research: Its Applications in Treating Mood Disorders.

PubMed

Çalıyurt, Okan

2017-12-01

Chronobiology is a field that studies the effects of time on biological systems. Periodicity is of particular interest. The master biological clock in the suprachiasmatic nucleus controls daily rhythms of core body temperature, rest-activity cycle, physiological and behavioral functions, psychomotor functions and mood in humans. The clock genes are involved in the generation of the circadian rhythms and the biological clock is synchronized to solar day by direct photic inputs. Various circadian rhythm abnormalities have been demonstrated in mood disorders such as unipolar depression, bipolar depression and seasonal affective disorder. Hypotheses involving circadian rhythm abnormalities related to the etiology of mood disorders have been raised. The resulting circadian rhythm changes can be measured and evaluated that these techniques can be used to identify subtypes of mood disorders associated with circadian rhythm changes. The data obtained from chronobiological studies reveal methods that manipulate circadian rhythms. The effects of light and melatonin on circadian rhythms are determined by these studies. Chronobiological research has been applied to the psychiatric clinic and light therapy has been used as a chronotherapeutic in the treatment of mood disorders. On the other hand, chronotherapeutic approaches with effects on circadian rhythms such as sleep deprivation therapy have been used in the treatment of mood disorders too. As a good example of translational psychiatry, chronobiological studies have been projected in the psychiatry clinic. It may be possible, the data obtained from the basic sciences are used in the diagnosis of mood disorders and in the treatment of psychiatric disorders as chronotherapeutic techniques. Developments in the field of chronobiology and data obtained from chronotherapeutics may enable the development of evidence-based diagnosis and treatment in psychiatry.

Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice.

PubMed

Landgraf, Dominic; Long, Jaimie E; Proulx, Christophe D; Barandas, Rita; Malinow, Roberto; Welsh, David K

2016-12-01

Major depressive disorder is associated with disturbed circadian rhythms. To investigate the causal relationship between mood disorders and circadian clock disruption, previous studies in animal models have employed light/dark manipulations, global mutations of clock genes, or brain area lesions. However, light can impact mood by noncircadian mechanisms; clock genes have pleiotropic, clock-independent functions; and brain lesions not only disrupt cellular circadian rhythms but also destroy cells and eliminate important neuronal connections, including light reception pathways. Thus, a definitive causal role for functioning circadian clocks in mood regulation has not been established. We stereotactically injected viral vectors encoding short hairpin RNA to knock down expression of the essential clock gene Bmal1 into the brain's master circadian pacemaker, the suprachiasmatic nucleus (SCN). In these SCN-specific Bmal1-knockdown (SCN-Bmal1-KD) mice, circadian rhythms were greatly attenuated in the SCN, while the mice were maintained in a standard light/dark cycle, SCN neurons remained intact, and neuronal connections were undisturbed, including photic inputs. In the learned helplessness paradigm, the SCN-Bmal1-KD mice were slower to escape, even before exposure to inescapable stress. They also spent more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. The SCN-Bmal1-KD mice also showed greater weight gain, an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress. Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioral despair, and anxiety-like behavior in mice, establishing SCN-Bmal1-KD mice as a new animal model of depression. Copyright © 2016 Society of Biological Psychiatry. All rights reserved.

Reference clock parameters for digital communications systems applications

NASA Technical Reports Server (NTRS)

Kartaschoff, P.

1981-01-01

The basic parameters relevant to the design of network timing systems describe the random and systematic time departures of the system elements, i.e., master (or reference) clocks, transmission links, and other clocks controlled over the links. The quantitative relations between these parameters were established and illustrated by means of numerical examples based on available measured data. The examples were limited to a simple PLL control system but the analysis can eventually be applied to more sophisticated systems at the cost of increased computational effort.

GPS timing products - Naval Oceanography Portal

Science.gov Websites

section Advanced Search... Sections Home Time Earth Orientation Astronomy Meteorology Oceanography Ice You are here: Home › USNO › Precise Time › GPS USNO Logo USNO Navigation Master Clock GPS Display Clocks TWSTT Telephone Time NTP Info GPS timing products USNO monitors the GPS constellation and provides

Precise Time - Naval Oceanography Portal

Science.gov Websites

section Advanced Search... Sections Home Time Earth Orientation Astronomy Meteorology Oceanography Ice You are here: Home › USNO › Precise Time USNO Logo USNO Navigation Master Clock GPS Display Clocks TWSTT Telephone Time NTP Info Precise Time The U. S. Naval Observatory is charged with maintaining the

Two-way Satellite Time Transfer - Naval Oceanography Portal

Science.gov Websites

section Advanced Search... Sections Home Time Earth Orientation Astronomy Meteorology Oceanography Ice You are here: Home › USNO › Precise Time › TWSTT USNO Logo USNO Navigation Master Clock GPS Display Clocks TWSTT What is TWSTT? Operational Services Calibration Services Precision Telephone Time NTP Info

Oxyntomodulin regulates resetting of the liver circadian clock by food

PubMed Central

Landgraf, Dominic; Tsang, Anthony H; Leliavski, Alexei; Koch, Christiane E; Barclay, Johanna L; Drucker, Daniel J; Oster, Henrik

2015-01-01

Circadian clocks coordinate 24-hr rhythms of behavior and physiology. In mammals, a master clock residing in the suprachiasmatic nucleus (SCN) is reset by the light–dark cycle, while timed food intake is a potent synchronizer of peripheral clocks such as the liver. Alterations in food intake rhythms can uncouple peripheral clocks from the SCN, resulting in internal desynchrony, which promotes obesity and metabolic disorders. Pancreas-derived hormones such as insulin and glucagon have been implicated in signaling mealtime to peripheral clocks. In this study, we identify a novel, more direct pathway of food-driven liver clock resetting involving oxyntomodulin (OXM). In mice, food intake stimulates OXM secretion from the gut, which resets liver transcription rhythms via induction of the core clock genes Per1 and 2. Inhibition of OXM signaling blocks food-mediated resetting of hepatocyte clocks. These data reveal a direct link between gastric filling with food and circadian rhythm phasing in metabolic tissues. DOI: http://dx.doi.org/10.7554/eLife.06253.001 PMID:25821984

Digital-data receiver synchronization

DOEpatents

Smith, Stephen F.; Turner, Gary W.

2005-08-02

Digital-data receiver synchronization is provided with composite phase-frequency detectors, mutually cross-connected comparison feedback or both to provide robust reception of digital data signals. A single master clock can be used to provide frequency signals. Advantages can include fast lock-up time in moderately to severely noisy conditions, greater tolerance to noise and jitter when locked, and improved tolerance to clock asymmetries.

Digital-data receiver synchronization method and apparatus

DOEpatents

Smith, Stephen F.; Turner, Gary W.

2005-12-06

Digital-data receiver synchronization is provided with composite phase-frequency detectors, mutually cross-connected comparison feedback or both to provide robust reception of digital data signals. A single master clock may be used to provide frequency signals. Advantages can include fast lock-up time in moderately to severely noisy conditions, greater tolerance to noise and jitter when locked, and improved tolerance to clock asymmetries.

Digital-data receiver synchronization method and apparatus

DOEpatents

Smith, Stephen F [Loudon, TN; Turner, Gary W [Clinton, TN

2009-09-08

Digital data receiver synchronization is provided with composite phase-frequency detectors, mutually cross-connected comparison feedback or both to provide robust reception of digital data signals. A single master clock can be used to provide frequency signals. Advantages can include fast lock-up time in moderately to severely noisy conditions, greater tolerance to noise and jitter when locked, and improved tolerance to clock asymmetries.

Telephone Time - Naval Oceanography Portal

Science.gov Websites

section Advanced Search... Sections Home Time Earth Orientation Astronomy Meteorology Oceanography Ice You are here: Home › USNO › Precise Time › Telephone Time USNO Logo USNO Navigation Master Clock GPS Display Clocks TWSTT Telephone Time NTP Info Telephone Time USNO provides both voice announcements of the

Network Time Protocol - Naval Oceanography Portal

Science.gov Websites

section Advanced Search... Sections Home Time Earth Orientation Astronomy Meteorology Oceanography Ice You are here: Home › USNO › Precise Time › NTP USNO Logo USNO Navigation Master Clock GPS Display Clocks TWSTT Telephone Time NTP Eastern TZ Mountain TZ DoD Customers Info Network Time Protocol Network

Neuronal oscillations on an ultra-slow timescale: daily rhythms in electrical activity and gene expression in the mammalian master circadian clockwork.

PubMed

Belle, Mino D C; Diekman, Casey O

2018-02-03

Neuronal oscillations of the brain, such as those observed in the cortices and hippocampi of behaving animals and humans, span across wide frequency bands, from slow delta waves (0.1 Hz) to ultra-fast ripples (600 Hz). Here, we focus on ultra-slow neuronal oscillators in the hypothalamic suprachiasmatic nuclei (SCN), the master daily clock that operates on interlocking transcription-translation feedback loops to produce circadian rhythms in clock gene expression with a period of near 24 h (< 0.001 Hz). This intracellular molecular clock interacts with the cell's membrane through poorly understood mechanisms to drive the daily pattern in the electrical excitability of SCN neurons, exhibiting an up-state during the day and a down-state at night. In turn, the membrane activity feeds back to regulate the oscillatory activity of clock gene programs. In this review, we emphasise the circadian processes that drive daily electrical oscillations in SCN neurons, and highlight how mathematical modelling contributes to our increasing understanding of circadian rhythm generation, synchronisation and communication within this hypothalamic region and across other brain circuits. © 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

On time scales and time synchronization using LORAN-C as a time reference signal

NASA Technical Reports Server (NTRS)

Chi, A. R.

1974-01-01

The long term performance of the eight LORAN-C chains is presented in terms of the Coordinated Universal Time (UTC) of the U.S. Naval Observatory (USNO); and the use of the LORAN-C navigation system for maintaining the user's clock to a UTC scale is described. The atomic time scale and the UTC of several national laboratories and observatories relative to the international atomic time are reported. Typical performance of several NASA tracking station clocks, relative to the USNO master clock, is also presented.

A versatile small form factor twisted-pair TFC FMC for MTCA AMCs

NASA Astrophysics Data System (ADS)

Meder, L.; Lebedev, J.; Becker, J.

2017-03-01

In continuous readout systems of particle physics experiments, the provision of a common clock and time reference and the distribution of critical low latency messages to the processing and fronted layers of the readout are crucial tasks. In the context of the Compressed Baryonic Matter (CBM) experiment, a versatile small form factor Timing and Fast-Control (TFC) interfacing FPGA Mezzanine Card (FMC) was developed, offering bidirectional twisted-pair (TP) links for the communication between TFC nodes. Also a versatile clocking including voltage controlled oscillators and a connection to the telecommunication clock lines of mTCA crates are available. Being designed for both TFC Master and Slaves, the card allows rapid system developments without additional Slave hardware circuits. Measurements show that it is possible to transmit over cable lengths of 25 m at a rate of 240 Mbit/s for all data channels simultaneously. A TFC Master-Slave system using two of these cards can be synchronized with a precision of ±10 ps to an user-defined phase setpoint.

Network news: prime time for systems biology of the plant circadian clock.

PubMed

McClung, C Robertson; Gutiérrez, Rodrigo A

2010-12-01

Whole-transcriptome analyses have established that the plant circadian clock regulates virtually every plant biological process and most prominently hormonal and stress response pathways. Systems biology efforts have successfully modeled the plant central clock machinery and an iterative process of model refinement and experimental validation has contributed significantly to the current view of the central clock machinery. The challenge now is to connect this central clock to the output pathways for understanding how the plant circadian clock contributes to plant growth and fitness in a changing environment. Undoubtedly, systems approaches will be needed to integrate and model the vastly increased volume of experimental data in order to extract meaningful biological information. Thus, we have entered an era of systems modeling, experimental testing, and refinement. This approach, coupled with advances from the genetic and biochemical analyses of clock function, is accelerating our progress towards a comprehensive understanding of the plant circadian clock network. Copyright © 2010 Elsevier Ltd. All rights reserved.

Common features in diverse insect clocks.

PubMed

Numata, Hideharu; Miyazaki, Yosuke; Ikeno, Tomoko

2015-01-01

This review describes common features among diverse biological clocks in insects, including circadian, circatidal, circalunar/circasemilunar, and circannual clocks. These clocks control various behaviors, physiological functions, and developmental events, enabling adaptation to periodic environmental changes. Circadian clocks also function in time-compensation for celestial navigation and in the measurement of day or night length for photoperiodism. Phase response curves for such clocks reported thus far exhibit close similarities; specifically, the circannual clock in Anthrenus verbasci shows striking similarity to circadian clocks in its phase response. It is suggested that diverse biological clocks share physiological properties in their phase responses irrespective of period length. Molecular and physiological mechanisms are best understood for the optic-lobe and mid-brain circadian clocks, although there is no direct evidence that these clocks are involved in rhythmic phenomena other than circadian rhythms in daily events. Circadian clocks have also been localized in peripheral tissues, and research on their role in various rhythmic phenomena has been started. Although clock genes have been identified as controllers of circadian rhythms in daily events, some of these genes have also been shown to be involved in photoperiodism and possibly in time-compensated celestial navigation. In contrast, there is no experimental evidence indicating that any known clock gene is involved in biological clocks other than circadian clocks.

Biological timing and the clock metaphor: oscillatory and hourglass mechanisms.

PubMed

Rensing, L; Meyer-Grahle, U; Ruoff, P

2001-05-01

Living organisms have developed a multitude of timing mechanisms--"biological clocks." Their mechanisms are based on either oscillations (oscillatory clocks) or unidirectional processes (hourglass clocks). Oscillatory clocks comprise circatidal, circalunidian, circadian, circalunar, and circannual oscillations--which keep time with environmental periodicities--as well as ultradian oscillations, ovarian cycles, and oscillations in development and in the brain, which keep time with biological timescales. These clocks mainly determine time points at specific phases of their oscillations. Hourglass clocks are predominantly found in development and aging and also in the brain. They determine time intervals (duration). More complex timing systems combine oscillatory and hourglass mechanisms, such as the case for cell cycle, sleep initiation, or brain clocks, whereas others combine external and internal periodicities (photoperiodism, seasonal reproduction). A definition of a biological clock may be derived from its control of functions external to its own processes and its use in determining temporal order (sequences of events) or durations. Biological and chemical oscillators are characterized by positive and negative feedback (or feedforward) mechanisms. During evolution, living organisms made use of the many existing oscillations for signal transmission, movement, and pump mechanisms, as well as for clocks. Some clocks, such as the circadian clock, that time with environmental periodicities are usually compensated (stabilized) against temperature, whereas other clocks, such as the cell cycle, that keep time with an organismic timescale are not compensated. This difference may be related to the predominance of negative feedback in the first class of clocks and a predominance of positive feedback (autocatalytic amplification) in the second class. The present knowledge of a compensated clock (the circadian oscillator) and an uncompensated clock (the cell cycle), as well as relevant models, are briefly re viewed. Hourglass clocks are based on linear or exponential unidirectional processes that trigger events mainly in the course of development and aging. An important hourglass mechanism within the aging process is the limitation of cell division capacity by the length of telomeres. The mechanism of this clock is briefly reviewed. In all clock mechanisms, thresholds at which "dependent variables" are triggered play an important role.

Vasculature on the clock: Circadian rhythm and vascular dysfunction.

PubMed

Crnko, Sandra; Cour, Martin; Van Laake, Linda W; Lecour, Sandrine

2018-05-17

The master mammalian circadian clock (i.e. central clock), located in the suprachiasmatic nucleus of the hypothalamus, orchestrates the synchronization of the daily behavioural and physiological rhythms to better adapt the organism to the external environment in an anticipatory manner. This central clock is entrained by a variety of signals, the best established being light and food. However, circadian cycles are not simply the consequences of these two cues but are generated by endogenous circadian clocks. Indeed, clock machinery is found in mainly all tissues and cell types, including cells of the vascular system such as endothelial cells, fibroblasts, smooth muscle cells and stem cells. This machinery physiologically contributes to modulate the daily vascular function, and its disturbance therefore plays a major role in the pathophysiology of vascular dysfunction. Therapies targeting the circadian rhythm may therefore be of benefit against vascular disease. Copyright © 2018 Elsevier Inc. All rights reserved.

Biological Clocks & Circadian Rhythms

ERIC Educational Resources Information Center

Robertson, Laura; Jones, M. Gail

2009-01-01

The study of biological clocks and circadian rhythms is an excellent way to address the inquiry strand in the National Science Education Standards (NSES) (NRC 1996). Students can study these everyday phenomena by designing experiments, gathering and analyzing data, and generating new experiments. As students explore biological clocks and circadian…

Sensor web

NASA Technical Reports Server (NTRS)

Delin, Kevin A. (Inventor); Jackson, Shannon P. (Inventor)

2011-01-01

A Sensor Web formed of a number of different sensor pods. Each of the sensor pods include a clock which is synchronized with a master clock so that all of the sensor pods in the Web have a synchronized clock. The synchronization is carried out by first using a coarse synchronization which takes less power, and subsequently carrying out a fine synchronization to make a fine sync of all the pods on the Web. After the synchronization, the pods ping their neighbors to determine which pods are listening and responded, and then only listen during time slots corresponding to those pods which respond.

Circadian aspects of adipokine regulation in rodents.

PubMed

Challet, Etienne

2017-12-01

Most hormones display daily fluctuations of secretion during the 24-h cycle. This is also the case for adipokines, in particular the anorexigenic hormone, leptin. The temporal organization of the endocrine system is principally controlled by a network of circadian clocks. The circadian network comprises a master circadian clock, located in the suprachiasmatic nucleus of the hypothalamus, synchronized to the ambient light, and secondary circadian clocks found in various peripheral organs, such as the adipose tissues. Besides circadian clocks, other factors such as meals and metabolic status impact daily profiles of hormonal levels. In turn, the precise daily pattern of hormonal release provides temporal signaling information. This review will describe the reciprocal links between the circadian clocks and rhythmic secretion of leptin, and discuss the metabolic impact of circadian desynchronization and altered rhythmic leptin. Copyright © 2017 Elsevier Ltd. All rights reserved.

Tick Tock: Your Body Clocks: Understanding Your Daily Rhythms

MedlinePlus

... has its own internal network of clocks? These biological clocks help you feel alert during the day, ... NIH’s Dr. Michael Sesma, an expert in circadian biology. “They affect almost every part of your physiology ...

Spectroscopy of 171Yb in an optical lattice based on laser linewidth transfer using a narrow linewidth frequency comb.

PubMed

Inaba, Hajime; Hosaka, Kazumoto; Yasuda, Masami; Nakajima, Yoshiaki; Iwakuni, Kana; Akamatsu, Daisuke; Okubo, Sho; Kohno, Takuya; Onae, Atsushi; Hong, Feng-Lei

2013-04-08

We propose a novel, high-performance, and practical laser source system for optical clocks. The laser linewidth of a fiber-based frequency comb is reduced by phase locking a comb mode to an ultrastable master laser at 1064 nm with a broad servo bandwidth. A slave laser at 578 nm is successively phase locked to a comb mode at 578 nm with a broad servo bandwidth without any pre-stabilization. Laser frequency characteristics such as spectral linewidth and frequency stability are transferred to the 578-nm slave laser from the 1064-nm master laser. Using the slave laser, we have succeeded in observing the clock transition of (171)Yb atoms confined in an optical lattice with a 20-Hz spectral linewidth.

Synchronization sampling method based on delta-sigma analog-digital converter for underwater towed array system.

PubMed

Jiang, Jia-Jia; Duan, Fa-Jie; Li, Yan-Chao; Hua, Xiang-Ning

2014-03-01

Synchronization sampling is very important in underwater towed array system where every acquisition node (AN) samples analog signals by its own analog-digital converter (ADC). In this paper, a simple and effective synchronization sampling method is proposed to ensure synchronized operation among different ANs of the underwater towed array system. We first present a master-slave synchronization sampling model, and then design a high accuracy phase-locked loop to synchronize all delta-sigma ADCs to a reference clock. However, when the master-slave synchronization sampling model is used, both the time-delay (TD) of messages traveling along the wired transmission medium and the jitter of the clocks will bring out synchronization sampling error (SSE). Therefore, a simple method is proposed to estimate and compensate the TD of the messages transmission, and then another effective method is presented to overcome the SSE caused by the jitter of the clocks. An experimental system with three ANs is set up, and the related experimental results verify the validity of the synchronization sampling method proposed in this paper.

Synchronization sampling method based on delta-sigma analog-digital converter for underwater towed array system

NASA Astrophysics Data System (ADS)

Jiang, Jia-Jia; Duan, Fa-Jie; Li, Yan-Chao; Hua, Xiang-Ning

2014-03-01

Synchronization sampling is very important in underwater towed array system where every acquisition node (AN) samples analog signals by its own analog-digital converter (ADC). In this paper, a simple and effective synchronization sampling method is proposed to ensure synchronized operation among different ANs of the underwater towed array system. We first present a master-slave synchronization sampling model, and then design a high accuracy phase-locked loop to synchronize all delta-sigma ADCs to a reference clock. However, when the master-slave synchronization sampling model is used, both the time-delay (TD) of messages traveling along the wired transmission medium and the jitter of the clocks will bring out synchronization sampling error (SSE). Therefore, a simple method is proposed to estimate and compensate the TD of the messages transmission, and then another effective method is presented to overcome the SSE caused by the jitter of the clocks. An experimental system with three ANs is set up, and the related experimental results verify the validity of the synchronization sampling method proposed in this paper.

Universal null DTE (data terminal equipment)

DOEpatents

George, M.; Pierson, L.G.; Wilkins, M.E.

1987-11-09

A communication device in the form of data terminal equipment permits two data communication equipments, each having its own master clock and operating at substantially the same nominal clock rate, to communicate with each other in a multi-segment circuit configuration of a general communication network even when phase or frequency errors exist between the two clocks. Data transmitted between communication equipments of two segments of the communication network is buffered. A variable buffer fill circuit is provided to fill the buffer to a selectable extent prior to initiation of data output clocking. Selection switches are provided to select the degree of buffer preload. A dynamic buffer fill circuit may be incorporated for automatically selecting the buffer fill level as a function of the difference in clock frequencies of the two equipments. Controllable alarm circuitry is provided for selectively generating an underflow or an overflow alarm to one or both of the communicating equipments. 5 figs.

Universal null DTE

DOEpatents

George, Michael; Pierson, Lyndon G.; Wilkins, Mark E.

1989-01-01

A communication device in the form of data terminal equipment permits two data communication equipments, each having its own master clock and operating at substantially the same nominal clock rate, to communicate with each other in a multi-segment circuit configuration of a general communication network even when phase or frequency errors exist between the two clocks. Data transmitted between communication equipments of two segments of the communication network is buffered. A variable buffer fill circuit is provided to fill the buffer to a selectable extent prior to initiation of data output clocking. Selection switches are provided to select the degree of buffer preload. A dynamic buffer fill circuit may be incorporated for automatically selecting the buffer fill level as a function of the difference in clock frequencies of the two equipments. Controllable alarm circuitry is provided for selectively generating an underflow or an overflow alarm to one or both of the communicating equipments.

The role of feeding rhythm, adrenal hormones and neuronal inputs in synchronizing daily clock gene rhythms in the liver.

PubMed

Su, Yan; Cailotto, Cathy; Foppen, Ewout; Jansen, Remi; Zhang, Zhi; Buijs, Ruud; Fliers, Eric; Kalsbeek, Andries

2016-02-15

The master clock in the hypothalamic suprachiasmatic nucleus (SCN) is assumed to distribute rhythmic information to the periphery via neural, humoral and/or behavioral connections. Until now, feeding, corticosterone and neural inputs are considered important signals for synchronizing daily rhythms in the liver. In this study, we investigated the necessity of neural inputs as well as of the feeding and adrenal hormone rhythms for maintaining daily hepatic clock gene rhythms. Clock genes kept their daily rhythm when only one of these three signals was disrupted, or when we disrupted hepatic neuronal inputs together with the adrenal hormone rhythm or with the daily feeding rhythm. However, all clock genes studied lost their daily expression rhythm after simultaneous disruption of the feeding and adrenal hormone rhythm. These data indicate that either a daily rhythm of feeding or adrenal hormones should be present to synchronize clock gene rhythms in the liver with the SCN. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Performance of Loran-C chains relative to UTC

NASA Technical Reports Server (NTRS)

Chi, A. R.

1974-01-01

The long term performance of the eight Loran-C chains in terms of the Coordinated Universal Time (UTC) of the U.S. Naval Observatory (USNO) and the use of the Loran-C navigation system to maintain the user's clock to a UTC scale, are examined. The atomic time (AT) scale and the UTC of several national laboratories and observatories relative to the international atomic time (TAI) are presented. In addition, typical performance of several NASA tracking station clocks, relative to the USNO master clock, is also presented. Recent revision of the Coordinated Universal Time (UTC) by the International Radio Consultative Committee (CCIR) is given in an appendix.

Non-Metastatic Cutaneous Melanoma Induces Chronodisruption in Central and Peripheral Circadian Clocks.

PubMed

de Assis, Leonardo Vinícius Monteiro; Moraes, Maria Nathália; Magalhães-Marques, Keila Karoline; Kinker, Gabriela Sarti; da Silveira Cruz-Machado, Sanseray; Castrucci, Ana Maria de Lauro

2018-04-03

The biological clock has received increasing interest due to its key role in regulating body homeostasis in a time-dependent manner. Cancer development and progression has been linked to a disrupted molecular clock; however, in melanoma, the role of the biological clock is largely unknown. We investigated the effects of the tumor on its micro- (TME) and macro-environments (TMaE) in a non-metastatic melanoma model. C57BL/6J mice were inoculated with murine B16-F10 melanoma cells and 2 weeks later the animals were euthanized every 6 h during 24 h. The presence of a localized tumor significantly impaired the biological clock of tumor-adjacent skin and affected the oscillatory expression of genes involved in light- and thermo-reception, proliferation, melanogenesis, and DNA repair. The expression of tumor molecular clock was significantly reduced compared to healthy skin but still displayed an oscillatory profile. We were able to cluster the affected genes using a human database and distinguish between primary melanoma and healthy skin. The molecular clocks of lungs and liver (common sites of metastasis), and the suprachiasmatic nucleus (SCN) were significantly affected by tumor presence, leading to chronodisruption in each organ. Taken altogether, the presence of non-metastatic melanoma significantly impairs the organism's biological clocks. We suggest that the clock alterations found in TME and TMaE could impact development, progression, and metastasis of melanoma; thus, making the molecular clock an interesting pharmacological target.

Fine tuning GPS clock estimation in the MCS

NASA Technical Reports Server (NTRS)

Hutsell, Steven T.

1995-01-01

With the completion of a 24 operational satellite constellation, GPS is fast approaching the critical milestone, Full Operational Capability (FOC). Although GPS is well capable of providing the timing accuracy and stability figures required by system specifications, the GPS community will continue to strive for further improvements in performance. The GPS Master Control Station (MCS) recently demonstrated that timing improvements are always composite Clock, and hence, Kalman Filter state estimation, providing a small improvement to user accuracy.

Resetting Biological Clocks

ERIC Educational Resources Information Center

Winfree, Arthur T.

1975-01-01

Reports on experiments conducted on two biological clocks, in organisms in the plant and animal kingdoms, which indicate that biological oscillation can be arrested by a single stimulus of a definite strength delivered at the proper time. (GS)

Time and frequency transfer by the Master-Slave Returnable Timing System technique - Application to solar power transmission

NASA Technical Reports Server (NTRS)

Lindsey, W. C.; Kantak, A. V.

1979-01-01

The concept of the Master Slave Returnable Timing System (MSRTS) is presented which combines the advantages of the master slave (MS) and the Returnable Timing System (RTS) for time and frequency transfer. The basic idea of MSRTS is to send the time-frequency signal received at a particular node back to the sending node. The delay accumulated by this return signal is used to advance the phase of the master (sending) node thereby canceling the effect of the delay introduced by the path. The method can be used in highly accurate clock distribution systems required in avionics, computer communications, and large retrodirective phased arrays such as the Solar Power Satellite.

Historical Photos, Artwork, and Objects - Naval Oceanography Portal

Science.gov Websites

section Advanced Search... Sections Home Time Earth Orientation Astronomy Meteorology Oceanography Ice You along with a vast collection of rare astronomy texts. USNO Master Clock Time Javascript must be Enabled

Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome.

PubMed

Depner, Christopher M; Melanson, Edward L; McHill, Andrew W; Wright, Kenneth P

2018-06-05

Proteomics holds great promise for understanding human physiology, developing health biomarkers, and precision medicine. However, how much the plasma proteome varies with time of day and is regulated by the master circadian suprachiasmatic nucleus brain clock, assessed here by the melatonin rhythm, is largely unknown. Here, we assessed 24-h time-of-day patterns of human plasma proteins in six healthy men during daytime food intake and nighttime sleep in phase with the endogenous circadian clock (i.e., circadian alignment) versus daytime sleep and nighttime food intake out of phase with the endogenous circadian clock (i.e., circadian misalignment induced by simulated nightshift work). We identified 24-h time-of-day patterns in 573 of 1,129 proteins analyzed, with 30 proteins showing strong regulation by the circadian cycle. Relative to circadian alignment, the average abundance and/or 24-h time-of-day patterns of 127 proteins were altered during circadian misalignment. Altered proteins were associated with biological pathways involved in immune function, metabolism, and cancer. Of the 30 circadian-regulated proteins, the majority peaked between 1400 hours and 2100 hours, and these 30 proteins were associated with basic pathways involved in extracellular matrix organization, tyrosine kinase signaling, and signaling by receptor tyrosine-protein kinase erbB-2. Furthermore, circadian misalignment altered multiple proteins known to regulate glucose homeostasis and/or energy metabolism, with implications for altered metabolic physiology. Our findings demonstrate the circadian clock, the behavioral wake-sleep/food intake-fasting cycle, and interactions between these processes regulate 24-h time-of-day patterns of human plasma proteins and help identify mechanisms of circadian misalignment that may contribute to metabolic dysregulation.

Network Design and Performance of the System Integration Test, Linked Simulators Phase.

DTIC Science & Technology

1998-01-01

community has primarily used UNIX systems. UNIX is not a real - time operating system and thus very accurate time stamping, i.e., millisecond accuracy, is... time operating system works against us. The clock time on the UNIX workstations drifts from the UTC standard over time and this drift varies from...loggers at each site use the Network Time Protocol to synchronize to the master clock on a workstation in the TCAC. Again, the fact that UNIX is not a real

Maintenance of Time and Frequency in the DSN Using the Global Positioning System

NASA Technical Reports Server (NTRS)

Clements, P. A.; Kirk, A.; Borutzki, S. E.

1985-01-01

The Deep Space Network must maintain time and frequency within specified limits in order to accurately track the spacecraft engaged in deep space exploration. The DSN has three tracking complexes, located approximately equidistantly around the Earth. Various methods are used to coordinate the clocks among the three complexes. These methods include Loran-C, TV Line 10, very long baseline interferometry (VLBI), and the Global Positioning System (GPS). The GPS is becoming increasingly important because of the accuracy, precision, and rapid availability of the data; GPS receivers have been installed at each of the DSN complexes and are used to obtain daily time offsets between the master clock at each site and UTC(USNO/NBS). Calculations are made to obtain frequency offsets and Allan variances. These data are analyzed and used to monitor the performance of the hydrogen masers that provide the reference frequencies for the DSN frequency and timing system (DFT). A brief history of the GPS timing receivers in the DSN, a description of the data and information flow, data on the performance of the DSN master clocks and GPS measurement system, and a description of hydrogen maser frequency steering using these data are presented.

The Plant Circadian Clock: From a Simple Timekeeper to a Complex Developmental Manager.

PubMed

Sanchez, Sabrina E; Kay, Steve A

2016-12-01

The plant circadian clock allows organisms to anticipate the predictable changes in the environment by adjusting their developmental and physiological traits. In the last few years, it was determined that responses known to be regulated by the oscillator are also able to modulate clock performance. These feedback loops and their multilayer communications create a complex web, and confer on the clock network a role that exceeds the measurement of time. In this article, we discuss the current knowledge of the wiring of the clock, including the interplay with metabolism, hormone, and stress pathways in the model species Arabidopsis thaliana We outline the importance of this system in crop agricultural traits, highlighting the identification of natural alleles that alter the pace of the timekeeper. We report evidence supporting the understanding of the circadian clock as a master regulator of plant life, and we hypothesize on its relevant role in the adaptability to the environment and the impact on the fitness of most organisms. Copyright © 2016 Cold Spring Harbor Laboratory Press; all rights reserved.

What to Do until the Microprocesser Arrives.

ERIC Educational Resources Information Center

Barzilla, Frank

1983-01-01

Advises administrators how to develop an energy master plan and how to reduce the usage of heating, ventilating, and air conditioning (HVAC) systems by means of a time clock, thermostat, and a scheduled preventive maintenance program. (MLF)

Constellation Program Electrical Ground Support Equipment Research and Development

NASA Technical Reports Server (NTRS)

McCoy, Keegan S.

2010-01-01

At the Kennedy Space Center, I engaged in the research and development of electrical ground support equipment for NASA's Constellation Program. Timing characteristics playa crucial role in ground support communications. Latency and jitter are two problems that must be understood so that communications are timely and consistent within the Kennedy Ground Control System (KGCS). I conducted latency and jitter tests using Alien-Bradley programmable logic controllers (PLCs) so that these two intrinsic network properties can be reduced. Time stamping and clock synchronization also play significant roles in launch processing and operations. Using RSLogix 5000 project files and Wireshark network protocol analyzing software, I verified master/slave PLC Ethernet module clock synchronization, master/slave IEEE 1588 communications, and time stamping capabilities. All of the timing and synchronization test results are useful in assessing the current KGCS operational level and determining improvements for the future.

Adrenal clocks and the role of adrenal hormones in the regulation of circadian physiology.

PubMed

Leliavski, Alexei; Dumbell, Rebecca; Ott, Volker; Oster, Henrik

2015-02-01

The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) and subordinate clocks that disseminate time information to various central and peripheral tissues. While the function of the SCN in circadian rhythm regulation has been extensively studied, we still have limited understanding of how peripheral tissue clock function contributes to the regulation of physiological processes. The adrenal gland plays a special role in this context as adrenal hormones show strong circadian secretion rhythms affecting downstream physiological processes. At the same time, they have been shown to affect clock gene expression in various other tissues, thus mediating systemic entrainment to external zeitgebers and promoting internal circadian alignment. In this review, we discuss the function of circadian clocks in the adrenal gland, how they are reset by the SCN and may further relay time-of-day information to other tissues. Focusing on glucocorticoids, we conclude by outlining the impact of adrenal rhythm disruption on neuropsychiatric, metabolic, immune, and malignant disorders. © 2014 The Author(s).

NAMPT-Mediated NAD Biosynthesis as the Internal Timing Mechanism: In NAD+ World, Time Is Running in Its Own Way.

PubMed

Poljsak, Borut

2017-09-08

The biological age of organisms differs from the chronological age and is determined by internal aging clock(s). How cells estimate time on a scale of 24 hours is relatively well studied; however, how biological time is measured by cells, tissues, organs, or organisms in longer time periods (years and decades) is largely unknown. What is clear and widely agreed upon is that the link to age and age-related diseases is not chronological, as it does not depend on a fixed passage of time. Rather, this link depends on the biological age of an individual cell, tissue, organ, or organism and not on time in a strictly chronological sense. Biological evolution does not invent new methods as often as improving upon already existing ones. It should be easier to evolve and remodel the existing (circadian) time clock mechanism to use it for measurement or regulation of longer time periods than to invent a new time mechanism/clock. Specifically, it will be demonstrated that the circadian clock can also be used to regulate circannual or even longer time periods. Nicotinamide phosphoribosyltransferase (NAMPT)-mediated nicotinamide adenine dinucleotide (NAD+) levels, being regulated by the circadian clock, might be the missing link between aging, cell cycle control, DNA damage repair, cellular metabolism and the aging clock, which is responsible for the biological age of an organism. The hypothesis that NAMPT/NAD+/SIRT1 might represent the time regulator that determines the organismal biological age will be presented. The biological age of tissues and organs might be regulated and synchronized through eNAMPT blood secretion. The "NAD World 2.0" concept will be upgraded with detailed insights into mechanisms that regulate NAD + -mediated aging clock ticking, the duration and amplitude of which are responsible for the aging rate of humans.

Glucocorticoids mediate circadian timing in peripheral osteoclasts resulting in the circadian expression rhythm of osteoclast-related genes.

PubMed

Fujihara, Yuko; Kondo, Hisataka; Noguchi, Toshihide; Togari, Akifumi

2014-04-01

Circadian rhythms are prevalent in bone metabolism. However, the molecular mechanisms involved are poorly understood. Recently, we suggested that output signals from the suprachiasmatic nucleus (SCN) are transmitted from the master circadian rhythm to peripheral osteoblasts through β-adrenergic and glucocorticoid signaling. In this study, we examined how the master circadian rhythm is transmitted to peripheral osteoclasts and the role of clock gene in osteoclast. Mice were maintained under 12-hour light/dark periods and sacrificed at Zeitgeber times 0, 4, 8, 12, 16 and 20. mRNA was extracted from femur (cancellous bone) and analyzed for the expression of osteoclast-related genes and clock genes. Osteoclast-related genes such as cathepsin K (CTSK) and nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) showed circadian rhythmicity like clock genes such as period 1 (PER1), PER2 and brain and muscle Arnt-like protein 1 (BMAL1). In an in vitro study, not β-agonist but glucocorticoid treatment remarkably synchronized clock and osteoclast-related genes in cultured osteoclasts. Chromatin immunoprecipitation (ChIP) assay showed the interaction between BMAL1 proteins and promoter region of CTSK and NFATc1. To examine whether endogenous glucocorticoids influence the osteoclast circadian rhythms, mice were adrenalectomized (ADX) and maintained under 12-hour light/dark periods at least two weeks before glucocorticoid injection. A glucocorticoid injection restarted the circadian expression of CTSK and NFATc1 in ADX mice. These results suggest that glucocorticoids mediate circadian timing to peripheral osteoclasts and osteoclast clock contributes to the circadian expression of osteoclast-related genes such as CTSK and NFATc1. Copyright © 2014 Elsevier Inc. All rights reserved.

Diurnal Variation in Vascular and Metabolic Function in Diet-Induced Obesity

PubMed Central

Prasai, Madhu J.; Mughal, Romana S.; Wheatcroft, Stephen B.; Kearney, Mark T.; Grant, Peter J.; Scott, Eleanor M.

2013-01-01

Circadian rhythms are integral to the normal functioning of numerous physiological processes. Evidence from human and mouse studies suggests that loss of rhythm occurs in obesity and cardiovascular disease and may be a neglected contributor to pathophysiology. Obesity has been shown to impair the circadian clock mechanism in liver and adipose tissue but its effect on cardiovascular tissues is unknown. We investigated the effect of diet-induced obesity in C57BL6J mice upon rhythmic transcription of clock genes and diurnal variation in vascular and metabolic systems. In obesity, clock gene function and physiological rhythms were preserved in the vasculature but clock gene transcription in metabolic tissues and rhythms of glucose tolerance and insulin sensitivity were blunted. The most pronounced attenuation of clock rhythm occurred in adipose tissue, where there was also impairment of clock-controlled master metabolic genes and both AMPK mRNA and protein. Across tissues, clock gene disruption was associated with local inflammation but diverged from impairment of insulin signaling. We conclude that vascular tissues are less sensitive to pathological disruption of diurnal rhythms during obesity than metabolic tissues and suggest that cellular disruption of clock gene rhythmicity may occur by mechanisms shared with inflammation but distinct from those leading to insulin resistance. PMID:23382450

Regulation of the Rhythmic Emission of Plant Volatiles by the Circadian Clock.

PubMed

Zeng, Lanting; Wang, Xiaoqin; Kang, Ming; Dong, Fang; Yang, Ziyin

2017-11-13

Like other organisms, plants have endogenous biological clocks that enable them to organize their metabolic, physiological, and developmental processes. The representative biological clock is the circadian system that regulates daily (24-h) rhythms. Circadian-regulated changes in growth have been observed in numerous plants. Evidence from many recent studies indicates that the circadian clock regulates a multitude of factors that affect plant metabolites, especially emitted volatiles that have important ecological functions. Here, we review recent progress in research on plant volatiles showing rhythmic emission under the regulation of the circadian clock, and on how the circadian clock controls the rhythmic emission of plant volatiles. We also discuss the potential impact of other factors on the circadian rhythmic emission of plant volatiles.

Sleep Deprivation and Caffeine Treatment Potentiate Photic Resetting of the Master Circadian Clock in a Diurnal Rodent.

PubMed

Jha, Pawan Kumar; Bouâouda, Hanan; Gourmelen, Sylviane; Dumont, Stephanie; Fuchs, Fanny; Goumon, Yannick; Bourgin, Patrice; Kalsbeek, Andries; Challet, Etienne

2017-04-19

Circadian rhythms in nocturnal and diurnal mammals are primarily synchronized to local time by the light/dark cycle. However, nonphotic factors, such as behavioral arousal and metabolic cues, can also phase shift the master clock in the suprachiasmatic nuclei (SCNs) and/or reduce the synchronizing effects of light in nocturnal rodents. In diurnal rodents, the role of arousal or insufficient sleep in these functions is still poorly understood. In the present study, diurnal Sudanian grass rats, Arvicanthis ansorgei , were aroused at night by sleep deprivation (gentle handling) or caffeine treatment that both prevented sleep. Phase shifts of locomotor activity were analyzed in grass rats transferred from a light/dark cycle to constant darkness and aroused in early night or late night. Early night, but not late night, sleep deprivation induced a significant phase shift. Caffeine on its own induced no phase shifts. Both sleep deprivation and caffeine treatment potentiated light-induced phase delays and phase advances in response to a 30 min light pulse, respectively. Sleep deprivation in early night, but not late night, potentiated light-induced c-Fos expression in the ventral SCN. Caffeine treatment in midnight triggered c-Fos expression in dorsal SCN. Both sleep deprivation and caffeine treatment potentiated light-induced c-Fos expression in calbindin-containing cells of the ventral SCN in early and late night. These findings indicate that, in contrast to nocturnal rodents, behavioral arousal induced either by sleep deprivation or caffeine during the sleeping period potentiates light resetting of the master circadian clock in diurnal rodents, and activation of calbindin-containing suprachiasmatic cells may be involved in this effect. SIGNIFICANCE STATEMENT Arousing stimuli have the ability to regulate circadian rhythms in mammals. Behavioral arousal in the sleeping period phase shifts the master clock in the suprachiasmatic nuclei and/or slows down the photic entrainment in nocturnal animals. How these stimuli act in diurnal species remains to be established. Our study in a diurnal rodent, the Grass rat, indicates that sleep deprivation in the early rest period induces phase delays of circadian locomotor activity rhythm. Contrary to nocturnal rodents, both sleep deprivation and caffeine-induced arousal potentiate the photic entrainment in a diurnal rodent. Such enhanced light-induced circadian responses could be relevant for developing chronotherapeutic strategies. Copyright © 2017 the authors 0270-6474/17/374343-16$15.00/0.

A functional genomics strategy reveals Rora as a component of the mammalian circadian clock.

PubMed

Sato, Trey K; Panda, Satchidananda; Miraglia, Loren J; Reyes, Teresa M; Rudic, Radu D; McNamara, Peter; Naik, Kinnery A; FitzGerald, Garret A; Kay, Steve A; Hogenesch, John B

2004-08-19

The mammalian circadian clock plays an integral role in timing rhythmic physiology and behavior, such as locomotor activity, with anticipated daily environmental changes. The master oscillator resides within the suprachiasmatic nucleus (SCN), which can maintain circadian rhythms in the absence of synchronizing light input. Here, we describe a genomics-based approach to identify circadian activators of Bmal1, itself a key transcriptional activator that is necessary for core oscillator function. Using cell-based functional assays, as well as behavioral and molecular analyses, we identified Rora as an activator of Bmal1 transcription within the SCN. Rora is required for normal Bmal1 expression and consolidation of daily locomotor activity and is regulated by the core clock in the SCN. These results suggest that opposing activities of the orphan nuclear receptors Rora and Rev-erb alpha, which represses Bmal1 expression, are important in the maintenance of circadian clock function.

Evaluation of the accuracy of LF and TV synchronization techniques inChina via portable clock.

NASA Astrophysics Data System (ADS)

Miao, Y.-R.; Pan, X.-P.; Song, J.-A.; Bian, Y.-J.; Luo, D.-C.; Zhuang, Q.-X.

Shanxi, Beijing and Shanghai observatories cooperated with the U. S. Naval Observatory in making two portable clock experiments in 1981 and 1982. A high performance cesium clock was compared with the 1 pps signals from master clock, Loran-C receiver and TV Line-6 receiver in different observatories. The comparison of the experimental results with the prediction of the time delay between transmitter and each observatory indicates that the accuracy of LF synchronization technique in China can reach ±1 μs, timing precision is 0.05 - 0.2 μs at a distance of 2000 km. (It has been shown that there is a systematic error in the Daily Relative Phase Values, Ser. 4 of the U. S. Naval Observatory for the Northwest Pacific Loran-C chain.) For passive CCTV synchronization, timing accuracy is 2 μs or better and daily frequency calibration precision is (2 - 20)×10-13.

Space-based augmentation for global navigation satellite systems.

PubMed

Grewal, Mohinder S

2012-03-01

This paper describes space-based augmentation for global navigation satellite systems (GNSS). Space-based augmentations increase the accuracy and integrity of the GNSS, thereby enhancing users' safety. The corrections for ephemeris, ionospheric delay, and clocks are calculated from reference station measurements of GNSS data in wide-area master stations and broadcast via geostationary earth orbit (GEO) satellites. This paper discusses the clock models, satellite orbit determination, ionospheric delay estimation, multipath mitigation, and GEO uplink subsystem (GUS) as used in the Wide Area Augmentation System developed by the FAA.

Simulating Future GPS Clock Scenarios with Two Composite Clock Algorithms

NASA Technical Reports Server (NTRS)

Suess, Matthias; Matsakis, Demetrios; Greenhall, Charles A.

2010-01-01

Using the GPS Toolkit, the GPS constellation is simulated using 31 satellites (SV) and a ground network of 17 monitor stations (MS). At every 15-minutes measurement epoch, the monitor stations measure the time signals of all satellites above a parameterized elevation angle. Once a day, the satellite clock estimates the station and satellite clocks. The first composite clock (B) is based on the Brown algorithm, and is now used by GPS. The second one (G) is based on the Greenhall algorithm. The composite clock of G and B performance are investigated using three ground-clock models. Model C simulates the current GPS configuration, in which all stations are equipped with cesium clocks, except for masers at USNO and Alternate Master Clock (AMC) sites. Model M is an improved situation in which every station is equipped with active hydrogen masers. Finally, Models F and O are future scenarios in which the USNO and AMC stations are equipped with fountain clocks instead of masers. Model F is a rubidium fountain, while Model O is more precise but futuristic Optical Fountain. Each model is evaluated using three performance metrics. The timing-related user range error having all satellites available is the first performance index (PI1). The second performance index (PI2) relates to the stability of the broadcast GPS system time itself. The third performance index (PI3) evaluates the stability of the time scales computed by the two composite clocks. A distinction is made between the "Signal-in-Space" accuracy and that available through a GNSS receiver.

Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior.

PubMed

Ben-Moshe Livne, Zohar; Alon, Shahar; Vallone, Daniela; Bayleyen, Yared; Tovin, Adi; Shainer, Inbal; Nisembaum, Laura G; Aviram, Idit; Smadja-Storz, Sima; Fuentes, Michael; Falcón, Jack; Eisenberg, Eli; Klein, David C; Burgess, Harold A; Foulkes, Nicholas S; Gothilf, Yoav

2016-11-01

The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior.

Genetically Blocking the Zebrafish Pineal Clock Affects Circadian Behavior

PubMed Central

Alon, Shahar; Vallone, Daniela; Tovin, Adi; Shainer, Inbal; Nisembaum, Laura G.; Aviram, Idit; Smadja-Storz, Sima; Fuentes, Michael; Falcón, Jack; Eisenberg, Eli; Klein, David C.; Burgess, Harold A.; Foulkes, Nicholas S.; Gothilf, Yoav

2016-01-01

The master circadian clock in fish has been considered to reside in the pineal gland. This dogma is challenged, however, by the finding that most zebrafish tissues contain molecular clocks that are directly reset by light. To further examine the role of the pineal gland oscillator in the zebrafish circadian system, we generated a transgenic line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland by a dominant-negative strategy. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted. Moreover, transcriptome analysis revealed that the circadian expression pattern of the majority of clock-controlled genes in the adult pineal gland is abolished. Importantly, circadian rhythms of behavior in zebrafish larvae were affected: rhythms of place preference under constant darkness were eliminated, and rhythms of locomotor activity under constant dark and constant dim light conditions were markedly attenuated. On the other hand, global peripheral molecular oscillators, as measured in whole larvae, were unaffected in this model. In conclusion, characterization of this novel transgenic model provides evidence that the molecular clock in the melatonin-producing cells of the pineal gland plays a key role, possibly as part of a multiple pacemaker system, in modulating circadian rhythms of behavior. PMID:27870848

Circadian factor BMAL1 in histaminergic neurons regulates sleep architecture.

PubMed

Yu, Xiao; Zecharia, Anna; Zhang, Zhe; Yang, Qianzi; Yustos, Raquel; Jager, Polona; Vyssotski, Alexei L; Maywood, Elizabeth S; Chesham, Johanna E; Ma, Ying; Brickley, Stephen G; Hastings, Michael H; Franks, Nicholas P; Wisden, William

2014-12-01

Circadian clocks allow anticipation of daily environmental changes. The suprachiasmatic nucleus (SCN) houses the master clock, but clocks are also widely expressed elsewhere in the body. Although some peripheral clocks have established roles, it is unclear what local brain clocks do. We tested the contribution of one putative local clock in mouse histaminergic neurons in the tuberomamillary nucleus to the regulation of the sleep-wake cycle. Histaminergic neurons are silent during sleep, and start firing after wake onset; the released histamine, made by the enzyme histidine decarboxylase (HDC), enhances wakefulness. We found that hdc gene expression varies with time of day. Selectively deleting the Bmal1 (also known as Arntl or Mop3) clock gene from histaminergic cells removes this variation, producing higher HDC expression and brain histamine levels during the day. The consequences include more fragmented sleep, prolonged wake at night, shallower sleep depth (lower nonrapid eye movement [NREM] δ power), increased NREM-to-REM transitions, hindered recovery sleep after sleep deprivation, and impaired memory. Removing BMAL1 from histaminergic neurons does not, however, affect circadian rhythms. We propose that for mammals with polyphasic/nonwake consolidating sleep, the local BMAL1-dependent clock directs appropriately timed declines and increases in histamine biosynthesis to produce an appropriate balance of wake and sleep within the overall daily cycle of rest and activity specified by the SCN. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Constant Light Desynchronizes Olfactory versus Object and Visuospatial Recognition Memory Performance

PubMed Central

Tam, Shu K.E.; Hasan, Sibah; Brown, Laurence A.; Jagannath, Aarti; Hankins, Mark W.; Foster, Russell G.; Vyazovskiy, Vladyslav V.

2017-01-01

Circadian rhythms optimize physiology and behavior to the varying demands of the 24 h day. The master circadian clock is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and it regulates circadian oscillators in tissues throughout the body to prevent internal desynchrony. Here, we demonstrate for the first time that, under standard 12 h:12 h light/dark (LD) cycles, object, visuospatial, and olfactory recognition performance in C57BL/6J mice is consistently better at midday relative to midnight. However, under repeated exposure to constant light (rLL), recognition performance becomes desynchronized, with object and visuospatial performance better at subjective midday and olfactory performance better at subjective midnight. This desynchrony in behavioral performance is mirrored by changes in expression of the canonical clock genes Period1 and Period2 (Per1 and Per2), as well as the immediate-early gene Fos in the SCN, dorsal hippocampus, and olfactory bulb. Under rLL, rhythmic Per1 and Fos expression is attenuated in the SCN. In contrast, hippocampal gene expression remains rhythmic, mirroring object and visuospatial performance. Strikingly, Per1 and Fos expression in the olfactory bulb is reversed, mirroring the inverted olfactory performance. Temporal desynchrony among these regions does not result in arrhythmicity because core body temperature and exploratory activity rhythms persist under rLL. Our data provide the first demonstration that abnormal lighting conditions can give rise to temporal desynchrony between autonomous circadian oscillators in different regions, with different consequences for performance across different sensory domains. Such a dispersed network of dissociable circadian oscillators may provide greater flexibility when faced with conflicting environmental signals. SIGNIFICANCE STATEMENT A master circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus regulates physiology and behavior across the 24 h day by synchronizing peripheral clocks throughout the brain and body. Without the SCN, these peripheral clocks rapidly become desynchronized. Here, we provide a unique demonstration that, under lighting conditions in which the central clock in the SCN is dampened, peripheral oscillators in the hippocampus and olfactory bulb become desynchronized, along with the behavioral processes mediated by these clocks. Multiple clocks that adopt different phase relationships may enable processes occurring in different brain regions to be optimized to specific phases of the 24 h day. Moreover, such a dispersed network of dissociable circadian clocks may provide greater flexibility when faced with conflicting environmental signals (e.g., seasonal changes in photoperiod). PMID:28264977

An Autonomous Satellite Time Synchronization System Using Remotely Disciplined VC-OCXOs.

PubMed

Gu, Xiaobo; Chang, Qing; Glennon, Eamonn P; Xu, Baoda; Dempseter, Andrew G; Wang, Dun; Wu, Jiapeng

2015-07-23

An autonomous remote clock control system is proposed to provide time synchronization and frequency syntonization for satellite to satellite or ground to satellite time transfer, with the system comprising on-board voltage controlled oven controlled crystal oscillators (VC-OCXOs) that are disciplined to a remote master atomic clock or oscillator. The synchronization loop aims to provide autonomous operation over extended periods, be widely applicable to a variety of scenarios and robust. A new architecture comprising the use of frequency division duplex (FDD), synchronous time division (STDD) duplex and code division multiple access (CDMA) with a centralized topology is employed. This new design utilizes dual one-way ranging methods to precisely measure the clock error, adopts least square (LS) methods to predict the clock error and employs a third-order phase lock loop (PLL) to generate the voltage control signal. A general functional model for this system is proposed and the error sources and delays that affect the time synchronization are discussed. Related algorithms for estimating and correcting these errors are also proposed. The performance of the proposed system is simulated and guidance for selecting the clock is provided.

A method of time transfer between remote stations via LRO

NASA Astrophysics Data System (ADS)

Hoffman, Evan; Sun, Xiaoli; Skillman, David R.; McGarry, Jan F.; Mao, Dandan

2014-05-01

Satellite Laser Ranging (SLR) is a standard geodetic technique that uses the round trip time of light from a ground station to a satellite to determine distance. When combined with a spacecraft detector and timing system, this technique can also be used to transfer time between ground stations, demonstrated by the Time Transfer by Laser Link (T2L2) project by the Centre National d'Etudes Spatiaes (CNES) and Observatorire de la Cote d'Azur (OCA) as well as the Laser Time Transfer (LTT) project by the Shanghai Astronomical Observatory. We describe an additional method of time transfer using simultaneous one-way laser ranging (LR) by two or more ground stations to the Lunar Reconnaissance Orbiter (LRO). A one way ranging is necessary, as two way ranging via retroreflectors for time transfer becomes impractical at lunar distances. The method will utilize the one-way LR currently being performed as a part of the LRO mission, allowing time transfer to be a by-product of the conventional usage of the data. Each ground station is referenced to a Master Clock using a multifrequency all-view GPS receiver at both the ground station and Master Clock locations.The Master Clock is located close enough to the ground station to make ionospheric differences in signal path negligible. Two or more stations range to LRO at the same time and their times of arrival are compared. Results from a ground-based experiment are shown, with sub-nanosecond precision shown to be achievable. Ultimately this measurement will provide a more precise and accurate relation of timing standards between stations, leading to a marked improvement in orbit determination.

Biochemical basis for the biological clock

NASA Technical Reports Server (NTRS)

Morre, D. James; Chueh, Pin-Ju; Pletcher, Jake; Tang, Xiaoyu; Wu, Lian-Ying; Morre, Dorothy M.

2002-01-01

NADH oxidases at the external surface of plant and animal cells (ECTO-NOX proteins) exhibit stable and recurring patterns of oscillations with potentially clock-related, entrainable, and temperature-compensated period lengths of 24 min. To determine if ECTO-NOX proteins might represent the ultradian time keepers (pacemakers) of the biological clock, COS cells were transfected with cDNAs encoding tNOX proteins having a period length of 22 min or with C575A or C558A cysteine to alanine replacements having period lengths of 36 or 42 min. Here we demonstrate that such transfectants exhibited 22, 36, or 40 to 42 h circadian patterns in the activity of glyceraldehyde-3-phosphate dehydrogenase, a common clock-regulated protein, in addition to the endogenous 24 h circadian period length. The fact that the expression of a single oscillatory ECTO-NOX protein determines the period length of a circadian biochemical marker (60 X the ECTO-NOX period length) provides compelling evidence that ECTO-NOX proteins are the biochemical ultradian drivers of the cellular biological clock.

Circadian expression profiles of chromatin remodeling factor genes in Arabidopsis.

PubMed

Lee, Hong Gil; Lee, Kyounghee; Jang, Kiyoung; Seo, Pil Joon

2015-01-01

The circadian clock is a biological time keeper mechanism that regulates biological rhythms to a period of approximately 24 h. The circadian clock enables organisms to anticipate environmental cycles and coordinates internal cellular physiology with external environmental cues. In plants, correct matching of the clock with the environment confers fitness advantages to plant survival and reproduction. Therefore, circadian clock components are regulated at multiple layers to fine-tune the circadian oscillation. Epigenetic regulation provides an additional layer of circadian control. However, little is known about which chromatin remodeling factors are responsible for circadian control. In this work, we analyzed circadian expression of 109 chromatin remodeling factor genes and identified 17 genes that display circadian oscillation. In addition, we also found that a candidate interacts with a core clock component, supporting that clock activity is regulated in part by chromatin modification. As an initial attempt to elucidate the relationship between chromatin modification and circadian oscillation, we identified novel regulatory candidates that provide a platform for future investigations of chromatin regulation of the circadian clock.

Early sex-specific modulation of the molecular clock in trauma.

PubMed

Mehraj, Vikram; Wiramus, Sandrine; Capo, Christian; Leone, Marc; Mege, Jean-Louis; Textoris, Julien

2014-01-01

Immune system biology and most physiologic functions are tightly linked to circadian rhythms. Time of day-dependent variations in many biologic parameters also play a fundamental role in the disease process. We previously showed that the genes encoding the peripheral molecular clock were modulated in a sex-dependent manner in Q fever. Here, we examined severe trauma patients at admission to the intensive care unit. Using quantitative real-time polymerase chain reaction, the whole-blood expression of the molecular clock components ARNTL, CLOCK, and PER2 was assessed in male and female trauma patients. Healthy volunteers of both sexes were used as controls. We observed a significant overexpression of both ARNTL and CLOCK in male trauma patients. We report, for the first time, the sex-related modulation of the molecular clock genes in the blood following severe trauma. These results emphasize the role of circadian rhythms in the immune response in trauma patients. Epidemiologic study, level IV.

Systems Chronobiology: Global Analysis of Gene Regulation in a 24-Hour Periodic World.

PubMed

Mermet, Jérôme; Yeung, Jake; Naef, Felix

2017-03-01

Mammals have evolved an internal timing system, the circadian clock, which synchronizes physiology and behavior to the daily light and dark cycles of the Earth. The master clock, located in the suprachiasmatic nucleus (SCN) of the brain, takes fluctuating light input from the retina and synchronizes other tissues to the same internal rhythm. The molecular clocks that drive these circadian rhythms are ticking in nearly all cells in the body. Efforts in systems chronobiology are now being directed at understanding, on a comprehensive scale, how the circadian clock controls different layers of gene regulation to provide robust timing cues at the cellular and tissue level. In this review, we introduce some basic concepts underlying periodicity of gene regulation, and then highlight recent genome-wide investigations on the propagation of rhythms across multiple regulatory layers in mammals, all the way from chromatin conformation to protein accumulation. Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.

(abstract) Precision Time and Frequency Transfer Utilizing SONET OC-3

NASA Technical Reports Server (NTRS)

Stein, Sam; Calhoun, Malcom; Kuhnle, Paul; Sydnor, Richard; Gifford, Al

1996-01-01

An innovative method of distributing precise time and reference frequency to users located several kilometers from a frequency standard and master clock has been developed by the Timing Solutions Corporation of Boulder, CO. The Optical Two-Way Time Transfer System (OTWTTS) utilizes a commercial SONET OC-3 facility interface to physically connect a master unit to multiple slave units at remote locations. Optical fiber is a viable alternative to standard copper cable and microwave transmission. This paper discusses measurements of frequency and timing stability over the OTWTTS.

Effects of continuous white light and 12h white-12h blue light-cycles on the expression of clock genes in diencephalon, liver, and skeletal muscle in chicks.

PubMed

Honda, Kazuhisa; Kondo, Makoto; Hiramoto, Daichi; Saneyasu, Takaoki; Kamisoyama, Hiroshi

2017-05-01

The core circadian clock mechanism relies on a feedback loop comprised of clock genes, such as the brain and muscle Arnt-like 1 (Bmal1), chriptochrome 1 (Cry1), and period 3 (Per3). Exposure to the light-dark cycle synchronizes the master circadian clock in the brain, and which then synchronizes circadian clocks in peripheral tissues. Birds have long been used as a model for the investigation of circadian rhythm in human neurobiology. In the present study, we examined the effects of continuous light and the combination of white and blue light on the expression of clock genes (Bmal1, Cry1, and Per3) in the central and peripheral tissues in chicks. Seventy two day-old male chicks were weighed, allocated to three groups and maintained under three light schedules: 12h white light-12h dark-cycles group (control); 24h white light group (WW group); 12h white light-12h blue light-cycles group (WB group). The mRNA levels of clock genes in the diencephalon were significantly different between the control and WW groups. On the other hand, the alteration in the mRNA levels of clock genes was similar between the control and WB groups. Similar phenomena were observed in the liver and skeletal muscle (biceps femoris). These results suggest that 12h white-12h blue light-cycles did not disrupt the circadian rhythm of clock gene expression in chicks. Copyright © 2017 Elsevier Inc. All rights reserved.

Regulation of Mammalian Physiology by Interconnected Circadian and Feeding Rhythms

PubMed Central

Atger, Florian; Mauvoisin, Daniel; Weger, Benjamin; Gobet, Cédric; Gachon, Frédéric

2017-01-01

Circadian clocks are endogenous timekeeping systems that adapt in an anticipatory fashion the physiology and behavior of most living organisms. In mammals, the master pacemaker resides in the suprachiasmatic nucleus and entrains peripheral clocks using a wide range of signals that differentially schedule physiology and gene expression in a tissue-specific manner. The peripheral clocks, such as those found in the liver, are particularly sensitive to rhythmic external cues like feeding behavior, which modulate the phase and amplitude of rhythmic gene expression. Consequently, the liver clock temporally tunes the expression of many genes involved in metabolism and physiology. However, the circadian modulation of cellular functions also relies on multiple layers of posttranscriptional and posttranslational regulation. Strikingly, these additional regulatory events may happen independently of any transcriptional oscillations, showing that complex regulatory networks ultimately drive circadian output functions. These rhythmic events also integrate feeding-related cues and adapt various metabolic processes to food availability schedules. The importance of such temporal regulation of metabolism is illustrated by metabolic dysfunctions and diseases resulting from circadian clock disruption or inappropriate feeding patterns. Therefore, the study of circadian clocks and rhythmic feeding behavior should be of interest to further advance our understanding of the prevention and therapy of metabolic diseases. PMID:28337174

Synchronization of Clocks Through 12 km of Strongly Turbulent Air Over a City.

PubMed

Sinclair, Laura C; Swann, William C; Bergeron, Hugo; Baumann, Esther; Cermak, Michael; Coddington, Ian; Deschênes, Jean-Daniel; Giorgetta, Fabrizio R; Juarez, Juan C; Khader, Isaac; Petrillo, Keith G; Souza, Katherine T; Dennis, Michael L; Newbury, Nathan R

2016-10-15

We demonstrate real-time, femtosecond-level clock synchronization across a low-lying, strongly turbulent, 12-km horizontal air path by optical two-way time transfer. For this long horizontal free-space path, the integrated turbulence extends well into the strong turbulence regime corresponding to multiple scattering with a Rytov variance up to 7 and with the number of signal interruptions exceeding 100 per second. Nevertheless, optical two-way time transfer is used to synchronize a remote clock to a master clock with femtosecond-level agreement and with a relative time deviation dropping as low as a few hundred attoseconds. Synchronization is shown for a remote clock based on either an optical or microwave oscillator and using either tip-tilt or adaptive-optics free-space optical terminals. The performance is unaltered from optical two-way time transfer in weak turbulence across short links. These results confirm that the two-way reciprocity of the free-space time-of-flight is maintained both under strong turbulence and with the use of adaptive optics. The demonstrated robustness of optical two-way time transfer against strong turbulence and its compatibility with adaptive optics is encouraging for future femtosecond clock synchronization over very long distance ground-to-air free-space paths.

Synchronization of Clocks Through 12 km of Strongly Turbulent Air Over a City

PubMed Central

Sinclair, Laura C.; Swann, William C.; Bergeron, Hugo; Baumann, Esther; Cermak, Michael; Coddington, Ian; Deschênes, Jean-Daniel; Giorgetta, Fabrizio R.; Juarez, Juan C.; Khader, Isaac; Petrillo, Keith G.; Souza, Katherine T.; Dennis, Michael L.; Newbury, Nathan R.

2018-01-01

We demonstrate real-time, femtosecond-level clock synchronization across a low-lying, strongly turbulent, 12-km horizontal air path by optical two-way time transfer. For this long horizontal free-space path, the integrated turbulence extends well into the strong turbulence regime corresponding to multiple scattering with a Rytov variance up to 7 and with the number of signal interruptions exceeding 100 per second. Nevertheless, optical two-way time transfer is used to synchronize a remote clock to a master clock with femtosecond-level agreement and with a relative time deviation dropping as low as a few hundred attoseconds. Synchronization is shown for a remote clock based on either an optical or microwave oscillator and using either tip-tilt or adaptive-optics free-space optical terminals. The performance is unaltered from optical two-way time transfer in weak turbulence across short links. These results confirm that the two-way reciprocity of the free-space time-of-flight is maintained both under strong turbulence and with the use of adaptive optics. The demonstrated robustness of optical two-way time transfer against strong turbulence and its compatibility with adaptive optics is encouraging for future femtosecond clock synchronization over very long distance ground-to-air free-space paths. PMID:29348695

Hormones and the autonomic nervous system are involved in suprachiasmatic nucleus modulation of glucose homeostasis.

PubMed

Ruiter, Marieke; Buijs, Ruud M; Kalsbeek, Andries

2006-05-01

Glucose is one of the most important energy sources for the body in general, and the brain in particular. It is essential for survival to keep glucose levels within strict boundaries. Acute disturbances of glucose homeostasis are rapidly corrected by hormonal and neuronal mechanisms. Furthermore, changes in energy expenditure associated with the light-dark cycle induce variations in the plasma glucose concentration that are more gradual. Organisms take advantage of adapting their internal physiology to the predictable daily changes in energy expenditure, because it enables them to anticipate these changes and to prevent unnecessary disturbance of homeostasis. The hypothalamic biological clock, located in the suprachiasmatic nucleus (SCN), receives light information from the eyes and transmits this information to the rest of the body to synchronize physiology to the environment. Here we review several studies providing evidence for biological clock control of the daily variation in several aspects of glucose metabolism. Although both hormones and the autonomic nervous system can stimulate glucose uptake or production by organs in the periphery, we have shown that the biological clock control of glucose metabolism mostly occurs through the autonomic nervous system. The critical involvement of the biological clock is also indicated by several studies, indicating that disturbance of the biological clock is often associated with metabolic diseases, such as obesity, diabetes mellitus and hypertension.

An Autonomous Satellite Time Synchronization System Using Remotely Disciplined VC-OCXOs

PubMed Central

Gu, Xiaobo; Chang, Qing; Glennon, Eamonn P.; Xu, Baoda; Dempseter, Andrew G.; Wang, Dun; Wu, Jiapeng

2015-01-01

An autonomous remote clock control system is proposed to provide time synchronization and frequency syntonization for satellite to satellite or ground to satellite time transfer, with the system comprising on-board voltage controlled oven controlled crystal oscillators (VC-OCXOs) that are disciplined to a remote master atomic clock or oscillator. The synchronization loop aims to provide autonomous operation over extended periods, be widely applicable to a variety of scenarios and robust. A new architecture comprising the use of frequency division duplex (FDD), synchronous time division (STDD) duplex and code division multiple access (CDMA) with a centralized topology is employed. This new design utilizes dual one-way ranging methods to precisely measure the clock error, adopts least square (LS) methods to predict the clock error and employs a third-order phase lock loop (PLL) to generate the voltage control signal. A general functional model for this system is proposed and the error sources and delays that affect the time synchronization are discussed. Related algorithms for estimating and correcting these errors are also proposed. The performance of the proposed system is simulated and guidance for selecting the clock is provided. PMID:26213929

Genetic differences in human circadian clock genes among worldwide populations.

PubMed

Ciarleglio, Christopher M; Ryckman, Kelli K; Servick, Stein V; Hida, Akiko; Robbins, Sam; Wells, Nancy; Hicks, Jennifer; Larson, Sydney A; Wiedermann, Joshua P; Carver, Krista; Hamilton, Nalo; Kidd, Kenneth K; Kidd, Judith R; Smith, Jeffrey R; Friedlaender, Jonathan; McMahon, Douglas G; Williams, Scott M; Summar, Marshall L; Johnson, Carl Hirschie

2008-08-01

The daily biological clock regulates the timing of sleep and physiological processes that are of fundamental importance to human health, performance, and well-being. Environmental parameters of relevance to biological clocks include (1) daily fluctuations in light intensity and temperature, and (2) seasonal changes in photoperiod (day length) and temperature; these parameters vary dramatically as a function of latitude and locale. In wide-ranging species other than humans, natural selection has genetically optimized adaptiveness along latitudinal clines. Is there evidence for selection of clock gene alleles along latitudinal/photoperiod clines in humans? A number of polymorphisms in the human clock genes Per2, Per3, Clock, and AANAT have been reported as alleles that could be subject to selection. In addition, this investigation discovered several novel polymorphisms in the human Arntl and Arntl2 genes that may have functional impact upon the expression of these clock transcriptional factors. The frequency distribution of these clock gene polymorphisms is reported for diverse populations of African Americans, European Americans, Ghanaians, Han Chinese, and Papua New Guineans (including 5 subpopulations within Papua New Guinea). There are significant differences in the frequency distribution of clock gene alleles among these populations. Population genetic analyses indicate that these differences are likely to arise from genetic drift rather than from natural selection.

Role of monochromatic light on daily variation of clock gene expression in the pineal gland of chick.

PubMed

Jiang, Nan; Wang, Zixu; Cao, Jing; Dong, Yulan; Chen, Yaoxing

2016-11-01

The avian pineal gland is a master clock that can receive external photic cues and translate them into output rhythms. To clarify whether a shift in light wavelength can influence the circadian expression in chick pineal gland, a total of 240 Arbor Acre male broilers were exposed to white light (WL), red light (RL), green light (GL) or blue light (BL). After 2weeks light illumination, circadian expressions of seven core clock genes in pineal gland and the level of melatonin in plasma were examined. The results showed after illumination with monochromatic light, 24h profiles of all clock gene mRNAs retained circadian oscillation, except that RL tended to disrupt the rhythm of cCry2. Compared to WL, BL advanced the acrophases of the negative elements (cCry1, cCry2, cPer2 and cPer3) by 0.1-1.5h and delayed those of positive elements (cClock, cBmal1 and cBmal2) by 0.2-0.8h. And, RL advanced all clock genes except cClock and cPer2 by 0.3-2.1h, while GL delayed all clock genes by 0.5-1.5h except cBmal2. Meanwhile, GL increased the amplitude and mesor of positive and reduced both parameters of negative clock genes, but RL showed the opposite pattern. Although the acrophase of plasma melatonin was advanced by both GL and RL, the melatonin level was significantly increased in GL and decreased in RL. This tendency was consistent with the variations in the positive clock gene mRNA levels under monochromatic light and contrasted with those of negative clock genes. Therefore, we speculate that GL may enhance positive clock genes expression, leading to melatonin synthesis, whereas RL may enhance negative genes expression, suppressing melatonin synthesis. Copyright © 2016 Elsevier B.V. All rights reserved.

A closer look at the concept of regional clocks for Precise Point Positioning

NASA Astrophysics Data System (ADS)

Weber, Robert; Karabatic, Ana; Thaler, Gottfried; Abart, Christoph; Huber, Katrin

2010-05-01

Under the precondition of at least two successfully tracked signals at different carrier frequencies we may obtain their ionosphere free linear combination. By introducing approximate values for geometric effects like orbits and tropospheric delay as well as an initial bias parameter N per individual satellite we can solve for the satellite clock with respect to the receiver clock. Noting, that residual effects like orbit errors, remaining tropospheric delays and a residual bias parameter map into these parameters, this procedure leaves us with a kind of virtual clock differences. These clocks cover regional effects and are therefore clearly correlated with clocks at nearby station. Therefore we call these clock differences, which are clearly different from clock solutions provided for instance by IGS, the "regional clocks". When introducing the regional clocks obtained from real-time data of a GNSS reference station network we are able to process the coordinates of a nearby isolated station via a PPP .In terms of PPP-convergence time which will be reduced down to 30 minutes or less, this procedure is clearly favorable. The accuracy is quite comparable with state of the art PPP procedures. Nevertheless, this approach cannot compete in fixing times with double-difference approaches but the correlation holds over hundreds of kilometers distance to our master station and the clock differences can easily by obtained, even in real-time. This presentation provides preliminary results of the project RA-PPP. RA-PPP is a research project financed by the Federal Ministry for Transport, Innovation and Technology, managed by the Austrian Research Promotion Agency (FFG) in the course of the 6th call of the Austrian Space Application Program (ASAP). RA-PPP stands for Rapid Precise Point Positioning, which denotes the wish for faster and more accurate algorithms for PPP. The concept of regional clocks which will be demonstrated in detail in this presentation is one out of 4 concepts to be evaluated in this project.

Reciprocal Control of the Circadian Clock and Cellular Redox State - a Critical Appraisal.

PubMed

Putker, Marrit; O'Neill, John Stuart

2016-01-01

Redox signalling comprises the biology of molecular signal transduction mediated by reactive oxygen (or nitrogen) species. By specific and reversible oxidation of redox-sensitive cysteines, many biological processes sense and respond to signals from the intracellular redox environment. Redox signals are therefore important regulators of cellular homeostasis. Recently, it has become apparent that the cellular redox state oscillates in vivo and in vitro, with a period of about one day (circadian). Circadian time-keeping allows cells and organisms to adapt their biology to resonate with the 24-hour cycle of day/night. The importance of this innate biological time-keeping is illustrated by the association of clock disruption with the early onset of several diseases (e.g. type II diabetes, stroke and several forms of cancer). Circadian regulation of cellular redox balance suggests potentially two distinct roles for redox signalling in relation to the cellular clock: one where it is regulated by the clock, and one where it regulates the clock. Here, we introduce the concepts of redox signalling and cellular timekeeping, and then critically appraise the evidence for the reciprocal regulation between cellular redox state and the circadian clock. We conclude there is a substantial body of evidence supporting circadian regulation of cellular redox state, but that it would be premature to conclude that the converse is also true. We therefore propose some approaches that might yield more insight into redox control of cellular timekeeping.

Multi-tissue DNA methylation age predictor in mouse.

PubMed

Stubbs, Thomas M; Bonder, Marc Jan; Stark, Anne-Katrien; Krueger, Felix; von Meyenn, Ferdinand; Stegle, Oliver; Reik, Wolf

2017-04-11

DNA methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse. We have generated a comprehensive set of genome-scale base-resolution methylation maps from multiple mouse tissues spanning a wide range of ages. Many CpG sites show significant tissue-independent correlations with age which allowed us to develop a multi-tissue predictor of age in the mouse. Our model, which estimates age based on DNA methylation at 329 unique CpG sites, has a median absolute error of 3.33 weeks and has similar properties to the recently described human epigenetic clock. Using publicly available datasets, we find that the mouse clock is accurate enough to measure effects on biological age, including in the context of interventions. While females and males show no significant differences in predicted DNA methylation age, ovariectomy results in significant age acceleration in females. Furthermore, we identify significant differences in age-acceleration dependent on the lipid content of the diet. Here we identify and characterise an epigenetic predictor of age in mice, the mouse epigenetic clock. This clock will be instrumental for understanding the biology of ageing and will allow modulation of its ticking rate and resetting the clock in vivo to study the impact on biological age.

Reciprocal Control of the Circadian Clock and Cellular Redox State - a Critical Appraisal

PubMed Central

Putker, Marrit; O’Neill, John Stuart

2016-01-01

Redox signalling comprises the biology of molecular signal transduction mediated by reactive oxygen (or nitrogen) species. By specific and reversible oxidation of redox-sensitive cysteines, many biological processes sense and respond to signals from the intracellular redox environment. Redox signals are therefore important regulators of cellular homeostasis. Recently, it has become apparent that the cellular redox state oscillates in vivo and in vitro, with a period of about one day (circadian). Circadian time-keeping allows cells and organisms to adapt their biology to resonate with the 24-hour cycle of day/night. The importance of this innate biological time-keeping is illustrated by the association of clock disruption with the early onset of several diseases (e.g. type II diabetes, stroke and several forms of cancer). Circadian regulation of cellular redox balance suggests potentially two distinct roles for redox signalling in relation to the cellular clock: one where it is regulated by the clock, and one where it regulates the clock. Here, we introduce the concepts of redox signalling and cellular timekeeping, and then critically appraise the evidence for the reciprocal regulation between cellular redox state and the circadian clock. We conclude there is a substantial body of evidence supporting circadian regulation of cellular redox state, but that it would be premature to conclude that the converse is also true. We therefore propose some approaches that might yield more insight into redox control of cellular timekeeping. PMID:26810072

Disruption of the circadian clock within the cardiomyocyte influences mycardial contractile function, metabolism, and gene expression

USDA-ARS?s Scientific Manuscript database

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology is poorly understood. We hypothesized that the circadian clock within the cardiomyocyte influences diurnal variatio...

Biological Signal Processing with a Genetic Toggle Switch

PubMed Central

Hillenbrand, Patrick; Fritz, Georg; Gerland, Ulrich

2013-01-01

Complex gene regulation requires responses that depend not only on the current levels of input signals but also on signals received in the past. In digital electronics, logic circuits with this property are referred to as sequential logic, in contrast to the simpler combinatorial logic without such internal memory. In molecular biology, memory is implemented in various forms such as biochemical modification of proteins or multistable gene circuits, but the design of the regulatory interface, which processes the input signals and the memory content, is often not well understood. Here, we explore design constraints for such regulatory interfaces using coarse-grained nonlinear models and stochastic simulations of detailed biochemical reaction networks. We test different designs for biological analogs of the most versatile memory element in digital electronics, the JK-latch. Our analysis shows that simple protein-protein interactions and protein-DNA binding are sufficient, in principle, to implement genetic circuits with the capabilities of a JK-latch. However, it also exposes fundamental limitations to its reliability, due to the fact that biological signal processing is asynchronous, in contrast to most digital electronics systems that feature a central clock to orchestrate the timing of all operations. We describe a seemingly natural way to improve the reliability by invoking the master-slave concept from digital electronics design. This concept could be useful to interpret the design of natural regulatory circuits, and for the design of synthetic biological systems. PMID:23874595

[Intercellular communication-based robust circadian oscillation of the suprachiasmatic nucleus in the brain: mechanisms beyond intracellular clock machinery].

PubMed

Doi, Masao

2013-12-01

Recent advances in circadian biology strongly suggest that there are still genes involved in the generation and maintenance of biological rhythms that remain to be identified. It has been generally appreciated that circadian rhythms are generated intracellularly through transcription/translation-based autoregulatory feedback circuits of the clock genes. However, the existence of new intracellular clock machinery that cannot be explained by existing clock genes has recently been reported. This clock manifests as oxidation-reduction cycles of peroxiredoxin proteins, implying that as-yet-undiscovered clock genes may exist within cells to regulate redox cycling. Moreover, great strides have also been made in understanding the cell-cell communication-based robust circadian oscillations of the suprachiasmatic nucleus (SCN), the central pacemaker in the brain. Thousands of neurons that constitute the SCN maintain a high degree of synchrony in a way that allows the SCN neurons to create coherent signals as a whole. Inactivation of the genes involved in the cell-cell synchronization of the SCN, which include the genes encoding VIP, VPAC2, and RGS16, leads to altered circadian rhythms in behavior and physiologies. The purpose of this review is to provide an overview of recent advances in the circadian biology, with a special emphasis on the importance of cell-cell interactions within the SCN.

Multifrequency zero-jitter delay-locked loop

NASA Astrophysics Data System (ADS)

Efendovich, Avner; Afek, Yachin; Sella, Coby; Bikowsky, Zeev

1994-01-01

The approach of an all-digital phase locked loop is used in this delay-locked loop circuit. This design is designated to a system with two processing units, a master CPU and a slave system chip, that share the same bus. It allows maximum utilization of the bus, as the minimal skew between the clocks of the two components significantly reduces idle periods, and also set-up and hold times. Changes in the operating frequency are possible, without falling out of synchronization. Due to the special lead-lag phase detector, the jitter of the clock is zero, when the loop is locked, under any working conditions.

Comportement de l'oscillateur DORIS/Jason au passage de l'anomalie sud-atlantique

NASA Astrophysics Data System (ADS)

Willis, Pascal; Haines, Bruce; Berthias, Jean-Paul; Sengenes, Pierre; Le Mouël, Jean-Louis

2004-07-01

We point out an acceleration of the DORIS clock on-board the Jason satellite during passes over the South Atlantic Anomaly (SAA). When this effect is ignored in the current geodetic positioning of the DORIS stations, derived coordinates show almost linear trends in time, corresponding to anomalous horizontal and vertical velocities of the order of 1 m yr -1. We propose a simple scientific explanation of this physical phenomenon that is corroborated by direct Jason/TOPEX clock comparisons with respect to the DORIS master beacons in Kourou and Toulouse. To cite this article: P. Willis et al., C. R. Geoscience 336 (2004).

New phone-in time service

NASA Astrophysics Data System (ADS)

If you want to know the precise time—in fact, the most precise time available—call 1-900-410-TIME. This will connect you with the U.S. Naval Observatory's Master Clock in Washington, D.C., keeper of the national time standard, where a voice announcement will give you the time accurate to within one billionth of a second per day.The new service, useful for the synchronization of clocks and communication satellites as well as other applications, is being made available to the military and scientific communities and to the general public. A constant ticking in the background of the recorded phone announcement allows scientific users to synchronize their equipment.

The intrinsic circadian clock within the cardiomyocyte directly regulates myocardial gene expression, metabolism, and contractile function

USDA-ARS?s Scientific Manuscript database

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology remains unknown. We hypothesized that circadian clock within the cardiomyocyte plays a role in regulating myocardia...

The intrinsic circadian clock within the cardiomyocyte directly regulates myocardial gene expression, metabolism, and contractile function

USDA-ARS?s Scientific Manuscript database

Virtually every mammalian cell, including cardiomyocytes, possesses an intrinsic circadian clock. The role of this transcriptionally based molecular mechanism in cardiovascular biology remains unknown. We hypothesized that the circadian clock within the cardiomyocyte plays a role in regulating myo...

Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits

PubMed Central

Snider, Kaitlin H.; Dziema, Heather; Aten, Sydney; Loeser, Jacob; Norona, Frances E.; Hoyt, Kari; Obrietan, Karl

2017-01-01

A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day. PMID:27091299

Entrainment to feeding but not to light: circadian phenotype of VPAC2 receptor-null mice.

PubMed

Sheward, W John; Maywood, Elizabeth S; French, Karen L; Horn, Jacqueline M; Hastings, Michael H; Seckl, Jonathan R; Holmes, Megan C; Harmar, Anthony J

2007-04-18

The master clock driving mammalian circadian rhythms is located in the suprachiasmatic nuclei (SCN) of the hypothalamus and entrained by daily light/dark cycles. SCN lesions abolish circadian rhythms of behavior and result in a loss of synchronized circadian rhythms of clock gene expression in peripheral organs (e.g., the liver) and of hormone secretion (e.g., corticosterone). We examined rhythms of behavior, hepatic clock gene expression, and corticosterone secretion in VPAC2 receptor-null (Vipr2-/-) mice, which lack a functional SCN clock. Unexpectedly, although Vipr2-/- mice lacked robust circadian rhythms of wheel-running activity and corticosterone secretion, hepatic clock gene expression was strongly rhythmic, but advanced in phase compared with that in wild-type mice. The timing of food availability is thought to be an important entrainment signal for circadian clocks outside the SCN. Vipr2-/- mice consumed food significantly earlier in the 24 h cycle than wild-type mice, consistent with the observed timing of peripheral rhythms of circadian gene expression. When restricted to feeding only during the daytime (RF), mice develop rhythms of activity and of corticosterone secretion in anticipation of feeding time, thought to be driven by a food-entrainable circadian oscillator, located outside the SCN. Under RF, mice of both genotypes developed food-anticipatory rhythms of activity and corticosterone secretion, and hepatic gene expression rhythms also became synchronized to the RF stimulus. Thus, food intake is an effective zeitgeber capable of coordinating circadian rhythms of behavior, peripheral clock gene expression, and hormone secretion, even in the absence of a functional SCN clock.

A modified implementation of tristate inverter based static master-slave flip-flop with improved power-delay-area product.

PubMed

Singh, Kunwar; Tiwari, Satish Chandra; Gupta, Maneesha

2014-01-01

The paper introduces novel architectures for implementation of fully static master-slave flip-flops for low power, high performance, and high density. Based on the proposed structure, traditional C(2)MOS latch (tristate inverter/clocked inverter) based flip-flop is implemented with fewer transistors. The modified C(2)MOS based flip-flop designs mC(2)MOSff1 and mC(2)MOSff2 are realized using only sixteen transistors each while the number of clocked transistors is also reduced in case of mC(2)MOSff1. Postlayout simulations indicate that mC(2)MOSff1 flip-flop shows 12.4% improvement in PDAP (power-delay-area product) when compared with transmission gate flip-flop (TGFF) at 16X capacitive load which is considered to be the best design alternative among the conventional master-slave flip-flops. To validate the correct behaviour of the proposed design, an eight bit asynchronous counter is designed to layout level. LVS and parasitic extraction were carried out on Calibre, whereas layouts were implemented using IC station (Mentor Graphics). HSPICE simulations were used to characterize the transient response of the flip-flop designs in a 180 nm/1.8 V CMOS technology. Simulations were also performed at 130 nm, 90 nm, and 65 nm to reveal the scalability of both the designs at modern process nodes.

A Modified Implementation of Tristate Inverter Based Static Master-Slave Flip-Flop with Improved Power-Delay-Area Product

PubMed Central

Tiwari, Satish Chandra; Gupta, Maneesha

2014-01-01

The paper introduces novel architectures for implementation of fully static master-slave flip-flops for low power, high performance, and high density. Based on the proposed structure, traditional C2MOS latch (tristate inverter/clocked inverter) based flip-flop is implemented with fewer transistors. The modified C2MOS based flip-flop designs mC2MOSff1 and mC2MOSff2 are realized using only sixteen transistors each while the number of clocked transistors is also reduced in case of mC2MOSff1. Postlayout simulations indicate that mC2MOSff1 flip-flop shows 12.4% improvement in PDAP (power-delay-area product) when compared with transmission gate flip-flop (TGFF) at 16X capacitive load which is considered to be the best design alternative among the conventional master-slave flip-flops. To validate the correct behaviour of the proposed design, an eight bit asynchronous counter is designed to layout level. LVS and parasitic extraction were carried out on Calibre, whereas layouts were implemented using IC station (Mentor Graphics). HSPICE simulations were used to characterize the transient response of the flip-flop designs in a 180 nm/1.8 V CMOS technology. Simulations were also performed at 130 nm, 90 nm, and 65 nm to reveal the scalability of both the designs at modern process nodes. PMID:24723808

Synchronized computational architecture for generalized bilateral control of robot arms

NASA Technical Reports Server (NTRS)

Szakaly, Zoltan F. (Inventor)

1991-01-01

A master six degree of freedom Force Reflecting Hand Controller (FRHC) is available at a master site where a received image displays, in essentially real time, a remote robotic manipulator which is being controlled in the corresponding six degree freedom by command signals which are transmitted to the remote site in accordance with the movement of the FRHC at the master site. Software is user-initiated at the master site in order to establish the basic system conditions, and then a physical movement of the FRHC in Cartesean space is reflected at the master site by six absolute numbers that are sensed, translated and computed as a difference signal relative to the earlier position. The change in position is then transmitted in that differential signal form over a high speed synchronized bilateral communication channel which simultaneously returns robot-sensed response information to the master site as forces applied to the FRHC so that the FRHC reflects the feel of what is taking place at the remote site. A system wide clock rate is selected at a sufficiently high rate that the operator at the master site experiences the Force Reflecting operation in real time.

Intrinsic control of rhabdom size and rhodopsin content in the crab compound eye by a circadian biological clock.

PubMed

Arikawa, K; Morikawa, Y; Suzuki, T; Eguchi, E

1988-03-15

Under conditions of constant darkness, rhabdom volume and the amount of visual pigment chromophore show circadian changes in the compound eye of the crab Hemigrapsus sanguineus. The present results indicate that an intrinsic circadian biological clock is involved in the control of the changes.

Fleet Weather Center- San Diego, California - Naval Oceanography Portal

Science.gov Websites

section Advanced Search... Sections Home Time Earth Orientation Astronomy Meteorology Oceanography Ice You Oceanography Portal at its new location: http://www.metoc.navy.mil/fwcsd/fwc-sd.html USNO Master Clock Time for Atlantic Tropical Warnings Naval Meteorology and Oceanography Command, 1100 Balch Blvd, Stennis

The Master Clock Building at USNO Infrastructure

DTIC Science & Technology

2008-12-01

type finish on top of about 3.5 inches of foam insulation. This along with cinder block, fiber glass insulation, and 5/8-inch-X drywall provides a...keep the building on temperature. The outside surface of the building is an “Exterior Finish Insulation Systems” (EFIS). This is made up of a stucco

The Functional and Clinical Significance of the 24-Hour Rhythm of Circulating Glucocorticoids

PubMed Central

Oster, Henrik; Challet, Etienne; Ott, Volker; Arvat, Emanuela; de Kloet, E. Ronald; Dijk, Derk-Jan; Lightman, Stafford; Vgontzas, Alexandros

2017-01-01

Adrenal glucocorticoids are major modulators of multiple functions, including energy metabolism, stress responses, immunity, and cognition. The endogenous secretion of glucocorticoids is normally characterized by a prominent and robust circadian (around 24 hours) oscillation, with a daily peak around the time of the habitual sleep-wake transition and minimal levels in the evening and early part of the night. It has long been recognized that this 24-hour rhythm partly reflects the activity of a master circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus. In the past decade, secondary circadian clocks based on the same molecular machinery as the central master pacemaker were found in other brain areas as well as in most peripheral tissues, including the adrenal glands. Evidence is rapidly accumulating to indicate that misalignment between central and peripheral clocks has a host of adverse effects. The robust rhythm in circulating glucocorticoid levels has been recognized as a major internal synchronizer of the circadian system. The present review examines the scientific foundation of these novel advances and their implications for health and disease prevention and treatment. PMID:27749086

Brain clock driven by neuropeptides and second messengers

NASA Astrophysics Data System (ADS)

Miro-Bueno, Jesus; Sosík, Petr

2014-09-01

The master circadian pacemaker in mammals is localized in a small portion of the brain called the suprachiasmatic nucleus (SCN). It is unclear how the SCN produces circadian rhythms. A common interpretation is that the SCN produces oscillations through the coupling of genetic oscillators in the neurons. The coupling is effected by a network of neuropeptides and second messengers. This network is crucial for the correct function of the SCN. However, models that study a possible oscillatory behavior of the network itself have received little attention. Here we propose and analyze a model to examine this oscillatory potential. We show that an intercellular oscillator emerges in the SCN as a result of the neuropeptide and second messenger dynamics. We find that this intercellular clock can produce circadian rhythms by itself with and without genetic clocks. We also found that the model is robust to perturbation of parameters and can be entrained by light-dark cycles.

Brain clock driven by neuropeptides and second messengers.

PubMed

Miro-Bueno, Jesus; Sosík, Petr

2014-09-01

The master circadian pacemaker in mammals is localized in a small portion of the brain called the suprachiasmatic nucleus (SCN). It is unclear how the SCN produces circadian rhythms. A common interpretation is that the SCN produces oscillations through the coupling of genetic oscillators in the neurons. The coupling is effected by a network of neuropeptides and second messengers. This network is crucial for the correct function of the SCN. However, models that study a possible oscillatory behavior of the network itself have received little attention. Here we propose and analyze a model to examine this oscillatory potential. We show that an intercellular oscillator emerges in the SCN as a result of the neuropeptide and second messenger dynamics. We find that this intercellular clock can produce circadian rhythms by itself with and without genetic clocks. We also found that the model is robust to perturbation of parameters and can be entrained by light-dark cycles.

"Molecular Clock" Analogs: A Relative Rates Exercise

ERIC Educational Resources Information Center

Wares, John P.

2008-01-01

Although molecular clock theory is a commonly discussed facet of evolutionary biology, undergraduates are rarely presented with the underlying information of how this theory is examined relative to empirical data. Here a simple contextual exercise is presented that not only provides insight into molecular clocks, but is also a useful exercise for…

Light Stimulates the Mouse Adrenal through a Retinohypothalamic Pathway Independent of an Effect on the Clock in the Suprachiasmatic Nucleus

PubMed Central

Kiessling, Silke; Sollars, Patricia J.; Pickard, Gary E.

2014-01-01

The brain's master circadian pacemaker resides within the hypothalamic suprachiasmatic nucleus (SCN). SCN clock neurons are entrained to the day/night cycle via the retinohypothalamic tract and the SCN provides temporal information to the central nervous system and to peripheral organs that function as secondary oscillators. The SCN clock-cell network is thought to be the hypothalamic link between the retina and descending autonomic circuits to peripheral organs such as the adrenal gland, thereby entraining those organs to the day/night cycle. However, there are at least three different routes or mechanisms by which retinal signals transmitted to the hypothalamus may be conveyed to peripheral organs: 1) via retinal input to SCN clock neurons; 2) via retinal input to non-clock neurons in the SCN; or 3) via retinal input to hypothalamic regions neighboring the SCN. It is very well documented that light-induced responses of the SCN clock (i.e., clock gene expression, neural activity, and behavioral phase shifts) occur primarily during the subjective night. Thus to determine the role of the SCN clock in transmitting photic signals to descending autonomic circuits, we compared the phase dependency of light-evoked responses in the SCN and a peripheral oscillator, the adrenal gland. We observed light-evoked clock gene expression in the mouse adrenal throughout the subjective day and subjective night. Light also induced adrenal corticosterone secretion during both the subjective day and subjective night. The irradiance threshold for light-evoked adrenal responses was greater during the subjective day compared to the subjective night. These results suggest that retinohypothalamic signals may be relayed to the adrenal clock during the subjective day by a retinal pathway or cellular mechanism that is independent of an effect of light on the SCN neural clock network and thus may be important for the temporal integration of physiology and metabolism. PMID:24658072

A sense of time: how molecular clocks organize metabolism.

PubMed

Kohsaka, Akira; Bass, Joseph

2007-01-01

The discovery of an internal temporal clockwork that coordinates behavior and metabolism according to the rising and setting of the sun was first revealed in flies and plants. However, in the past decade, a molecular transcription-translation feedback loop with similar properties has also been identified in mammals. In mammals, this transcriptional oscillator programs 24-hour cycles in sleep, activity and feeding within the master pacemaker neurons of the suprachiasmatic nucleus of the hypothalamus. More recent studies have shown that the core transcription mechanism is also present in other locations within the brain, in addition to many peripheral tissues. Processes ranging from glucose transport to gluconeogenesis, lipolysis, adipogenesis and mitochondrial oxidative phosphorylation are controlled through overlapping transcription networks that are tied to the clock and are thus time sensitive. Because disruption of tissue timing occurs when food intake, activity and sleep are altered, understanding how these many tissue clocks are synchronized to tick at the same time each day, and determining how each tissue 'senses time' set by these molecular clocks might open new insight into human disease, including disorders of sleep, circadian disruption, diabetes and obesity.

Synthesizing genetic sequential logic circuit with clock pulse generator.

PubMed

Chuang, Chia-Hua; Lin, Chun-Liang

2014-05-28

Rhythmic clock widely occurs in biological systems which controls several aspects of cell physiology. For the different cell types, it is supplied with various rhythmic frequencies. How to synthesize a specific clock signal is a preliminary but a necessary step to further development of a biological computer in the future. This paper presents a genetic sequential logic circuit with a clock pulse generator based on a synthesized genetic oscillator, which generates a consecutive clock signal whose frequency is an inverse integer multiple to that of the genetic oscillator. An analogous electronic waveform-shaping circuit is constructed by a series of genetic buffers to shape logic high/low levels of an oscillation input in a basic sinusoidal cycle and generate a pulse-width-modulated (PWM) output with various duty cycles. By controlling the threshold level of the genetic buffer, a genetic clock pulse signal with its frequency consistent to the genetic oscillator is synthesized. A synchronous genetic counter circuit based on the topology of the digital sequential logic circuit is triggered by the clock pulse to synthesize the clock signal with an inverse multiple frequency to the genetic oscillator. The function acts like a frequency divider in electronic circuits which plays a key role in the sequential logic circuit with specific operational frequency. A cascaded genetic logic circuit generating clock pulse signals is proposed. Based on analogous implement of digital sequential logic circuits, genetic sequential logic circuits can be constructed by the proposed approach to generate various clock signals from an oscillation signal.

Identification of the Molecular Clockwork of the Oyster Crassostrea gigas

PubMed Central

Perrigault, Mickael; Tran, Damien

2017-01-01

Molecular clock system constitutes the origin of biological rhythms that allow organisms to anticipate cyclic environmental changes and adapt their behavior and physiology. Components of the molecular clock are largely conserved across a broad range of species but appreciable diversity in clock structure and function is also present especially in invertebrates. The present work aimed at identify and characterize molecular clockwork components in relationship with the monitoring of valve activity behavior in the oyster Crassostrea gigas. Results provided the characterization of most of canonical clock gene including clock, bmal/cycle, period, timeless, vertebrate-type cry, rev-erb, ror as well as other members of the cryptochrome/photolyase family (plant-like cry, 6–4 photolyase). Analyses of transcriptional variations of clock candidates in oysters exposed to light / dark regime and to constant darkness led to the generation of a putative and original clockwork model in C. gigas, intermediate of described systems in vertebrates and insects. This study is the first characterization of a mollusk clockwork. It constitutes essential bases to understand interactions of the different components of the molecular clock in C. gigas as well as the global mechanisms associated to the generation and the synchronization of biological rhythms in oysters. PMID:28072861

A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3beta.

PubMed

Hirota, Tsuyoshi; Lewis, Warren G; Liu, Andrew C; Lee, Jae Wook; Schultz, Peter G; Kay, Steve A

2008-12-30

The circadian clock controls daily oscillations of gene expression at the cellular level. We report the development of a high-throughput circadian functional assay system that consists of luminescent reporter cells, screening automation, and a data analysis pipeline. We applied this system to further dissect the molecular mechanisms underlying the mammalian circadian clock using a chemical biology approach. We analyzed the effect of 1,280 pharmacologically active compounds with diverse structures on the circadian period length that is indicative of the core clock mechanism. Our screening paradigm identified many compounds previously known to change the circadian period or phase, demonstrating the validity of the assay system. Furthermore, we found that small molecule inhibitors of glycogen synthase kinase 3 (GSK-3) consistently caused a strong short period phenotype in contrast to the well-known period lengthening by lithium, another presumed GSK-3 inhibitor. siRNA-mediated knockdown of GSK-3beta also caused a short period, confirming the phenotype obtained with the small molecule inhibitors. These results clarify the role of GSK-3beta in the period regulation of the mammalian clockworks and highlight the effectiveness of chemical biology in exploring unidentified mechanisms of the circadian clock.

The peripheral clock regulates human pigmentation.

PubMed

Hardman, Jonathan A; Tobin, Desmond J; Haslam, Iain S; Farjo, Nilofer; Farjo, Bessam; Al-Nuaimi, Yusur; Grimaldi, Benedetto; Paus, Ralf

2015-04-01

Although the regulation of pigmentation is well characterized, it remains unclear whether cell-autonomous controls regulate the cyclic on-off switching of pigmentation in the hair follicle (HF). As human HFs and epidermal melanocytes express clock genes and proteins, and given that core clock genes (PER1, BMAL1) modulate human HF cycling, we investigated whether peripheral clock activity influences human HF pigmentation. We found that silencing BMAL1 or PER1 in human HFs increased HF melanin content. Furthermore, tyrosinase expression and activity, as well as TYRP1 and TYRP2 mRNA levels, gp100 protein expression, melanocyte dendricity, and the number gp100+ HF melanocytes, were all significantly increased in BMAL1 and/or PER1-silenced HFs. BMAL1 or PER1 silencing also increased epidermal melanin content, gp100 protein expression, and tyrosinase activity in human skin. These effects reflect direct modulation of melanocytes, as BMAL1 and/or PER1 silencing in isolated melanocytes increased tyrosinase activity and TYRP1/2 expression. Mechanistically, BMAL1 knockdown reduces PER1 transcription, and PER1 silencing induces phosphorylation of the master regulator of melanogenesis, microphthalmia-associated transcription factor, thus stimulating human melanogenesis and melanocyte activity in situ and in vitro. Therefore, the molecular clock operates as a cell-autonomous modulator of human pigmentation and may be targeted for future therapeutic strategies.

Transcriptional oscillation of canonical clock genes in mouse peripheral tissues

PubMed Central

Yamamoto, Takuro; Nakahata, Yasukazu; Soma, Haruhiko; Akashi, Makoto; Mamine, Takayoshi; Takumi, Toru

2004-01-01

Background The circadian rhythm of about 24 hours is a fundamental physiological function observed in almost all organisms from prokaryotes to humans. Identification of clock genes has allowed us to study the molecular bases for circadian behaviors and temporal physiological processes such as hormonal secretion, and has prompted the idea that molecular clocks reside not only in a central pacemaker, the suprachiasmatic nuclei (SCN) of hypothalamus in mammals, but also in peripheral tissues, even in immortalized cells. Furthermore, previous molecular dissection revealed that the mechanism of circadian oscillation at a molecular level is based on transcriptional regulation of clock and clock-controlled genes. Results We systematically analyzed the mRNA expression of clock and clock-controlled genes in mouse peripheral tissues. Eight genes (mBmal1, mNpas2, mRev-erbα, mDbp, mRev-erbβ, mPer3, mPer1 and mPer2; given in the temporal order of the rhythm peak) showed robust circadian expressions of mRNAs in all tissues except testis, suggesting that these genes are core molecules of the molecular biological clock. The bioinformatics analysis revealed that these genes have one or a combination of 3 transcriptional elements (RORE, DBPE, and E-box), which are conserved among human, mouse, and rat genome sequences, and indicated that these 3 elements may be responsible for the biological timing of expression of canonical clock genes. Conclusions The observation of oscillatory profiles of canonical clock genes is not only useful for physiological and pathological examination of the circadian clock in various organs but also important for systematic understanding of transcriptional regulation on a genome-wide basis. Our finding of the oscillatory expression of canonical clock genes with a temporal order provides us an interesting hypothesis, that cyclic timing of all clock and clock-controlled genes may be dependent on several transcriptional elements including 3 known elements, E-box, RORE, and DBPE. PMID:15473909

Functional Peptidomics: Combining Discovery-Based Mass Spectrometry and Neurophysiology to Explore Communication of Phase-Resetting Cues in the Rat Suprachiasmatic Nucleus

ERIC Educational Resources Information Center

Atkins, Norman, Jr.

2009-01-01

Intercellular signaling is vital to communication within neuronal circuits. The suprachiasmatic nucleus (SCN), the master circadian clock of mammals, contains a dense collection of neurons that align their intrinsic rhythmicity with environmental stimulus and physiological state. While peptide physiology has been demonstrated as a contributor to…

Programmed Controls for an All-Electric School.

ERIC Educational Resources Information Center

Novak, W.J.

1965-01-01

Heating and ventilating equipment used in the all-electric upper Elementary School in Bedford, New Hampshire, is controlled to insure optimum comfort while the school is occupied and optimum economy of standby operation while it is not in use. A master clock programs all control functions while its mechanism drives two types of tapes--(1) a 365…

Dual PDF signaling pathways reset clocks via TIMELESS and acutely excite target neurons to control circadian behavior.

PubMed

Seluzicki, Adam; Flourakis, Matthieu; Kula-Eversole, Elzbieta; Zhang, Luoying; Kilman, Valerie; Allada, Ravi

2014-03-01

Molecular circadian clocks are interconnected via neural networks. In Drosophila, PIGMENT-DISPERSING FACTOR (PDF) acts as a master network regulator with dual functions in synchronizing molecular oscillations between disparate PDF(+) and PDF(-) circadian pacemaker neurons and controlling pacemaker neuron output. Yet the mechanisms by which PDF functions are not clear. We demonstrate that genetic inhibition of protein kinase A (PKA) in PDF(-) clock neurons can phenocopy PDF mutants while activated PKA can partially rescue PDF receptor mutants. PKA subunit transcripts are also under clock control in non-PDF DN1p neurons. To address the core clock target of PDF, we rescued per in PDF neurons of arrhythmic per⁰¹ mutants. PDF neuron rescue induced high amplitude rhythms in the clock component TIMELESS (TIM) in per-less DN1p neurons. Complete loss of PDF or PKA inhibition also results in reduced TIM levels in non-PDF neurons of per⁰¹ flies. To address how PDF impacts pacemaker neuron output, we focally applied PDF to DN1p neurons and found that it acutely depolarizes and increases firing rates of DN1p neurons. Surprisingly, these effects are reduced in the presence of an adenylate cyclase inhibitor, yet persist in the presence of PKA inhibition. We have provided evidence for a signaling mechanism (PKA) and a molecular target (TIM) by which PDF resets and synchronizes clocks and demonstrates an acute direct excitatory effect of PDF on target neurons to control neuronal output. The identification of TIM as a target of PDF signaling suggests it is a multimodal integrator of cell autonomous clock, environmental light, and neural network signaling. Moreover, these data reveal a bifurcation of PKA-dependent clock effects and PKA-independent output effects. Taken together, our results provide a molecular and cellular basis for the dual functions of PDF in clock resetting and pacemaker output.

Dual PDF Signaling Pathways Reset Clocks Via TIMELESS and Acutely Excite Target Neurons to Control Circadian Behavior

PubMed Central

Seluzicki, Adam; Flourakis, Matthieu; Kula-Eversole, Elzbieta; Zhang, Luoying; Kilman, Valerie; Allada, Ravi

2014-01-01

Molecular circadian clocks are interconnected via neural networks. In Drosophila, PIGMENT-DISPERSING FACTOR (PDF) acts as a master network regulator with dual functions in synchronizing molecular oscillations between disparate PDF(+) and PDF(−) circadian pacemaker neurons and controlling pacemaker neuron output. Yet the mechanisms by which PDF functions are not clear. We demonstrate that genetic inhibition of protein kinase A (PKA) in PDF(−) clock neurons can phenocopy PDF mutants while activated PKA can partially rescue PDF receptor mutants. PKA subunit transcripts are also under clock control in non-PDF DN1p neurons. To address the core clock target of PDF, we rescued per in PDF neurons of arrhythmic per01 mutants. PDF neuron rescue induced high amplitude rhythms in the clock component TIMELESS (TIM) in per-less DN1p neurons. Complete loss of PDF or PKA inhibition also results in reduced TIM levels in non-PDF neurons of per01 flies. To address how PDF impacts pacemaker neuron output, we focally applied PDF to DN1p neurons and found that it acutely depolarizes and increases firing rates of DN1p neurons. Surprisingly, these effects are reduced in the presence of an adenylate cyclase inhibitor, yet persist in the presence of PKA inhibition. We have provided evidence for a signaling mechanism (PKA) and a molecular target (TIM) by which PDF resets and synchronizes clocks and demonstrates an acute direct excitatory effect of PDF on target neurons to control neuronal output. The identification of TIM as a target of PDF signaling suggests it is a multimodal integrator of cell autonomous clock, environmental light, and neural network signaling. Moreover, these data reveal a bifurcation of PKA-dependent clock effects and PKA-independent output effects. Taken together, our results provide a molecular and cellular basis for the dual functions of PDF in clock resetting and pacemaker output. PMID:24643294

Adrenal-dependent and -independent stress-induced Per1 mRNA in hypothalamic paraventricular nucleus and prefrontal cortex of male and female rats.

PubMed

Chun, Lauren E; Christensen, Jenny; Woodruff, Elizabeth R; Morton, Sarah J; Hinds, Laura R; Spencer, Robert L

2018-01-01

Oscillating clock gene expression gives rise to a molecular clock that is present not only in the body's master circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN), but also in extra-SCN brain regions. These extra-SCN molecular clocks depend on the SCN for entrainment to a light:dark cycle. The SCN has limited neural efferents, so it may entrain extra-SCN molecular clocks through its well-established circadian control of glucocorticoid hormone secretion. Glucocorticoids can regulate the normal rhythmic expression of clock genes in some extra-SCN tissues. Untimely stress-induced glucocorticoid secretion may compromise extra-SCN molecular clock function. We examined whether acute restraint stress during the rat's inactive phase can rapidly (within 30 min) alter clock gene (Per1, Per2, Bmal1) and cFos mRNA (in situ hybridization) in the SCN, hypothalamic paraventricular nucleus (PVN), and prefrontal cortex (PFC) of male and female rats (6 rats per treatment group). Restraint stress increased Per1 and cFos mRNA in the PVN and PFC of both sexes. Stress also increased cFos mRNA in the SCN of male rats, but not when subsequently tested during their active phase. We also examined in male rats whether endogenous glucocorticoids are necessary for stress-induced Per1 mRNA (6-7 rats per treatment group). Adrenalectomy attenuated stress-induced Per1 mRNA in the PVN and ventral orbital cortex, but not in the medial PFC. These data indicate that increased Per1 mRNA may be a means by which extra-SCN molecular clocks adapt to environmental stimuli (e.g. stress), and in the PFC this effect is largely independent of glucocorticoids.

Modulation of learning and memory by the targeted deletion of the circadian clock gene Bmal1 in forebrain circuits.

PubMed

Snider, Kaitlin H; Dziema, Heather; Aten, Sydney; Loeser, Jacob; Norona, Frances E; Hoyt, Kari; Obrietan, Karl

2016-07-15

A large body of literature has shown that the disruption of circadian clock timing has profound effects on mood, memory and complex thinking. Central to this time keeping process is the master circadian pacemaker located within the suprachiasmatic nucleus (SCN). Of note, within the central nervous system, clock timing is not exclusive to the SCN, but rather, ancillary oscillatory capacity has been detected in a wide range of cell types and brain regions, including forebrain circuits that underlie complex cognitive processes. These observations raise questions about the hierarchical and functional relationship between the SCN and forebrain oscillators, and, relatedly, about the underlying clock-gated synaptic circuitry that modulates cognition. Here, we utilized a clock knockout strategy in which the essential circadian timing gene Bmal1 was selectively deleted from excitatory forebrain neurons, whilst the SCN clock remained intact, to test the role of forebrain clock timing in learning, memory, anxiety, and behavioral despair. With this model system, we observed numerous effects on hippocampus-dependent measures of cognition. Mice lacking forebrain Bmal1 exhibited deficits in both acquisition and recall on the Barnes maze. Notably, loss of forebrain Bmal1 abrogated time-of-day dependent novel object location memory. However, the loss of Bmal1 did not alter performance on the elevated plus maze, open field assay, and tail suspension test, indicating that this phenotype specifically impairs cognition but not affect. Together, these data suggest that forebrain clock timing plays a critical role in shaping the efficiency of learning and memory retrieval over the circadian day. Copyright © 2016 Elsevier B.V. All rights reserved.

Immunity's fourth dimension: approaching the circadian-immune connection.

PubMed

Arjona, Alvaro; Silver, Adam C; Walker, Wendy E; Fikrig, Erol

2012-12-01

The circadian system ensures the generation and maintenance of self-sustained ~24-h rhythms in physiology that are linked to internal and environmental changes. In mammals, daily variations in light intensity and other cues are integrated by a hypothalamic master clock that conveys circadian information to peripheral molecular clocks that orchestrate physiology. Multiple immune parameters also vary throughout the day and disruption of circadian homeostasis is associated with immune-related disease. Here, we discuss the molecular links between the circadian and immune systems and examine their outputs and disease implications. Understanding the mechanisms that underlie circadian-immune crosstalk may prove valuable for devising novel prophylactic and therapeutic interventions. Copyright © 2012 Elsevier Ltd. All rights reserved.

Synthesizing genetic sequential logic circuit with clock pulse generator

PubMed Central

2014-01-01

Background Rhythmic clock widely occurs in biological systems which controls several aspects of cell physiology. For the different cell types, it is supplied with various rhythmic frequencies. How to synthesize a specific clock signal is a preliminary but a necessary step to further development of a biological computer in the future. Results This paper presents a genetic sequential logic circuit with a clock pulse generator based on a synthesized genetic oscillator, which generates a consecutive clock signal whose frequency is an inverse integer multiple to that of the genetic oscillator. An analogous electronic waveform-shaping circuit is constructed by a series of genetic buffers to shape logic high/low levels of an oscillation input in a basic sinusoidal cycle and generate a pulse-width-modulated (PWM) output with various duty cycles. By controlling the threshold level of the genetic buffer, a genetic clock pulse signal with its frequency consistent to the genetic oscillator is synthesized. A synchronous genetic counter circuit based on the topology of the digital sequential logic circuit is triggered by the clock pulse to synthesize the clock signal with an inverse multiple frequency to the genetic oscillator. The function acts like a frequency divider in electronic circuits which plays a key role in the sequential logic circuit with specific operational frequency. Conclusions A cascaded genetic logic circuit generating clock pulse signals is proposed. Based on analogous implement of digital sequential logic circuits, genetic sequential logic circuits can be constructed by the proposed approach to generate various clock signals from an oscillation signal. PMID:24884665

Oscillator networks with tissue-specific circadian clocks in plants.

PubMed

Inoue, Keisuke; Araki, Takashi; Endo, Motomu

2017-09-08

Many organisms rely on circadian clocks to synchronize their biological processes with the 24-h rotation of the earth. In mammals, the circadian clock consists of a central clock in the suprachiasmatic nucleus and peripheral clocks in other tissues. The central clock is tightly coupled to synchronize rhythmicity and can organize peripheral clocks through neural and hormonal signals. In contrast to mammals, it has long been assumed that the circadian clocks in each plant cell is able to be entrained by external light, and they are only weakly coupled to each other. Recently, however, several reports have demonstrated that plants have unique oscillator networks with tissue-specific circadian clocks. Here, we introduce our current view regarding tissue-specific properties and oscillator networks of plant circadian clocks. Accumulating evidence suggests that plants have multiple oscillators, which show distinct properties and reside in different tissues. A direct tissue-isolation technique and micrografting have clearly demonstrated that plants have hierarchical oscillator networks consisting of multiple tissue-specific clocks. Copyright © 2017. Published by Elsevier Ltd.

CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial

USDA-ARS?s Scientific Manuscript database

Background Circadian rhythms regulate key biological processes influencing metabolic pathways. Dysregulation is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop involving core clock genes. CLOCK...

Circadian clocks in the cnidaria: environmental entrainment, molecular regulation, and organismal outputs.

PubMed

Reitzel, Adam M; Tarrant, Ann M; Levy, Oren

2013-07-01

The circadian clock is a molecular network that translates predictable environmental signals, such as light levels, into organismal responses, including behavior and physiology. Regular oscillations of the molecular components of the clock enable individuals to anticipate regularly fluctuating environmental conditions. Cnidarians play important roles in benthic and pelagic marine environments and also occupy a key evolutionary position as the likely sister group to the bilaterians. Together, these attributes make members of this phylum attractive as models for testing hypotheses on roles for circadian clocks in regulating behavior, physiology, and reproduction as well as those regarding the deep evolutionary conservation of circadian regulatory pathways in animal evolution. Here, we review and synthesize the field of cnidarian circadian biology by discussing the diverse effects of daily light cycles on cnidarians, summarizing the molecular evidence for the conservation of a bilaterian-like circadian clock in anthozoan cnidarians, and presenting new empirical data supporting the presence of a conserved feed-forward loop in the starlet sea anemone, Nematostella vectensis. Furthermore, we discuss critical gaps in our current knowledge about the cnidarian clock, including the functions directly regulated by the clock and the precise molecular interactions that drive the oscillating gene-expression patterns. We conclude that the field of cnidarian circadian biology is moving rapidly toward linking molecular mechanisms with physiology and behavior.

Daily NO rhythms in peripheral clocks in aging male Wistar rats: protective effects of exogenous melatonin.

PubMed

Vinod, Ch; Jagota, Anita

2016-11-01

In mammals suprachiasmatic nucleus (SCN), acts as a light entrainable master clock and by generation of temporal oscillations regulates the peripheral organs acting as autonomous clocks resulting in overt behavioral and physiological rhythms. SCN also controls synthesis and release of melatonin (hormonal message for darkness) from pineal. Nitric Oxide (NO) acts as an important neurotransmitter in generating the phase shifts of circadian rhythms and participates in sleep-wake processes, maintenance of vascular tone as well as signalling and regulating inflammatory processes. Aging is associated with disruption of circadian timing system and decline in endogenous melatonin leading to several physiological disorders. Here we report the effect of aging on NO daily rhythms in various peripheral clocks such as kidney, intestine, liver, heart, lungs and testis. NO levels were measured at zeitgeber time (ZT) 0, 6, 12 and 18 in these tissues using Griess assay in male Wistar rats. Aging resulted in alteration of NO levels as well as phase of NO in both 12 and 24 months groups. Correlation analysis demonstrated loss of stoichiometric interaction between the various peripheral clocks with aging. Age induced alterations in NO daily rhythms were found to be most significant in liver and, interestingly least in lungs. Neurohormone melatonin, an endogenous synchroniser and an antiaging agent decreases with aging. We report further differential restoration with exogenous melatonin administration of age induced alterations in NO daily rhythms and mean levels in kidney, intestine and liver and the stoichiometric interactions between the various peripheral clocks.

The Biological Clock: A Pivotal Hub in Non-alcoholic Fatty Liver Disease Pathogenesis

PubMed Central

Mazzoccoli, Gianluigi; De Cosmo, Salvatore; Mazza, Tommaso

2018-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most frequent hepatic pathology in the Western world and may evolve into steatohepatitis (NASH), increasing the risk of cirrhosis, portal hypertension and hepatocellular carcinoma. NAFLD derives from the accumulation of hepatic fat due to discrepant free fatty acid metabolism. Other factors contributing to this are deranged nutrients and bile acids fluxes as well as alterations in nuclear receptors, hormones, and intermediary metabolites, which impact on signaling pathways involved in metabolism and inflammation. Autophagy and host gut-microbiota interplay are also relevant to NAFLD pathogenesis. Notably, liver metabolic pathways and bile acid synthesis as well as autophagic and immune/inflammatory processes all show circadian patterns driven by the biological clock. Gut microbiota impacts on the biological clock, at the same time as the appropriate timing of metabolic fluxes, hormone secretion, bile acid turnover, autophagy and inflammation with behavioural cycles of fasting/feeding and sleeping/waking is required to circumvent hepatosteatosis, indicating significant interactions of the gut and circadian processes in NAFLD pathophysiology. Several time-related factors and processes interplay in NAFLD development, with the biological clock proposed to act as a network level hub. Deranged physiological rhythms (chronodisruption) may also play a role in liver steatosis pathogenesis. The current article reviews how the circadian clock circuitry intimately interacts with several mechanisms involved in the onset of hepatosteatosis and its progression to NASH, thereby contributing to the global NAFLD epidemic. PMID:29662454

A fluorescence spotlight on the clockwork development and metabolism of bone.

PubMed

Iimura, Tadahiro; Nakane, Ayako; Sugiyama, Mayu; Sato, Hiroki; Makino, Yuji; Watanabe, Takashi; Takagi, Yuzo; Numano, Rika; Yamaguchi, Akira

2012-05-01

Biological phenomena that exhibit periodic activity are often referred as biorhythms or biological clocks. Among these, circadian rhythms, cyclic patterns reflecting a 24-h cycle, are the most obvious in many physiological activities including bone growth and metabolism. In the late 1990s, several clock genes were isolated and their primary structures and functions were identified. The feedback loop model of transcriptional factors was proposed to work as a circadian core oscillator not only in the suprachiasmatic nuclei of the anterior hypothalamus, which is recognized as the mammalian central clock, but also in various peripheral tissues including cartilage and bone. Looking back to embryonic development, the fundamental architecture of skeletal patterning is regulated by ultradian clocks that are defined as biorhythms that cycle more than once every 24 h. As post-genomic approaches, transcriptome analysis by micro-array and bioimaging assays to detect luminescent and fluorescent signals have been exploited to uncover a more comprehensive set of genes and spatio-temporal regulation of the clockwork machinery in animal models. In this review paper, we provide an overview of topics related to these molecular clocks in skeletal biology and medicine, and discuss how fluorescence imaging approaches can contribute to widening our views of this realm of biomedical science.

The "fourth dimension" of gene transcription.

PubMed

O'Malley, Bert W

2009-05-01

The three dimensions of space provide our relationship to position on the earth, but the fourth dimension of time has an equally profound influence on our lives. Everything from light and sound to weather and biology operate on the principle of measurable temporal periodicity. Consequently, a wide variety of time clocks affect all aspects of our existence. The annual (and biannual) cycles of activity, metabolism, and mating, the monthly physiological clocks of women and men, and the 24-h diurnal rhythms of humans are prime examples. Should it be surprising to us that the fourth dimension also impinges upon gene expression and that the genome itself is regulated by the fastest running of all biological clocks? Recent evidence substantiates the existence of such a ubiquitin-dependent transcriptional clock that is based upon the activation and destruction of transcriptional coactivators.

The “Fourth Dimension” of Gene Transcription

PubMed Central

O'Malley, Bert W.

2009-01-01

The three dimensions of space provide our relationship to position on the earth, but the fourth dimension of time has an equally profound influence on our lives. Everything from light and sound to weather and biology operate on the principle of measurable temporal periodicity. Consequently, a wide variety of time clocks affect all aspects of our existence. The annual (and biannual) cycles of activity, metabolism, and mating, the monthly physiological clocks of women and men, and the 24-h diurnal rhythms of humans are prime examples. Should it be surprising to us that the fourth dimension also impinges upon gene expression and that the genome itself is regulated by the fastest running of all biological clocks? Recent evidence substantiates the existence of such a ubiquitin-dependent transcriptional clock that is based upon the activation and destruction of transcriptional coactivators. PMID:19221049

Reciprocity Between Robustness of Period and Plasticity of Phase in Biological Clocks

NASA Astrophysics Data System (ADS)

Hatakeyama, Tetsuhiro S.; Kaneko, Kunihiko

2015-11-01

Circadian clocks exhibit the robustness of period and plasticity of phase against environmental changes such as temperature and nutrient conditions. Thus far, however, it is unclear how both are simultaneously achieved. By investigating distinct models of circadian clocks, we demonstrate reciprocity between robustness and plasticity: higher robustness in the period implies higher plasticity in the phase, where changes in period and in phase follow a linear relationship with a negative coefficient. The robustness of period is achieved by the adaptation on the limit cycle via a concentration change of a buffer molecule, whose temporal change leads to a phase shift following a shift of the limit-cycle orbit in phase space. Generality of reciprocity in clocks with the adaptation mechanism is confirmed with theoretical analysis of simple models, while biological significance is discussed.

The Circadian Clock Coordinates Ribosome Biogenesis

PubMed Central

Symul, Laura; Martin, Eva; Atger, Florian; Naef, Felix; Gachon, Frédéric

2013-01-01

Biological rhythms play a fundamental role in the physiology and behavior of most living organisms. Rhythmic circadian expression of clock-controlled genes is orchestrated by a molecular clock that relies on interconnected negative feedback loops of transcription regulators. Here we show that the circadian clock exerts its function also through the regulation of mRNA translation. Namely, the circadian clock influences the temporal translation of a subset of mRNAs involved in ribosome biogenesis by controlling the transcription of translation initiation factors as well as the clock-dependent rhythmic activation of signaling pathways involved in their regulation. Moreover, the circadian oscillator directly regulates the transcription of ribosomal protein mRNAs and ribosomal RNAs. Thus the circadian clock exerts a major role in coordinating transcription and translation steps underlying ribosome biogenesis. PMID:23300384

Sleep, rhythms, and the endocrine brain: influence of sex and gonadal hormones.

PubMed

Mong, Jessica A; Baker, Fiona C; Mahoney, Megan M; Paul, Ketema N; Schwartz, Michael D; Semba, Kazue; Silver, Rae

2011-11-09

While much is known about the mechanisms that underlie sleep and circadian rhythms, the investigation into sex differences and gonadal steroid modulation of sleep and biological rhythms is in its infancy. There is a growing recognition of sex disparities in sleep and rhythm disorders. Understanding how neuroendocrine mediators and sex differences influence sleep and biological rhythms is central to advancing our understanding of sleep-related disorders. While it is known that ovarian steroids affect circadian rhythms in rodents, the role of androgen is less understood. Surprising findings that androgens, acting via androgen receptors in the master "circadian clock" within the suprachiasmatic nucleus, modulate photic effects on activity in males point to novel mechanisms of circadian control. Work in aromatase-deficient mice suggests that some sex differences in photic responsiveness are independent of gonadal hormone effects during development. In parallel, aspects of sex differences in sleep are also reported to be independent of gonadal steroids and may involve sex chromosome complement. This a summary of recent work illustrating how sex differences and gonadal hormones influence sleep and circadian rhythms that was presented at a Mini-Symposium at the 2011 annual meeting of the Society for Neuroscience.

External Link Disclaimer - Naval Oceanography Portal

Science.gov Websites

, the United States Department of the Navy or [command name] of the linked web sites, or the information purpose of this DoD web site. USNO Master Clock Time Javascript must be Enabled The Sky This Week The Sky | navy.com | Freedom of Information Act (FOIA) | External Link Disclaimer This is an official U.S. Navy web

A feasibility study of a data acquisition system for a silicon strip detector with a digital readout scheme

NASA Astrophysics Data System (ADS)

Ikeda, Hirokazu; Ikeda, Mitsuo; Inaba, Susumu; Tanaka, Manobu

1993-06-01

We describe a prototype data acquisition system for a silicon strip detector, which has been developed in terms of a digital readout scheme. The system consists of a master timing generator, readout controller, and a detector emulator card on which we use custom VLSI shift registers with operating clock frequency of 30 MHz.

Galileo Timing Applications

DTIC Science & Technology

2007-11-01

available architecture for time and synchronization information distribution was at that time implemented with a single Master Clock. The signal of...a hierarchical approach. Moreover, analyzing this architecture , it is clear that there is signal performance degradation due to the distribution...applications. Figure 2 depicts the time distribution architecture implemented via GNSS. The main difference with respect to the previous one is that all the

Biochemical Frequency Control by Synchronisation of Coupled Repressilators: An In Silico Study of Modules for Circadian Clock Systems

PubMed Central

Hinze, Thomas; Schumann, Mathias; Bodenstein, Christian; Heiland, Ines; Schuster, Stefan

2011-01-01

Exploration of chronobiological systems emerges as a growing research field within bioinformatics focusing on various applications in medicine, agriculture, and material sciences. From a systems biological perspective, the question arises whether biological control systems for regulation of oscillatory signals and their technical counterparts utilise similar mechanisms. If so, modelling approaches and parameterisation adopted from building blocks can help to identify general components for frequency control in circadian clocks along with gaining insight into mechanisms of clock synchronisation to external stimuli like the daily rhythm of sunlight and darkness. Phase-locked loops could be an interesting candidate in this context. Both, biology and engineering, can benefit from a unified view resulting from systems modularisation. In a first experimental study, we analyse a model of coupled repressilators. We demonstrate its ability to synchronise clock signals in a monofrequential manner. Several oscillators initially deviate in phase difference and frequency with respect to explicit reaction and diffusion rates. Accordingly, the duration of the synchronisation process depends on dedicated reaction and diffusion parameters whose settings still lack to be sufficiently captured analytically. PMID:22046179

Development of a strontium optical lattice clock for space applications

NASA Astrophysics Data System (ADS)

Singh, Yeshpal

2016-07-01

With timekeeping being of paramount importance for modern life, much research and major scientific advances have been undertaken in the field of frequency metrology, particularly over the last few years. New Nobel-prize winning technologies have enabled a new era of atomic clocks; namely the optical clock. These have been shown to perform significantly better than the best microwave clocks reaching an inaccuracy of 1.6x10-18 [1]. With such results being found in large lab based apparatus, the focus now has shifted to portability - to enable the accuracy of various ground based clocks to be measured, and compact autonomous performance - to enable such technologies to be tested in space. This could lead to a master clock in space, improving not only the accuracy of technologies on which modern life has come to require such as GPS and communication networks. But also more fundamentally, this could lead to the redefinition of the second and tests of fundamental physics including applications in the fields of ground based and satellite geodesy, metrology, positioning, navigation, transport and logistics etc. Within the European collaboration, Space Optical Clocks (SOC2) [2-3] consisting of various institutes and industry partners across Europe we have tried to tackle this problem of miniaturisation whilst maintaining stability, accuracy (5x10-17) and robustness whilst keeping power consumption to a minimum - necessary for space applications. We will present the most recent results of the Sr optical clock in SOC2 and also the novel compact design features, new methods employed and outlook. References [1] B. J. Bloom, T. L. Nicholson, J. R. Williams, S. L. Campbell, M. Bishof, X. Zhang, W. Zhang, S. L. Bromley, and J. Ye, "An optical lattice clock with accuracy and stability at the 10-18 level," Nature 506, 71-75 (2014). [2] S. Schiller et al. "Towards Neutral-atom Space Optical Clocks (SOC2): Development of high-performance transportable and breadboard optical clocks and advanced subsystems" on "Let's embrace space, volume II" 45, 452-463 (2012). ISBN 978-92-79-22207-8. [3] www.soc2.eu

Motivational Modulation of Rhythms of the Expression of the Clock Protein PER2 in the Limbic Forebrain.

PubMed

Amir, Shimon; Stewart, Jane

2009-05-15

Key molecular components of the mammalian circadian clock are expressed rhythmically in many brain areas and peripheral tissues in mammals. Here we review findings from our work on rhythms of expression of the clock protein Period2 (PER2) in four regions of the limbic forebrain known to be important in the regulation of motivational and emotional states. These regions include the oval nucleus of the bed nucleus of the stria terminalis (BNSTov), the central nucleus of the amygdala (CEA), the basolateral amygdala (BLA), and the dentate gyrus (DG). Daily rhythms in the expression of PER2 in these regions are controlled by the master circadian pacemaker, the suprachiasmatic nucleus (SCN), but, importantly, they are also sensitive to homeostatic perturbations and to hormonal states that directly influence motivated behavior. Thus, circadian information from the SCN and homeostatic signals are integrated in these regions of the limbic forebrain to affect the temporal organization of motivational and emotional processes.

An expanding universe of circadian networks in higher plants.

PubMed

Pruneda-Paz, Jose L; Kay, Steve A

2010-05-01

Extensive circadian clock networks regulate almost every biological process in plants. Clock-controlled physiological responses are coupled with daily oscillations in environmental conditions resulting in enhanced fitness and growth vigor. Identification of core clock components and their associated molecular interactions has established the basic network architecture of plant clocks, which consists of multiple interlocked feedback loops. A hierarchical structure of transcriptional feedback overlaid with regulated protein turnover sets the pace of the clock and ultimately drives all clock-controlled processes. Although originally described as linear entities, increasing evidence suggests that many signaling pathways can act as both inputs and outputs within the overall network. Future studies will determine the molecular mechanisms involved in these complex regulatory loops. 2010 Elsevier Ltd. All rights reserved.

A tunable artificial circadian clock in clock-defective mice

PubMed Central

D'Alessandro, Matthew; Beesley, Stephen; Kim, Jae Kyoung; Chen, Rongmin; Abich, Estela; Cheng, Wayne; Yi, Paul; Takahashi, Joseph S.; Lee, Choogon

2015-01-01

Self-sustaining oscillations are essential for diverse physiological functions such as the cell cycle, insulin secretion and circadian rhythms. Synthetic oscillators using biochemical feedback circuits have been generated in cell culture. These synthetic systems provide important insight into design principles for biological oscillators, but have limited similarity to physiological pathways. Here we report the generation of an artificial, mammalian circadian clock in vivo, capable of generating robust, tunable circadian rhythms. In mice deficient in Per1 and Per2 genes (thus lacking circadian rhythms), we artificially generate PER2 rhythms and restore circadian sleep/wake cycles with an inducible Per2 transgene. Our artificial clock is tunable as the period and phase of the rhythms can be modulated predictably. This feature, and other design principles of our work, might enhance the study and treatment of circadian dysfunction and broader aspects of physiology involving biological oscillators. PMID:26617050

The pedestrian watchmaker: Genetic clocks from engineered oscillators

PubMed Central

Cookson, Natalie A.; Tsimring, Lev S.; Hasty, Jeff

2010-01-01

The crucial role of time-keeping has required organisms to develop sophisticated regulatory networks to ensure the reliable propagation of periodic behavior. These biological clocks have long been a focus of research; however, a clear understanding of how they maintain oscillations in the face of unpredictable environments and the inherent noise of biological systems remains elusive. Here, we review the current understanding of circadian oscillations using Drosophila melanogaster as a typical example and discuss the utility of an alternative synthetic biology approach to studying these highly intricate systems. PMID:19903483

The metabolic sensor AKIN10 modulates the Arabidopsis circadian clock in a light-dependent manner.

PubMed

Shin, Jieun; Sánchez-Villarreal, Alfredo; Davis, Amanda M; Du, Shen-Xiu; Berendzen, Kenneth W; Koncz, Csaba; Ding, Zhaojun; Li, Cuiling; Davis, Seth J

2017-07-01

Plants generate rhythmic metabolism during the repetitive day/night cycle. The circadian clock produces internal biological rhythms to synchronize numerous metabolic processes such that they occur at the required time of day. Metabolism conversely influences clock function by controlling circadian period and phase and the expression of core-clock genes. Here, we show that AKIN10, a catalytic subunit of the evolutionarily conserved key energy sensor sucrose non-fermenting 1 (Snf1)-related kinase 1 (SnRK1) complex, plays an important role in the circadian clock. Elevated AKIN10 expression led to delayed peak expression of the circadian clock evening-element GIGANTEA (GI) under diurnal conditions. Moreover, it lengthened clock period specifically under light conditions. Genetic analysis showed that the clock regulator TIME FOR COFFEE (TIC) is required for this effect of AKIN10. Taken together, we propose that AKIN10 conditionally works in a circadian clock input pathway to the circadian oscillator. © 2017 John Wiley & Sons Ltd.

Circadian Clocks in the Cnidaria: Environmental Entrainment, Molecular Regulation, and Organismal Outputs

PubMed Central

Reitzel, Adam M.; Tarrant, Ann M.; Levy, Oren

2013-01-01

The circadian clock is a molecular network that translates predictable environmental signals, such as light levels, into organismal responses, including behavior and physiology. Regular oscillations of the molecular components of the clock enable individuals to anticipate regularly fluctuating environmental conditions. Cnidarians play important roles in benthic and pelagic marine environments and also occupy a key evolutionary position as the likely sister group to the bilaterians. Together, these attributes make members of this phylum attractive as models for testing hypotheses on roles for circadian clocks in regulating behavior, physiology, and reproduction as well as those regarding the deep evolutionary conservation of circadian regulatory pathways in animal evolution. Here, we review and synthesize the field of cnidarian circadian biology by discussing the diverse effects of daily light cycles on cnidarians, summarizing the molecular evidence for the conservation of a bilaterian-like circadian clock in anthozoan cnidarians, and presenting new empirical data supporting the presence of a conserved feed-forward loop in the starlet sea anemone, Nematostella vectensis. Furthermore, we discuss critical gaps in our current knowledge about the cnidarian clock, including the functions directly regulated by the clock and the precise molecular interactions that drive the oscillating gene-expression patterns. We conclude that the field of cnidarian circadian biology is moving rapidly toward linking molecular mechanisms with physiology and behavior. PMID:23620252

Life's Dance to the Music of Time: The Clocks within Us.

ERIC Educational Resources Information Center

Lloyd, David

1988-01-01

Describes circadian timekeeping which matches internal states with environmental changes, and the ultradian clock which coordinates intracellular processes including energy cycles, protein turnover, and cell division. Presents discussions of biological rhythms and its characteristics. (RT)

Endlessly Circulating Messages in IEEE 1588-2008 Systems

DTIC Science & Technology

2014-05-13

section 13.5 of the standard. Once the timing topology is established by the BMC algo- rithm, each clock synchronizes to its master by exchanging timing ...Endlessly Circulating Messages in IEEE 1588-2008 Systems David Broman Patricia Derler Ankush Desai John Eidson Sanjit A. Seshia Electrical...estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the

New Steering Strategies for the USNO Master Clocks

DTIC Science & Technology

1999-12-01

1992. P. Koppang and R. Leland , “Linear quadratic stochastic control of atomic hydrogen masers,” IEEE Trans. Ultrason., Ferroelect., Freq. Contr...vol. 46, pp. 517-522, May 1999. P. Koppang and R. Leland , “Steering of frequency standards by the use of linear quadratic gaussian control theory...3lst Annual Precise Time and Time Interval (PTTI) Meeting NEWSTEERINGSTRATEGIESFOR THEUSNOMASTERCLOCKS Paul A. Koppang Datum, Inc. Beverly, MA

Time Service Dept., United States Naval Observatory

Science.gov Websites

Features What Time is it? USNO Master Clock Cesium Fountain Linear Ion Trap GPS Satellite Time Transfer Network Time Service Telephone Time US Time Zones Systems of Time Leap Seconds Highlights Daily Home ntp.org Contact the USNO The Sky This Week Sun Rise/Set Tour Info Travel Directions Department of

Reconfiguration of a Multi-oscillator Network by Light in the Drosophila Circadian Clock.

PubMed

Chatterjee, Abhishek; Lamaze, Angélique; De, Joydeep; Mena, Wilson; Chélot, Elisabeth; Martin, Béatrice; Hardin, Paul; Kadener, Sebastian; Emery, Patrick; Rouyer, François

2018-06-07

The brain clock that drives circadian rhythms of locomotor activity relies on a multi-oscillator neuronal network. In addition to synchronizing the clock with day-night cycles, light also reformats the clock-driven daily activity pattern. How changes in lighting conditions modify the contribution of the different oscillators to remodel the daily activity pattern remains largely unknown. Our data in Drosophila indicate that light readjusts the interactions between oscillators through two different modes. We show that a morning s-LNv > DN1p circuit works in series, whereas two parallel evening circuits are contributed by LNds and other DN1ps. Based on the photic context, the master pacemaker in the s-LNv neurons swaps its enslaved partner-oscillator-LNd in the presence of light or DN1p in the absence of light-to always link up with the most influential phase-determining oscillator. When exposure to light further increases, the light-activated LNd pacemaker becomes independent by decoupling from the s-LNvs. The calibration of coupling by light is layered on a clock-independent network interaction wherein light upregulates the expression of the PDF neuropeptide in the s-LNvs, which inhibits the behavioral output of the DN1p evening oscillator. Thus, light modifies inter-oscillator coupling and clock-independent output-gating to achieve flexibility in the network. It is likely that the light-induced changes in the Drosophila brain circadian network could reveal general principles of adapting to varying environmental cues in any neuronal multi-oscillator system. Copyright © 2018 Elsevier Ltd. All rights reserved.

Depression-like behaviour in mice is associated with disrupted circadian rhythms in nucleus accumbens and periaqueductal grey.

PubMed

Landgraf, Dominic; Long, Jaimie E; Welsh, David K

2016-05-01

An association between circadian rhythms and mood regulation is well established, and disturbed circadian clocks are believed to contribute to the development of mood disorders, including major depressive disorder. The circadian system is coordinated by the suprachiasmatic nucleus (SCN), the master pacemaker in the hypothalamus that receives light input from the retina and synchronizes circadian oscillators in other brain regions and peripheral tissues. Lacking the tight neuronal network that couples single-cell oscillators in the SCN, circadian clocks outside the SCN may be less stable and more susceptible to disturbances, for example by clock gene mutations or uncontrollable stress. However, non-SCN circadian clocks have not been studied extensively in rodent models of mood disorders. In the present study, it was hypothesized that disturbances of local circadian clocks in mood-regulating brain areas are associated with depression-like behaviour in mice. Using the learned helplessness procedure, depression-like behaviour was evoked in mice bearing the PER2::LUC circadian reporter, and then circadian rhythms of PER2 expression were examined in brain slices from these mice using luminometry and bioluminescence imaging. It was found that helplessness is associated with absence of circadian rhythms in the nucleus accumbens and the periaqueductal grey, two of the most critical brain regions within the reward circuit. The current study provides evidence that susceptibility of mice to depression-like behaviour is associated with disturbed local circadian clocks in a subset of mood-regulating brain areas, but the direction of causality remains to be determined. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Development of a beam test telescope based on the Alibava readout system

NASA Astrophysics Data System (ADS)

Marco-Hernández, R.

2011-01-01

A telescope for a beam test have been developed as a result of a collaboration among the University of Liverpool, Centro Nacional de Microelectrónica (CNM) of Barcelona and Instituto de Física Corpuscular (IFIC) of Valencia. This system is intended to carry out both analogue charge collection and spatial resolution measurements with different types of microstrip or pixel silicon detectors in a beam test environment. The telescope has four XY measurement as well as trigger planes (XYT board) and it can accommodate up to twelve devices under test (DUT board). The DUT board uses two Beetle ASICs for the readout of chilled silicon detectors. The board could operate in a self-triggering mode. The board features a temperature sensor and it can be mounted on a rotary stage. A peltier element is used for cooling the DUT. Each XYT board measures the track space points using two silicon strip detectors connected to two Beetle ASICs. It can also trigger on the particle tracks in the beam test. The board includes a CPLD which allows for the synchronization of the trigger signal to a common clock frequency, delaying and implementing coincidence with other XYT boards. An Alibava mother board is used to read out and to control each XYT/DUT board from a common trigger signal and a common clock signal. The Alibava board has a TDC on board to have a time stamp of each trigger. The data collected by each Alibava board is sent to a master card by means of a local data/address bus following a custom digital protocol. The master board distributes the trigger, clock and reset signals. It also merges the data streams from up to sixteen Alibava boards. The board has also a test channel for testing in a standard mode a XYT or DUT board. This board is implemented with a Xilinx development board and a custom patch board. The master board is connected with the DAQ software via 100M Ethernet. Track based alignment software has also been developed for the data obtained with the DAQ software.

Putative melatonin receptors in a human biological clock

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reppert, S.M.; Weaver, D.R.; Rivkees, S.A.

In vitro autoradiography with /sup 125/I-labeled melatonin was used to examine melatonin binding sites in human hypothalamus. Specific /sup 125/I-labeled melatonin binding was localized to the suprachiasmatic nuclei, the site of a putative biological clock, and was not apparent in other hypothalamic regions. Specific /sup 125/I-labeled melatonin binding was consistently found in the suprachiasmatic nuclei of hypothalami from adults and fetuses. Densitometric analysis of competition experiments with varying concentrations of melatonin showed monophasic competition curves, with comparable half-maximal inhibition values for the suprachiasmatic nuclei of adults (150 picomolar) and fetuses (110 picomolar). Micromolar concentrations of the melatonin agonist 6-chloromelatonin completelymore » inhibited specific /sup 125/I-labeled melatonin binding, whereas the same concentrations of serotonin and norepinephrine caused only a partial reduction in specific binding. The results suggest that putative melatonin receptors are located in a human biological clock.« less

Loran-C time management

NASA Technical Reports Server (NTRS)

Justice, Charles; Mason, Norm; Taggart, Doug

1994-01-01

As of 1 Oct. 1993, the US Coast Guard (USCG) supports and operates fifteen Loran-C chains. With the introduction of the Global Positioning Systems (GPS) and the termination of the Department of Defense (DOD) overseas need for Loran-C, the USCG will cease operating the three remaining overseas chains by 31 Dec. 1994. Following this date, the USCG Loran-C system will consist of twelve chains. Since 1971, management of time synchronization of the Loran-C system has been conducted under a Memorandum of Agreement between the US Naval Observatory (USNO) and the USCG. The requirement to maintain synchronization with Coordinated Universal Time (UTC) was initially specified as +/- 25 microseconds. This tolerance was rapidly lowered to +/- 2.5 microseconds in 1974. To manage this synchronization requirement, the USCG incorporated administrative practices which kept the USNO appraised of all aspects of the master timing path. This included procedures for responding to timing path failures, timing adjustments, and time steps. Conducting these aspects of time synchronization depended on message traffic between the various master stations and the USNO. To determine clock adjustment the USCG relied upon the USNO's Series 4 and 100 updates so that the characteristics of the master clock could be plotted and controls appropriately applied. In 1987, Public Law 100-223, under the Airport and Airway Improvement Act Amendment, reduced the synchronization tolerance to approximately 100 nanoseconds for chains serving the National Airspace System (NAS). This action caused changes in the previous administrative procedures and techniques. The actions taken by the USCG to meet the requirements of this law are presented.

Protein malnutrition after weaning disrupts peripheral clock and daily insulin secretion in mice.

PubMed

Borck, Patricia Cristine; Batista, Thiago Martins; Vettorazzi, Jean Franciesco; Camargo, Rafael Ludemann; Boschero, Antonio Carlos; Vieira, Elaine; Carneiro, Everardo Magalhães

2017-12-01

Changes in nutritional state may alter circadian rhythms through alterations in expression of clock genes. Protein deficiency has a profound effect on body metabolism, but the effect of this nutrient restriction after weaning on biological clock has not been explored. Thus, this study aims to investigate whether the protein restriction affects the daily oscillation in the behavior and metabolic rhythms, as well as expression of clock genes in peripheral tissues. Male C57BL/6 J mice, after weaning, were fed a normal-protein (NP) diet or a low-protein (LP) diet for 8 weeks. Mice fed an LP diet did not show difference in locomotor activity and energy expenditure, but the food intake was increased, with parallel increased expression of the orexigenic neuropeptide Npy and disruption of the anorexigenic Pomc oscillatory pattern in the hypothalamus. LP mice showed disruption in the daily rhythmic patterns of plasma glucose, triglycerides and insulin. Also, the rhythmic expression of clock genes in peripheral tissues and pancreatic islets was altered in LP mice. In pancreatic islets, the disruption of clock genes was followed by impairment of daily glucose-stimulated insulin secretion and the expression of genes involved in exocytosis. Pharmacological activation of REV-ERBα could not restore the insulin secretion in LP mice. The present study demonstrates that protein restriction, leading to development of malnutrition, alters the peripheral clock and metabolic outputs, suggesting that this nutrient provides important entraining cues to regulate the daily fluctuation of biological clock. Copyright © 2017 Elsevier Inc. All rights reserved.

Systems approach identifies an organic nitrogen-responsive gene network that is regulated by the master clock control gene CCA1.

PubMed

Gutiérrez, Rodrigo A; Stokes, Trevor L; Thum, Karen; Xu, Xiaodong; Obertello, Mariana; Katari, Manpreet S; Tanurdzic, Milos; Dean, Alexis; Nero, Damion C; McClung, C Robertson; Coruzzi, Gloria M

2008-03-25

Understanding how nutrients affect gene expression will help us to understand the mechanisms controlling plant growth and development as a function of nutrient availability. Nitrate has been shown to serve as a signal for the control of gene expression in Arabidopsis. There is also evidence, on a gene-by-gene basis, that downstream products of nitrogen (N) assimilation such as glutamate (Glu) or glutamine (Gln) might serve as signals of organic N status that in turn regulate gene expression. To identify genome-wide responses to such organic N signals, Arabidopsis seedlings were transiently treated with ammonium nitrate in the presence or absence of MSX, an inhibitor of glutamine synthetase, resulting in a block of Glu/Gln synthesis. Genes that responded to organic N were identified as those whose response to ammonium nitrate treatment was blocked in the presence of MSX. We showed that some genes previously identified to be regulated by nitrate are under the control of an organic N-metabolite. Using an integrated network model of molecular interactions, we uncovered a subnetwork regulated by organic N that included CCA1 and target genes involved in N-assimilation. We validated some of the predicted interactions and showed that regulation of the master clock control gene CCA1 by Glu or a Glu-derived metabolite in turn regulates the expression of key N-assimilatory genes. Phase response curve analysis shows that distinct N-metabolites can advance or delay the CCA1 phase. Regulation of CCA1 by organic N signals may represent a novel input mechanism for N-nutrients to affect plant circadian clock function.

Tales around the clock: Poly(A) tails in circadian gene expression.

PubMed

Beta, Rafailia A A; Balatsos, Nikolaos A A

2018-06-17

Circadian rhythms are ubiquitous time-keeping processes in eukaryotes with a period of ~24 hr. Light is perhaps the main environmental cue (zeitgeber) that affects several aspects of physiology and behaviour, such as sleep/wake cycles, orientation of birds and bees, and leaf movements in plants. Temperature can serve as the main zeitgeber in the absence of light cycles, even though it does not lead to rhythmicity through the same mechanism as light. Additional cues include feeding patterns, humidity, and social rhythms. At the molecular level, a master oscillator orchestrates circadian rhythms and organizes molecular clocks located in most cells. The generation of the 24 hr molecular clock is based on transcriptional regulation, as it drives intrinsic rhythmic changes based on interlocked transcription/translation feedback loops that synchronize expression of genes. Thus, processes and factors that determine rhythmic gene expression are important to understand circadian rhythms. Among these, the poly(A) tails of RNAs play key roles in their stability, translational efficiency and degradation. In this article, we summarize current knowledge and discuss perspectives on the role and significance of poly(A) tails and associating factors in the context of the circadian clock. This article is categorized under: RNA Turnover and Surveillance > Regulation of RNA Stability RNA Processing > 3' End Processing. © 2018 Wiley Periodicals, Inc.

The Catalytic and Non-catalytic Functions of the Brahma Chromatin-Remodeling Protein Collaborate to Fine-Tune Circadian Transcription in Drosophila

PubMed Central

Kwok, Rosanna S.; Li, Ying H.; Lei, Anna J.; Edery, Isaac; Chiu, Joanna C.

2015-01-01

Daily rhythms in gene expression play a critical role in the progression of circadian clocks, and are under regulation by transcription factor binding, histone modifications, RNA polymerase II (RNAPII) recruitment and elongation, and post-transcriptional mechanisms. Although previous studies have shown that clock-controlled genes exhibit rhythmic chromatin modifications, less is known about the functions performed by chromatin remodelers in animal clockwork. Here we have identified the Brahma (Brm) complex as a regulator of the Drosophila clock. In Drosophila, CLOCK (CLK) is the master transcriptional activator driving cyclical gene expression by participating in an auto-inhibitory feedback loop that involves stimulating the expression of the main negative regulators, period (per) and timeless (tim). BRM functions catalytically to increase nucleosome density at the promoters of per and tim, creating an overall restrictive chromatin landscape to limit transcriptional output during the active phase of cycling gene expression. In addition, the non-catalytic function of BRM regulates the level and binding of CLK to target promoters and maintains transient RNAPII stalling at the per promoter, likely by recruiting repressive and pausing factors. By disentangling its catalytic versus non-catalytic functions at the promoters of CLK target genes, we uncovered a multi-leveled mechanism in which BRM fine-tunes circadian transcription. PMID:26132408

Application of Control Theory in the Formation of a Timescale

DTIC Science & Technology

2004-09-01

York). [3] P. Koppang and R. Leland , 1999, “Linear quadratic stochastic control of atomic hydrogen masers,” IEEE Transactions on Ultrasonics... Koppang , D. Johns, and J. Skinner U.S. Naval Observatory Abstract We have created a timescale that joins the short-term stability of...comparison. REFERENCES [1] D. Matsakis, M. Miranian, and P. Koppang , 1999, “Steering the U.S. Naval Observatory (USNO) Master Clock,” in

USNO Master Clock Design Enhancements

DTIC Science & Technology

2007-01-01

25-27 January 1999, San Diego, California, USA (ION, Alexandria, Virginia), pp. 871-880. [3] R. Brown and P. Hwang , 1992, Introduction to Random...to the system include the use of a Kalman filter for phase and frequency estimates, decreasing the time interval between steers, and the redesign of...present operational system utilizes the dynamic mean as described in the previous section, but uses a Kalman filter to estimate the phase and frequency

Time synchronization via lunar radar.

NASA Technical Reports Server (NTRS)

Higa, W. H.

1972-01-01

The advent of round-trip radar measurements has permitted the determination of the ranges to the nearby planets with greater precision than was previously possible. When the distances to the planets are known with high precision, the propagation delay for electromagnetic waves reflected by the planets may be calculated and used to synchronize remotely located clocks. Details basic to the operation of a lunar radar indicate a capability for clock synchronization to plus or minus 20 microsec. One of the design goals for this system was to achieve a simple semiautomatic receiver for remotely located tracking stations. The lunar radar system is in operational use for deep space tracking at Jet Propulsion Laboratory and synchronizes five world-wide tracking stations with a master clock at Goldstone, Calif. Computers are programmed to correct the Goldstone transmissions for transit time delay and Doppler shifts so as to be received on time at the tracking stations; this dictates that only one station can be synchronized at a given time period and that the moon must be simultaneously visible to both the transmitter and receiver for a minimum time of 10 min.-

Signals from the brainstem sleep/wake centers regulate behavioral timing via the circadian clock.

PubMed

Abbott, Sabra M; Arnold, Jennifer M; Chang, Qing; Miao, Hai; Ota, Nobutoshi; Cecala, Christine; Gold, Paul E; Sweedler, Jonathan V; Gillette, Martha U

2013-01-01

Sleep-wake cycling is controlled by the complex interplay between two brain systems, one which controls vigilance state, regulating the transition between sleep and wake, and the other circadian, which communicates time-of-day. Together, they align sleep appropriately with energetic need and the day-night cycle. Neural circuits connect brain stem sites that regulate vigilance state with the suprachiasmatic nucleus (SCN), the master circadian clock, but the function of these connections has been unknown. Coupling discrete stimulation of pontine nuclei controlling vigilance state with analytical chemical measurements of intra-SCN microdialysates in mouse, we found significant neurotransmitter release at the SCN and, concomitantly, resetting of behavioral circadian rhythms. Depending upon stimulus conditions and time-of-day, SCN acetylcholine and/or glutamate levels were augmented and generated shifts of behavioral rhythms. These results establish modes of neurochemical communication from brain regions controlling vigilance state to the central circadian clock, with behavioral consequences. They suggest a basis for dynamic integration across brain systems that regulate vigilance states, and a potential vulnerability to altered communication in sleep disorders.

Drosophila CLOCK target gene characterization: implications for circadian tissue-specific gene expression

PubMed Central

Abruzzi, Katharine Compton; Rodriguez, Joseph; Menet, Jerome S.; Desrochers, Jennifer; Zadina, Abigail; Luo, Weifei; Tkachev, Sasha; Rosbash, Michael

2011-01-01

CLOCK (CLK) is a master transcriptional regulator of the circadian clock in Drosophila. To identify CLK direct target genes and address circadian transcriptional regulation in Drosophila, we performed chromatin immunoprecipitation (ChIP) tiling array assays (ChIP–chip) with a number of circadian proteins. CLK binding cycles on at least 800 sites with maximal binding in the early night. The CLK partner protein CYCLE (CYC) is on most of these sites. The CLK/CYC heterodimer is joined 4–6 h later by the transcriptional repressor PERIOD (PER), indicating that the majority of CLK targets are regulated similarly to core circadian genes. About 30% of target genes also show cycling RNA polymerase II (Pol II) binding. Many of these generate cycling RNAs despite not being documented in prior RNA cycling studies. This is due in part to different RNA isoforms and to fly head tissue heterogeneity. CLK has specific targets in different tissues, implying that important CLK partner proteins and/or mechanisms contribute to gene-specific and tissue-specific regulation. PMID:22085964

Assembly of a Comprehensive Regulatory Network for the Mammalian Circadian Clock: A Bioinformatics Approach

PubMed Central

Lehmann, Robert; Abreu, Monica; Fuhr, Luise; Herzel, Hanspeter; Leser, Ulf; Relógio, Angela

2015-01-01

By regulating the timing of cellular processes, the circadian clock provides a way to adapt physiology and behaviour to the geophysical time. In mammals, a light-entrainable master clock located in the suprachiasmatic nucleus (SCN) controls peripheral clocks that are present in virtually every body cell. Defective circadian timing is associated with several pathologies such as cancer and metabolic and sleep disorders. To better understand the circadian regulation of cellular processes, we developed a bioinformatics pipeline encompassing the analysis of high-throughput data sets and the exploitation of published knowledge by text-mining. We identified 118 novel potential clock-regulated genes and integrated them into an existing high-quality circadian network, generating the to-date most comprehensive network of circadian regulated genes (NCRG). To validate particular elements in our network, we assessed publicly available ChIP-seq data for BMAL1, REV-ERBα/β and RORα/γ proteins and found strong evidence for circadian regulation of Elavl1, Nme1, Dhx6, Med1 and Rbbp7 all of which are involved in the regulation of tumourigenesis. Furthermore, we identified Ncl and Ddx6, as targets of RORγ and REV-ERBα, β, respectively. Most interestingly, these genes were also reported to be involved in miRNA regulation; in particular, NCL regulates several miRNAs, all involved in cancer aggressiveness. Thus, NCL represents a novel potential link via which the circadian clock, and specifically RORγ, regulates the expression of miRNAs, with particular consequences in breast cancer progression. Our findings bring us one step forward towards a mechanistic understanding of mammalian circadian regulation, and provide further evidence of the influence of circadian deregulation in cancer. PMID:25945798

Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice

PubMed Central

Landgraf, Dominic; Long, Jaimie E.; Proulx, Christophe D.; Barandas, Rita; Malinow, Roberto; Welsh, David K.

2016-01-01

Background Major depressive disorder is associated with disturbed circadian rhythms. To investigate the causal relationship between mood disorders and circadian clock disruption, previous studies in animal models have employed light/dark manipulations, global mutations of clock genes, or brain area lesions. However, light can impact mood by noncircadian mechanisms; clock genes have pleiotropic, clock-independent functions; and brain lesions not only disrupt cellular circadian rhythms but also destroy cells and eliminate important neuronal connections, including light reception pathways. Thus, a definitive causal role for functioning circadian clocks in mood regulation has not been established. Methods We stereotactically injected viral vectors encoding short hairpin RNA to knock down expression of the essential clock gene Bmal1 into the brain's master circadian pacemaker, the suprachiasmatic nucleus (SCN). Results In these SCN-specific Bmal1-knockdown (SCN-Bmal1-KD) mice, circadian rhythms were greatly attenuated in the SCN, while the mice were maintained in a standard light/dark cycle, SCN neurons remained intact, and neuronal connections were undisturbed, including photic inputs. In the learned helplessness paradigm, the SCN-Bmal1-KD mice were slower to escape, even before exposure to inescapable stress. They also spent more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. The SCN-Bmal1-KD mice also showed greater weight gain, an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress. Conclusions Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioral despair, and anxiety-like behavior in mice, establishing SCN-Bmal1-KD mice as a new animal model of depression. PMID:27113500

Regulation of circadian clock transcriptional output by CLOCK:BMAL1

PubMed Central

Trott, Alexandra J.

2018-01-01

The mammalian circadian clock relies on the transcription factor CLOCK:BMAL1 to coordinate the rhythmic expression of 15% of the transcriptome and control the daily regulation of biological functions. The recent characterization of CLOCK:BMAL1 cistrome revealed that although CLOCK:BMAL1 binds synchronously to all of its target genes, its transcriptional output is highly heterogeneous. By performing a meta-analysis of several independent genome-wide datasets, we found that the binding of other transcription factors at CLOCK:BMAL1 enhancers likely contribute to the heterogeneity of CLOCK:BMAL1 transcriptional output. While CLOCK:BMAL1 rhythmic DNA binding promotes rhythmic nucleosome removal, it is not sufficient to generate transcriptionally active enhancers as assessed by H3K27ac signal, RNA Polymerase II recruitment, and eRNA expression. Instead, the transcriptional activity of CLOCK:BMAL1 enhancers appears to rely on the activity of ubiquitously expressed transcription factors, and not tissue-specific transcription factors, recruited at nearby binding sites. The contribution of other transcription factors is exemplified by how fasting, which effects several transcription factors but not CLOCK:BMAL1, either decreases or increases the amplitude of many rhythmically expressed CLOCK:BMAL1 target genes. Together, our analysis suggests that CLOCK:BMAL1 promotes a transcriptionally permissive chromatin landscape that primes its target genes for transcription activation rather than directly activating transcription, and provides a new framework to explain how environmental or pathological conditions can reprogram the rhythmic expression of clock-controlled genes. PMID:29300726

The in vitro real-time oscillation monitoring system identifies potential entrainment factors for circadian clocks

PubMed Central

Nakahata, Yasukazu; Akashi, Makoto; Trcka, Daniel; Yasuda, Akio; Takumi, Toru

2006-01-01

Background Circadian rhythms are endogenous, self-sustained oscillations with approximately 24-hr rhythmicity that are manifested in various physiological and metabolic processes. The circadian organization of these processes in mammals is governed by the master oscillator within the suprachiasmatic nuclei (SCN) of the hypothalamus. Recent findings revealed that circadian oscillators exist in most organs, tissues, and even in immortalized cells, and that the oscillators in peripheral tissues are likely to be coordinated by SCN, the master oscillator. Some candidates for endogenous entrainment factors have sporadically been reported, however, their details remain mainly obscure. Results We developed the in vitro real-time oscillation monitoring system (IV-ROMS) by measuring the activity of luciferase coupled to the oscillatory gene promoter using photomultiplier tubes and applied this system to screen and identify factors able to influence circadian rhythmicity. Using this IV-ROMS as the primary screening of entrainment factors for circadian clocks, we identified 12 candidates as the potential entrainment factor in a total of 299 peptides and bioactive lipids. Among them, four candidates (endothelin-1, all-trans retinoic acid, 9-cis retinoic acid, and 13-cis retinoic acid) have already been reported as the entrainment factors in vivo and in vitro. We demonstrated that one of the novel candidates, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a natural ligand of the peroxisome proliferator-activated receptor-γ (PPAR-γ), triggers the rhythmic expression of endogenous clock genes in NIH3T3 cells. Furthermore, we showed that 15d-PGJ2 transiently induces Cry1, Cry2, and Rorα mRNA expressions and that 15d-PGJ2-induced entrainment signaling pathway is PPAR-γ – and MAPKs (ERK, JNK, p38MAPK)-independent. Conclusion Here, we identified 15d-PGJ2 as an entrainment factor in vitro. Using our developed IV-ROMS to screen 299 compounds, we found eight novel and four known molecules to be potential entrainment factors for circadian clocks, indicating that this assay system is a powerful and useful tool in initial screenings. PMID:16483373

Ambient temperature response establishes ELF3 as a required component of the Arabidopsis core circadian clock

USDA-ARS?s Scientific Manuscript database

Circadian clocks synchronize internal processes with environmental cycles to ensure optimal timing of biological events on daily and seasonal timescales. External light and temperature cues set the core molecular oscillator to local conditions. In Arabidopsis, EARLY FLOWERING 3 (ELF3) is thought to ...

The inception and evolution of a unique masters program in cancer biology, prevention and control.

PubMed

Cousin, Carolyn; Blancato, Jan

2010-09-01

The University of the District of Columbia (UDC) and the Lombardi Comprehensive Cancer Center (LCCC), Georgetown University Medical Center established a Masters Degree Program in Cancer Biology, Prevention and Control at UDC that is jointly administered and taught by UDC and LCCC faculty. The goal of the Masters Degree Program is to educate students as master-level cancer professionals capable of conducting research and service in cancer biology, prevention, and control or to further advance the education of students to pursue doctoral studies. The Program's unique nature is reflected in its philosophy "the best cancer prevention and control researchers are those with a sound understanding of cancer biology". This program is a full-time, 2-year, 36-credit degree in which students take half of their coursework at UDC and half of their coursework at LCCC. During the second year, students are required to conduct research either at LCCC or UDC. Unlike most cancer biology programs, this unique Program emphasizes both cancer biology and cancer outreach training.

The Automatic Meteorological Station System AN/TMQ-30 ( ).

DTIC Science & Technology

1982-08-01

network, the station electronics initiate the above operating sequence. 3.2.1 Meteorological Parameters Vindspeed. Windspeed measurements are made over a...much like a pocket calculator. Provision has been made to enable the operator to set or read the clock of the master station and to * set, modify, or...conditions is occuring during a regular cycle period. A normal report is not made under these conditions. Control is passed to the read data module under

Network time synchronization servers at the US Naval Observatory

NASA Technical Reports Server (NTRS)

Schmidt, Richard E.

1995-01-01

Responding to an increased demand for reliable, accurate time on the Internet and Milnet, the U.S. Naval Observatory Time Service has established the network time servers, tick.usno.navy.mil and tock.usno.navy.mil. The system clocks of these HP9000/747i industrial work stations are synchronized to within a few tens of microseconds of USNO Master Clock 2 using VMEbus IRIG-B interfaces. Redundant time code is available from a VMEbus GPS receiver. UTC(USNO) is provided over the network via a number of protocols, including the Network Time Protocol (NTP) (DARPA Network Working Group Report RFC-1305), the Daytime Protocol (RFC-867), and the Time protocol (RFC-868). Access to USNO network time services is presently open and unrestricted. An overview of USNO time services and results of LAN and WAN time synchronization tests will be presented.

Femtosecond-level timing fluctuation suppression in atmospheric frequency transfer with passive phase conjunction correction.

PubMed

Sun, Fuyu; Hou, Dong; Zhang, Danian; Tian, Jie; Hu, Jianguo; Huang, Xianhe; Chen, Shijun

2017-09-04

We demonstrate femtosecond-level timing fluctuation suppression in indoor atmospheric comb-based frequency transfer with a passive phase conjunction correction technique. Timing fluctuations and Allan deviations are both measured to characterize the excess frequency instability incurred during the frequency transfer process. By transferring a 2 GHz microwave over a 52-m long free-space link in 5000 s, the total root-mean-square (RMS) timing fluctuation was measured to be about 280 fs with a fractional frequency instability on the order of 3 × 10 -13 at 1 s and 6 × 10 -17 at 1000 s. This atmospheric comb-based frequency transfer with passive phase conjunction correction can be used to build an atomic clock-based free-space frequency transmission link because its instability is less than that of a commercial Cs or H-master clock.

Organ specificity in the plant circadian system is explained by different light inputs to the shoot and root clocks.

PubMed

Bordage, Simon; Sullivan, Stuart; Laird, Janet; Millar, Andrew J; Nimmo, Hugh G

2016-10-01

Circadian clocks allow the temporal compartmentalization of biological processes. In Arabidopsis, circadian rhythms display organ specificity but the underlying molecular causes have not been identified. We investigated the mechanisms responsible for the similarities and differences between the clocks of mature shoots and roots in constant conditions and in light : dark cycles. We developed an imaging system to monitor clock gene expression in shoots and light- or dark-grown roots, modified a recent mathematical model of the Arabidopsis clock and used this to simulate our new data. We showed that the shoot and root circadian clocks have different rhythmic properties (period and amplitude) and respond differently to light quality. The root clock was entrained by direct exposure to low-intensity light, even in antiphase to the illumination of shoots. Differences between the clocks were more pronounced in conditions where light was present than in constant darkness, and persisted in the presence of sucrose. We simulated the data successfully by modifying those parameters of a clock model that are related to light inputs. We conclude that differences and similarities between the shoot and root clocks can largely be explained by organ-specific light inputs. This provides mechanistic insight into the developing field of organ-specific clocks. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Circadian variations in biologically closed electrochemical circuits in Aloe vera and Mimosa pudica.

PubMed

Volkov, Alexander G; Baker, Kara; Foster, Justin C; Clemmons, Jacqueline; Jovanov, Emil; Markin, Vladislav S

2011-04-01

The circadian clock regulates a wide range of electrophysiological and developmental processes in plants. This paper presents, for the first time, the direct influence of a circadian clock on biologically closed electrochemical circuits in vivo. Here we show circadian variation of the plant responses to electrical stimulation. The biologically closed electrochemical circuits in the leaves of Aloe vera and Mimosa pudica, which regulate their physiology, were analyzed using the charge stimulation method. The electrostimulation was provided with different timing and different voltages. Resistance between Ag/AgCl electrodes in the leaf of Aloe vera was higher during the day than at night. Discharge of the capacitor in Aloe vera at night was faster than during the day. Discharge of the capacitor in a pulvinus of Mimosa pudica was faster during the day. The biologically closed electrical circuits with voltage gated ion channels in Mimosa pudica are also activated the next day, even in the darkness. These results show that the circadian clock can be maintained endogenously and has electrochemical oscillators, which can activate ion channels in biologically closed electrochemical circuits. We present the equivalent electrical circuits in both plants and their circadian variation to explain the experimental data. Copyright © 2011 Elsevier B.V. All rights reserved.

Population specific biomarkers of human aging: a big data study using South Korean, Canadian and Eastern European patient populations.

PubMed

Mamoshina, Polina; Kochetov, Kirill; Putin, Evgeny; Cortese, Franco; Aliper, Alexander; Lee, Won-Suk; Ahn, Sung-Min; Uhn, Lee; Skjodt, Neil; Kovalchuk, Olga; Scheibye-Knudsen, Morten; Zhavoronkov, Alex

2018-01-11

Accurate and physiologically meaningful biomarkers for human aging are key to assessing anti-aging therapies. Given ethnic differences in health, diet, lifestyle, behaviour, environmental exposures and even average rate of biological aging, it stands to reason that aging clocks trained on datasets obtained from specific ethnic populations are more likely to account for these potential confounding factors, resulting in an enhanced capacity to predict chronological age and quantify biological age. Here we present a deep learning-based hematological aging clock modeled using the large combined dataset of Canadian, South Korean and Eastern European population blood samples that show increased predictive accuracy in individual populations compared to population-specific hematologic aging clocks. The performance of models was also evaluated on publicly-available samples of the American population from the National Health and Nutrition Examination Survey (NHANES). In addition, we explored the association between age predicted by both population-specific and combined hematological clocks and all-cause mortality. Overall, this study suggests a) the population-specificity of aging patterns and b) hematologic clocks predicts all-cause mortality. Proposed models added to the freely available Aging.AI system allowing improved ability to assess human aging. © The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America.

The 1993 Gordon Research Conference on Chronobiology

NASA Technical Reports Server (NTRS)

Schwartz, William J.

1993-01-01

The study of biological timekeeping is now at a particularly fertile stage, encompassing multiple levels of biological organization, recruiting a wide array of disciplines and methodologies and uniting a host of investigators. This report summarizes a research conference on Chronobiology. Some of the topics focused on transcriptional and translational mechanisms of circadian rhythmicity, with discussions of putative 'clock genes' in cyanobacteria, algae, fungi, fruitflies, and hamsters. Cellular analysis, with emphasis on photoreceptors in frogs, neurons in molluscs, and testis in moths was addressed. New methods for investigating the circadian clock in the suprachiasmatic nucleus were introduced.

Aging, Rejuvenation, and Epigenetic Reprogramming: Resetting the Aging Clock

PubMed Central

Rando, Thomas A.; Chang, Howard Y.

2012-01-01

The underlying cause of aging remains one of the central mysteries of biology. Recent studies in several different systems suggest that not only may the rate of aging be modified by environmental and genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues. This Review focuses on the emerging biology of rejuvenation through the lens of epigenetic reprogramming. By defining youthfulness and senescence as epigenetic states, a framework for asking new questions about the aging process emerges. PMID:22265401

NASA Adds Leap Second to Master Clock

NASA Image and Video Library

2017-12-08

On Dec. 31, 2016, official clocks around the world will add a leap second just before midnight Coordinated Universal Time — which corresponds to 6:59:59 p.m. EST. NASA missions will also have to make the switch, including the Solar Dynamics Observatory, or SDO, which watches the sun 24/7. Clocks do this to keep in sync with Earth's rotation, which gradually slows down over time. When the dinosaurs roamed Earth, for example, our globe took only 23 hours to make a complete rotation. In space, millisecond accuracy is crucial to understanding how satellites orbit. "SDO moves about 1.9 miles every second," said Dean Pesnell, the project scientist for SDO at NASA's Goddard Space Flight Center in Greenbelt, Maryland. "So does every other object in orbit near SDO. We all have to use the same time to make sure our collision avoidance programs are accurate. So we all add a leap second to the end of 2016, delaying 2017 by one second." The leap second is also key to making sure that SDO is in sync with the Coordinated Universal Time, or UTC, used to label each of its images. SDO has a clock that counts the number of seconds since the beginning of the mission. To convert that count to UTC requires knowing just how many leap seconds have been added to Earth-bound clocks since the mission started. When the spacecraft wants to provide a time in UTC, it calls a software module that takes into consideration both the mission's second count and the number of leap seconds — and then returns a time in UTC.

Metabolic and reward feeding synchronises the rhythmic brain.

PubMed

Challet, Etienne; Mendoza, Jorge

2010-07-01

Daily brain rhythmicity, which controls the sleep-wake cycle and neuroendocrine functions, is generated by an endogenous circadian timing system. Within the multi-oscillatory circadian network, a master clock is located in the suprachiasmatic nuclei of the hypothalamus, whose main synchroniser (Zeitgeber) is light. In contrast, imposed meal times and temporally restricted feeding are potent synchronisers for secondary clocks in peripheral organs such as the liver and in brain regions, although not for the suprachiasmatic nuclei. Even when animals are exposed to a light-dark cycle, timed calorie restriction (i.e. when only a hypocaloric diet is given every day) is a synchroniser powerful enough to modify the suprachiasmatic clockwork and increase the synchronising effects of light. A daily chocolate snack in animals fed ad libitum with chow diet entrains the suprachiasmatic clockwork only under the conditions of constant darkness and decreases the synchronising effects of light. Secondary clocks in the brain outside the suprachiasmatic nuclei are differentially influenced by meal timing. Circadian oscillations can either be highly sensitive to food-related metabolic or reward cues (i.e. their phase is shifted according to the timed meal schedule) in some structures or hardly affected by meal timing (palatable or not) in others. Furthermore, animals will manifest food-anticipatory activity prior to their expected meal time. Anticipation of a palatable or regular meal may rely on a network of brain clocks, involving metabolic and reward systems and the cerebellum.

Implications of Circadian Rhythm in Dopamine and Mood Regulation.

PubMed

Kim, Jeongah; Jang, Sangwon; Choe, Han Kyoung; Chung, Sooyoung; Son, Gi Hoon; Kim, Kyungjin

2017-07-31

Mammalian physiology and behavior are regulated by an internal time-keeping system, referred to as circadian rhythm. The circadian timing system has a hierarchical organization composed of the master clock in the suprachiasmatic nucleus (SCN) and local clocks in extra-SCN brain regions and peripheral organs. The circadian clock molecular mechanism involves a network of transcription-translation feedback loops. In addition to the clinical association between circadian rhythm disruption and mood disorders, recent studies have suggested a molecular link between mood regulation and circadian rhythm. Specifically, genetic deletion of the circadian nuclear receptor Rev-erbα induces mania-like behavior caused by increased midbrain dopaminergic (DAergic) tone at dusk. The association between circadian rhythm and emotion-related behaviors can be applied to pathological conditions, including neurodegenerative diseases. In Parkinson's disease (PD), DAergic neurons in the substantia nigra pars compacta progressively degenerate leading to motor dysfunction. Patients with PD also exhibit non-motor symptoms, including sleep disorder and neuropsychiatric disorders. Thus, it is important to understand the mechanisms that link the molecular circadian clock and brain machinery in the regulation of emotional behaviors and related midbrain DAergic neuronal circuits in healthy and pathological states. This review summarizes the current literature regarding the association between circadian rhythm and mood regulation from a chronobiological perspective, and may provide insight into therapeutic approaches to target psychiatric symptoms in neurodegenerative diseases involving circadian rhythm dysfunction.

Circadian Modulation of Short-Term Memory in "Drosophila"

ERIC Educational Resources Information Center

Lyons, Lisa C.; Roman, Gregg

2009-01-01

Endogenous biological clocks are widespread regulators of behavior and physiology, allowing for a more efficient allocation of efforts and resources over the course of a day. The extent that different processes are regulated by circadian oscillators, however, is not fully understood. We investigated the role of the circadian clock on short-term…

HYDROBS: a long-term autonomous mooring for passive acoustic monitoring

NASA Astrophysics Data System (ADS)

Hello, Y.; Royer, J. Y.; Yegikyan, M.

2017-12-01

Passive acoustics proves an effective way for monitoring the low-level seismic activity of the ocean floor and low-frequency sounds from the ocean (baleen whales, sea-state, icebergs). Networks of synchronized autonomous hydrophones have thus been commonly deployed in the world ocean to monitor large sections of mid-oceanic ridges. HYDROBS is an improved system that meet two requirements: an easy access to the data collected by the instruments together with long-term deployments - up to 4 consecutive years - reducing the need of large vessels capable of yearly mooring operations in open seas. The system has two components: a data logger, up-to-date but similar to previous systems, and three messengers, releasable on demand to collect the data. The mooring line itself is classical, with an expandable weight at the sea-bottom to maintain the mooring, an acoustic release to free the mooring line for recovery, a line adjustable to the seafloor depth, and an immerged buoy, holding the acquisition system, to maintain the sensors at a constant depth and to bring the mooring line to the surface for its recovery. The data logger is based on a low-power microprocessor, an A/D-32bit convertor sampling at 250Hz, a 10-8 real time clock and SD card storage. Lithium batteries provide 3-4 years of autonomy. Acoustic communications with the surface-ship provide control over all functionalities at deployment and a health bulletin on demand. The 3 shuttles, encapsulated in 13" glass spheres, use the same CPU board and clock as the main station. Data transfer from the data logger to the shuttles is wireless (1Mbit/s digital inductive through water). Data are duplicated once per day on shuttles N and N+1 for redundancy. Prior to their release by acoustic command, the shuttles are synchronized with the master clock. At sea-surface, shuttles (as the main unit) look for GPS time and calculate their clock drift. So, the master clock drift can be monitored over time at every shuttle release until its final recovery. Shuttles and main unit are located on the sea-surface by AIS. Iridium communications can also be set to warn the user of a false release. A non-specialist can thus easily handle a shuttle recovery from a ship of opportunity. With 4-channels, this system is also suitable to monitor other parameters in the water column, continuously and over long periods.

Reciprocal interactions between circadian clocks and aging.

PubMed

Banks, Gareth; Nolan, Patrick M; Peirson, Stuart N

2016-08-01

Virtually, all biological processes in the body are modulated by an internal circadian clock which optimizes physiological and behavioral performance according to the changing demands of the external 24-h world. This circadian clock undergoes a number of age-related changes, at both the physiological and molecular levels. While these changes have been considered to be part of the normal aging process, there is increasing evidence that disruptions to the circadian system can substantially impact upon aging and these impacts will have clear health implications. Here we review the current data of how both the physiological and core molecular clocks change with age and how feedback from external cues may modulate the aging of the circadian system.

Seismic refraction profile, Kingdom of Saudi Arabia: field operations, instrumentation, and initial results

USGS Publications Warehouse

Blank, H. Richard; Healy, J.H.; Roller, John; Lamson, Ralph; Fisher, Fred; McClearn, Robert; Allen, Steve

1979-01-01

In February 1978 a seismic deep-refraction profile was recorded by the USGS along a 1000-km line across the Arabian Shield in western Saudi Arabia. The line begins in Paleozoic and Mesozoic cover rocks near Riyadh on the Arabian Platform, leads southwesterly across three major Precambrian tectonic provinces, traverses Cenozoic rocks of the coastal plain near Jizan (Tihamat Asir), and terminates at the outer edge of the Farasan Bank in the southern Red Sea. More than 500 surveyed recording sites were occupied, including 19 in the Farasan Islands. Six shot points were used--five on land, with charges placed mostly below water table in drill holes, and one at sea, with charges placed on the sea floor and fired from a ship. The total charge consumed was slightly in excess of 61 metric tons in 21 discrete firings. Seismic energy was recorded by means of a set of 100 newly developed portable seismic stations. Each station consists of a standard 2-Hz vertical geophone coupled to a self-contained analog recording instrument equipped with a magnetic-tape cassette. The stations were deployed in groups of 20 by five observer teams, each generally consisting of two scientist-technicians and a surveyor-guide. On the day prior to deployment, the instruments were calibrated and programmed for automatic operation by means of a specially designed device called a hand-held tester. At each of ten pre-selected recording time windows on a designated firing day, the instruments were programmed to turn on, stabilize, record internal calibration signals, record the seismic signals at three levels of amplification, and then deactivate. After the final window in the firing sequence, all instruments were retrieved and their data tapes removed for processing. A specially designed, field tape- dubbing system was utilized at shot point camps to organize and edit data recorded on the cassette tapes. The main functions of this system are to concatenate all data from each shot on any given day onto a single shot tape, and to provide hard copy for monitoring recorder performance so that any problems can be corrected prior to the next deployment. Composite digital record sections were produced from the dubbed tapes for each shot point by a portable processing and plotting system. The heart of this system is a DEC PDP 11VO3 computer, which controls a cassette playback unit identical to those used in the recorders and dubbers, a set of discriminators, a time-code translator, a digitizer, and a digital plotter. The system was used to maintain various informational data sets and to produce tabulations and listings of various sorts during the field operations, in addition to its main task of producing digital record sections. Two master clocks, both set to time signals broadcast by the British Broadcasting Corporation, provided absolute time for the recording operations. One was located on the ship and the other was stationed at a base camp on the mainland. The land-based master clock was used to set three additional master clocks located at the other active shot points a few days in advance of each firing, and these clocks were then used to set the internal clocks in the portable seismic stations via the hand-held tester. A master clock signal was also linked to the firing system at each shot point for determination of the absolute shot instant. It is possible to construct a generalized crustal model from examination of the six shot point composite record sections obtained in the field. Such a model rests upon a number of simplifying assumptions and will almost certainly be modified at a later stage of interpretation. The main assumptions are that the crust consists of two homogeneous isotropic layers having no velocity inversion,, that the Mohorovicic discontinuity is sharp, and that effects of surface inhomogeneities and elevation changes can be ignored. The main characteristics of the tentative model are the following: (1) The thickness of th

Ras-mediated deregulation of the circadian clock in cancer.

PubMed

Relógio, Angela; Thomas, Philippe; Medina-Pérez, Paula; Reischl, Silke; Bervoets, Sander; Gloc, Ewa; Riemer, Pamela; Mang-Fatehi, Shila; Maier, Bert; Schäfer, Reinhold; Leser, Ulf; Herzel, Hanspeter; Kramer, Achim; Sers, Christine

2014-01-01

Circadian rhythms are essential to the temporal regulation of molecular processes in living systems and as such to life itself. Deregulation of these rhythms leads to failures in biological processes and eventually to the manifestation of pathological phenotypes including cancer. To address the questions as to what are the elicitors of a disrupted clock in cancer, we applied a systems biology approach to correlate experimental, bioinformatics and modelling data from several cell line models for colorectal and skin cancer. We found strong and weak circadian oscillators within the same type of cancer and identified a set of genes, which allows the discrimination between the two oscillator-types. Among those genes are IFNGR2, PITX2, RFWD2, PPARγ, LOXL2, Rab6 and SPARC, all involved in cancer-related pathways. Using a bioinformatics approach, we extended the core-clock network and present its interconnection to the discriminative set of genes. Interestingly, such gene signatures link the clock to oncogenic pathways like the RAS/MAPK pathway. To investigate the potential impact of the RAS/MAPK pathway - a major driver of colorectal carcinogenesis - on the circadian clock, we used a computational model which predicted that perturbation of BMAL1-mediated transcription can generate the circadian phenotypes similar to those observed in metastatic cell lines. Using an inducible RAS expression system, we show that overexpression of RAS disrupts the circadian clock and leads to an increase of the circadian period while RAS inhibition causes a shortening of period length, as predicted by our mathematical simulations. Together, our data demonstrate that perturbations induced by a single oncogene are sufficient to deregulate the mammalian circadian clock.

Circadian control of the daily plasma glucose rhythm: an interplay of GABA and glutamate.

PubMed

Kalsbeek, Andries; Foppen, Ewout; Schalij, Ingrid; Van Heijningen, Caroline; van der Vliet, Jan; Fliers, Eric; Buijs, Ruud M

2008-09-15

The mammalian biological clock, located in the hypothalamic suprachiasmatic nuclei (SCN), imposes its temporal structure on the organism via neural and endocrine outputs. To further investigate SCN control of the autonomic nervous system we focused in the present study on the daily rhythm in plasma glucose concentrations. The hypothalamic paraventricular nucleus (PVN) is an important target area of biological clock output and harbors the pre-autonomic neurons that control peripheral sympathetic and parasympathetic activity. Using local administration of GABA and glutamate receptor (ant)agonists in the PVN at different times of the light/dark-cycle we investigated whether daily changes in the activity of autonomic nervous system contribute to the control of plasma glucose and plasma insulin concentrations. Activation of neuronal activity in the PVN of non-feeding animals, either by administering a glutamatergic agonist or a GABAergic antagonist, induced hyperglycemia. The effect of the GABA-antagonist was time dependent, causing increased plasma glucose concentrations only when administered during the light period. The absence of a hyperglycemic effect of the GABA-antagonist in SCN-ablated animals provided further evidence for a daily change in GABAergic input from the SCN to the PVN. On the other hand, feeding-induced plasma glucose and insulin responses were suppressed by inhibition of PVN neuronal activity only during the dark period. These results indicate that the pre-autonomic neurons in the PVN are controlled by an interplay of inhibitory and excitatory inputs. Liver-dedicated sympathetic pre-autonomic neurons (responsible for hepatic glucose production) and pancreas-dedicated pre-autonomic parasympathetic neurons (responsible for insulin release) are controlled by inhibitory GABAergic contacts that are mainly active during the light period. Both sympathetic and parasympathetic pre-autonomic PVN neurons also receive excitatory inputs, either from the biological clock (sympathetic pre-autonomic neurons) or from non-clock areas (para-sympathetic pre-autonomic neurons), but the timing information is mainly provided by the GABAergic outputs of the biological clock.

Circadian Control of the Daily Plasma Glucose Rhythm: An Interplay of GABA and Glutamate

PubMed Central

Kalsbeek, Andries; Foppen, Ewout; Schalij, Ingrid; Van Heijningen, Caroline; van der Vliet, Jan; Fliers, Eric; Buijs, Ruud M.

2008-01-01

The mammalian biological clock, located in the hypothalamic suprachiasmatic nuclei (SCN), imposes its temporal structure on the organism via neural and endocrine outputs. To further investigate SCN control of the autonomic nervous system we focused in the present study on the daily rhythm in plasma glucose concentrations. The hypothalamic paraventricular nucleus (PVN) is an important target area of biological clock output and harbors the pre-autonomic neurons that control peripheral sympathetic and parasympathetic activity. Using local administration of GABA and glutamate receptor (ant)agonists in the PVN at different times of the light/dark-cycle we investigated whether daily changes in the activity of autonomic nervous system contribute to the control of plasma glucose and plasma insulin concentrations. Activation of neuronal activity in the PVN of non-feeding animals, either by administering a glutamatergic agonist or a GABAergic antagonist, induced hyperglycemia. The effect of the GABA-antagonist was time dependent, causing increased plasma glucose concentrations only when administered during the light period. The absence of a hyperglycemic effect of the GABA-antagonist in SCN-ablated animals provided further evidence for a daily change in GABAergic input from the SCN to the PVN. On the other hand, feeding-induced plasma glucose and insulin responses were suppressed by inhibition of PVN neuronal activity only during the dark period. These results indicate that the pre-autonomic neurons in the PVN are controlled by an interplay of inhibitory and excitatory inputs. Liver-dedicated sympathetic pre-autonomic neurons (responsible for hepatic glucose production) and pancreas-dedicated pre-autonomic parasympathetic neurons (responsible for insulin release) are controlled by inhibitory GABAergic contacts that are mainly active during the light period. Both sympathetic and parasympathetic pre-autonomic PVN neurons also receive excitatory inputs, either from the biological clock (sympathetic pre-autonomic neurons) or from non-clock areas (para-sympathetic pre-autonomic neurons), but the timing information is mainly provided by the GABAergic outputs of the biological clock. PMID:18791643

The cyanobacterial circadian clock follows midday in vivo and in vitro

PubMed Central

Leypunskiy, Eugene; Lin, Jenny; Yoo, Haneul; Lee, UnJin; Dinner, Aaron R; Rust, Michael J

2017-01-01

Circadian rhythms are biological oscillations that schedule daily changes in physiology. Outside the laboratory, circadian clocks do not generally free-run but are driven by daily cues whose timing varies with the seasons. The principles that determine how circadian clocks align to these external cycles are not well understood. Here, we report experimental platforms for driving the cyanobacterial circadian clock both in vivo and in vitro. We find that the phase of the circadian rhythm follows a simple scaling law in light-dark cycles, tracking midday across conditions with variable day length. The core biochemical oscillator comprised of the Kai proteins behaves similarly when driven by metabolic pulses in vitro, indicating that such dynamics are intrinsic to these proteins. We develop a general mathematical framework based on instantaneous transformation of the clock cycle by external cues, which successfully predicts clock behavior under many cycling environments. DOI: http://dx.doi.org/10.7554/eLife.23539.001 PMID:28686160

FAD Regulates CRYPTOCHROME Protein Stability and Circadian Clock in Mice.

PubMed

Hirano, Arisa; Braas, Daniel; Fu, Ying-Hui; Ptáček, Louis J

2017-04-11

The circadian clock generates biological rhythms of metabolic and physiological processes, including the sleep-wake cycle. We previously identified a missense mutation in the flavin adenine dinucleotide (FAD) binding pocket of CRYPTOCHROME2 (CRY2), a clock protein that causes human advanced sleep phase. This prompted us to examine the role of FAD as a mediator of the clock and metabolism. FAD stabilized CRY proteins, leading to increased protein levels. In contrast, knockdown of Riboflavin kinase (Rfk), an FAD biosynthetic enzyme, enhanced CRY degradation. RFK protein levels and FAD concentrations oscillate in the nucleus, suggesting that they are subject to circadian control. Knockdown of Rfk combined with a riboflavin-deficient diet altered the CRY levels in mouse liver and the expression profiles of clock and clock-controlled genes (especially those related to metabolism including glucose homeostasis). We conclude that light-independent mechanisms of FAD regulate CRY and contribute to proper circadian oscillation of metabolic genes in mammals. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Entrainment in the master equation.

PubMed

Margaliot, Michael; Grüne, Lars; Kriecherbauer, Thomas

2018-04-01

The master equation plays an important role in many scientific fields including physics, chemistry, systems biology, physical finance and sociodynamics. We consider the master equation with periodic transition rates. This may represent an external periodic excitation like the 24 h solar day in biological systems or periodic traffic lights in a model of vehicular traffic. Using tools from systems and control theory, we prove that under mild technical conditions every solution of the master equation converges to a periodic solution with the same period as the rates. In other words, the master equation entrains (or phase locks) to periodic excitations. We describe two applications of our theoretical results to important models from statistical mechanics and epidemiology.

Entrainment in the master equation

PubMed Central

Grüne, Lars; Kriecherbauer, Thomas

2018-01-01

The master equation plays an important role in many scientific fields including physics, chemistry, systems biology, physical finance and sociodynamics. We consider the master equation with periodic transition rates. This may represent an external periodic excitation like the 24 h solar day in biological systems or periodic traffic lights in a model of vehicular traffic. Using tools from systems and control theory, we prove that under mild technical conditions every solution of the master equation converges to a periodic solution with the same period as the rates. In other words, the master equation entrains (or phase locks) to periodic excitations. We describe two applications of our theoretical results to important models from statistical mechanics and epidemiology. PMID:29765669

Butyrate Infusions in the Ovine Fetus Delay the Biologic Clock for Globin Gene Switching

NASA Astrophysics Data System (ADS)

Perrine, Susan P.; Rudolph, Abraham; Faller, Douglas V.; Roman, Christine; Cohen, Ruth A.; Chen, Shao-Jing; Kan, Yuet Wai

1988-11-01

The switch from fetal to adult hemoglobin expression is regulated in many mammalian species by a developmental clock-like mechanism and determined by the gestational age of the fetus. Prolonging fetal globin gene expression is of considerable interest for therapeutic potential in diseases caused by abnormal β -globin genes. Butyric acid, which is found in increased plasma concentrations in infants of diabetic mothers who have delayed globin gene switching, was infused into catheterized fetal lambs in utero during the time of the normal globin gene switch period. The globin gene switch was significantly delayed in three of four butyrate-treated fetuses compared with controls and was entirely prevented in one fetus in whom the infusion was begun before the globin switch was under way. These data provide a model for investigating and arresting the biologic clock of hemoglobin switching.

Highly parallel reconfigurable computer architecture for robotic computation having plural processor cells each having right and left ensembles of plural processors

NASA Technical Reports Server (NTRS)

Fijany, Amir (Inventor); Bejczy, Antal K. (Inventor)

1994-01-01

In a computer having a large number of single-instruction multiple data (SIMD) processors, each of the SIMD processors has two sets of three individual processor elements controlled by a master control unit and interconnected among a plurality of register file units where data is stored. The register files input and output data in synchronism with a minor cycle clock under control of two slave control units controlling the register file units connected to respective ones of the two sets of processor elements. Depending upon which ones of the register file units are enabled to store or transmit data during a particular minor clock cycle, the processor elements within an SIMD processor are connected in rings or in pipeline arrays, and may exchange data with the internal bus or with neighboring SIMD processors through interface units controlled by respective ones of the two slave control units.

Analysis of Circadian Leaf Movements.

PubMed

Müller, Niels A; Jiménez-Gómez, José M

2016-01-01

The circadian clock is a molecular timekeeper that controls a wide variety of biological processes. In plants, clock outputs range from the molecular level, with rhythmic gene expression and metabolite content, to physiological processes such as stomatal conductance or leaf movements. Any of these outputs can be used as markers to monitor the state of the circadian clock. In the model plant Arabidopsis thaliana, much of the current knowledge about the clock has been gained from time course experiments profiling expression of endogenous genes or reporter constructs regulated by the circadian clock. Since these methods require labor-intensive sample preparation or transformation, monitoring leaf movements is an interesting alternative, especially in non-model species and for natural variation studies. Technological improvements both in digital photography and image analysis allow cheap and easy monitoring of circadian leaf movements. In this chapter we present a protocol that uses an autonomous point and shoot camera and free software to monitor circadian leaf movements in tomato.

Inheritance of Cell-Cycle Duration in the Presence of Periodic Forcing

NASA Astrophysics Data System (ADS)

Mosheiff, Noga; Martins, Bruno M. C.; Pearl-Mizrahi, Sivan; Grünberger, Alexander; Helfrich, Stefan; Mihalcescu, Irina; Kohlheyer, Dietrich; Locke, James C. W.; Glass, Leon; Balaban, Nathalie Q.

2018-04-01

Periodic forcing of nonlinear oscillators leads to a large number of dynamic behaviors. The coupling of the cell cycle to the circadian clock provides a biological realization of such forcing. A previous model of forcing leads to nontrivial relations between correlations along cell lineages. Here, we present a simplified two-dimensional nonlinear map for the periodic forcing of the cell cycle. Using high-throughput single-cell microscopy, we have studied the correlations between cell-cycle duration in discrete lineages of several different organisms, including those with known coupling to a circadian clock and those without known coupling to a circadian clock. The model reproduces the paradoxical correlations and predicts new features that can be compared with the experimental data. By fitting the model to the data, we extract the important parameters that govern the dynamics. Interestingly, the model reproduces bimodal distributions for cell-cycle duration, as well as the gating of cell division by the phase of the clock, without having been explicitly fed into the model. In addition, the model predicts that circadian coupling may increase cell-to-cell variability in a clonal population of cells. In agreement with this prediction, deletion of the circadian clock reduces variability. Our results show that simple correlations can identify systems under periodic forcing and that studies of nonlinear coupling of biological oscillators provide insight into basic cellular processes of growth.

Pseudolite Architecture and Performance Analysis for the FAA’s NextGen Airspace

DTIC Science & Technology

2013-03-01

acquired, signals were tracked at a range of 66km. Recall, the 746 th ’ s minimum range to acquire and track was 48km. During the flight test data was...in 1Mbps messages encoded on 978 MHz carrier channel (Radio Technical Commission for Aeronautics, SC-186 2009) s . The ADS-B Out information is...not in sight, the pseudolite will synchronize its clock to another pseudolite that is in view of the master. The pseudolites are then “ daisy

Report on the Time and Frequency Activities of the Time Service Department of the U.S. Naval Observatory

DTIC Science & Technology

2001-11-01

1999, Dana Point, California, USA (U.S. Naval Observatory, Washington, 30 1 D.C.), pp. 277-284. [5] P. Koppang and R. Leland , 1999, “Linear Quadratic...Miranian, and P. A. Koppang , 1999, “Steering the US. Naval Observatory (USNO) Master Clock, ” in Proceedings of 1999 ION Technical Meeting, 25-27...January 1999, San Diego, California, USA (Institute of Navigation, Alexandria, Virginia), pp. 87 1-879. D. N. Matsakis, M. Miranian, and P. A. Koppang

USNO GPS program

NASA Technical Reports Server (NTRS)

Putkovich, K.

1981-01-01

Initial test results indicated that the Global Positioning System/Time Transfer Unit (GPS/TTU) performed well within the + or - 100 nanosecond range required by the original system specification. Subsequent testing involved the verification of GPS time at the master control site via portable clocks and the acquisition and tracking of as many passes of the space vehicles currently in operation as possible. A description and discussion of the testing, system modifications, test results obtained, and an evaluation of both GPS and the GPS/TTU are presented.

Photoperiod regulates multiple gene expression in the suprachiasmatic nuclei and pars tuberalis of the Siberian hamster (Phodopus sungorus).

PubMed

Johnston, Jonathan D; Ebling, Francis J P; Hazlerigg, David G

2005-06-01

Photoperiod regulates the seasonal physiology of many mammals living in temperate latitudes. Photoperiodic information is decoded by the master circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus and then transduced via pineal melatonin secretion. This neurochemical signal is interpreted by tissues expressing melatonin receptors (e.g. the pituitary pars tuberalis, PT) to drive physiological changes. In this study we analysed the photoperiodic regulation of the circadian clockwork in the SCN and PT of the Siberian hamster. Female hamsters were exposed to either long or short photoperiod for 8 weeks and sampled at 2-h intervals across the 24-h cycle. In the SCN, rhythmic expression of the clock genes Per1, Per2, Cry1, Rev-erbalpha, and the clock-controlled genes arginine vasopressin (AVP) and d-element binding protein (DBP) was modulated by photoperiod. All of these E-box-containing genes tracked dawn, with earlier peak mRNA expression in long, compared to short, photoperiod. This response occurred irrespective of the presence of additional regulatory cis-elements, suggesting photoperiodic regulation of SCN gene expression through a common E-box-related mechanism. In long photoperiod, expression of Cry1 and Per1 in the PT tracked the onset and offset of melatonin secretion, respectively. However, whereas Cry1 tracked melatonin onset in short period, Per1 expression was not detectably rhythmic. We therefore propose that, in the SCN, photoperiodic regulation of clock gene expression primarily occurs via E-boxes, whereas melatonin-driven signal transduction drives the phasing of a subset of clock genes in the PT, independently of the E-box.

Role of light and the circadian clock in the rhythmic oscillation of intraocular pressure: Studies in VPAC2 receptor and PACAP deficient mice.

PubMed

Fahrenkrug, Jan; Georg, Birgitte; Hannibal, Jens; Jørgensen, Henrik Løvendahl

2018-04-01

The intraocular pressure of mice displays a daily rhythmicity being highest during the dark period. The present study was performed to elucidate the role of the circadian clock and light in the diurnal and the circadian variations in intraocular pressure in mice, by using animals with disrupted clock function (VPAC2 receptor knockout mice) or impaired light information to the clock (PACAP knockout mice). In wildtype mice, intraocular pressure measured under light/dark conditions showed a statistically significant 24 h sinusoidal rhythm with nadir during the light phase and peak during the dark phase. After transfer of the wildtype mice into constant darkness, the intraocular pressure increased, but the rhythmic changes in intraocular pressure continued with a pattern identical to that obtained during the light/dark cycle. The intraocular pressure in VPAC2 receptor deficient mice during light/dark conditions also showed a sinusoidal pattern with significant changes as a function of a 24 h cycle. However, transfer of the VPAC2 receptor knockout mice into constant darkness completely abolished the rhythmic changes in intraocular pressure. The intraocular pressure in PACAP deficient mice oscillated significantly during both 24 h light and darkness and during constant darkness. During LD conditions, the amplitude of PACAP deficient was significantly lower compared to wildtype mice, resulting in higher daytime and lower nighttime values. In conclusion, by studying the VPAC2 receptor knockout mouse which lacks circadian control and the PACAP knockout mouse which displays impaired light signaling, we provided evidence that the daily intraocular pressure rhythms are primarily generated by the circadian master clock and to a lesser extent by environmental light and darkness. Copyright © 2018 Elsevier Ltd. All rights reserved.

THE mPER2 CLOCK GENE MODULATES COCAINE ACTIONS IN THE MOUSE CIRCADIAN SYSTEM

PubMed Central

Brager, Allison J.; Stowie, Adam C.; Prosser, Rebecca A.; Glass, J. David

2014-01-01

Cocaine is a potent disruptor of photic and non-photic pathways for circadian entrainment of the master circadian clock of the suprachiasmatic nucleus (SCN). These actions of cocaine likely involve its modulation of molecular (clock gene) components for SCN clock timekeeping. At present, however, the physiological basis of such an interaction is unclear. To address this question, we compared photic and non-photic phase-resetting responses between wild-type (WT) and Per2 mutant mice expressing nonfunctional PER2 protein to systemic and intra-SCN cocaine administrations. In the systemic trials, cocaine was administered i.p. (20 mg/kg) either at midday or prior to a light pulse in the early night to assess its non-photic and photic behavioral phase-resetting actions, respectively. In the intra-SCN trial, cocaine was administered by reverse microdialysis at midday to determine if the SCN is a direct target for its non-photic phase-resetting action. Non-photic phase-advancing responses to i.p. cocaine at midday were significantly (~3.5-fold) greater in Per2 mutants than WTs. However, the phase-advancing action of intra-SCN cocaine perfusion at midday did not differ between genotypes. In the light pulse trial, Per2 mutants exhibited larger photic phase-delays than did WTs, and the attenuating action of cocaine on this response was proportionately larger than in WTs. These data indicate that the Per2 clock gene is a potent modulator of cocaine’s actions in the circadian system. With regard to non-photic phase-resetting, the SCN is confirmed as a direct target of cocaine action; however, Per2 modulation of this effect likely occurs outside of the SCN. PMID:23333842

Relativistic parameters of senescence.

PubMed

Stathatos, Marios A

2005-01-01

The laws of biochemistry and biology are governed by parameters whose description in mathematical formulas is based on the three-dimensional space. It is a fact, however, that the life span of a cell and its specific functions, though limited, can be extended or diminished depending on the genetic code but also, on the natural pressure of the environment. The plasticity exhibited by a cellular system has been attributed to the change of the three-dimensional structure of the cell, with time being a simple measure of this change. The model of biological relativity proposed here, considers time as a flexible fourth dimension that corresponds directly to the inertial status of the cells. Two types of clocks are defined: the relativistic biological clock (RBC) and the mechanical clock (MC). In contrast to the MCs that show the astrological reference time, the time shown by the RBCs delay because it depends on cellular activity. The maximum and the expected life span of the cells and/or the organisms can be therefore relied on time transformation. One of the most important factors that can affect time flow is the energy that is produced during metabolic work. Based on this observation, RBCs can be constructed following series of theoretical experiments in order to assess biological time and life span changes.

Clock gene modulates roles of OXTR and AVPR1b genes in prosociality.

PubMed

Ci, Haipeng; Wu, Nan; Su, Yanjie

2014-01-01

The arginine vasopressin receptor (AVPR) and oxytocin receptor (OXTR) genes have been demonstrated to contribute to prosocial behavior. Recent research has focused on the manner by which these simple receptor genes influence prosociality, particularly with regard to the AVP system, which is modulated by the clock gene. The clock gene is responsible for regulating the human biological clock, affecting sleep, emotion and behavior. The current study examined in detail whether the influences of the OXTR and AVPR1b genes on prosociality are dependent on the clock gene. This study assessed interactions between the clock gene (rs1801260, rs6832769) and the OXTR (rs1042778, rs237887) and AVPR1b (rs28373064) genes in association with individual differences in prosociality in healthy male Chinese subjects (n = 436). The Prosocial Tendencies Measure (PTM-R) was used to assess prosociality. Participants carrying both the GG/GA variant of AVPR1b rs28373064 and the AA variant of clock rs6832769 showed the highest scores on the Emotional PTM. Carriers of both the T allele of OXTR rs1042778 and the C allele of clock rs1801260 showed the lowest total PTM scores compared with the other groups. The observed interaction effects provide converging evidence that the clock gene and OXT/AVP systems are intertwined and contribute to human prosociality.

The Suprachiasmatic Nucleus of the Dromedary Camel (Camelus dromedarius): Cytoarchitecture and Neurochemical Anatomy

PubMed Central

El Allali, Khalid; Achaâban, Mohamed R.; Piro, Mohammed; Ouassat, Mohammed; Challet, Etienne; Errami, Mohammed; Lakhdar-Ghazal, Nouria; Calas, André; Pévet, Paul

2017-01-01

In mammals, biological rhythms are driven by a master circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Recently, we have demonstrated that in the camel, the daily cycle of environmental temperature is able to entrain the master clock. This raises several questions about the structure and function of the SCN in this species. The current work is the first neuroanatomical investigation of the camel SCN. We carried out a cartography and cytoarchitectural study of the nucleus and then studied its cell types and chemical neuroanatomy. Relevant neuropeptides involved in the circadian system were investigated, including arginine-vasopressin (AVP), vasoactive intestinal polypeptide (VIP), met-enkephalin (Met-Enk), neuropeptide Y (NPY), as well as oxytocin (OT). The neurotransmitter serotonin (5-HT) and the enzymes tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) were also studied. The camel SCN is a large and elongated nucleus, extending rostrocaudally for 9.55 ± 0.10 mm. Based on histological and immunofluorescence findings, we subdivided the camel SCN into rostral/preoptic (rSCN), middle/main body (mSCN) and caudal/retrochiasmatic (cSCN) divisions. Among mammals, the rSCN is unusual and appears as an assembly of neurons that protrudes from the main mass of the hypothalamus. The mSCN exhibits the triangular shape described in rodents, while the cSCN is located in the retrochiasmatic area. As expected, VIP-immunoreactive (ir) neurons were observed in the ventral part of mSCN. AVP-ir neurons were located in the rSCN and mSCN. Results also showed the presence of OT-ir and TH-ir neurons which seem to be a peculiarity of the camel SCN. OT-ir neurons were either scattered or gathered in one isolated cluster, while TH-ir neurons constituted two defined populations, dorsal parvicellular and ventral magnocellular neurons, respectively. TH colocalized with VIP in some rSCN neurons. Moreover, a high density of Met-Enk-ir, 5-HT-ir and NPY-ir fibers were observed within the SCN. Both the cytoarchitecture and the distribution of neuropeptides are unusual in the camel SCN as compared to other mammals. The presence of OT and TH in the camel SCN suggests their role in the modulation of circadian rhythms and the adaptation to photic and non-photic cues under desert conditions. PMID:29249943

Alternative splicing and nonsense-mediated decay of circadian clock genes under environmental stress conditions in Arabidopsis

PubMed Central

2014-01-01

Background The circadian clock enables living organisms to anticipate recurring daily and seasonal fluctuations in their growth habitats and synchronize their biology to the environmental cycle. The plant circadian clock consists of multiple transcription-translation feedback loops that are entrained by environmental signals, such as light and temperature. In recent years, alternative splicing emerges as an important molecular mechanism that modulates the clock function in plants. Several clock genes are known to undergo alternative splicing in response to changes in environmental conditions, suggesting that the clock function is intimately associated with environmental responses via the alternative splicing of the clock genes. However, the alternative splicing events of the clock genes have not been studied at the molecular level. Results We systematically examined whether major clock genes undergo alternative splicing under various environmental conditions in Arabidopsis. We also investigated the fates of the RNA splice variants of the clock genes. It was found that the clock genes, including EARLY FLOWERING 3 (ELF3) and ZEITLUPE (ZTL) that have not been studied in terms of alternative splicing, undergo extensive alternative splicing through diverse modes of splicing events, such as intron retention, exon skipping, and selection of alternative 5′ splice site. Their alternative splicing patterns were differentially influenced by changes in photoperiod, temperature extremes, and salt stress. Notably, the RNA splice variants of TIMING OF CAB EXPRESSION 1 (TOC1) and ELF3 were degraded through the nonsense-mediated decay (NMD) pathway, whereas those of other clock genes were insensitive to NMD. Conclusion Taken together, our observations demonstrate that the major clock genes examined undergo extensive alternative splicing under various environmental conditions, suggesting that alternative splicing is a molecular scheme that underlies the linkage between the clock and environmental stress adaptation in plants. It is also envisioned that alternative splicing of the clock genes plays more complex roles than previously expected. PMID:24885185

Chronobiology of crickets: a review.

PubMed

Tomioka, Kenji

2014-10-01

Crickets provide a good model for the study of mechanisms underlying circadian rhythms and photoperiodic responses. They show clear circadian rhythms in their overt behavior and the sensitivity of the visual system. Classical neurobiological studies revealed that a pair of optic lobes is the locus of the circadian clock controlling these rhythms and that the compound eye is the major photoreceptor necessary for synchronization to environmental light cycles. The two optic lobe clocks are mutually coupled through a neural pathway and the coupling regulates an output circadian waveform and a free-running period. Recent molecular studies revealed that the cricket's clock consists of cyclic expression of so-called clock genes and that the clock mechanism is featured by both Drosophila-like and mammalian-like traits. Molecular oscillation is also observed in some extra-optic lobe tissues and depends on the optic lobe clock in a tissue dependent manner. Interestingly, the clock is also involved in adaptation to seasonally changing environment. It fits its waveform to a given photoperiod and may be an indispensable part of a photoperiodic time-measurement mechanism. With adoption of modern molecular technologies, the cricket becomes a much more important and promising model animal for the study of circadian and photoperiodic biology.

Interband optical pulse injection locking of quantum dot mode-locked semiconductor laser.

PubMed

Kim, Jimyung; Delfyett, Peter J

2008-07-21

We experimentally demonstrate optical clock recovery from quantum dot mode-locked semiconductor lasers by interband optical pulse injection locking. The passively mode-locked slave laser oscillating on the ground state or the first excited state transition is locked through the injection of optical pulses generated via the opposite transition bands, i.e. the first excited state or the ground state transition from the hybridly mode-locked master laser, respectively. When an optical pulse train generated via the first excited state from the master laser is injected to the slave laser oscillating via ground state, the slave laser shows an asymmetric locking bandwidth around the nominal repetition rate of the slave laser. In the reverse injection case of, i.e. the ground state (master laser) to the first excited state (slave laser), the slave laser does not lock even though both lasers oscillate at the same cavity frequency. In this case, the slave laser only locks to higher injection rates as compared to its own nominal repetition rate, and also shows a large locking bandwidth of 6.7 MHz.

Modeling a synthetic multicellular clock: repressilators coupled by quorum sensing.

PubMed

Garcia-Ojalvo, Jordi; Elowitz, Michael B; Strogatz, Steven H

2004-07-27

Diverse biochemical rhythms are generated by thousands of cellular oscillators that somehow manage to operate synchronously. In fields ranging from circadian biology to endocrinology, it remains an exciting challenge to understand how collective rhythms emerge in multicellular structures. Using mathematical and computational modeling, we study the effect of coupling through intercell signaling in a population of Escherichia coli cells expressing a synthetic biological clock. Our results predict that a diverse and noisy community of such genetic oscillators interacting through a quorum-sensing mechanism should self-synchronize in a robust way, leading to a substantially improved global rhythmicity in the system. As such, the particular system of coupled genetic oscillators considered here might be a good candidate to provide the first quantitative example of a synchronization transition in a population of biological oscillators.

Modeling a synthetic multicellular clock: Repressilators coupled by quorum sensing

NASA Astrophysics Data System (ADS)

Garcia-Ojalvo, Jordi; Elowitz, Michael B.; Strogatz, Steven H.

2004-07-01

Diverse biochemical rhythms are generated by thousands of cellular oscillators that somehow manage to operate synchronously. In fields ranging from circadian biology to endocrinology, it remains an exciting challenge to understand how collective rhythms emerge in multicellular structures. Using mathematical and computational modeling, we study the effect of coupling through intercell signaling in a population of Escherichia coli cells expressing a synthetic biological clock. Our results predict that a diverse and noisy community of such genetic oscillators interacting through a quorum-sensing mechanism should self-synchronize in a robust way, leading to a substantially improved global rhythmicity in the system. As such, the particular system of coupled genetic oscillators considered here might be a good candidate to provide the first quantitative example of a synchronization transition in a population of biological oscillators.

Light at night alters daily patterns of cortisol and clock proteins in female Siberian hamsters.

PubMed

Bedrosian, T A; Galan, A; Vaughn, C A; Weil, Z M; Nelson, R J

2013-06-01

Humans and other organisms have adapted to a 24-h solar cycle in response to life on Earth. The rotation of the planet on its axis and its revolution around the sun cause predictable daily and seasonal patterns in day length. To successfully anticipate and adapt to these patterns in the environment, a variety of biological processes oscillate with a daily rhythm of approximately 24 h in length. These rhythms arise from hierarchally-coupled cellular clocks generated by positive and negative transcription factors of core circadian clock gene expression. From these endogenous cellular clocks, overt rhythms in activity and patterns in hormone secretion and other homeostatic processes emerge. These circadian rhythms in physiology and behaviour can be organised by a variety of cues, although they are most potently entrained by light. In recent history, there has been a major change from naturally-occurring light cycles set by the sun, to artificial and sometimes erratic light cycles determined by the use of electric lighting. Virtually every individual living in an industrialised country experiences light at night (LAN) but, despite its prevalence, the biological effects of such unnatural lighting have not been fully considered. Using female Siberian hamsters (Phodopus sungorus), we investigated the effects of chronic nightly exposure to dim light on daily rhythms in locomotor activity, serum cortisol concentrations and brain expression of circadian clock proteins (i.e. PER1, PER2, BMAL1). Although locomotor activity remained entrained to the light cycle, the diurnal fluctuation of cortisol concentrations was blunted and the expression patterns of clock proteins in the suprachiasmatic nucleus and hippocampus were altered. These results demonstrate that chronic exposure to dim LAN can dramatically affect fundamental cellular function and emergent physiology. © 2013 British Society for Neuroendocrinology.

Evolution and the Distribution of Glutaminyl and Asparaginyl Residues in Proteins

PubMed Central

Robinson, Arthur B.

1974-01-01

Recent experiments on the deamidation of glutaminyl and asparaginyl residues in peptides and proteins support the hypothesis that these residues may serve as molecular clocks that control biological processes. A hypothesis is now offered that suggests that these molecular clocks are set by rejection or accumulation of appropriate sequences of residues including a glutaminyl or asparaginyl residue during evolution. PMID:4522799

nocte Is Required for Integrating Light and Temperature Inputs in Circadian Clock Neurons of Drosophila.

PubMed

Chen, Chenghao; Xu, Min; Anantaprakorn, Yuto; Rosing, Mechthild; Stanewsky, Ralf

2018-05-21

Circadian clocks organize biological processes to occur at optimized times of day and thereby contribute to overall fitness. While the regular daily changes of environmental light and temperature synchronize circadian clocks, extreme external conditions can bypass the temporal constraints dictated by the clock. Despite advanced knowledge about how the daily light-dark changes synchronize the clock, relatively little is known with regard to how the daily temperature changes influence daily timing and how temperature and light signals are integrated. In Drosophila, a network of ∼150 brain clock neurons exhibit 24-hr oscillations of clock gene expression to regulate daily activity and sleep. We show here that a temperature input pathway from peripheral sensory organs, which depends on the gene nocte, targets specific subsets of these clock neurons to synchronize molecular and behavioral rhythms to temperature cycles. Strikingly, while nocte 1 mutant flies synchronize normally to light-dark cycles at constant temperatures, the combined presence of light-dark and temperature cycles inhibits synchronization. nocte 1 flies exhibit altered siesta sleep, suggesting that the sleep-regulating clock neurons are an important target for nocte-dependent temperature input, which dominates a parallel light input into these cells. In conclusion, we reveal a nocte-dependent temperature input pathway to central clock neurons and show that this pathway and its target neurons are important for the integration of sensory light and temperature information in order to temporally regulate activity and sleep during daily light and temperature cycles. Copyright © 2018 Elsevier Ltd. All rights reserved.

Machine Learning Helps Identify CHRONO as a Circadian Clock Component

PubMed Central

Venkataraman, Anand; Ramanathan, Chidambaram; Kavakli, Ibrahim H.; Hughes, Michael E.; Baggs, Julie E.; Growe, Jacqueline; Liu, Andrew C.; Kim, Junhyong; Hogenesch, John B.

2014-01-01

Over the last decades, researchers have characterized a set of “clock genes” that drive daily rhythms in physiology and behavior. This arduous work has yielded results with far-reaching consequences in metabolic, psychiatric, and neoplastic disorders. Recent attempts to expand our understanding of circadian regulation have moved beyond the mutagenesis screens that identified the first clock components, employing higher throughput genomic and proteomic techniques. In order to further accelerate clock gene discovery, we utilized a computer-assisted approach to identify and prioritize candidate clock components. We used a simple form of probabilistic machine learning to integrate biologically relevant, genome-scale data and ranked genes on their similarity to known clock components. We then used a secondary experimental screen to characterize the top candidates. We found that several physically interact with known clock components in a mammalian two-hybrid screen and modulate in vitro cellular rhythms in an immortalized mouse fibroblast line (NIH 3T3). One candidate, Gene Model 129, interacts with BMAL1 and functionally represses the key driver of molecular rhythms, the BMAL1/CLOCK transcriptional complex. Given these results, we have renamed the gene CHRONO (computationally highlighted repressor of the network oscillator). Bi-molecular fluorescence complementation and co-immunoprecipitation demonstrate that CHRONO represses by abrogating the binding of BMAL1 to its transcriptional co-activator CBP. Most importantly, CHRONO knockout mice display a prolonged free-running circadian period similar to, or more drastic than, six other clock components. We conclude that CHRONO is a functional clock component providing a new layer of control on circadian molecular dynamics. PMID:24737000

Master plan nurse duty roster using the 0-1 goal programming technique

NASA Astrophysics Data System (ADS)

Ismail, Wan Rosmanira; Jenal, Ruzzakiah

2013-04-01

The scheduling of nurses is particularly challenging because of the nature of the work which is around the clock. In addition, inefficient duty roster can have an effect on the nurses well being as well as their job satisfaction. In nurse scheduling problem (NSP), nurses are generally allocated to periods of work over a specified time horizon. A typical length of the schedule varies from a few weeks to a month. The schedule will be consistently rebuilt after the specified time period and will result in a time-consuming task for the administrative staff involved. Moreover, the task becomes overwhelming when the staff needs to consider the previous duty rosters in order to maintain the quality of schedules. Therefore, this study suggests the development of a master plan for a nurse duty roster for approximately one year. The master plan starts with the development of a blue print for the nurse duty roster using a 0-1 goal programming technique. The appropriate working period for this blue print is formulated based on the number of night shifts and the number of required nurses for night shift per schedule. Subsequently, the blue print is repeated to complete the annual nurse duty roster. These newly developed procedures were then tested on several data sets. The test results found that the master plan has successfully distributed the annual workload evenly among nurses. In addition, the master plan allows nurses to arrange their career and social activities in advance.

Tick Tock: Circadian Regulation of Plant Innate Immunity.

PubMed

Lu, Hua; McClung, C Robertson; Zhang, Chong

2017-08-04

Many living organisms on Earth have evolved the ability to integrate environmental and internal signals to determine time and thereafter adjust appropriately their metabolism, physiology, and behavior. The circadian clock is the endogenous timekeeper critical for multiple biological processes in many organisms. A growing body of evidence supports the importance of the circadian clock for plant health. Plants activate timed defense with various strategies to anticipate daily attacks of pathogens and pests and to modulate responses to specific invaders in a time-of-day-dependent manner (gating). Pathogen infection is also known to reciprocally modulate clock activity. Such a cross talk likely reflects the adaptive nature of plants to coordinate limited resources for growth, development, and defense. This review summarizes recent progress in circadian regulation of plant innate immunity with a focus on the molecular events linking the circadian clock and defense. More and better knowledge of clock-defense cross talk could help to improve disease resistance and productivity in economically important crops.

The circadian clock of Neurospora crassa.

PubMed

Baker, Christopher L; Loros, Jennifer J; Dunlap, Jay C

2012-01-01

Circadian clocks organize our inner physiology with respect to the external world, providing life with the ability to anticipate and thereby better prepare for major fluctuations in its environment. Circadian systems are widely represented in nearly all major branches of life, except archaebacteria, and within the eukaryotes, the filamentous fungus Neurospora crassa has served for nearly half a century as a durable model organism for uncovering the basic circadian physiology and molecular biology. Studies using Neurospora have clarified our fundamental understanding of the clock as nested positive and negative feedback loops regulated through transcriptional and post-transcriptional processes. These feedback loops are centered on a limited number of proteins that form molecular complexes, and their regulation provides a physical explanation for nearly all clock properties. This review will introduce the basics of circadian rhythms, the model filamentous fungus N. crassa, and provide an overview of the molecular components and regulation of the circadian clock. © 2011 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

ROS signaling pathways and biological rhythms: perspectives in crustaceans.

PubMed

Fanjul-Moles, Maria Luisa

2013-01-01

This work reviews concepts regarding the endogenous circadian clock and the relationship between oxidative stress (OS), light and entrainment in different organisms including crustaceans, particularly crayfish. In the first section, the molecular control of circadian rhythms in invertebrates, particularly in Drosophila, is reviewed, and this model is contrasted with recent reports on the circadian genes and proteins in crayfish. Second, the redox mechanisms and signaling pathways that participate in the entrainment of the circadian clock in different organisms are reviewed. Finally, the light signals and transduction pathways involved in the entrainment of the circadian clock, specifically in relation to cryptochromes (CRYs) and their dual role in the circadian clock of different animal groups and their possible relationship to the circadian clock and redox mechanisms in crustaceans is discussed. The relationship between metabolism, ROS signals and transcription factors, such as HIF-1 alpha in crayfish, as well as the possibility that HIF-1 alpha participates in the regulation of circadian control genes (ccgs) in crustaceans is discussed.

A Robust Molecular Network Motif for Period-Doubling Devices.

PubMed

Cuba Samaniego, Christian; Franco, Elisa

2018-01-19

Life is sustained by a variety of cyclic processes such as cell division, muscle contraction, and neuron firing. The periodic signals powering these processes often direct a variety of other downstream systems, which operate at different time scales and must have the capacity to divide or multiply the period of the master clock. Period modulation is also an important challenge in synthetic molecular systems, where slow and fast components may have to be coordinated simultaneously by a single oscillator whose frequency is often difficult to tune. Circuits that can multiply the period of a clock signal (frequency dividers), such as binary counters and flip-flops, are commonly encountered in electronic systems, but design principles to obtain similar devices in biological systems are still unclear. We take inspiration from the architecture of electronic flip-flops, and we propose to build biomolecular period-doubling networks by combining a bistable switch with negative feedback modules that preprocess the circuit inputs. We identify a network motif and we show it can be "realized" using different biomolecular components; two of the realizations we propose rely on transcriptional gene networks and one on nucleic acid strand displacement systems. We examine the capacity of each realization to perform period-doubling by studying how bistability of the motif is affected by the presence of the input; for this purpose, we employ mathematical tools from algebraic geometry that provide us with valuable insights on the input/output behavior as a function of the realization parameters. We show that transcriptional network realizations operate correctly also in a stochastic regime when processing oscillations from the repressilator, a canonical synthetic in vivo oscillator. Finally, we compare the performance of different realizations in a range of realistic parameters via numerical sensitivity analysis of the period-doubling region, computed with respect to the input period and amplitude. Our mathematical and computational analysis suggests that the motif we propose is generally robust with respect to specific implementation details: functionally equivalent circuits can be built as long as the species-interaction topology is respected. This indicates that experimental construction of the circuit is possible with a variety of components within the rapidly expanding libraries available in synthetic biology.

Identification and temporal expression of putative circadian clock transcripts in the amphipod crustacean Talitrus saltator

PubMed Central

O’Grady, Joseph F.; Hoelters, Laura S.; Swain, Martin T.

2016-01-01

Background Talitrus saltator is an amphipod crustacean that inhabits the supralittoral zone on sandy beaches in the Northeast Atlantic and Mediterranean. T. saltator exhibits endogenous locomotor activity rhythms and time-compensated sun and moon orientation, both of which necessitate at least one chronometric mechanism. Whilst their behaviour is well studied, currently there are no descriptions of the underlying molecular components of a biological clock in this animal, and very few in other crustacean species. Methods We harvested brain tissue from animals expressing robust circadian activity rhythms and used homology cloning and Illumina RNAseq approaches to sequence and identify the core circadian clock and clock-related genes in these samples. We assessed the temporal expression of these genes in time-course samples from rhythmic animals using RNAseq. Results We identified a comprehensive suite of circadian clock gene homologues in T. saltator including the ‘core’ clock genes period (Talper), cryptochrome 2 (Talcry2), timeless (Taltim), clock (Talclk), and bmal1 (Talbmal1). In addition we describe the sequence and putative structures of 23 clock-associated genes including two unusual, extended isoforms of pigment dispersing hormone (Talpdh). We examined time-course RNAseq expression data, derived from tissues harvested from behaviourally rhythmic animals, to reveal rhythmic expression of these genes with approximately circadian period in Talper and Talbmal1. Of the clock-related genes, casein kinase IIβ (TalckIIβ), ebony (Talebony), jetlag (Taljetlag), pigment dispensing hormone (Talpdh), protein phosphatase 1 (Talpp1), shaggy (Talshaggy), sirt1 (Talsirt1), sirt7 (Talsirt7) and supernumerary limbs (Talslimb) show temporal changes in expression. Discussion We report the sequences of principle genes that comprise the circadian clock of T. saltator and highlight the conserved structural and functional domains of their deduced cognate proteins. Our sequencing data contribute to the growing inventory of described comparative clocks. Expression profiling of the identified clock genes illuminates tantalising targets for experimental manipulation to elucidate the molecular and cellular control of clock-driven phenotypes in this crustacean. PMID:27761341

Chronobiology of micturition: putative role of the circadian clock.

PubMed

Negoro, Hiromitsu; Kanematsu, Akihiro; Yoshimura, Koji; Ogawa, Osamu

2013-09-01

Mammals urinate less frequently during the sleep period than the awake period. This is modulated by a triad of factors, including decreased arousal in the brain, a decreased urine production rate in the kidneys and increased functional bladder capacity during sleep. The circadian clock is genetic transcription-translation feedback machinery. It exists in most organs and cells, termed the peripheral clock, which is orchestrated by the central clock in the suprachiasmatic nucleus of the brain. We discuss the linkage between the day and night change in micturition frequency and the genetic rhythm maintained by the circadian clock system, focusing on the brain, kidney and bladder. We performed an inclusive review of the literature on the diurnal change in micturition frequency, urine volume, functional bladder capacity and urodynamics in humans and rodents, relating this to recent basic biological findings about the circadian clock. In humans various behavioral studies demonstrated a diurnal functional change in the kidney and bladder. Conversely, patients with nocturnal enuresis and nocturia showed impairment in this triad of factors. Rats and mice, which are nocturnal animals, also have a micturition frequency rhythm that is decreased during the day, which is the sleep phase for them. Mice with a genetically defective circadian clock system show impaired physiological rhythms in the triad of factors. The existence of the circadian clock has been proven in the brain, kidney and bladder, in which thousands of circadian oscillating genes exist. In the kidney they include genes involved in the regulation of water and major electrolytes. In the bladder they include connexin 43, a gene associated with the regulation of bladder capacity. Recent progress in molecular biology about the circadian clock provides an opportunity to investigate the genetic basis of the micturition rhythm or impairment of the rhythm in nocturnal enuresis and nocturia. If this approach is to be translated clinically, a strategy is to analyze and treat the triad of micturition factors as separate parts of 1 problem. The other way could be to cope with this triad of problems simultaneously, if possible, by treating the circadian physiological rhythm itself. The discoveries reviewed point toward further investigation of the micturition rhythm by basic and translational chronobiology. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

[Melatonin, synthetic analogs, and the sleep/wake rhythm].

PubMed

Escames, G; Acuña-Castroviejo, D

Melatonin, a widespread hormone in the animal kingdom, is produced by several organs and tissues besides the pineal gland. Whilst extrapineal melatonin behaves as a cytoprotective molecule, the pineal produces the hormone in a rhythmic manner. The discovery of melatonin in 1958, and the characterization of its synthesis somewhat later, let to the description of its photoperiodic regulation and its relationship with the biological rhythms such as the sleep/wake rhythm. The suprachiasmatic nuclei are the anatomical seat of the biological clock, represented by the clock genes, which code for the period and frequency of the rhythms. The photoperiod synchronizes the activity of the auprachiasmatic biological clock, which in turn induces the melatonin's rhythm. The rhythm of melatonin, peaking at 2-3 am, acts as an endogenous synchronizer that translates the environmental photoperiodic signal in chemical information for the cells. The sleep/wake cycle is a typical biological rhythm synchronized by melatonin, and the sleep/wake cycle alterations of chronobiological origin, are very sensitive to melatonin treatment. Taking advantage of the chronobiotic and antidepressive properties of melatonin, a series of synthetic analogs of this hormone, with high interest in insomnia, are now available. Melatonin is a highly effective chronobiotic in the treatment of chronobiological alterations of the sleep/wake cycle. From a pharmacokinetic point of view, the synthetic drugs derived from melatonin are interesting tools in the therapy of these alterations.

Optical timing receiver for the NASA laser ranging system. Part 2: High precision time interval digitizer

NASA Technical Reports Server (NTRS)

Leskovar, B.; Turko, B.

1977-01-01

The development of a high precision time interval digitizer is described. The time digitizer is a 10 psec resolution stop watch covering a range of up to 340 msec. The measured time interval is determined as a separation between leading edges of a pair of pulses applied externally to the start input and the stop input of the digitizer. Employing an interpolation techniques and a 50 MHz high precision master oscillator, the equivalent of a 100 GHz clock frequency standard is achieved. Absolute accuracy and stability of the digitizer are determined by the external 50 MHz master oscillator, which serves as a standard time marker. The start and stop pulses are fast 1 nsec rise time signals, according to the Nuclear Instrument means of tunnel diode discriminators. Firing level of the discriminator define start and stop points between which the time interval is digitized.

The Trade-Off Mechanism in Mammalian Circadian Clock Model with Two Time Delays

NASA Astrophysics Data System (ADS)

Yan, Jie; Kang, Xiaxia; Yang, Ling

Circadian clock is an autonomous oscillator which orchestrates the daily rhythms of physiology and behaviors. This study is devoted to explore how a positive feedback loop affects the dynamics of mammalian circadian clock. We simplify an experimentally validated mathematical model in our previous work, to a nonlinear differential equation with two time delays. This simplified mathematical model incorporates the pacemaker of mammalian circadian clock, a negative primary feedback loop, and a critical positive auxiliary feedback loop, Rev-erbα/Cry1 loop. We perform analytical studies of the system. Delay-dependent conditions for the asymptotic stability of the nontrivial positive steady state of the model are investigated. We also prove the existence of Hopf bifurcation, which leads to self-sustained oscillation of mammalian circadian clock. Our theoretical analyses show that the oscillatory regime is reduced upon the participation of the delayed positive auxiliary loop. However, further simulations reveal that the auxiliary loop can enable the circadian clock gain widely adjustable amplitudes and robust period. Thus, the positive auxiliary feedback loop may provide a trade-off mechanism, to use the small loss in the robustness of oscillation in exchange for adaptable flexibility in mammalian circadian clock. The results obtained from the model may gain new insights into the dynamics of biological oscillators with interlocked feedback loops.

Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle

PubMed Central

Feillet, Céline; Krusche, Peter; Tamanini, Filippo; Janssens, Roel C.; Downey, Mike J.; Martin, Patrick; Teboul, Michèle; Saito, Shoko; Lévi, Francis A.; Bretschneider, Till; van der Horst, Gijsbertus T. J.; Delaunay, Franck; Rand, David A.

2014-01-01

Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence its biological relevance, is not understood. In particular, we do not know how the temporal organization of cell division at the single-cell level produces this daily rhythm at the tissue level. Here we use multispectral imaging of single live cells, computational methods, and mathematical modeling to address this question in proliferating mouse fibroblasts. We show that in unsynchronized cells the cell cycle and circadian clock robustly phase lock each other in a 1:1 fashion so that in an expanding cell population the two oscillators oscillate in a synchronized way with a common frequency. Dexamethasone-induced synchronization reveals additional clock states. As well as the low-period phase-locked state there are distinct coexisting states with a significantly higher period clock. Cells transition to these states after dexamethasone synchronization. The temporal coordination of cell division by phase locking to the clock at a single-cell level has significant implications because disordered circadian function is increasingly being linked to the pathogenesis of many diseases, including cancer. PMID:24958884

Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.

PubMed

Feillet, Céline; Krusche, Peter; Tamanini, Filippo; Janssens, Roel C; Downey, Mike J; Martin, Patrick; Teboul, Michèle; Saito, Shoko; Lévi, Francis A; Bretschneider, Till; van der Horst, Gijsbertus T J; Delaunay, Franck; Rand, David A

2014-07-08

Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence its biological relevance, is not understood. In particular, we do not know how the temporal organization of cell division at the single-cell level produces this daily rhythm at the tissue level. Here we use multispectral imaging of single live cells, computational methods, and mathematical modeling to address this question in proliferating mouse fibroblasts. We show that in unsynchronized cells the cell cycle and circadian clock robustly phase lock each other in a 1:1 fashion so that in an expanding cell population the two oscillators oscillate in a synchronized way with a common frequency. Dexamethasone-induced synchronization reveals additional clock states. As well as the low-period phase-locked state there are distinct coexisting states with a significantly higher period clock. Cells transition to these states after dexamethasone synchronization. The temporal coordination of cell division by phase locking to the clock at a single-cell level has significant implications because disordered circadian function is increasingly being linked to the pathogenesis of many diseases, including cancer.

Local Citation Analysis of Graduate Biology Theses: Collection Development Implications

ERIC Educational Resources Information Center

Miller, Laura Newton

2011-01-01

This paper will focus on the citation analysis of graduate masters theses from Carleton University's Biology Department with implications for library collection management decisions. Twenty-five masters theses were studied to determine citation types and percentages, ranking of journals by frequency of citation and by number of authors citing, and…

Modeling a synthetic multicellular clock: Repressilators coupled by quorum sensing

PubMed Central

Garcia-Ojalvo, Jordi; Elowitz, Michael B.; Strogatz, Steven H.

2004-01-01

Diverse biochemical rhythms are generated by thousands of cellular oscillators that somehow manage to operate synchronously. In fields ranging from circadian biology to endocrinology, it remains an exciting challenge to understand how collective rhythms emerge in multicellular structures. Using mathematical and computational modeling, we study the effect of coupling through intercell signaling in a population of Escherichia coli cells expressing a synthetic biological clock. Our results predict that a diverse and noisy community of such genetic oscillators interacting through a quorum-sensing mechanism should self-synchronize in a robust way, leading to a substantially improved global rhythmicity in the system. As such, the particular system of coupled genetic oscillators considered here might be a good candidate to provide the first quantitative example of a synchronization transition in a population of biological oscillators. PMID:15256602

Circadian clock gene LATE ELONGATED HYPOCOTYL directly regulates the timing of floral scent emission in Petunia

PubMed Central

Fenske, Myles P.; Hewett Hazelton, Kristen D.; Hempton, Andrew K.; Shim, Jae Sung; Yamamoto, Breanne M.; Riffell, Jeffrey A.; Imaizumi, Takato

2015-01-01

Flowers present a complex display of signals to attract pollinators, including the emission of floral volatiles. Volatile emission is highly regulated, and many species restrict emissions to specific times of the day. This rhythmic emission of scent is regulated by the circadian clock; however, the mechanisms have remained unknown. In Petunia hybrida, volatile emissions are dominated by products of the floral volatile benzenoid/phenylpropanoid (FVBP) metabolic pathway. Here we demonstrate that the circadian clock gene P. hybrida LATE ELONGATED HYPOCOTYL (LHY; PhLHY) regulates the daily expression patterns of the FVBP pathway genes and floral volatile production. PhLHY expression peaks in the morning, antiphasic to the expression of P. hybrida GIGANTEA (PhGI), the master scent regulator ODORANT1 (ODO1), and many other evening-expressed FVBP genes. Overexpression phenotypes of PhLHY in Arabidopsis caused an arrhythmic clock phenotype, which resembles those of LHY overexpressors. In Petunia, constitutive expression of PhLHY depressed the expression levels of PhGI, ODO1, evening-expressed FVBP pathway genes, and FVBP emission in flowers. Additionally, in the Petunia lines in which PhLHY expression was reduced, the timing of peak expression of PhGI, ODO1, and the FVBP pathway genes advanced to the morning. Moreover, PhLHY protein binds to cis-regulatory elements called evening elements that exist in promoters of ODO1 and other FVBP genes. Thus, our results imply that PhLHY directly sets the timing of floral volatile emission by restricting the expression of ODO1 and other FVBP genes to the evening in Petunia. PMID:26124104

Circadian clock gene LATE ELONGATED HYPOCOTYL directly regulates the timing of floral scent emission in Petunia.

PubMed

Fenske, Myles P; Hewett Hazelton, Kristen D; Hempton, Andrew K; Shim, Jae Sung; Yamamoto, Breanne M; Riffell, Jeffrey A; Imaizumi, Takato

2015-08-04

Flowers present a complex display of signals to attract pollinators, including the emission of floral volatiles. Volatile emission is highly regulated, and many species restrict emissions to specific times of the day. This rhythmic emission of scent is regulated by the circadian clock; however, the mechanisms have remained unknown. In Petunia hybrida, volatile emissions are dominated by products of the floral volatile benzenoid/phenylpropanoid (FVBP) metabolic pathway. Here we demonstrate that the circadian clock gene P. hybrida LATE ELONGATED HYPOCOTYL (LHY; PhLHY) regulates the daily expression patterns of the FVBP pathway genes and floral volatile production. PhLHY expression peaks in the morning, antiphasic to the expression of P. hybrida GIGANTEA (PhGI), the master scent regulator ODORANT1 (ODO1), and many other evening-expressed FVBP genes. Overexpression phenotypes of PhLHY in Arabidopsis caused an arrhythmic clock phenotype, which resembles those of LHY overexpressors. In Petunia, constitutive expression of PhLHY depressed the expression levels of PhGI, ODO1, evening-expressed FVBP pathway genes, and FVBP emission in flowers. Additionally, in the Petunia lines in which PhLHY expression was reduced, the timing of peak expression of PhGI, ODO1, and the FVBP pathway genes advanced to the morning. Moreover, PhLHY protein binds to cis-regulatory elements called evening elements that exist in promoters of ODO1 and other FVBP genes. Thus, our results imply that PhLHY directly sets the timing of floral volatile emission by restricting the expression of ODO1 and other FVBP genes to the evening in Petunia.

Interactions of Circadian Rhythmicity, Stress and Orexigenic Neuropeptide Systems: Implications for Food Intake Control.

PubMed

Blasiak, Anna; Gundlach, Andrew L; Hess, Grzegorz; Lewandowski, Marian H

2017-01-01

Many physiological processes fluctuate throughout the day/night and daily fluctuations are observed in brain and peripheral levels of several hormones, neuropeptides and transmitters. In turn, mediators under the "control" of the "master biological clock" reciprocally influence its function. Dysregulation in the rhythmicity of hormone release as well as hormone receptor sensitivity and availability in different tissues, is a common risk-factor for multiple clinical conditions, including psychiatric and metabolic disorders. At the same time circadian rhythms remain in a strong, reciprocal interaction with the hypothalamic-pituitary-adrenal (HPA) axis. Recent findings point to a role of circadian disturbances and excessive stress in the development of obesity and related food consumption and metabolism abnormalities, which constitute a major health problem worldwide. Appetite, food intake and energy balance are under the influence of several brain neuropeptides, including the orexigenic agouti-related peptide, neuropeptide Y, orexin, melanin-concentrating hormone and relaxin-3. Importantly, orexigenic neuropeptide neurons remain under the control of the circadian timing system and are highly sensitive to various stressors, therefore the potential neuronal mechanisms through which disturbances in the daily rhythmicity and stress-related mediator levels contribute to food intake abnormalities rely on reciprocal interactions between these elements.

The Pathophysiologic Role of Disrupted Circadian and Neuroendocrine Rhythms in Breast Carcinogenesis.

PubMed

Ball, Lonnele J; Palesh, Oxana; Kriegsfeld, Lance J

2016-10-01

Most physiological processes in the brain and body exhibit daily (circadian) rhythms coordinated by an endogenous master clock located in the suprachiasmatic nucleus of the hypothalamus that are essential for normal health and functioning. Exposure to sunlight during the day and darkness at night optimally entrains biological rhythms to promote homeostasis and human health. Unfortunately, a major consequence of the modern lifestyle is increased exposure to sun-free environments during the day and artificial lighting at night. Additionally, behavioral disruptions to circadian rhythms (ie, repeated transmeridian flights, night or rotating shift work, or sleep disturbances) have a profound influence on health and have been linked to a number of pathological conditions, including endocrine-dependent cancers. Specifically, night shift work has been identified as a significant risk factor for breast cancer in industrialized countries. Several mechanisms have been proposed by which shift work-induced circadian disruptions promote cancer. In this review, we examine the importance of the brain-body link through which circadian disruptions contribute to endocrine-dependent diseases, including breast carcinogenesis, by negatively impacting neuroendocrine and neuroimmune cells, and we consider preventive measures directed at maximizing circadian health.

The Pathophysiologic Role of Disrupted Circadian and Neuroendocrine Rhythms in Breast Carcinogenesis

PubMed Central

Ball, Lonnele J.; Palesh, Oxana

2016-01-01

Most physiological processes in the brain and body exhibit daily (circadian) rhythms coordinated by an endogenous master clock located in the suprachiasmatic nucleus of the hypothalamus that are essential for normal health and functioning. Exposure to sunlight during the day and darkness at night optimally entrains biological rhythms to promote homeostasis and human health. Unfortunately, a major consequence of the modern lifestyle is increased exposure to sun-free environments during the day and artificial lighting at night. Additionally, behavioral disruptions to circadian rhythms (ie, repeated transmeridian flights, night or rotating shift work, or sleep disturbances) have a profound influence on health and have been linked to a number of pathological conditions, including endocrine-dependent cancers. Specifically, night shift work has been identified as a significant risk factor for breast cancer in industrialized countries. Several mechanisms have been proposed by which shift work-induced circadian disruptions promote cancer. In this review, we examine the importance of the brain-body link through which circadian disruptions contribute to endocrine-dependent diseases, including breast carcinogenesis, by negatively impacting neuroendocrine and neuroimmune cells, and we consider preventive measures directed at maximizing circadian health. PMID:27712099

Body weight, metabolism and clock genes

PubMed Central

2010-01-01

Biological rhythms are present in the lives of almost all organisms ranging from plants to more evolved creatures. These oscillations allow the anticipation of many physiological and behavioral mechanisms thus enabling coordination of rhythms in a timely manner, adaption to environmental changes and more efficient organization of the cellular processes responsible for survival of both the individual and the species. Many components of energy homeostasis exhibit circadian rhythms, which are regulated by central (suprachiasmatic nucleus) and peripheral (located in other tissues) circadian clocks. Adipocyte plays an important role in the regulation of energy homeostasis, the signaling of satiety and cellular differentiation and proliferation. Also, the adipocyte circadian clock is probably involved in the control of many of these functions. Thus, circadian clocks are implicated in the control of energy balance, feeding behavior and consequently in the regulation of body weight. In this regard, alterations in clock genes and rhythms can interfere with the complex mechanism of metabolic and hormonal anticipation, contributing to multifactorial diseases such as obesity and diabetes. The aim of this review was to define circadian clocks by describing their functioning and role in the whole body and in adipocyte metabolism, as well as their influence on body weight control and the development of obesity. PMID:20712885

Metabolism as an Integral Cog in the Mammalian Circadian Clockwork

PubMed Central

Gamble, Karen L.; Young, Martin E.

2013-01-01

Circadian rhythms are an integral part of life. These rhythms are apparent in virtually all biological processes studies to date, ranging from the individual cell (e.g., DNA synthesis) to the whole organism (e.g., behaviors such as physical activity). Oscillations in metabolism have been characterized extensively in various organisms, including mammals. These metabolic rhythms often parallel behaviors such as sleep/wake and fasting/feeding cycles that occur on a daily basis. What has become increasingly clear over the past several decades is that many metabolic oscillations are driven by cell autonomous circadian clocks, which orchestrate metabolic processes in a temporally appropriate manner. During the process of identifying the mechanisms by which clocks influence metabolism, molecular-based studies have revealed that metabolism should be considered an integral circadian clock component. The implications of such an interrelationship include the establishment of a vicious cycle during cardiometabolic disease states, wherein metabolism-induced perturbations in the circadian clock exacerbate metabolic dysfunction. The purpose of this review is therefore to highlight recent insights gained regarding links between cell autonomous circadian clocks and metabolism, and the implications of clock dysfunction in the pathogenesis of cardiometabolic diseases. PMID:23594144

Functional Peptidomics: Stimulus- and Time-of-Day-Specific Peptide Release in the Mammalian Circadian Clock.

PubMed

Atkins, Norman; Ren, Shifang; Hatcher, Nathan; Burgoon, Penny W; Mitchell, Jennifer W; Sweedler, Jonathan V; Gillette, Martha U

2018-06-20

Daily oscillations of brain and body states are under complex temporal modulation by environmental light and the hypothalamic suprachiasmatic nucleus (SCN), the master circadian clock. To better understand mediators of differential temporal modulation, we characterize neuropeptide releasate profiles by nonselective capture of secreted neuropeptides in an optic nerve horizontal SCN brain slice model. Releasates are collected following electrophysiological stimulation of the optic nerve/retinohypothalamic tract under conditions that alter the phase of the SCN activity state. Secreted neuropeptides are identified by intact mass via matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). We found time-of-day-specific suites of peptides released downstream of optic nerve stimulation. Peptide release was modified differentially with respect to time-of-day by stimulus parameters and by inhibitors of glutamatergic or PACAPergic neurotransmission. The results suggest that SCN physiology is modulated by differential peptide release of both known and unexpected peptides that communicate time-of-day-specific photic signals via previously unreported neuropeptide signatures.

Maintenance of time and frequency in the Jet Propulsion Laboratory's Deep Space Network using the Global Positioning System

NASA Technical Reports Server (NTRS)

Clements, P. A.; Borutzki, S. E.; Kirk, A.

1984-01-01

The Deep Space Network (DSN), managed by the Jet Propulsion Laboratory for NASA, must maintain time and frequency within specified limits in order to accurately track the spacecraft engaged in deep space exploration. Various methods are used to coordinate the clocks among the three tracking complexes. These methods include Loran-C, TV Line 10, Very Long Baseline Interferometry (VLBI), and the Global Positioning System (GPS). Calculations are made to obtain frequency offsets and Allan variances. These data are analyzed and used to monitor the performance of the hydrogen masers that provide the reference frequencies for the DSN Frequency and Timing System (DFT). Areas of discussion are: (1) a brief history of the GPS timing receivers in the DSN, (2) a description of the data and information flow, (3) data on the performance of the DSN master clocks and GPS measurement system, and (4) a description of hydrogen maser frequency steering using these data.

Ideas for Future GPS Timing Improvements

NASA Technical Reports Server (NTRS)

Hutsell, Steven T.

1996-01-01

Having recently met stringent criteria for full operational capability (FOC) certification, the Global Positioning System (GPS) now has higher customer expectations than ever before. In order to maintain customer satisfaction, and the meet the even high customer demands of the future, the GPS Master Control Station (MCS) must play a critical role in the process of carefully refining the performance and integrity of the GPS constellation, particularly in the area of timing. This paper will present an operational perspective on several ideas for improving timing in GPS. These ideas include the desire for improving MCS - US Naval Observatory (USNO) data connectivity, an improved GPS-Coordinated Universal Time (UTC) prediction algorithm, a more robust Kalman Filter, and more features in the GPS reference time algorithm (the GPS composite clock), including frequency step resolution, a more explicit use of the basic time scale equation, and dynamic clock weighting. Current MCS software meets the exceptional challenge of managing an extremely complex constellation of 24 navigation satellites. The GPS community will, however, always seek to improve upon this performance and integrity.

Real-time recording of circadian liver gene expression in freely moving mice reveals the phase-setting behavior of hepatocyte clocks

PubMed Central

Saini, Camille; Liani, André; Curie, Thomas; Gos, Pascal; Kreppel, Florian; Emmenegger, Yann; Bonacina, Luigi; Wolf, Jean-Pierre; Poget, Yves-Alain; Franken, Paul; Schibler, Ueli

2013-01-01

The mammalian circadian timing system consists of a master pacemaker in the suprachiasmatic nucleus (SCN) in the hypothalamus, which is thought to set the phase of slave oscillators in virtually all body cells. However, due to the lack of appropriate in vivo recording technologies, it has been difficult to study how the SCN synchronizes oscillators in peripheral tissues. Here we describe the real-time recording of bioluminescence emitted by hepatocytes expressing circadian luciferase reporter genes in freely moving mice. The technology employs a device dubbed RT-Biolumicorder, which consists of a cylindrical cage with reflecting conical walls that channel photons toward a photomultiplier tube. The monitoring of circadian liver gene expression revealed that hepatocyte oscillators of SCN-lesioned mice synchronized more rapidly to feeding cycles than hepatocyte clocks of intact mice. Hence, the SCN uses signaling pathways that counteract those of feeding rhythms when their phase is in conflict with its own phase. PMID:23824542

Cryptochrome Mediates Light-Dependent Magnetosensitivity of Drosophila's Circadian Clock

PubMed Central

Yoshii, Taishi; Ahmad, Margaret; Helfrich-Förster, Charlotte

2009-01-01

Since 1960, magnetic fields have been discussed as Zeitgebers for circadian clocks, but the mechanism by which clocks perceive and process magnetic information has remained unknown. Recently, the radical-pair model involving light-activated photoreceptors as magnetic field sensors has gained considerable support, and the blue-light photoreceptor cryptochrome (CRY) has been proposed as a suitable molecule to mediate such magnetosensitivity. Since CRY is expressed in the circadian clock neurons and acts as a critical photoreceptor of Drosophila's clock, we aimed to test the role of CRY in magnetosensitivity of the circadian clock. In response to light, CRY causes slowing of the clock, ultimately leading to arrhythmic behavior. We expected that in the presence of applied magnetic fields, the impact of CRY on clock rhythmicity should be altered. Furthermore, according to the radical-pair hypothesis this response should be dependent on wavelength and on the field strength applied. We tested the effect of applied static magnetic fields on the circadian clock and found that flies exposed to these fields indeed showed enhanced slowing of clock rhythms. This effect was maximal at 300 μT, and reduced at both higher and lower field strengths. Clock response to magnetic fields was present in blue light, but absent under red-light illumination, which does not activate CRY. Furthermore, cryb and cryOUT mutants did not show any response, and flies overexpressing CRY in the clock neurons exhibited an enhanced response to the field. We conclude that Drosophila's circadian clock is sensitive to magnetic fields and that this sensitivity depends on light activation of CRY and on the applied field strength, consistent with the radical pair mechanism. CRY is widespread throughout biological systems and has been suggested as receptor for magnetic compass orientation in migratory birds. The present data establish the circadian clock of Drosophila as a model system for CRY-dependent magnetic sensitivity. Furthermore, given that CRY occurs in multiple tissues of Drosophila, including those potentially implicated in fly orientation, future studies may yield insights that could be applicable to the magnetic compass of migratory birds and even to potential magnetic field effects in humans. PMID:19355790

Expression conservation within the circadian clock of a monocot: natural variation at barley Ppd-H1 affects circadian expression of flowering time genes, but not clock orthologs.

PubMed

Campoli, Chiara; Shtaya, Munqez; Davis, Seth J; von Korff, Maria

2012-06-21

The circadian clock is an endogenous mechanism that coordinates biological processes with daily changes in the environment. In plants, circadian rhythms contribute to both agricultural productivity and evolutionary fitness. In barley, the photoperiod response regulator and flowering-time gene Ppd-H1 is orthologous to the Arabidopsis core-clock gene PRR7. However, relatively little is known about the role of Ppd-H1 and other components of the circadian clock in temperate crop species. In this study, we identified barley clock orthologs and tested the effects of natural genetic variation at Ppd-H1 on diurnal and circadian expression of clock and output genes from the photoperiod-response pathway. Barley clock orthologs HvCCA1, HvGI, HvPRR1, HvPRR37 (Ppd-H1), HvPRR73, HvPRR59 and HvPRR95 showed a high level of sequence similarity and conservation of diurnal and circadian expression patterns, when compared to Arabidopsis. The natural mutation at Ppd-H1 did not affect diurnal or circadian cycling of barley clock genes. However, the Ppd-H1 mutant was found to be arrhythmic under free-running conditions for the photoperiod-response genes HvCO1, HvCO2, and the MADS-box transcription factor and vernalization responsive gene Vrn-H1. We suggest that the described eudicot clock is largely conserved in the monocot barley. However, genetic differentiation within gene families and differences in the function of Ppd-H1 suggest evolutionary modification in the angiosperm clock. Our data indicates that natural variation at Ppd-H1 does not affect the expression level of clock genes, but controls photoperiodic output genes. Circadian control of Vrn-H1 in barley suggests that this vernalization responsive gene is also controlled by the photoperiod-response pathway. Structural and functional characterization of the barley circadian clock will set the basis for future studies of the adaptive significance of the circadian clock in Triticeae species.

Concepts in human biological rhythms

PubMed Central

Reinberg, Alain; Ashkenazi, Israel

2003-01-01

Biological rhythms and their temporal organization are adaptive phenomena to periodic changes in environmental factors linked to the earth's rotation on its axis and around the sun. Experimental data from the plant and animal kingdoms have led to many models and concepts related to biological clocks that help describe and understand the mechanisms of these changes. Many of the prevailing concepts apply to all organisms, but most of the experimental data are insufficient to explain the dynamics of human biological clocks. This review presents phenomena thai are mainly characteristic ofand unique to - human chronobiology, and which cannot be fully explained by concepts and models drawn from laboratory experiments. We deal with the functional advantages of the human temporal organization and the problem of desynchronization, with special reference to the period (τ) of the circadian rhythm and its interindividual and intraindividual variability. We describe the differences between right- and left-hand rhythms suggesting the existence of different biological clocks in the right and left cortices, Desynchronization of rhythms is rather frequent (one example is night shift workers). In some individuals, desynchronization causes no clinical symptoms and we propose the concept of “allochronism” to designate a variant of the human temporal organization with no pathological implications. We restrict the term “dyschronism” to changes or alterations in temporal organization associated with a set of symptoms similar to those observed in subjects intolerant to shift work, eg, persisting fatigue and mood and sleep alterations. Many diseases involve chronic deprivation of sleep at night and constitute conditions mimicking thai of night shift workers who are intolerant to desynchronization. We also present a genetic model (the dian-circadian model) to explain interindividual differences in the period of biological rhythms in certain conditions. PMID:22033796

Multiple circadian transcriptional elements cooperatively regulate cell-autonomous transcriptional oscillation of Period3, a mammalian clock gene.

PubMed

Matsumura, Ritsuko; Akashi, Makoto

2017-09-29

Cell-autonomous oscillation in clock gene expression drives circadian rhythms. The development of comprehensive analytical techniques, such as bioinformatics and ChIP-sequencing, has enabled the genome-wide identification of potential circadian transcriptional elements that regulate the transcriptional oscillation of clock genes. However, detailed analyses using traditional biochemical and molecular-biological approaches, such as binding and reporter assays, are still necessary to determine whether these potential circadian transcriptional elements are actually functional and how significantly they contribute to driving transcriptional oscillation. Here, we focused on the molecular mechanism of transcriptional oscillations in the mammalian clock gene Period3 ( Per3 ). The PER3 protein is essential for robust peripheral clocks and is a key component in circadian output processes. We found three E box-like elements located upstream of human Per3 transcription start sites that additively contributed to cell-autonomous transcriptional oscillation. However, we also found that Per3 is still expressed in a circadian manner when all three E box-like elements are functionally impaired. We noted that Per3 transcription was activated by the synergistic actions of two D box-like elements and the three E box-like elements, leading to a drastic increase in circadian amplitude. Interestingly, circadian expression of Per3 was completely disrupted only when all five transcriptional elements were functionally impaired. These results indicate that three E box-like and two D box-like elements cooperatively and redundantly regulate cell-autonomous transcriptional oscillation of Per3 . © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The circadian clock of teleost fish: a comparative analysis reveals distinct fates for duplicated genes.

PubMed

Toloza-Villalobos, Jessica; Arroyo, José Ignacio; Opazo, Juan C

2015-01-01

The circadian clock is a central oscillator that coordinates endogenous rhythms. Members of six gene families underlie the metabolic machinery of this system. Although this machinery appears to correspond to a highly conserved genetic system in metazoans, it has been recognized that vertebrates possess a more diverse gene inventory than that of non-vertebrates. This difference could have originated in the two successive rounds of whole-genome duplications that took place in the common ancestor of the group. Teleost fish underwent an extra event of whole-genome duplication, which is thought to have provided an abundance of raw genetic material for the biological innovations that facilitated the radiation of the group. In this study, we assessed the relative contributions of whole-genome duplication and small-scale gene duplication to generate the repertoire of genes associated with the circadian clock of teleost fish. To achieve this goal, we annotated genes from six gene families associated with the circadian clock in eight teleost fish species, and we reconstructed their evolutionary history by inferring phylogenetic relationships. Our comparative analysis indicated that teleost species possess a variable repertoire of genes related to the circadian clock gene families and that the actual diversity of these genes has been shaped by a variety of phenomena, such as the complete deletion of ohnologs, the differential retention of genes, and lineage-specific gene duplications. From a functional perspective, the subfunctionalization of two ohnolog genes (PER1a and PER1b) in zebrafish highlights the power of whole-genome duplications to generate biological diversity.

A Programme-Wide Training Framework to Facilitate Scientific Communication Skills Development amongst Biological Sciences Masters Students

ERIC Educational Resources Information Center

Divan, Aysha; Mason, Sam

2016-01-01

In this article we describe the effectiveness of a programme-wide communication skills training framework incorporated within a one-year biological sciences taught Masters course designed to enhance the competency of students in communicating scientific research principally to a scientific audience. In one class we analysed the numerical marks…

Clock-like mutational processes in human somatic cells

DOE PAGES

Alexandrov, Ludmil B.; Jones, Philip H.; Wedge, David C.; ...

2015-11-09

During the course of a lifetime, somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals, and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutationmore » rates in different tissues. However, their mutation rates are not correlated, indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This paper provides the first survey of clock-like mutational processes operating in human somatic cells.« less

Clock-like mutational processes in human somatic cells

PubMed Central

Alexandrov, Ludmil B.; Jones, Philip H.; Wedge, David C.; Sale, Julian E.; Campbell, Peter J.; Nik-Zainal, Serena; Stratton, Michael R.

2016-01-01

During the course of a lifetime somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell’s genome. Some processes generate mutations throughout life at a constant rate in all individuals and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This study provides the first survey of clock-like mutational processes operative in human somatic cells. PMID:26551669

Facilitation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor transmission in the suprachiasmatic nucleus by aniracetam enhances photic responses of the biological clock in rodents.

PubMed

Moriya, Takahiro; Ikeda, Masayuki; Teshima, Koji; Hara, Reiko; Kuriyama, Koji; Yoshioka, Tohru; Allen, Charles N; Shibata, Shigenobu

2003-05-01

This study was designed to test whether the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-facilitating drug, aniracetam, could potentiate photic responses of the biological clock in the suprachiasmatic nucleus (SCN) of rodents. Using the whole-cell patch technique, we first demonstrated that AMPA currents elicited by either local AMPA application or optic chiasm stimulation were augmented by aniracetam in the neurons of the SCN. The AMPA application-elicited increase of intracellular Ca2+ concentration in SCN slices was also enhanced by aniracetam treatment. The systemic injection of aniracetam dose-dependently (10-100 mg/kg) potentiated the phase delay in behavioral rhythm induced by brief light exposure of low intensity (3 lux) but not high intensity (10 or 60 lux) during early subjective night. Under the blockade of NMDA receptors by (+) MK801, aniracetam failed to potentiate a light (3 lux)-induced phase delay in behavioral rhythm. Aniracetam increased the photic induction of c-Fos protein in the SCN that was elicited by low intensity light exposure (3 lux). These results suggest that AMPA receptor-mediated responses facilitated by aniracetam can explain enhanced photic responses of the biological clock in the SCN of rodents.

A Gravity-Responsive Time-Keeping Protein of the Plant and Animal Cell Surface

NASA Technical Reports Server (NTRS)

Morre, D. James

2003-01-01

The hypothesis under investigation was that a ubiquinol (NADH) oxidase protein of the cell surface with protein disulfide-thiol interchange activity (= NOX protein) is a plant and animal time-keeping ultradian (period of less than 24 h) driver of both cell enlargement and the biological clock that responds to gravity. Despite considerable work in a large number of laboratories spanning several decades, this is, to my knowledge, our work is the first demonstration of a time-keeping biochemical reaction that is both gravity-responsive and growth-related and that has been shown to determine circadian periodicity. As such, the NOX protein may represent both the long-sought biological gravity receptor and the core oscillator of the cellular biological clock. Completed studies have resulted in 12 publications and two issued NASA-owned patents of the clock activity. The gravity response and autoentrainment were characterized in cultured mammalian cells and in two plant systems together with entrainment by light and small molecules (melatonin). The molecular basis of the oscillatory behavior was investigated using spectroscopic methods (Fourier transform infrared and circular dichroism) and high resolution electron microscopy. We have also applied these findings to an understanding of the response to hypergravity. Statistical methods for analysis of time series phenomena were developed (Foster et al., 2003).

Molecular Cogs: Interplay between Circadian Clock and Cell Cycle.

PubMed

Gaucher, Jonathan; Montellier, Emilie; Sassone-Corsi, Paolo

2018-05-01

The cell cycle and the circadian clock operate as biological oscillators whose timed functions are tightly regulated. Accumulating evidence illustrates the presence of molecular links between these two oscillators. This mutual interplay utilizes various coupling mechanisms, such as the use of common regulators. The connection between these two cyclic systems has unique interest in the context of aberrant cell proliferation since both of these oscillators are frequently misregulated in cancer cells. Further studies will provide deeper understanding of the detailed molecular connections between the cell cycle and the circadian clock and may also serve as a basis for the design of innovative therapeutic strategies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Roles of PACAP-containing retinal ganglion cells in circadian timing.

PubMed

Hannibal, Jens

2006-01-01

The brain's biological clock located in the suprachiasmatic nucleus (SCN) generates circadian rhythms in physiology and behavior. The clock-driven rhythms need daily adjustment (entrainment) to be synchronized with the astronomical day of 24 h. The most important stimulus for entrainment of the clock is the light-dark (LD) cycle. In this review functional elements of the light entrainment pathway will be considered with special focus on the neurotransmitter pituitary adenylate cyclase-activating polypeptide (PACAP), which is found exclusively in the monosynaptic neuronal pathway mediating light information to the SCN, the retinohypothalamic tract (RHT). The retinal ganglion cells of the RHT are intrinsically photosensitive due to the expression of melanopsin and seem to constitute a non-image forming photosensitive system in the mammalian eye regulating circadian timing, masking behavior, light-regulated melatonin secretion, and the pupillary light reflex. Evidence from in vitro and in vivo studies and studies of mice lacking PACAP and the specific PACAP receptor (PAC1) indicate that PACAP and glutamate are neurotransmitters in the RHT which in a clock and concentration-dependent manner interact during light entrainment of the clock.

Rhythm and mood: relationships between the circadian clock and mood-related behavior.

PubMed

Schnell, Anna; Albrecht, Urs; Sandrelli, Federica

2014-06-01

Mood disorders are multifactorial and heterogeneous diseases caused by the interplay of several genetic and environmental factors. In humans, mood disorders are often accompanied by abnormalities in the organization of the circadian system, which normally synchronizes activities and functions of cells and tissues. Studies on animal models suggest that the basic circadian clock mechanism, which runs in essentially all cells, is implicated in the modulation of biological phenomena regulating affective behaviors. In particular, recent findings highlight the importance of the circadian clock mechanisms in neurological pathways involved in mood, such as monoaminergic neurotransmission, hypothalamus-pituitary-adrenal axis regulation, suprachiasmatic nucleus and olfactory bulb activities, and neurogenesis. Defects at the level of both, the circadian clock mechanism and system, may contribute to the etiology of mood disorders. Modification of the circadian system using chronotherapy appears to be an effective treatment for mood disorders. Additionally, understanding the role of circadian clock mechanisms, which affect the regulation of different mood pathways, will open up the possibility for targeted pharmacological treatments. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Setting the pace: host rhythmic behaviour and gene expression patterns in the facultatively symbiotic cnidarian Aiptasia are determined largely by Symbiodinium.

PubMed

Sorek, Michal; Schnytzer, Yisrael; Ben-Asher, Hiba Waldman; Caspi, Vered Chalifa; Chen, Chii-Shiarng; Miller, David J; Levy, Oren

2018-05-09

All organisms employ biological clocks to anticipate physical changes in the environment; however, the integration of biological clocks in symbiotic systems has received limited attention. In corals, the interpretation of rhythmic behaviours is complicated by the daily oscillations in tissue oxygen tension resulting from the photosynthetic and respiratory activities of the associated algal endosymbiont Symbiodinium. In order to better understand the integration of biological clocks in cnidarian hosts of Symbiodinium, daily rhythms of behaviour and gene expression were studied in symbiotic and aposymbiotic morphs of the sea-anemone Aiptasia diaphana. The results showed that whereas circatidal (approx. 12-h) cycles of activity and gene expression predominated in aposymbiotic morphs, circadian (approx. 24-h) patterns were the more common in symbiotic morphs, where the expression of a significant number of genes shifted from a 12- to 24-h rhythm. The behavioural experiments on symbiotic A. diaphana displayed diel (24-h) rhythmicity in body and tentacle contraction under the light/dark cycles, whereas aposymbiotic morphs showed approximately 12-h (circatidal) rhythmicity. Reinfection experiments represent an important step in understanding the hierarchy of endogenous clocks in symbiotic associations, where the aposymbiotic Aiptasia morphs returned to a 24-h behavioural rhythm after repopulation with algae. Whilst some modification of host metabolism is to be expected, the extent to which the presence of the algae modified host endogenous behavioural and transcriptional rhythms implies that it is the symbionts that influence the pace. Our results clearly demonstrate the importance of the endosymbiotic algae in determining the timing and the duration of the extension and contraction of the body and tentacles and temporal gene expression.

Improving Ion Mobility Spectrometry Detection Methods for Trace Forensics and Military Field Applications

DTIC Science & Technology

2016-10-11

UNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES F. EDWARD HEBERT SCHOOL OF MEDICINE 4301 JONES BRIDGE ROAD BETHESDA, MARYLAND 20814-4799...ofPublic Health (Dr.P.H.) Master ofScience Degrees Departmental -Clinical Psychology -Environmental Health Sciences -Medical Psychology -Medical...Zoology -Pathology Interdisciplinary -Emerging Infectious Diseases -Molecular & Cell Biology -Neuroscience -Molecular & Cell Biology -Public Health Masters

Intrinsic near-24-h pacemaker period determines limits of circadian entrainment to a weak synchronizer in humans

NASA Technical Reports Server (NTRS)

Wright, K. P. Jr; Hughes, R. J.; Kronauer, R. E.; Dijk, D. J.; Czeisler, C. A.

2001-01-01

Endogenous circadian clocks are robust regulators of physiology and behavior. Synchronization or entrainment of biological clocks to environmental time is adaptive and important for physiological homeostasis and for the proper timing of species-specific behaviors. We studied subjects in the laboratory for up to 55 days each to determine the ability to entrain the human clock to a weak circadian synchronizing stimulus [scheduled activity-rest cycle in very dim (approximately 1.5 lux in the angle of gaze) light-dark cycle] at three approximately 24-h periods: 23.5, 24.0, and 24.6 h. These studies allowed us to test two competing hypotheses as to whether the period of the human circadian pacemaker is near to or much longer than 24 h. We report here that imposition of a sleep-wake schedule with exposure to the equivalent of candle light during wakefulness and darkness during sleep is usually sufficient to maintain circadian entrainment to the 24-h day but not to a 23.5- or 24.6-h day. Our results demonstrate functionally that, in normally entrained sighted adults, the average intrinsic circadian period of the human biological clock is very close to 24 h. Either exposure to very dim light and/or the scheduled sleep-wake cycle itself can entrain this near-24-h intrinsic period of the human circadian pacemaker to the 24-h day.

Evolution of circadian rhythms in Drosophila melanogaster populations reared in constant light and dark regimes for over 330 generations.

PubMed

Shindey, Radhika; Varma, Vishwanath; Nikhil, K L; Sharma, Vijay Kumar

2017-01-01

Organisms are believed to have evolved circadian clocks as adaptations to deal with cyclic environmental changes, and therefore it has been hypothesized that evolution in constant environments would lead to regression of such clocks. However, previous studies have yielded mixed results, and evolution of circadian clocks under constant conditions has remained an unsettled topic of debate in circadian biology. In continuation of our previous studies, which reported persistence of circadian rhythms in Drosophila melanogaster populations evolving under constant light, here we intended to examine whether circadian clocks and the associated properties evolve differently under constant light and constant darkness. In this regard, we assayed activity-rest, adult emergence and oviposition rhythms of D. melanogaster populations which have been maintained for over 19 years (~330 generations) under three different light regimes - constant light (LL), light-dark cycles of 12:12 h (LD) and constant darkness (DD). We observed that while circadian rhythms in all the three behaviors persist in both LL and DD stocks with no differences in circadian period, they differed in certain aspects of the entrained rhythms when compared to controls reared in rhythmic environment (LD). Interestingly, we also observed that DD stocks have evolved significantly higher robustness or power of free-running activity-rest and adult emergence rhythms compared to LL stocks. Thus, our study, in addition to corroborating previous results of circadian clock evolution in constant light, also highlights that, contrary to the expected regression of circadian clocks, rearing in constant darkness leads to the evolution of more robust circadian clocks which may be attributed to an intrinsic adaptive advantage of circadian clocks and/or pleiotropic functions of clock genes in other traits.

Circadian CLOCK gene polymorphisms in relation to sleep patterns and obesity in African Americans: findings from the Jackson heart study.

PubMed

Riestra, Pia; Gebreab, Samson Y; Xu, Ruihua; Khan, Rumana J; Gaye, Amadou; Correa, Adolfo; Min, Nancy; Sims, Mario; Davis, Sharon K

2017-06-23

Circadian rhythms regulate key biological processes and the dysregulation of the intrinsic clock mechanism affects sleep patterns and obesity onset. The CLOCK (circadian locomotor output cycles protein kaput) gene encodes a core transcription factor of the molecular circadian clock influencing diverse metabolic pathways, including glucose and lipid homeostasis. The primary objective of this study was to evaluate the associations between CLOCK single nucleotide polymorphisms (SNPs) and body mass index (BMI). We also evaluated the association of SNPs with BMI related factors such as sleep duration and quality, adiponectin and leptin, in 2962 participants (1116 men and 1810 women) from the Jackson Heart Study. Genotype data for the selected 23 CLOCK gene SNPS was obtained by imputation with IMPUTE2 software and reference phase data from the 1000 genome project. Genetic analyses were conducted with PLINK RESULTS: We found a significant association between the CLOCK SNP rs2070062 and sleep duration, participants carriers of the T allele showed significantly shorter sleep duration compared to non-carriers after the adjustment for individual proportions of European ancestry (PEA), socio economic status (SES), body mass index (BMI), alcohol consumption and smoking status that reach the significance threshold after multiple testing correction. In addition, we found nominal associations of the CLOCK SNP rs6853192 with longer sleep duration and the rs6820823, rs3792603 and rs11726609 with BMI. However, these associations did not reach the significance threshold after correction for multiple testing. In this work, CLOCK gene variants were associated with sleep duration and BMI suggesting that the effects of these polymorphisms on circadian rhythmicity may affect sleep duration and body weight regulation in Africans Americans.

BMAL1 and CLOCK proteins in regulating UVB-induced apoptosis and DNA damage responses in human keratinocytes.

PubMed

Sun, Yang; Wang, Peiling; Li, Hongyu; Dai, Jun

2018-06-26

A diverse array of biological processes are under circadian controls. In mouse skin, ultraviolet ray (UVR)-induced apoptosis and DNA damage responses are time-of-day dependent, which are controlled by core clock proteins. This study investigates the roles of clock proteins in regulating UVB responses in human keratinocytes (HKCs). We found that the messenger RNA expression of brain and muscle ARNT-like 1 (BMAL1) and circadian locomotor output cycles kaput (CLOCK) genes is altered by low doses (5 mJ/cm 2 ) of UVB in the immortalized HaCat HKCs cell line. Although depletion of BMAL1 or CLOCK has no effect on the activation of Rad3-related protein kinases-checkpoint kinase 1-p53 mediated DNA damage checkpoints, it leads to suppression of UVB-stimulated apoptotic responses, and downregulation of UVB-elevated expression of DNA damage marker γ-H2AX and cell cycle inhibitor p21. Diminished apoptotic responses are also observed in primary HKCs depleted of BMAL1 or CLOCK after UVB irradiation. While CLOCK depletion shows a suppressive effect on UVB-induced p53 protein accumulation, depletion of either clock gene triggers early keratinocyte differentiation of HKCs at their steady state. These results suggest that UVB-induced apoptosis and DNA damage responses are controlled by clock proteins, but via different mechanisms in the immortalized human adult low calcium temperature and primary HKCs. Given the implication of UVB in photoaging and photocarcinogenesis, mechanistic elucidation of circadian controls on UVB effects in human skin will be critical and beneficial for prevention and treatment of skin cancers and other skin-related diseases. © 2018 Wiley Periodicals, Inc.

Light and chronobiology: implications for health and disease.

PubMed

Münch, Mirjam; Bromundt, Vivien

2012-12-01

Environmental light synchronizes the primary mammalian biological clock in the suprachiasmatic nuclei, as well as many peripheral clocks in tissues and cells, to the solar 24-hour day. Light is the strongest synchronizing agent (zeitgeber) for the circadian system, and therefore keeps most biological and psychological rhythms internally synchronized, which is important for optimum function. Circadian sleep-wake disruptions and chronic circadian misalignment, as often observed in psychiatric and neurodegenerative illness, can be treated with light therapy. The beneficial effect on circadian synchronization, sleep quality, mood, and cognitive performance depends on timing, intensity, and spectral composition of light exposure. Tailoring and optimizing indoor lighting conditions may be an approach to improve wellbeing, alertness, and cognitive performance and, in the long term, producing health benefits.

Synchrony and entrainment properties of robust circadian oscillators

PubMed Central

Bagheri, Neda; Taylor, Stephanie R.; Meeker, Kirsten; Petzold, Linda R.; Doyle, Francis J.

2008-01-01

Systems theoretic tools (i.e. mathematical modelling, control, and feedback design) advance the understanding of robust performance in complex biological networks. We highlight phase entrainment as a key performance measure used to investigate dynamics of a single deterministic circadian oscillator for the purpose of generating insight into the behaviour of a population of (synchronized) oscillators. More specifically, the analysis of phase characteristics may facilitate the identification of appropriate coupling mechanisms for the ensemble of noisy (stochastic) circadian clocks. Phase also serves as a critical control objective to correct mismatch between the biological clock and its environment. Thus, we introduce methods of investigating synchrony and entrainment in both stochastic and deterministic frameworks, and as a property of a single oscillator or population of coupled oscillators. PMID:18426774

Light and chronobiology: implications for health and disease

PubMed Central

Münch, Mirjam; Bromundt, Vivien

2012-01-01

Environmental light synchronizes the primary mammalian biological clock in the suprachiasmatic nuclei, as well as many peripheral clocks in tissues and cells, to the solar 24-hour day. Light is the strongest synchronizing agent (zeitgeber) for the circadian system, and therefore keeps most biological and psychological rhythms internally synchronized, which is important for optimum function. Circadian sleep-wake disruptions and chronic circadian misalignment, as often observed in psychiatric and neurodegenerative illness, can be treated with light therapy. The beneficial effect on circadian synchronization, sleep quality, mood, and cognitive performance depends on timing, intensity, and spectral composition of light exposure. Tailoring and optimizing indoor lighting conditions may be an approach to improve wellbeing, alertness, and cognitive performance and, in the long term, producing health benefits. PMID:23393421

Strengthening cancer biology research, prevention, and control while reducing cancer disparities: student perceptions of a collaborative master's degree program in cancer biology, preventions, and control.

PubMed

Jillson, I A; Cousin, C E; Blancato, J K

2013-09-01

This article provides the findings of a survey of previous and current students in the UDC/GU-LCCC master's degree program. This master's degree program, Cancer Biology, Prevention, and Control is administered and taught jointly by faculty of a Minority Serving Institution, the University of the District of Columbia, and the Lombardi Comprehensive Cancer Center to incorporate the strengths of a community-based school with a research intensive medical center. The program was initiated in 2008 through agreements with both University administrations and funding from the National Cancer Institute. The master's degree program is 36 credits with a focus on coursework in biostatistics, epidemiology, tumor biology, cancer prevention, medical ethics, and cancer outreach program design. For two semesters during the second year, students work full-time with a faculty person on a laboratory or outreach project that is a requirement for graduation. Students are supported and encouraged to transition to a doctoral degree after they obtain the master's and many of them are currently in doctorate programs. Since the inception of the program, 45 students have initiated the course of study, 28 have completed the program, and 13 are currently enrolled in the program. The survey was designed to track the students in their current activities, as well as determine which courses, program enhancements, and research experiences were the least and most useful, and to discern students' perceptions of knowledge acquired on various aspects of Cancer Biology Prevention, and Control Master's Program. Thirty of the 35 individuals to whom email requests were sent responded to the survey, for a response rate of 85.7%. The results of this study will inform the strengthening of the Cancer Biology program by the Education Advisory Committee. They can also be used in the development of comparable collaborative master's degree programs designed to address the significant disparities in prevalence of cancer, low screening awareness, and access to and outcomes of cancer prevention and treatment services. This, in turn, will contribute to the elimination of the dearth of underrepresented minority scientists who address these disparities. By far, the students were satisfied with the program and believe that it has had significant impact on their ability to contribute to cancer prevention and control. They provided both general and specific recommendations to strengthen the program.

Measuring circadian and acute light responses in mice using wheel running activity.

PubMed

LeGates, Tara A; Altimus, Cara M

2011-02-04

Circadian rhythms are physiological functions that cycle over a period of approximately 24 hours (circadian- circa: approximate and diem: day). They are responsible for timing our sleep/wake cycles and hormone secretion. Since this timing is not precisely 24-hours, it is synchronized to the solar day by light input. This is accomplished via photic input from the retina to the suprachiasmatic nucleus (SCN) which serves as the master pacemaker synchronizing peripheral clocks in other regions of the brain and peripheral tissues to the environmental light dark cycle. The alignment of rhythms to this environmental light dark cycle organizes particular physiological events to the correct temporal niche, which is crucial for survival. For example, mice sleep during the day and are active at night. This ability to consolidate activity to either the light or dark portion of the day is referred to as circadian photoentrainment and requires light input to the circadian clock. Activity of mice at night is robust particularly in the presence of a running wheel. Measuring this behavior is a minimally invasive method that can be used to evaluate the functionality of the circadian system as well as light input to this system. Methods that will covered here are used to examine the circadian clock, light input to this system, as well as the direct influence of light on wheel running behavior.

Relating the Hadamard Variance to MCS Kalman Filter Clock Estimation

NASA Technical Reports Server (NTRS)

Hutsell, Steven T.

1996-01-01

The Global Positioning System (GPS) Master Control Station (MCS) currently makes significant use of the Allan Variance. This two-sample variance equation has proven excellent as a handy, understandable tool, both for time domain analysis of GPS cesium frequency standards, and for fine tuning the MCS's state estimation of these atomic clocks. The Allan Variance does not explicitly converge for the nose types of alpha less than or equal to minus 3 and can be greatly affected by frequency drift. Because GPS rubidium frequency standards exhibit non-trivial aging and aging noise characteristics, the basic Allan Variance analysis must be augmented in order to (a) compensate for a dynamic frequency drift, and (b) characterize two additional noise types, specifically alpha = minus 3, and alpha = minus 4. As the GPS program progresses, we will utilize a larger percentage of rubidium frequency standards than ever before. Hence, GPS rubidium clock characterization will require more attention than ever before. The three sample variance, commonly referred to as a renormalized Hadamard Variance, is unaffected by linear frequency drift, converges for alpha is greater than minus 5, and thus has utility for modeling noise in GPS rubidium frequency standards. This paper demonstrates the potential of Hadamard Variance analysis in GPS operations, and presents an equation that relates the Hadamard Variance to the MCS's Kalman filter process noises.

Population clocks: motor timing with neural dynamics

PubMed Central

Buonomano, Dean V.; Laje, Rodrigo

2010-01-01

An understanding of sensory and motor processing will require elucidation of the mechanisms by which the brain tells time. Open questions relate to whether timing relies on dedicated or intrinsic mechanisms and whether distinct mechanisms underlie timing across scales and modalities. Although experimental and theoretical studies support the notion that neural circuits are intrinsically capable of sensory timing on short scales, few general models of motor timing have been proposed. For one class of models, population clocks, it is proposed that time is encoded in the time-varying patterns of activity of a population of neurons. We argue that population clocks emerge from the internal dynamics of recurrently connected networks, are biologically realistic and account for many aspects of motor timing. PMID:20889368

Geography of the circadian gene clock and photoperiodic response in western North American populations of the three-spined stickleback Gasterosteus aculeatus.

PubMed

O'Brien, C; Unruh, L; Zimmerman, C; Bradshaw, W E; Holzapfel, C M; Cresko, W A

2013-03-01

Controlled laboratory experiments were used to show that Oregon and Alaskan three-spined stickleback Gasterosteus aculeatus, collected from locations differing by 18° of latitude, exhibited no significant variation in length of the polyglutamine domain of the clock protein or in photoperiodic response within or between latitudes despite the fact that male and female G. aculeatus are photoperiodic at both latitudes. Hence, caution is urged when interpreting variation in the polyglutamine repeat (PolyQ) domain of the gene clock in the context of seasonal activities or in relationship to photoperiodism along geographical gradients. © 2013 The Authors. Journal of Fish Biology © 2013 The Fisheries Society of the British Isles.

Irradiation with X-rays phase-advances the molecular clockwork in liver, adrenal gland and pancreas.

PubMed

Müller, Mareike Hildegard; Rödel, Franz; Rüb, Udo; Korf, Horst-Werner

2015-02-01

The circadian clock of man and mammals shows a hierarchic organization. The master clock, located in the suprachiasmatic nuclei (SCN), controls peripheral oscillators distributed throughout the body. Rhythm generation depends on molecular clockworks based on transcriptional/translational interaction of clock genes. Numerous studies have shown that the clockwork in peripheral oscillators is capable to maintain circadian rhythms for several cycles in vitro, i.e. in the absence of signals from the SCN. The aim of the present study is to analyze the effects of irradiation with X-rays on the clockwork of liver, adrenal and pancreas. To this end organotypic slice cultures of liver (OLSC) and organotypic explant cultures of adrenal glands (OAEC) and pancreas (OPEC) were prepared from transgenic mPer2(luc) mice which express luciferase under the control of the promoter of an important clock gene, Per2, and allow to study the dynamics of the molecular clockwork by bioluminometry. The preparations were cultured in a membrane-based liquid-air interface culturing system and irradiated with X-rays at doses of 10 Gy and 50 Gy or left untreated. Bioluminometric real-time recordings show a stable oscillation of all OLSC, OAEC and OPEC for up to 12 days in vitro. Oscillations persist after irradiation with X-rays. However, a dose of 50 Gy caused a phase advance in the rhythm of the OLSC by 5 h, in the OPEC by 7 h and in the OAEC by 6 h. Our study shows that X-rays affect the molecular clockwork in liver, pancreas and adrenal leading to phase advances. Our results confirm and extend previous studies showing a phase-advancing effect of X-rays at the level of the whole animal and single cells.

The Art and Practice of Gratitude: Practicing an Overlooked Skill to Help Undergraduate Biology Students Become Successful Professionals

ERIC Educational Resources Information Center

Halpin, Patricia A.; Landon, Jennifer

2015-01-01

In a fast-paced, technology-driven world, the age-old custom and etiquette of writing a thank-you note may often be forgotten. Educators need to provide students with the opportunity to master this important professional skill. One might assume that undergraduate biology students have mastered the art of crafting a thoughtful and articulate…

Rate variation and estimation of divergence times using strict and relaxed clocks.

PubMed

Brown, Richard P; Yang, Ziheng

2011-09-26

Understanding causes of biological diversity may be greatly enhanced by knowledge of divergence times. Strict and relaxed clock models are used in Bayesian estimation of divergence times. We examined whether: i) strict clock models are generally more appropriate in shallow phylogenies where rate variation is expected to be low, ii) the likelihood ratio test of the clock (LRT) reliably informs which model is appropriate for dating divergence times. Strict and relaxed models were used to analyse sequences simulated under different levels of rate variation. Published shallow phylogenies (Black bass, Primate-sucking lice, Podarcis lizards, Gallotiinae lizards, and Caprinae mammals) were also analysed to determine natural levels of rate variation relative to the performance of the different models. Strict clock analyses performed well on data simulated under the independent rates model when the standard deviation of log rate on branches, σ, was low (≤ 0.1), but were inappropriate when σ>0.1 (95% of rates fall within 0.0082-0.0121 subs/site/Ma when σ = 0.1, for a mean rate of 0.01). The independent rates relaxed clock model performed well at all levels of rate variation, although posterior intervals on times were significantly wider than for the strict clock. The strict clock is therefore superior when rate variation is low. The performance of a correlated rates relaxed clock model was similar to the strict clock. Increased numbers of independent loci led to slightly narrower posteriors under the relaxed clock while older root ages provided proportionately narrower posteriors. The LRT had low power for σ = 0.01-0.1, but high power for σ = 0.5-2.0. Posterior means of σ2 were useful for assessing rate variation in published datasets. Estimates of natural levels of rate variation ranged from 0.05-3.38 for different partitions. Differences in divergence times between relaxed and strict clock analyses were greater in two datasets with higher σ2 for one or more partitions, supporting the simulation results. The strict clock can be superior for trees with shallow roots because of low levels of rate variation between branches. The LRT allows robust assessment of suitability of the clock model as does examination of posteriors on σ2.

APS Conference on Understanding the Biological Clock: From Genetics to Physiology

NASA Technical Reports Server (NTRS)

Frank, Martin

1996-01-01

The Conference was designed to take advantage of the fusion of two intellectually dominant but heretofore separate lines of clock research, vertebrate physiology and invertebrate and microbial genetics. The APS Conference attracted 251 scientists, 68 of whom were students. In addition to the excellent speaker program organized by Dunlap and Loros, the attendees also submitted 93 volunteer abstracts that were programmed in poster sessions. Thirty-four percent of the submitted abstracts were first authorized by a female student or scientist.

Test results of the STI GPS time transfer receiver

NASA Technical Reports Server (NTRS)

Hall, D. L.; Handlan, J.; Wheeler, P.

1983-01-01

Global time transfer, or synchronization, between a user clock and USNO UTC time can be performed using the Global Positioning System (GPS), and commercially available time transfer receivers. This paper presents the test results of time transfer using the GPS system and a Stanford Telecommunications, Inc. (STI) Time Transfer System (TTS) Model 502. Tests at the GPS Master Control Site (MCS) in Vandenburg, California and at the United States Naval Observatory (USNO) in Washington, D.C. are described. An overview of GPS, and the STI TTS 502 is presented. A discussion of the time transfer process and test concepts is included.

Upper-Bounds on Qubit Coherence Set by Master Clock Instabilities

DTIC Science & Technology

2016-01-10

PhysRevLett.95.060502 [3] Olmschenk S, Younge K C, Moehring D L, Matsukevich D N , Maunz P and Monroe C 2007 Phys. Rev. A 76 052314 [4] Soare A, Ball H...Sekiguchi T, Itoh K M, Jamieson D N , McCallum J C, Dzurak A S and Morello A 2014 Nature Nanotechnology 9 986–991 [9] Brown K R, Wilson A C, Colombe Y...Cleland A and Martinis J M 2014 Phys. Rev. Lett. 112(24) 240504 [11] Harty T P, Allcock D, Ballance C J, Guidoni L, Janacek H A, Linke N M, Stacey D N

Intensity noise properties of a compact laser device based on a miniaturized MOPA system for spectroscopic applications

NASA Astrophysics Data System (ADS)

Baumgärtner, S.; Juhl, S.; Opalevs, D.; Sahm, A.; Hofmann, J.; Leisching, P.; Paschke, K.

2018-02-01

We present a novel compact laser device based on a semiconductor master-oscillator power-amplifier (MOPA) emitting at 772 nm, suitable for quantum optic and spectroscopy. The optical performance of the laser device is characterized. For miniaturized lasers the thermal management is challenging, we therefore perform thermal simulations and measurements. The first demonstrator is emitting more than 3 W optical power with a linewidth below 2lMHz. Using this MOPA design also compact devices for quantum optics (e.g. rubidium atomic clock) and seed lasers for frequency conversion can be realized [1].

Evidence for an Overlapping Role of CLOCK and NPAS2 Transcription Factors in Liver Circadian Oscillators▿

PubMed Central

Bertolucci, Cristiano; Cavallari, Nicola; Colognesi, Ilaria; Aguzzi, Jacopo; Chen, Zheng; Caruso, Pierpaolo; Foá, Augusto; Tosini, Gianluca; Bernardi, Francesco; Pinotti, Mirko

2008-01-01

The mechanisms underlying the circadian control of gene expression in peripheral tissues and influencing many biological pathways are poorly defined. Factor VII (FVII), the protease triggering blood coagulation, represents a valuable model to address this issue in liver since its plasma levels oscillate in a circadian manner and its promoter contains E-boxes, which are putative DNA-binding sites for CLOCK-BMAL1 and NPAS2-BMAL1 heterodimers and hallmarks of circadian regulation. The peaks of FVII mRNA levels in livers of wild-type mice preceded those in plasma, indicating a transcriptional regulation, and were abolished in Clock−/−; Npas2−/− mice, thus demonstrating a role for CLOCK and NPAS2 circadian transcription factors. The investigation of Npas2−/− and ClockΔ19/Δ19 mice, which express functionally defective heterodimers, revealed robust rhythms of FVII expression in both animal models, suggesting a redundant role for NPAS2 and CLOCK. The molecular bases of these observations were established through reporter gene assays. FVII transactivation activities of the NPAS2-BMAL1 and CLOCK-BMAL1 heterodimers were (i) comparable (a fourfold increase), (ii) dampened by the negative circadian regulators PER2 and CRY1, and (iii) abolished upon E-box mutagenesis. Our data provide the first evidence in peripheral oscillators for an overlapping role of CLOCK and NPAS2 in the regulation of circadianly controlled genes. PMID:18316400

A Discourse Analysis of Master's Theses across Disciplines with a Focus on Introductions

ERIC Educational Resources Information Center

Samraj, Betty

2008-01-01

There have been a growing number of discourse studies in recent years on written academic genres produced by students. However, the master's thesis has not received as much attention as the PhD dissertation. This investigation of master's theses from three disciplines, biology, philosophy and linguistics, employs both discourse analysis and…

Suicide attempts in children and adolescents: The place of clock genes and early rhythm dysfunction.

PubMed

Olliac, Bertrand; Ouss, Lisa; Charrier, Annaëlle

2016-11-01

Suicide remains one of the leading causes of death among young people, and suicidal ideation and behavior are relatively common in healthy and clinical populations. Suicide risk in childhood and adolescence is often approached from the perspective of nosographic categories to which predictive variables for suicidal acts are often linked. The cascading effects resulting from altered clock genes in a pediatric population could participate in biological rhythm abnormalities and the emergence of suicide attempts through impaired regulation of circadian rhythms and emotional states with neurodevelopmental effects. Also, early trauma and stressful life events can alter the expression of clock genes and contribute to the emergence of suicide attempts. Alteration of clock genes might lead to desynchronized and abnormal circadian rhythms impairing in turn the synchronization between external and internal rhythms and therefore the adaptation of the individual to his/her internal and external environment with the development of psychiatric disorders associated with increased risk for suicide attempts. Copyright © 2017 Elsevier Ltd. All rights reserved.

Robust and tunable circadian rhythms from differentially sensitive catalytic domains

PubMed Central

Phong, Connie; Markson, Joseph S.; Wilhoite, Crystal M.; Rust, Michael J.

2013-01-01

Circadian clocks are ubiquitous biological oscillators that coordinate an organism’s behavior with the daily cycling of the external environment. To ensure synchronization with the environment, the period of the clock must be maintained near 24 h even as amplitude and phase are altered by input signaling. We show that, in a reconstituted circadian system from cyanobacteria, these conflicting requirements are satisfied by distinct functions for two domains of the central clock protein KaiC: the C-terminal autokinase domain integrates input signals through the ATP/ADP ratio, and the slow N-terminal ATPase acts as an input-independent timer. We find that phosphorylation in the C-terminal domain followed by an ATPase cycle in the N-terminal domain is required to form the inhibitory KaiB•KaiC complexes that drive the dynamics of the clock. We present a mathematical model in which this ATPase-mediated delay in negative feedback gives rise to a compensatory mechanism that allows a tunable phase and amplitude while ensuring a robust circadian period. PMID:23277568

Circadian Rhythms in Cyanobacteria

PubMed Central

Golden, Susan S.

2015-01-01

SUMMARY Life on earth is subject to daily and predictable fluctuations in light intensity, temperature, and humidity created by rotation of the earth. Circadian rhythms, generated by a circadian clock, control temporal programs of cellular physiology to facilitate adaptation to daily environmental changes. Circadian rhythms are nearly ubiquitous and are found in both prokaryotic and eukaryotic organisms. Here we introduce the molecular mechanism of the circadian clock in the model cyanobacterium Synechococcus elongatus PCC 7942. We review the current understanding of the cyanobacterial clock, emphasizing recent work that has generated a more comprehensive understanding of how the circadian oscillator becomes synchronized with the external environment and how information from the oscillator is transmitted to generate rhythms of biological activity. These results have changed how we think about the clock, shifting away from a linear model to one in which the clock is viewed as an interactive network of multifunctional components that are integrated into the context of the cell in order to pace and reset the oscillator. We conclude with a discussion of how this basic timekeeping mechanism differs in other cyanobacterial species and how information gleaned from work in cyanobacteria can be translated to understanding rhythmic phenomena in other prokaryotic systems. PMID:26335718

The Root Pressure Phenomenon

ERIC Educational Resources Information Center

Marsh, A. R.

1972-01-01

Describes experiments demonstrating that root pressure in plants is probably controlled by a circadian rhythm (biological clock). Root pressure phenomenon plays significant part in water transport in contradiction with prevalent belief. (PS)

Core clock, SUB1, and ABAR genes mediate flooding and drought responses via alternative splicing in soybean.

PubMed

Syed, Naeem H; Prince, Silvas J; Mutava, Raymond N; Patil, Gunvant; Li, Song; Chen, Wei; Babu, Valliyodan; Joshi, Trupti; Khan, Saad; Nguyen, Henry T

2015-12-01

Circadian clocks are a great evolutionary innovation and provide competitive advantage during the day/night cycle and under changing environmental conditions. The circadian clock mediates expression of a large proportion of genes in plants, achieving a harmonious relationship between energy metabolism, photosynthesis, and biotic and abiotic stress responses. Here it is shown that multiple paralogues of clock genes are present in soybean (Glycine max) and mediate flooding and drought responses. Differential expression of many clock and SUB1 genes was found under flooding and drought conditions. Furthermore, natural variation in the amplitude and phase shifts in PRR7 and TOC1 genes was also discovered under drought and flooding conditions, respectively. PRR3 exhibited flooding- and drought-specific splicing patterns and may work in concert with PRR7 and TOC1 to achieve energy homeostasis under flooding and drought conditions. Higher expression of TOC1 also coincides with elevated levels of abscisic acid (ABA) and variation in glucose levels in the morning and afternoon, indicating that this response to abiotic stress is mediated by ABA, endogenous sugar levels, and the circadian clock to fine-tune photosynthesis and energy utilization under stress conditions. It is proposed that the presence of multiple clock gene paralogues with variation in DNA sequence, phase, and period could be used to screen exotic germplasm to find sources for drought and flooding tolerance. Furthermore, fine tuning of multiple clock gene paralogues (via a genetic engineering approach) should also facilitate the development of flooding- and drought-tolerant soybean varieties. © The Author 2015. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Circadian gene expression regulates pulsatile gonadotropin-releasing hormone (GnRH) secretory patterns in the hypothalamic GnRH-secreting GT1-7 cell line.

PubMed

Chappell, Patrick E; White, Rachel S; Mellon, Pamela L

2003-12-03

Although it has long been established that episodic secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus is required for normal gonadotropin release, the molecular and cellular mechanisms underlying the synchronous release of GnRH are primarily unknown. We used the GT1-7 mouse hypothalamic cell line as a model for GnRH secretion, because these cells release GnRH in a pulsatile pattern similar to that observed in vivo. To explore possible molecular mechanisms governing secretory timing, we investigated the role of the molecular circadian clock in regulation of GnRH secretion. GT1-7 cells express many known core circadian clock genes, and we demonstrate that oscillations of these components can be induced by stimuli such as serum and the adenylyl cyclase activator forskolin, similar to effects observed in fibroblasts. Strikingly, perturbation of circadian clock function in GT1-7 cells by transient expression of the dominant-negative Clock-Delta19 gene disrupts normal ultradian patterns of GnRH secretion, significantly decreasing mean pulse frequency. Additionally, overexpression of the negative limb clock gene mCry1 in GT1-7 cells substantially increases GnRH pulse amplitude without a commensurate change in pulse frequency, demonstrating that an endogenous biological clock is coupled to the mechanism of neurosecretion in these cells and can regulate multiple secretory parameters. Finally, mice harboring a somatic mutation in the Clock gene are subfertile and exhibit a substantial increase in estrous cycle duration as revealed by examination of vaginal cytology. This effect persists in normal light/dark (LD) cycles, suggesting that a suprachiasmatic nucleus-independent endogenous clock in GnRH neurons is required for eliciting normal pulsatile patterns of GnRH secretion.

Effects of Different PER Translational Kinetics on the Dynamics of a Core Circadian Clock Model

PubMed Central

Nieto, Paula S.; Revelli, Jorge A.; Garbarino-Pico, Eduardo; Condat, Carlos A.; Guido, Mario E.; Tamarit, Francisco A.

2015-01-01

Living beings display self-sustained daily rhythms in multiple biological processes, which persist in the absence of external cues since they are generated by endogenous circadian clocks. The period (per) gene is a central player within the core molecular mechanism for keeping circadian time in most animals. Recently, the modulation PER translation has been reported, both in mammals and flies, suggesting that translational regulation of clock components is important for the proper clock gene expression and molecular clock performance. Because translational regulation ultimately implies changes in the kinetics of translation and, therefore, in the circadian clock dynamics, we sought to study how and to what extent the molecular clock dynamics is affected by the kinetics of PER translation. With this objective, we used a minimal mathematical model of the molecular circadian clock to qualitatively characterize the dynamical changes derived from kinetically different PER translational mechanisms. We found that the emergence of self-sustained oscillations with characteristic period, amplitude, and phase lag (time delays) between per mRNA and protein expression depends on the kinetic parameters related to PER translation. Interestingly, under certain conditions, a PER translation mechanism with saturable kinetics introduces longer time delays than a mechanism ruled by a first-order kinetics. In addition, the kinetic laws of PER translation significantly changed the sensitivity of our model to parameters related to the synthesis and degradation of per mRNA and PER degradation. Lastly, we found a set of parameters, with realistic values, for which our model reproduces some experimental results reported recently for Drosophila melanogaster and we present some predictions derived from our analysis. PMID:25607544

Effects of different per translational kinetics on the dynamics of a core circadian clock model.

PubMed

Nieto, Paula S; Revelli, Jorge A; Garbarino-Pico, Eduardo; Condat, Carlos A; Guido, Mario E; Tamarit, Francisco A

2015-01-01

Living beings display self-sustained daily rhythms in multiple biological processes, which persist in the absence of external cues since they are generated by endogenous circadian clocks. The period (per) gene is a central player within the core molecular mechanism for keeping circadian time in most animals. Recently, the modulation PER translation has been reported, both in mammals and flies, suggesting that translational regulation of clock components is important for the proper clock gene expression and molecular clock performance. Because translational regulation ultimately implies changes in the kinetics of translation and, therefore, in the circadian clock dynamics, we sought to study how and to what extent the molecular clock dynamics is affected by the kinetics of PER translation. With this objective, we used a minimal mathematical model of the molecular circadian clock to qualitatively characterize the dynamical changes derived from kinetically different PER translational mechanisms. We found that the emergence of self-sustained oscillations with characteristic period, amplitude, and phase lag (time delays) between per mRNA and protein expression depends on the kinetic parameters related to PER translation. Interestingly, under certain conditions, a PER translation mechanism with saturable kinetics introduces longer time delays than a mechanism ruled by a first-order kinetics. In addition, the kinetic laws of PER translation significantly changed the sensitivity of our model to parameters related to the synthesis and degradation of per mRNA and PER degradation. Lastly, we found a set of parameters, with realistic values, for which our model reproduces some experimental results reported recently for Drosophila melanogaster and we present some predictions derived from our analysis.

Short-term stability improvements of an optical frequency standard based on free Ca atoms

NASA Astrophysics Data System (ADS)

Sherman, Jeff; Oates, Chris

2010-03-01

Compared to optical frequency standards featuring trapped ions or atoms in optical lattices, the strength of a standard using freely expanding neutral calcium atoms is not ultimate accuracy but rather short-term stability and experimental simplicity. Recently, a fractional frequency instability of 4 x10-15 at 1 second was demonstrated for the Ca standard at 657 nm [1]. The short cycle time (˜2 ms) combined with only a moderate interrogation duty cycle (˜15 %) is thought to introduce excess, and potentially critically limiting technical noise due to the Dick effect---high-frequency noise on the laser oscillator is not averaged away but is instead down-sampled by aliasing. We will present results of two strategies employed to minimize this effect: the reduction of clock laser noise by filtering the master clock oscillator through a high-finesse optical cavity [2], and an optimization of the interrogation cycle to match our laser's noise spectrum.[4pt] [1] Oates et al., Optics Letters, 25(21), 1603--5 (2000)[0pt] [2] Nazarova et al., J. Opt. Soc. Am. B, 5(10), 1632--8 (2008)

Differential roles of AVP and VIP signaling in the postnatal changes of neural networks for coherent circadian rhythms in the SCN

PubMed Central

Ono, Daisuke; Honma, Sato; Honma, Ken-ichi

2016-01-01

The suprachiasmatic nucleus (SCN) is the site of the master circadian clock in mammals. The SCN neural network plays a critical role in expressing the tissue-level circadian rhythm. Previously, we demonstrated postnatal changes in the SCN network in mice, in which the clock gene products CRYPTOCHROMES (CRYs) are involved. Here, we show that vasoactive intestinal polypeptide (VIP) signaling is essential for the tissue-level circadian PER2::LUC rhythm in the neonatal SCN of CRY double-deficient mice (Cry1,2−/−). VIP and arginine vasopressin (AVP) signaling showed redundancy in expressing the tissue-level circadian rhythm in the SCN. AVP synthesis was significantly attenuated in the Cry1,2−/− SCN, which contributes to aperiodicity in the adult mice together with an attenuation of VIP signaling as a natural process of ontogeny. The SCN network consists of multiple clusters of cellular circadian rhythms that are differentially integrated by AVP and VIP signaling, depending on the postnatal period. PMID:27626074

The choroid plexus harbors a circadian oscillator modulated by estrogens.

PubMed

Quintela, Telma; Albuquerque, Tânia; Lundkvist, Gabriella; Carmine Belin, Andrea; Talhada, Daniela; Gonçalves, Isabel; Carro, Eva; Santos, Cecília R A

2018-02-01

The suprachiasmatic nucleus (SCN) of the hypothalamus is considered the master circadian oscillator in mammals. However, extra-SCN structures in the brain also display daily rhythms. Recently, we have demonstrated that the choroid plexus (CP) expresses core clock genes that are subjected to circadian regulation in a sex-dependent manner. By using CP explants cultured from female knock-in mice carrying the Period-luciferase transgene, we show that CP exhibits endogenous circadian rhythms of PERIOD2::LUCIFERASE expression. Furthermore, we demonstrate that estrogen declines following ovariectomy modulates the daily rhythm expression of Bmal1, Per1 and Per2 in female rat CP, corroborating data obtained in experiments where rat CP epithelial cell (CPEC) cultures were incubated with 17β-estradiol (E2). The molecular mechanism underlying these effects was also investigated, and we provide evidence that the estrogen receptor (ER) mediates the response of clock genes to E2. In conclusion, our study proves that the CP harbors a circadian oscillator that is modulated by estrogens and demonstrates that E2 regulation occurs through an estrogen-receptor-dependent mechanism.

The Circadian Oscillator of the Cerebral Cortex: Molecular, Biochemical and Behavioral Effects of Deleting the Arntl Clock Gene in Cortical Neurons.

PubMed

Bering, Tenna; Carstensen, Mikkel Bloss; Wörtwein, Gitta; Weikop, Pia; Rath, Martin Fredensborg

2018-02-01

A molecular circadian oscillator resides in neurons of the cerebral cortex, but its role is unknown. Using the Cre-LoxP method, we have here abolished the core clock gene Arntl in those neurons. This mouse represents the first model carrying a deletion of a circadian clock component specifically in an extrahypothalamic cell type of the brain. Molecular analyses of clock gene expression in the cerebral cortex of the Arntl conditional knockout mouse revealed disrupted circadian expression profiles, whereas clock gene expression in the suprachiasmatic nucleus was still rhythmic, thus showing that Arntl is required for normal function of the cortical circadian oscillator. Daily rhythms in running activity and temperature were not influenced, whereas the resynchronization response to experimental jet-lag exhibited minor though significant differences between genotypes. The tail-suspension test revealed significantly prolonged immobility periods in the knockout mouse indicative of a depressive-like behavioral state. This phenotype was accompanied by reduced norepinephrine levels in the cerebral cortex. Our data show that Arntl is required for normal cortical clock function and further give reason to suspect that the circadian oscillator of the cerebral cortex is involved in regulating both circadian biology and mood-related behavior and biochemistry. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Laser Ranging to the Lunar Reconnaissance Orbiter: improved timing and orbits

NASA Astrophysics Data System (ADS)

Mao, D.; Mcgarry, J.; Sun, X.; Torrence, M. H.; Skillman, D.; Hoffman, E.; Mazarico, E.; Rowlands, D. D.; Golder, J.; Barker, M. K.; Neumann, G. A.; Smith, D. E.; Zuber, M. T.

2013-12-01

The Laser ranging (LR) experiment to the Lunar Reconnaissance Orbiter (LRO) has been under operation for more than 4 years, since the launch of the spacecraft in June 2009. Led by NASA's Next Generation Satellite Laser Ranging(NGSLR) station at Greenbelt, Maryland, ten laser ranging stations over the world have been participating in the experiment and have collected over 3,200 hours of ranging data. These range measurements are used to monitor the behavior of the LRO clock and to generate orbital solutions for LRO. To achieve high-quality results in range, ground stations like NGSLR are using H-maser clocks to obtain a stable and continuous time baseline for the orbit solutions. An All-View GPS receiver was included at NGSLR since January 2013 which monitors the H-maser time against the master clock at the United State Naval Observatory (USNO) via the GPS satellites. NGSLR has successfully established nano-second level epoch time accuracy and 10-15 clock stability since then. Time transfer experiments using LRO as a common receiver have been verified in ground testing between NGSLR and MOBLAS7 via a ground terminal with a Lunar Orbiter Laser Altimeter (LOLA)-like receiver at Greenbelt, Maryland. Two hour-long ground tests using a LOLA-like detector and two different ground targets yielded results consistent with each other, and those from the previous 10-minute test completed one year ago. Time transfer tests between NGSLR and MOBLAS7 via LRO are ongoing. More time transfer tests are being planned from NGSLR to McDonald Laser Ranging Station (MLRS) in Texas and later from NGSLR to European satellite laser ranging (SLR) stations. Upon the completion of these time transfer experiments, nanosecond-level epoch time accuracy will be brought to stations besides NGSLR, and such high precision of the ground time can contribute to the LRO precision orbit determination (POD) process. Presently, by using the high-resolution GRAIL gravity models, the LRO orbits determined from LR data alone have a total position error of 10 meters in average, and show the same quality as those generated using conventional radiometric tracking data. In these LR orbital solutions, a bias was adjusted to compensate both the ground and spacecraft clock characteristics. By taking advantage of the knowledge we have gained through LR of the long-term stability of the LRO clock, the spacecraft clock behavior is separated from the ground station clocks and modeled over a 10-month time span in our current POD process. Here we present the results from this new approach, and further improvements in the quality of the orbital reconstruction.

Synchronizing stochastic circadian oscillators in single cells of Neurospora crassa

NASA Astrophysics Data System (ADS)

Deng, Zhaojie; Arsenault, Sam; Caranica, Cristian; Griffith, James; Zhu, Taotao; Al-Omari, Ahmad; Schüttler, Heinz-Bernd; Arnold, Jonathan; Mao, Leidong

2016-10-01

The synchronization of stochastic coupled oscillators is a central problem in physics and an emerging problem in biology, particularly in the context of circadian rhythms. Most measurements on the biological clock are made at the macroscopic level of millions of cells. Here measurements are made on the oscillators in single cells of the model fungal system, Neurospora crassa, with droplet microfluidics and the use of a fluorescent recorder hooked up to a promoter on a clock controlled gene-2 (ccg-2). The oscillators of individual cells are stochastic with a period near 21 hours (h), and using a stochastic clock network ensemble fitted by Markov Chain Monte Carlo implemented on general-purpose graphical processing units (or GPGPUs) we estimated that >94% of the variation in ccg-2 expression was stochastic (as opposed to experimental error). To overcome this stochasticity at the macroscopic level, cells must synchronize their oscillators. Using a classic measure of similarity in cell trajectories within droplets, the intraclass correlation (ICC), the synchronization surface ICC is measured on >25,000 cells as a function of the number of neighboring cells within a droplet and of time. The synchronization surface provides evidence that cells communicate, and synchronization varies with genotype.

The advantage of being slow: The quasi-neutral contact process.

PubMed

de Oliveira, Marcelo Martins; Dickman, Ronald

2017-01-01

According to the competitive exclusion principle, in a finite ecosystem, extinction occurs naturally when two or more species compete for the same resources. An important question that arises is: when coexistence is not possible, which mechanisms confer an advantage to a given species against the other(s)? In general, it is expected that the species with the higher reproductive/death ratio will win the competition, but other mechanisms, such as asymmetry in interspecific competition or unequal diffusion rates, have been found to change this scenario dramatically. In this work, we examine competitive advantage in the context of quasi-neutral population models, including stochastic models with spatial structure as well as macroscopic (mean-field) descriptions. We employ a two-species contact process in which the "biological clock" of one species is a factor of α slower than that of the other species. Our results provide new insights into how stochasticity and competition interact to determine extinction in finite spatial systems. We find that a species with a slower biological clock has an advantage if resources are limited, winning the competition against a species with a faster clock, in relatively small systems. Periodic or stochastic environmental variations also favor the slower species, even in much larger systems.

Synchronizing stochastic circadian oscillators in single cells of Neurospora crassa

PubMed Central

Deng, Zhaojie; Arsenault, Sam; Caranica, Cristian; Griffith, James; Zhu, Taotao; Al-Omari, Ahmad; Schüttler, Heinz-Bernd; Arnold, Jonathan; Mao, Leidong

2016-01-01

The synchronization of stochastic coupled oscillators is a central problem in physics and an emerging problem in biology, particularly in the context of circadian rhythms. Most measurements on the biological clock are made at the macroscopic level of millions of cells. Here measurements are made on the oscillators in single cells of the model fungal system, Neurospora crassa, with droplet microfluidics and the use of a fluorescent recorder hooked up to a promoter on a clock controlled gene-2 (ccg-2). The oscillators of individual cells are stochastic with a period near 21 hours (h), and using a stochastic clock network ensemble fitted by Markov Chain Monte Carlo implemented on general-purpose graphical processing units (or GPGPUs) we estimated that >94% of the variation in ccg-2 expression was stochastic (as opposed to experimental error). To overcome this stochasticity at the macroscopic level, cells must synchronize their oscillators. Using a classic measure of similarity in cell trajectories within droplets, the intraclass correlation (ICC), the synchronization surface ICC is measured on >25,000 cells as a function of the number of neighboring cells within a droplet and of time. The synchronization surface provides evidence that cells communicate, and synchronization varies with genotype. PMID:27786253

The role of the circadian system in fractal neurophysiological control

PubMed Central

Pittman-Polletta, Benjamin R.; Scheer, Frank A.J.L.; Butler, Matthew P.; Shea, Steven A.; Hu, Kun

2013-01-01

Many neurophysiological variables such as heart rate, motor activity, and neural activity are known to exhibit intrinsic fractal fluctuations - similar temporal fluctuation patterns at different time scales. These fractal patterns contain information about health, as many pathological conditions are accompanied by their alteration or absence. In physical systems, such fluctuations are characteristic of critical states on the border between randomness and order, frequently arising from nonlinear feedback interactions between mechanisms operating on multiple scales. Thus, the existence of fractal fluctuations in physiology challenges traditional conceptions of health and disease, suggesting that high levels of integrity and adaptability are marked by complex variability, not constancy, and are properties of a neurophysiological network, not individual components. Despite the subject's theoretical and clinical interest, the neurophysiological mechanisms underlying fractal regulation remain largely unknown. The recent discovery that the circadian pacemaker (suprachiasmatic nucleus) plays a crucial role in generating fractal patterns in motor activity and heart rate sheds an entirely new light on both fractal control networks and the function of this master circadian clock, and builds a bridge between the fields of circadian biology and fractal physiology. In this review, we sketch the emerging picture of the developing interdisciplinary field of fractal neurophysiology by examining the circadian system’s role in fractal regulation. PMID:23573942

42 CFR 493.1489 - Standard; Testing personnel qualifications.

Code of Federal Regulations, 2012 CFR

2012-10-01

... have earned a doctoral, master's or bachelor's degree in a chemical, physical, biological or clinical... biology; and (iii) Twelve semester hours of chemistry, biology, or medical laboratory technology in any...

42 CFR 493.1489 - Standard; Testing personnel qualifications.

Code of Federal Regulations, 2011 CFR

2011-10-01

... have earned a doctoral, master's or bachelor's degree in a chemical, physical, biological or clinical... biology; and (iii) Twelve semester hours of chemistry, biology, or medical laboratory technology in any...

42 CFR 493.1489 - Standard; Testing personnel qualifications.

Code of Federal Regulations, 2013 CFR

2013-10-01

... have earned a doctoral, master's or bachelor's degree in a chemical, physical, biological or clinical... biology; and (iii) Twelve semester hours of chemistry, biology, or medical laboratory technology in any...

42 CFR 493.1489 - Standard; Testing personnel qualifications.

Code of Federal Regulations, 2010 CFR

2010-10-01

... have earned a doctoral, master's or bachelor's degree in a chemical, physical, biological or clinical... biology; and (iii) Twelve semester hours of chemistry, biology, or medical laboratory technology in any...

42 CFR 493.1489 - Standard; Testing personnel qualifications.

Code of Federal Regulations, 2014 CFR

2014-10-01

... have earned a doctoral, master's or bachelor's degree in a chemical, physical, biological or clinical... biology; and (iii) Twelve semester hours of chemistry, biology, or medical laboratory technology in any...

Characterisation of circadian rhythms of various duckweeds.

PubMed

Muranaka, T; Okada, M; Yomo, J; Kubota, S; Oyama, T

2015-01-01

The plant circadian clock controls various physiological phenomena that are important for adaptation to natural day-night cycles. Many components of the circadian clock have been identified in Arabidopsis thaliana, the model plant for molecular genetic studies. Recent studies revealed evolutionary conservation of clock components in green plants. Homologues of clock-related genes have been isolated from Lemna gibba and Lemna aequinoctialis, and it has been demonstrated that these homologues function in the clock system in a manner similar to their functioning in Arabidopsis. While clock components are widely conserved, circadian phenomena display diversity even within the Lemna genus. In order to survey the full extent of diversity in circadian rhythms among duckweed plants, we characterised the circadian rhythms of duckweed by employing a semi-transient bioluminescent reporter system. Using a particle bombardment method, circadian bioluminescent reporters were introduced into nine strains representing five duckweed species: Spirodela polyrhiza, Landoltia punctata, Lemna gibba, L. aequinoctialis and Wolffia columbiana. We then monitored luciferase (luc+) reporter activities driven by AtCCA1, ZmUBQ1 or CaMV35S promoters under entrainment and free-running conditions. Under entrainment, AtCCA1::luc+ showed similar diurnal rhythms in all strains. This suggests that the mechanism of biological timing under day-night cycles is conserved throughout the evolution of duckweeds. Under free-running conditions, we observed circadian rhythms of AtCCA1::luc+, ZmUBQ1::luc+ and CaMV35S::luc+. These circadian rhythms showed diversity in period length and sustainability, suggesting that circadian clock mechanisms are somewhat diversified among duckweeds. © 2014 German Botanical Society and The Royal Botanical Society of the Netherlands.

Circadian Rhythms in Diet-Induced Obesity.

PubMed

Engin, Atilla

2017-01-01

The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronizes these with daily cycles, feeding patterns also regulates circadian clocks. The clock genes and adipocytokines show circadian rhythmicity. Dysfunction of these genes are involved in the alteration of these adipokines during the development of obesity. Food availability promotes the stimuli associated with food intake which is a circadian oscillator outside of the suprachiasmatic nucleus (SCN). Its circadian rhythm is arranged with the predictable daily mealtimes. Food anticipatory activity is mediated by a self-sustained circadian timing and its principal component is food entrained oscillator. However, the hypothalamus has a crucial role in the regulation of energy balance rather than food intake. Fatty acids or their metabolites can modulate neuronal activity by brain nutrient-sensing neurons involved in the regulation of energy and glucose homeostasis. The timing of three-meal schedules indicates close association with the plasma levels of insulin and preceding food availability. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition can lead to uncoupling of peripheral clocks from the central pacemaker and to the development of metabolic disorders. Metabolic dysfunction is associated with circadian disturbances at both central and peripheral levels and, eventual disruption of circadian clock functioning can lead to obesity. While CLOCK expression levels are increased with high fat diet-induced obesity, peroxisome proliferator-activated receptor (PPAR) alpha increases the transcriptional level of brain and muscle ARNT-like 1 (BMAL1) in obese subjects. Consequently, disruption of clock genes results in dyslipidemia, insulin resistance and obesity. Modifying the time of feeding alone can greatly affect body weight. Changes in the circadian clock are associated with temporal alterations in feeding behavior and increased weight gain. Thus, shift work is associated with increased risk for obesity, diabetes and cardio-vascular diseases as a result of unusual eating time and disruption of circadian rhythm.

The Impact of Biology/Geology School Teachers Masters Courses on the Improvement of Science Education Quality in Portugal

ERIC Educational Resources Information Center

Pombo, Lucia; Costa, Nilza

2009-01-01

In this paper we report a large-scale study designed to evaluate the impact of masters courses on the professional development of science school teachers and, consequently, on the improvement of the quality of science education. The underlying assumption of this study is that masters teachers are widely recognized as assuming a relevant role to…

The expression of Per1 and Aa-nat genes in the pineal gland of postnatal rats.

PubMed

Wongchitrat, Prapimpun; Govitrapong, Piyarat; Phansuwan-Pujito, Pansiri

2012-12-01

The circadian rhythm of melatonin synthesis is controlled by the master clock, suprachiasmatic nucleus (SCN). The level of melatonin changes throughout the aging process. The SCN's rhythm is driven by autoregulatory feedback loop composed of a set of clock genes families and their corresponding proteins. The Period (Per1), one of clock gene develops gradually during postnatal ontogenesis in the rat SCN and is also expressed in the pineal gland. It is of interest to study the relationship between the postnatal development of Per1 and Aa-nat, genes that produce the rate-limiting enzyme in melatonin synthesis, in the pineal. Daily profiles of mRNA expression of Per1 and Aa-nat were analyzed in the pineal gland of pups at postnatal ages 4 (P4), P8, P16 and P32, at puberty age of 6 weeks; and in 8 week-old adult rats by real-time PCR. As early as P4, Per1 and Aa-nat mRNAs were expressed and existed at relatively high levels during the nighttime. They gradually increased until puberty and decreased at 8 weeks of age. Additionally, the nocturnal changes of Per1 and Aa-nat mRNA levels in the rat pineal gland from P4 to adults were strongly correlated at r = 0.97 (p < 0.01). The present data indicate that there is a close relationship between the expression pattern of Per1 and that of melatonin synthesis during the development of postnatal rats.

The circadian system and the balance of the autonomic nervous system.

PubMed

Buijs, Ruud M; Escobar, Carolina; Swaab, Dick F

2013-01-01

Our biological clock, the suprachiasmatic nucleus (SCN), sets the pace of our life: it provides a rhythmic function to our sleep-wake cycle. In order to do so properly the SCN synchronizes our physiology to behavioral patterns by directing the autonomic and hormonal output of the hypothalamus to the different organs of the body that require a different setting - activity or inactivity - during particular phases of the day or night. In this chapter we show that this delicate balance requires that the SCN should not only provide an output to these organs but also be informed about the physiological state of the organs in order to adapt its output. This occurs via a hypothalamic neuronal network that provides the necessary input to the SCN. We argue that the feedback that the SCN receives from its hypothalamic target structures is essential to maintain a balance in our physiological functions, which fluctuate during the sleep-wake cycle. We propose that this crucial role of the hypothalamus in the homeostatic response is the reason why, e.g., in aging or depression, changes in the functioning of the biological clock, the SCN, lead to the development of pathology. In addition, if this balance is not adequately organized, for example, if the signals of the biological clock are violated by being active and eating during the night, as in shift work, one will be more susceptible to diseases such as hypertension, obesity, diabetes, and metabolic syndrome. © 2013, Elsevier B.V. All rights reserved.

The Characterization of Biological Rhythms in Mild Cognitive Impairment

PubMed Central

Díaz-Mardomingo, Carmen; García-Herranz, Sara; Pereda-Pérez, Inmaculada; Peraita, Herminia; Venero, César; Madrid, Juan Antonio; Rol, Maria Angeles

2014-01-01

Introduction. Patients with dementia, especially Alzheimer's disease, present several circadian impairments related to an accelerated perturbation of their biological clock that is caused by the illness itself and not merely age-related. Thus, the objective of this work was to elucidate whether these circadian system alterations were already present in patients with mild cognitive impairment (MCI), as compared to healthy age-matched subjects. Methods. 40 subjects (21 patients diagnosed with MCI, 74.1 ± 1.5 y.o., and 19 healthy subjects, 71.7 ± 1.4 y.o.) were subjected to ambulatory monitoring, recording wrist skin temperature, motor activity, body position, and the integrated variable TAP (including temperature, activity, and position) for one week. Nonparametrical analyses were then applied. Results. MCI patients exhibited a significant phase advance with respect to the healthy group for the following phase markers: temperature M5 (mean ± SEM: 04:20 ± 00:21 versus 02:52 ± 00:21) and L10 (14:35 ± 00:27 versus 13:24 ± 00:16) and TAP L5 (04:18 ± 00:14 versus 02:55 ± 00:30) and M10 (14:30 ± 00:18 versus 13:28 ± 00:23). Conclusions. These results suggest that significant advances in the biological clock begin to occur in MCI patients, evidenced by an accelerated aging of the circadian clock, as compared to a healthy population of the same age. PMID:25157363

The evolution of vision.

PubMed

Gehring, Walter J

2014-01-01

In this review, the evolution of vision is retraced from its putative origins in cyanobacteria to humans. Circadian oscillatory clocks, phototropism, and phototaxis require the capability to detect light. Photosensory proteins allow us to reconstruct molecular phylogenetic trees. The evolution of animal eyes leading from an ancestral prototype to highly complex image forming eyes can be deciphered on the basis of evolutionary developmental genetic experiments and comparative genomics. As all bilaterian animals share the same master control gene, Pax6, and the same retinal and pigment cell determination genes, we conclude that the different eye-types originated monophyletically and subsequently diversified by divergent, parallel, or convergent evolution. © 2012 Wiley Periodicals, Inc.

UTC Dissemination to the Real-Time User: The Role of USNO

NASA Technical Reports Server (NTRS)

Miranian, Mihran

1996-01-01

Coordinated Universal Time (UTC) is available worldwide via the Global Positioning System (GPS). The UTC disseminated by GPS is referenced to the US Naval Observatory Master Clock UTC(USNO) which is regularly steered and maintained as close as possible to UTC Bureau International des Poids et Mesures (BIPM), the international time scale. This paper will describe the role of the USNO in monitoring the time disseminated by the GPS and the steps involved to ensure its accuracy to the user. The paper will also discuss the other sources of UTC(USNO) and the process by which UTC(USNO) is steered to UTC(BIPM).

ACTS TDMA network control. [Advanced Communication Technology Satellite

NASA Technical Reports Server (NTRS)

Inukai, T.; Campanella, S. J.

1984-01-01

This paper presents basic network control concepts for the Advanced Communications Technology Satellite (ACTS) System. Two experimental systems, called the low-burst-rate and high-burst-rate systems, along with ACTS ground system features, are described. The network control issues addressed include frame structures, acquisition and synchronization procedures, coordinated station burst-time plan and satellite-time plan changes, on-board clock control based on ground drift measurements, rain fade control by means of adaptive forward-error-correction (FEC) coding and transmit power augmentation, and reassignment of channel capacities on demand. The NASA ground system, which includes a primary station, diversity station, and master control station, is also described.

Topology and Dynamics of the Zebrafish Segmentation Clock Core Circuit

PubMed Central

Schröter, Christian; Isakova, Alina; Hens, Korneel; Soroldoni, Daniele; Gajewski, Martin; Jülicher, Frank; Maerkl, Sebastian J.; Deplancke, Bart; Oates, Andrew C.

2012-01-01

During vertebrate embryogenesis, the rhythmic and sequential segmentation of the body axis is regulated by an oscillating genetic network termed the segmentation clock. We describe a new dynamic model for the core pace-making circuit of the zebrafish segmentation clock based on a systematic biochemical investigation of the network's topology and precise measurements of somitogenesis dynamics in novel genetic mutants. We show that the core pace-making circuit consists of two distinct negative feedback loops, one with Her1 homodimers and the other with Her7:Hes6 heterodimers, operating in parallel. To explain the observed single and double mutant phenotypes of her1, her7, and hes6 mutant embryos in our dynamic model, we postulate that the availability and effective stability of the dimers with DNA binding activity is controlled in a “dimer cloud” that contains all possible dimeric combinations between the three factors. This feature of our model predicts that Hes6 protein levels should oscillate despite constant hes6 mRNA production, which we confirm experimentally using novel Hes6 antibodies. The control of the circuit's dynamics by a population of dimers with and without DNA binding activity is a new principle for the segmentation clock and may be relevant to other biological clocks and transcriptional regulatory networks. PMID:22911291

Spatial gradients of protein-level time delays set the pace of the traveling segmentation clock waves

PubMed Central

Ay, Ahmet; Holland, Jack; Sperlea, Adriana; Devakanmalai, Gnanapackiam Sheela; Knierer, Stephan; Sangervasi, Sebastian; Stevenson, Angel; Özbudak, Ertuğrul M.

2014-01-01

The vertebrate segmentation clock is a gene expression oscillator controlling rhythmic segmentation of the vertebral column during embryonic development. The period of oscillations becomes longer as cells are displaced along the posterior to anterior axis, which results in traveling waves of clock gene expression sweeping in the unsegmented tissue. Although various hypotheses necessitating the inclusion of additional regulatory genes into the core clock network at different spatial locations have been proposed, the mechanism underlying traveling waves has remained elusive. Here, we combined molecular-level computational modeling and quantitative experimentation to solve this puzzle. Our model predicts the existence of an increasing gradient of gene expression time delays along the posterior to anterior direction to recapitulate spatiotemporal profiles of the traveling segmentation clock waves in different genetic backgrounds in zebrafish. We validated this prediction by measuring an increased time delay of oscillatory Her1 protein production along the unsegmented tissue. Our results refuted the need for spatial expansion of the core feedback loop to explain the occurrence of traveling waves. Spatial regulation of gene expression time delays is a novel way of creating dynamic patterns; this is the first report demonstrating such a control mechanism in any tissue and future investigations will explore the presence of analogous examples in other biological systems. PMID:25336742

Disruption of adolescents' circadian clock: The vicious circle of media use, exposure to light at night, sleep loss and risk behaviors.

PubMed

Touitou, Yvan; Touitou, David; Reinberg, Alain

2016-11-01

Although sleep is a key element in adolescent development, teens are spending increasing amounts of time online with health risks related to excessive use of electronic media (computers, smartphones, tablets, consoles…) negatively associated with daytime functioning and sleep outcomes. Adolescent sleep becomes irregular, shortened and delayed in relation with later sleep onset and early waking time due to early school starting times on weekdays which results in rhythm desynchronization and sleep loss. In addition, exposure of adolescents to the numerous electronic devices prior to bedtime has become a great concern because LEDs emit much more blue light than white incandescent bulbs and compact fluorescent bulbs and have therefore a greater impact on the biological clock. A large number of adolescents move to evening chronotype and experience a misalignment between biological and social rhythms which, added to sleep loss, results in e.g. fatigue, daytime sleepiness, behavioral problems and poor academic achievement. This paper on adolescent circadian disruption will review the sensitivity of adolescents to light including LEDs with the effects on the circadian system, the crosstalk between the clock and the pineal gland, the role of melatonin, and the behavior of some adolescents(media use, alcohol consumption, binge drinking, smoking habits, stimulant use…). Lastly, some practical recommendations and perspectives are put forward. The permanent social jet lag resulting in clock misalignment experienced by a number of adolescents should be considered as a matter of public health. Copyright © 2017 Elsevier Ltd. All rights reserved.

Uncertainty in the Timing of Origin of Animals and the Limits of Precision in Molecular Timescales

PubMed Central

dos Reis, Mario; Thawornwattana, Yuttapong; Angelis, Konstantinos; Telford, Maximilian J.; Donoghue, Philip C.J.; Yang, Ziheng

2015-01-01

Summary The timing of divergences among metazoan lineages is integral to understanding the processes of animal evolution, placing the biological events of species divergences into the correct geological timeframe. Recent fossil discoveries and molecular clock dating studies have suggested a divergence of bilaterian phyla >100 million years before the Cambrian, when the first definite crown-bilaterian fossils occur. Most previous molecular clock dating studies, however, have suffered from limited data and biases in methodologies, and virtually all have failed to acknowledge the large uncertainties associated with the fossil record of early animals, leading to inconsistent estimates among studies. Here we use an unprecedented amount of molecular data, combined with four fossil calibration strategies (reflecting disparate and controversial interpretations of the metazoan fossil record) to obtain Bayesian estimates of metazoan divergence times. Our results indicate that the uncertain nature of ancient fossils and violations of the molecular clock impose a limit on the precision that can be achieved in estimates of ancient molecular timescales. For example, although we can assert that crown Metazoa originated during the Cryogenian (with most crown-bilaterian phyla diversifying during the Ediacaran), it is not possible with current data to pinpoint the divergence events with sufficient accuracy to test for correlations between geological and biological events in the history of animals. Although a Cryogenian origin of crown Metazoa agrees with current geological interpretations, the divergence dates of the bilaterians remain controversial. Thus, attempts to build evolutionary narratives of early animal evolution based on molecular clock timescales appear to be premature. PMID:26603774

Role of Bacopa monnieri in the temporal regulation of oxidative stress in clock mutant (cryb) of Drosophila melanogaster.

PubMed

Subramanian, Perumal; Prasanna, Vinoth; Jayapalan, Jaime Jacqueline; Abdul Rahman, Puteri Shafinaz; Hashim, Onn Haji

2014-06-01

Accruing evidences imply that circadian organization of biochemical, endocrinological, cellular and physiological processes contribute to wellness of organisms and in the development of pathologies such as malignancy, sleep and endocrine disorders. Oxidative stress is known to mediate a number of diseases and it is notable to comprehend the orchestration of circadian clock of a model organism of circadian biology, Drosophila melanogaster, under oxidative stress. We investigated the nexus between circadian clock and oxidative stress susceptibility by exposing D. melanogaster to hydrogen peroxide (H2O2) or rotenone; the reversibility of rhythms following exposure to Bacopa monnieri extract (ayurvedic medicine rich in antioxidants) was also investigated. Abolishment of 24h rhythms in physiological response (negative geotaxis), oxidative stress markers (protein carbonyl and thiobarbituric acid reactive substances) and antioxidants (superoxide dismutase, catalase, glutathione-S-transferase and reduced glutathione) were observed under oxidative stress. Furthermore, abolishment of per mRNA rhythm in H2O2 treated wild type flies and augmented susceptibility to oxidative stress in clock mutant (cry(b)) flies connotes the role of circadian clock in reactive oxygen species (ROS) homeostasis. Significant reversibility of rhythms was noted following B. monnieri treatment in wild type flies than cry(b) flies. Our experimental approach revealed a relationship involving oxidative stress and circadian clock in fruit fly and the utility of Drosophila model in screening putative antioxidative phytomedicines prior to their use in mammalian systems. Copyright © 2014 Elsevier Ltd. All rights reserved.

The regulations and role of circadian clock and melatonin in uterine receptivity and pregnancy-An immunological perspective.

PubMed

Man, Gene Chi Wai; Zhang, Tao; Chen, Xiaoyan; Wang, Jianzhang; Wu, Fangrong; Liu, Yingyu; Wang, Chi Chiu; Cheong, Ying; Li, Tin Chiu

2017-08-01

During normal pregnancy, the mechanism by which the fetus escapes immunological rejection by the maternal womb remains elusive. Given the biological complexities, the immunological mechanism is unlikely to be simply an allograft response in acceptance or rejection of the early pregnancy. Circadian clock responsible for the mammalian circadian rhythm is an endogenously generated rhythm associated with almost all physiological processes including reproduction. There is now growing evidence to suggest that the circadian clocks are intricately linked to the immune system and pregnancy. When perturbed, the role of immune cells can be affected on maintaining the enriched vascular system needed for placentation. This alteration can be triggered by the irregular production of maternal and placental melatonin. Hence, the role of circadian rhythm modulators such as melatonin offers intriguing opportunities for therapy. In this review, we evaluate the complex interaction between the circadian clock and melatonin within the immune system and their roles in the circadian regulation and maintenance of normal pregnancy. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Isoform switching facilitates period control in the Neurospora crassa circadian clock.

PubMed

Akman, Ozgur E; Locke, James C W; Tang, Sanyi; Carré, Isabelle; Millar, Andrew J; Rand, David A

2008-01-01

A striking and defining feature of circadian clocks is the small variation in period over a physiological range of temperatures. This is referred to as temperature compensation, although recent work has suggested that the variation observed is a specific, adaptive control of period. Moreover, given that many biological rate constants have a Q(10) of around 2, it is remarkable that such clocks remain rhythmic under significant temperature changes. We introduce a new mathematical model for the Neurospora crassa circadian network incorporating experimental work showing that temperature alters the balance of translation between a short and long form of the FREQUENCY (FRQ) protein. This is used to discuss period control and functionality for the Neurospora system. The model reproduces a broad range of key experimental data on temperature dependence and rhythmicity, both in wild-type and mutant strains. We present a simple mechanism utilising the presence of the FRQ isoforms (isoform switching) by which period control could have evolved, and argue that this regulatory structure may also increase the temperature range where the clock is robustly rhythmic.

Post-transcriptional control of the mammalian circadian clock: implications for health and disease.

PubMed

Preußner, Marco; Heyd, Florian

2016-06-01

Many aspects of human physiology and behavior display rhythmicity with a period of approximately 24 h. Rhythmic changes are controlled by an endogenous time keeper, the circadian clock, and include sleep-wake cycles, physical and mental performance capability, blood pressure, and body temperature. Consequently, many diseases, such as metabolic, sleep, autoimmune and mental disorders and cancer, are connected to the circadian rhythm. The development of therapies that take circadian biology into account is thus a promising strategy to improve treatments of diverse disorders, ranging from allergic syndromes to cancer. Circadian alteration of body functions and behavior are, at the molecular level, controlled and mediated by widespread changes in gene expression that happen in anticipation of predictably changing requirements during the day. At the core of the molecular clockwork is a well-studied transcription-translation negative feedback loop. However, evidence is emerging that additional post-transcriptional, RNA-based mechanisms are required to maintain proper clock function. Here, we will discuss recent work implicating regulated mRNA stability, translation and alternative splicing in the control of the mammalian circadian clock, and its role in health and disease.

Multiple layers of posttranslational regulation refine circadian clock activity in Arabidopsis.

PubMed

Seo, Pil Joon; Mas, Paloma

2014-01-01

The circadian clock is a cellular time-keeper mechanism that regulates biological rhythms with a period of ~24 h. The circadian rhythms in metabolism, physiology, and development are synchronized by environmental cues such as light and temperature. In plants, proper matching of the internal circadian time with the external environment confers fitness advantages on plant survival and propagation. Accordingly, plants have evolved elaborated regulatory mechanisms that precisely control the circadian oscillations. Transcriptional feedback regulation of several clock components has been well characterized over the past years. However, the importance of additional regulatory mechanisms such as chromatin remodeling, protein complexes, protein phosphorylation, and stability is only starting to emerge. The multiple layers of circadian regulation enable plants to properly synchronize with the environmental cycles and to fine-tune the circadian oscillations. This review focuses on the diverse posttranslational events that regulate circadian clock function. We discuss the mechanistic insights explaining how plants articulate a high degree of complexity in their regulatory networks to maintain circadian homeostasis and to generate highly precise waveforms of circadian expression and activity.

Biological Clocks. Testing Our Internal Timing.

ERIC Educational Resources Information Center

Jones, M. Gail

1991-01-01

Presented are seven investigations that examine circadian rhythms. Topics include attention span, body temperature, rhythms found in rodents and spiders, and possible genetic determination of circadian rhythms. Background information on plants and animals is given. (KR)

Teen Sleep: Why Is Your Teen So Tired?

MedlinePlus

... Everyone has an internal clock that influences body temperature, sleep cycles, appetite and hormonal changes. The biological ... factors such as part-time jobs, early-morning classes, homework, extracurricular activities, social demands, and use of ...

The two-way time synchronization system via a satellite voice channel

NASA Technical Reports Server (NTRS)

Heng-Qiu, Zheng; Ren-Huan, Zhang; Yong-Hui, HU

1994-01-01

A newly developed two-way time synchronization system is described in this paper. The system uses one voice channel at a SCPC satellite digital communication earth station, whose bandwidth is only 45 kHz, thus saving satellite resources greatly. The system is composed of one master station and one or several, up to sixty-two, secondary stations. The master and secondary stations are equipped with the same equipment, including a set of timing equipment, a synthetic data terminal for time synchronizing, and a interface unit between the data terminal and the satellite earth station. The synthetic data terminal for time synchronization also has an IRIG-B code generator and a translator. The data terminal of master station is the key part of whole system. The system synchronization process is full automatic, which is controlled by the master station. Employing an autoscanning technique and conversational mode, the system accomplishes the following tasks: linking up liaison with each secondary station in turn, establishing a coarse time synchronization, calibrating date (years, months, days) and time of day (hours, minutes, seconds), precisely measuring the time difference between local station and the opposite station, exchanging measurement data, statistically processing the data, rejecting error terms, printing the data, calculating the clock difference and correcting the phase, thus realizing real-time synchronization from one point to multiple points. We also designed an adaptive phase circuit to eliminate the phase ambiguity of the PSK demodulator. The experiments have shown that the time synchronization accuracy is better than 2 mu S. The system has been put into regular operation.

Identification, Characterization, and Diel Pattern of Expression of Canonical Clock Genes in Nephrops norvegicus (Crustacea: Decapoda) Eyestalk

PubMed Central

Sbragaglia, Valerio; Lamanna, Francesco; M. Mat, Audrey; Rotllant, Guiomar; Joly, Silvia; Ketmaier, Valerio; de la Iglesia, Horacio O.; Aguzzi, Jacopo

2015-01-01

The Norway lobster, Nephrops norvegicus, is a burrowing decapod with a rhythmic burrow emergence (24 h) governed by the circadian system. It is an important resource for European fisheries and its behavior deeply affects its availability. The current knowledge of Nephrops circadian biology is phenomenological as it is currently the case for almost all crustaceans. In attempt to elucidate the putative molecular mechanisms underlying circadian gene regulation in Nephrops, we used a transcriptomics approach on cDNA extracted from the eyestalk, a structure playing a crucial role in controlling behavior of decapods. We studied 14 male lobsters under 12–12 light-darkness blue light cycle. We used the Hiseq 2000 Illumina platform to sequence two eyestalk libraries (under light and darkness conditions) obtaining about 90 millions 100-bp paired-end reads. Trinity was used for the de novo reconstruction of transcriptomes; the size at which half of all assembled bases reside in contigs (N50) was equal to 1796 (light) and 2055 (darkness). We found a list of candidate clock genes and focused our attention on canonical ones: timeless, period, clock and bmal1. The cloning of assembled fragments validated Trinity outputs. The putative Nephrops clock genes showed high levels of identity (blastx on NCBI) with known crustacean clock gene homologs such as Eurydice pulchra (period: 47%, timeless: 59%, bmal1: 79%) and Macrobrachium rosenbergii (clock: 100%). We also found a vertebrate-like cryptochrome 2. RT-qPCR showed that only timeless had a robust diel pattern of expression. Our data are in accordance with the current knowledge of the crustacean circadian clock, reinforcing the idea that the molecular clockwork of this group shows some differences with the established model in Drosophila melanogaster. PMID:26524198

Ghrelin, Sleep Reduction and Evening Preference: Relationships to CLOCK 3111 T/C SNP and Weight Loss

PubMed Central

Garaulet, Marta; Sánchez-Moreno, Carmen; Smith, Caren E.; Lee, Yu-Chi; Nicolás, Francisco; Ordovás, Jose M.

2011-01-01

Background Circadian Locomotor Output Cycles Kaput (CLOCK), an essential element of the positive regulatory arm in the human biological clock, is involved in metabolic regulation. The aim was to investigate the behavioral (sleep duration, eating patterns and chronobiological characteristics) and hormonal (plasma ghrelin and leptin concentrations) factors which could explain the previously reported association between the CLOCK 3111T/C SNP and weight loss. Methodology/Principal Findings We recruited 1495 overweight/obese subjects (BMI: 25–40 kg/m2) of 20–65 y. who attended outpatient obesity clinics in Murcia, in southeastern Spain. We detected an association between the CLOCK 3111T/C SNP and weight loss, which was particularly evident after 12–14 weeks of treatment (P = 0.038). Specifically, carriers of the minor C allele were more resistant to weight loss than TT individuals (Mean±SEM) (8.71±0.59 kg vs 10.4±0.57 kg) C and TT respectively. In addition, our data show that minor C allele carriers had: 1. shorter sleep duration Mean ± SEM (7.0±0.05 vs 7.3±0.05) C and TT respectively (P = 0.039), 2. higher plasma ghrelin concentrations Mean ± SEM (pg/ml) (1108±49 vs 976±47)(P = 0.034); 3. delayed breakfast time; 4. evening preference and 5. less compliance with a Mediterranean Diet pattern, as compared with TT homozygotes. Conclusions/Significance Sleep reduction, changes in ghrelin values, alterations of eating behaviors and evening preference that characterized CLOCK 3111C carriers could be affecting weight loss. Our results support the hypothesis that the influence of the CLOCK gene may extend to a broad range of variables linked with human behaviors. PMID:21386998

Ghrelin, sleep reduction and evening preference: relationships to CLOCK 3111 T/C SNP and weight loss.

PubMed

Garaulet, Marta; Sánchez-Moreno, Carmen; Smith, Caren E; Lee, Yu-Chi; Nicolás, Francisco; Ordovás, Jose M

2011-02-28

Circadian Locomotor Output Cycles Kaput (CLOCK), an essential element of the positive regulatory arm in the human biological clock, is involved in metabolic regulation. The aim was to investigate the behavioral (sleep duration, eating patterns and chronobiological characteristics) and hormonal (plasma ghrelin and leptin concentrations) factors which could explain the previously reported association between the CLOCK 3111T/C SNP and weight loss. We recruited 1495 overweight/obese subjects (BMI: 25-40 kg/m(2)) of 20-65 y. who attended outpatient obesity clinics in Murcia, in southeastern Spain. We detected an association between the CLOCK 3111T/C SNP and weight loss, which was particularly evident after 12-14 weeks of treatment (P = 0.038). Specifically, carriers of the minor C allele were more resistant to weight loss than TT individuals (Mean±SEM) (8.71±0.59 kg vs 10.4±0.57 kg) C and TT respectively. In addition, our data show that minor C allele carriers had: 1. shorter sleep duration Mean ± SEM (7.0±0.05 vs 7.3±0.05) C and TT respectively (P = 0.039), 2. higher plasma ghrelin concentrations Mean ± SEM (pg/ml) (1108±49 vs 976±47)(P = 0.034); 3. delayed breakfast time; 4. evening preference and 5. less compliance with a Mediterranean Diet pattern, as compared with TT homozygotes. Sleep reduction, changes in ghrelin values, alterations of eating behaviors and evening preference that characterized CLOCK 3111C carriers could be affecting weight loss. Our results support the hypothesis that the influence of the CLOCK gene may extend to a broad range of variables linked with human behaviors.

Evolution of circadian rhythms: from bacteria to human.

PubMed

Bhadra, Utpal; Thakkar, Nirav; Das, Paromita; Pal Bhadra, Manika

2017-07-01

The human body persists in its rhythm as per its initial time zone, and transition always occur according to solar movements around the earth over 24 h. While traveling across different latitudes and longitudes, at the pace exceeding the earth's movement, the changes in the external cues exceed the level of toleration of the body's biological clock. This poses an alteration in our physiological activities of sleep-wake pattern, mental alertness, organ movement, and eating habits, causing them to temporarily lose the track of time. This is further re-synchronized with the physiological cues of the destination over time. The mechanism of resetting of the clocks with varying time zones and cues occur in organisms from bacteria to humans. It is the result of the evolution of different pathways and molecular mechanisms over the time. There has been evolution of numerous comprehensive mechanisms using various research tools to get a deeper insight into the rapid turnover of molecular mechanisms in various species. This review reports insights into the evolution of the circadian mechanism and its evolutionary shift which is vital and plays a major role in assisting different organisms to adapt in different zones and controls their internal biological clocks with changing external cues. Copyright © 2017 Elsevier B.V. All rights reserved.

[Master files: less paper, more substance. Special rules for special medicines: Plasma Master File and Vaccine Antigen Master File].

PubMed

Seitz, Rainer; Haase, M

2008-07-01

The process of reviewing the European pharmaceutical legislation resulted in a codex, which contains two new instruments related to marketing authorisation of biological medicines: Plasma Master File (PMF) and Vaccine Antigen Master File (VAMF). In the manufacture of plasma derivatives (e. g. coagulation factors, albumin, immunoglobulins), usually the same starting material, i. e. a plasma pool, is used for several products. In the case of vaccines, the same active substance, i.e. vaccine antigen, may be included in several combination vaccine products. The intention behind the introduction of PMF and VAMF was to avoid unnecessary and redundant documentation, and to improve and harmonise assessment by means of procedures for certification of master files on the community level.

Association of intrinsic circadian period with morningness-eveningness, usual wake time, and circadian phase

NASA Technical Reports Server (NTRS)

Duffy, J. F.; Rimmer, D. W.; Czeisler, C. A.

2001-01-01

The biological basis of preferences for morning or evening activity patterns ("early birds" and "night owls") has been hypothesized but has remained elusive. The authors reported that, compared with evening types, the circadian pacemaker of morning types was entrained to an earlier hour with respect to both clock time and wake time. The present study explores a chronobiological mechanism by which the biological clock of morning types may be set to an earlier hour. Intrinsic period, a fundamental property of the circadian system, was measured in a month-long inpatient study. A subset of participants also had their circadian phase assessed. Participants completed a morningness-eveningness questionnaire before study. Circadian period was correlated with morningness-eveningness, circadian phase, and wake time, demonstrating that a fundamental property of the circadian pacemaker is correlated with the behavioral trait of morningness-eveningness.

The development of the hardware for studying biological clock systems under microgravity conditions, using scorpions as animal models

NASA Astrophysics Data System (ADS)

Serafini, L.; Viganò, W.; Donati, A.; Porciani, M.; Zolesi, V.; Schulze-Varnholt, D.; Manieri, P.; El-Din Sallam, A.; Schmäh, M.; Horn, E. R.

2007-02-01

The study of internal clock systems of scorpions in weightless conditions is the goal of the SCORPI experiment. SCORPI was selected for flight on the International Space Station (ISS) and will be mounted in the European facility BIOLAB, the European Space Agency (ESA) laboratory designed to support biological experiments on micro-organisms, cells, tissue, cultures, small plants and small invertebrates. This paper outlines the main features of a breadboard designed and developed in order to allow the analysis of critical aspects of the experiment. It is a complete tool to simulate the experiment mission on ground and it can be customised, adapted and tuned to the scientific requirements. The paper introduces the SCORPI-T experiment which represents an important precursor for the success of the SCORPI on BIOLAB. The capabilities of the hardware developed show its potential use for future similar experiments in space.

Development of the Astyanax mexicanus circadian clock and non-visual light responses.

PubMed

Frøland Steindal, Inga A; Beale, Andrew D; Yamamoto, Yoshiyuki; Whitmore, David

2018-06-23

Most animals and plants live on the planet exposed to periods of rhythmic light and dark. As such, they have evolved endogenous circadian clocks to regulate their physiology rhythmically, and non-visual light detection mechanisms to set the clock to the environmental light-dark cycle. In the case of fish, circadian pacemakers are not only present in the majority of tissues and cells, but these tissues are themselves directly light-sensitive, expressing a wide range of opsin photopigments. This broad non-visual light sensitivity exists to set the clock, but also impacts a wide range of fundamental cell biological processes, such as DNA repair regulation. In this context, Astyanax mexicanus is a very intriguing model system with which to explore non-visual light detection and circadian clock function. Previous work has shown that surface fish possess the same directly light entrainable circadian clocks, described above. The same is true for cave strains of Astyanax in the laboratory, though no daily rhythms have been observed under natural dark conditions in Mexico. There are, however, clear alterations in the cave strain light response and changes to the circadian clock, with a difference in phase of peak gene expression and a reduction in amplitude. In this study, we expand these early observations by exploring the development of non-visual light sensitivity and clock function between surface and cave populations. When does the circadian pacemaker begin to oscillate during development, and are there differences between the various strains? Is the difference in acute light sensitivity, seen in adults, apparent from the earliest stages of development? Our results show that both cave and surface populations must experience daily light exposure to establish a larval gene expression rhythm. These oscillations begin early, around the third day of development in all strains, but gene expression rhythms show a significantly higher amplitude in surface fish larvae. In addition, the light induction of clock genes is developmentally delayed in cave populations. Zebrafish embryonic light sensitivity has been shown to be critical not only for clock entrainment, but also for transcriptional activation of DNA repair processes. Similar downstream transcriptional responses to light also occur in Astyanax. Interestingly, the establishment of the adult timing profile of clock gene expression takes several days to become apparent. This fact may provide mechanistic insight into the key differences between the cave and surface fish clock mechanisms. Copyright © 2018. Published by Elsevier Inc.

The circadian clock controls toll-like receptor 9-mediated innate and adaptive immunity

PubMed Central

Silver, Adam C.; Arjona, Alvaro; Walker, Wendy E.; Fikrig, Erol

2012-01-01

Circadian rhythms refer to biologic processes that oscillate with a period of approximately 24 hours. These rhythms are sustained by a molecular clock and provide a temporal matrix that ensures the coordination of homeostatic processes with the periodicity of environmental challenges. We demonstrate the circadian molecular clock controls the expression and function of toll like receptor 9 (TLR9). In a vaccination model using TLR9 ligand as adjuvant, mice immunized at the time of enhanced TLR9 responsiveness presented weeks later with an improved adaptive immune response. In a TLR9-dependent mouse model of sepsis, we found that disease severity was dependent on the timing of sepsis induction, coinciding with the daily changes in TLR9 expression and function. These findings unveil a direct molecular link between the circadian and innate immune systems with important implications for immunoprophylaxis and immunotherapy. PMID:22342842

Circadian Entrainment to the Natural Light-Dark Cycle Across Seasons and the Weekend

PubMed Central

Stothard, Ellen R.; McHill, Andrew W.; Depner, Christopher M.; Birks, Brian R.; Moehlman, Thomas M.; Ritchie, Hannah K.; Guzzetti, Jacob R.; Chinoy, Evan D.; LeBourgeois, Monique K.; Axelsson, John; Wright, Kenneth P.

2017-01-01

Summary Reduced exposure to daytime sunlight and increased exposure to electrical lighting at night leads to late circadian and sleep timing [1–3]. We have previously shown that exposure to a natural summer 14 hr 40 min:9 hr 20 min light-dark cycle entrains the human circadian clock to solar time, such that the internal biological night begins near sunset and ends near sunrise [1]. Here we show the beginning of the biological night and sleep occur earlier after a week exposure to a natural winter 9 hr 20 min:14 hr 40 min light-dark cycle as compared to the modern electrical lighting environment. Further, we find the human circadian clock is sensitive to seasonal changes in the natural light-dark cycle showing an expansion of the biological night in winter compared to summer—akin to that seen in non-humans [4–8]. We also show circadian and sleep timing occur earlier after spending a weekend camping in a summer 14 hr 39 min:9 hr 21 min natural light-dark cycle compared to a typical weekend in the modern environment. Weekend exposure to natural light was sufficient to achieve ~69% of the shift in circadian timing we previously reported after one week exposure to natural light [1]. These findings provide evidence that the human circadian clock adapts to seasonal changes in the natural light-dark cycle and is timed later in the modern environment in both winter and summer. Further, we demonstrate earlier circadian timing can be rapidly achieved through natural light exposure during a weekend spent camping. PMID:28162893

A circannual clock drives expression of genes central for seasonal reproduction.

PubMed

Sáenz de Miera, Cristina; Monecke, Stefanie; Bartzen-Sprauer, Julien; Laran-Chich, Marie-Pierre; Pévet, Paul; Hazlerigg, David G; Simonneaux, Valérie

2014-07-07

Animals living in temperate zones anticipate seasonal environmental changes to adapt their biological functions, especially reproduction and metabolism. Two main physiological mechanisms have evolved for this adaptation: intrinsic long-term timing mechanisms with an oscillating period of approximately 1 year, driven by a circannual clock [1], and synchronization of biological rhythms to the sidereal year using day length (photoperiod) [2]. In mammals, the pineal hormone melatonin relays photoperiodic information to the hypothalamus to control seasonal physiology through well-defined mechanisms [3-6]. In contrast, little is known about how the circannual clock drives endogenous changes in seasonal functions. The aim of this study was to determine whether genes involved in photoperiodic time measurement (TSHβ and Dio2) and central control of reproduction (Rfrp and Kiss1) display circannual rhythms in expression under constant conditions. Male European hamsters, deprived of seasonal time cues by pinealectomy and maintenance in constant photoperiod, were selected when expressing a subjective summer or subjective winter state in their circannual cycle of body weight, temperature, and testicular size. TSHβ expression in the pars tuberalis (PT) displayed a robust circannual variation with highest level in the subjective summer state, which was positively correlated with hypothalamic Dio2 and Rfrp expression. The negative sex steroid feedback was found to act specifically on arcuate Kiss1 expression. Our findings reveal TSH as a circannual output of the PT, which in turn regulates hypothalamic neurons controlling reproductive activity. Therefore, both the circannual and the melatonin signals converge on PT TSHβ expression to synchronize seasonal biological activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

A software controllable modular RF signal generator with multichannel transmission capabilities.

PubMed

Shaw, Z; Feilner, W; Esser, B; Dickens, J C; Neuber, A A

2017-09-01

A software controllable system which generates and transmits user defined RF signals is discussed. The system is implemented with multiple, modular transmitting channels that allow the user to easily replace parts such as amplifiers or antennas. Each channel is comprised of a data pattern generator (DPG), a digital to analog converter (DAC), a power amplifier, and a transmitting antenna. All channels are controlled through a host PC and synchronized through a master clock signal provided to each DAC by an external clock source. Signals to be transmitted are generated through the DPG control software on the PC or can be created by the user in a numerical computing environment. Three experiments are discussed using a two- and four-channel antenna array incorporating Chebyshev tapered TEM horn antennas. Transmitting distinct sets of nonperiodic bipolar impulses through each of the antennas in the array enabled synthesizing a sinusoidal signal of specific frequency in free space. Opposite to the standard phased array approach, each antenna radiates a distinctly different signal rather than the same signal simply phase shifted. The presented approach may be employed as a physical layer of encryption dependent on the position of the receiving antenna.

Synchronous circadian voltage rhythms with asynchronous calcium rhythms in the suprachiasmatic nucleus

PubMed Central

Enoki, Ryosuke; Oda, Yoshiaki; Mieda, Michihiro; Ono, Daisuke; Honma, Sato; Honma, Ken-ichi

2017-01-01

The suprachiasmatic nucleus (SCN), the master circadian clock, contains a network composed of multiple types of neurons which are thought to form a hierarchical and multioscillator system. The molecular clock machinery in SCN neurons drives membrane excitability and sends time cue signals to various brain regions and peripheral organs. However, how and at what time of the day these neurons transmit output signals remain largely unknown. Here, we successfully visualized circadian voltage rhythms optically for many days using a genetically encoded voltage sensor, ArcLightD. Unexpectedly, the voltage rhythms are synchronized across the entire SCN network of cultured slices, whereas simultaneously recorded Ca2+ rhythms are topologically specific to the dorsal and ventral regions. We further found that the temporal order of these two rhythms is cell-type specific: The Ca2+ rhythms phase-lead the voltage rhythms in AVP neurons but Ca2+ and voltage rhythms are nearly in phase in VIP neurons. We confirmed that circadian firing rhythms are also synchronous and are coupled with the voltage rhythms. These results indicate that SCN networks with asynchronous Ca2+ rhythms produce coherent voltage rhythms. PMID:28270612

Clock Scan Protocol for Image Analysis: ImageJ Plugins.

PubMed

Dobretsov, Maxim; Petkau, Georg; Hayar, Abdallah; Petkau, Eugen

2017-06-19

The clock scan protocol for image analysis is an efficient tool to quantify the average pixel intensity within, at the border, and outside (background) a closed or segmented convex-shaped region of interest, leading to the generation of an averaged integral radial pixel-intensity profile. This protocol was originally developed in 2006, as a visual basic 6 script, but as such, it had limited distribution. To address this problem and to join similar recent efforts by others, we converted the original clock scan protocol code into two Java-based plugins compatible with NIH-sponsored and freely available image analysis programs like ImageJ or Fiji ImageJ. Furthermore, these plugins have several new functions, further expanding the range of capabilities of the original protocol, such as analysis of multiple regions of interest and image stacks. The latter feature of the program is especially useful in applications in which it is important to determine changes related to time and location. Thus, the clock scan analysis of stacks of biological images may potentially be applied to spreading of Na + or Ca ++ within a single cell, as well as to the analysis of spreading activity (e.g., Ca ++ waves) in populations of synaptically-connected or gap junction-coupled cells. Here, we describe these new clock scan plugins and show some examples of their applications in image analysis.

Studying the Evolution of the Vertebrate Circadian Clock: The Power of Fish as Comparative Models.

PubMed

Foulkes, N S; Whitmore, D; Vallone, D; Bertolucci, C

2016-01-01

The utility of any model species cannot be judged solely in terms of the tools and approaches it provides for genetic analysis. A fundamental consideration is also how its biology has been shaped by the environment and the ecological niche which it occupies. By comparing different species occupying very different habitats we can learn how molecular and cellular mechanisms change during evolution in order to optimally adapt to their environment. Such knowledge is as important as understanding how these mechanisms work. This is illustrated by the use of fish models for studying the function and evolution of the circadian clock. In this review we outline our current understanding of how fish clocks sense and respond to light and explain how this differs fundamentally from the situation with mammalian clocks. In addition, we present results from comparative studies involving two species of blind cavefish, Astyanax mexicanus and Phreatichthys andruzzii. This work reveals the consequences of evolution in perpetual darkness for the circadian clock and its regulation by light as well as for other mechanisms such as DNA repair, sleep, and metabolism which directly or indirectly are affected by regular exposure to sunlight. Major differences in the cave habitats inhabited by these two cavefish species have a clear impact on shaping the molecular and cellular adaptations to life in complete darkness. Copyright © 2016 Elsevier Inc. All rights reserved.

Suprachiasmatic astrocytes modulate the circadian clock in response to TNF-α1

PubMed Central

Duhart, José M.; Leone, María Juliana; Paladino, Natalia; Evans, Jennifer A.; Castanon-Cervantes, Oscar; Davidson, Alec J.; Golombek, Diego A.

2013-01-01

The immune and the circadian systems interact in a bidirectional fashion. The master circadian oscillator, located in the suprachiasmatic nuclei of the hypothalamus (SCN), responds to peripheral and local immune stimuli, such as proinflammatory cytokines and bacterial endotoxin. Astrocytes exert several immune functions in the central nervous system and there is growing evidence that points towards a role of these cells in the regulation of circadian rhythms. The aim of this work was to assess the response of SCN astrocytes to immune stimuli, particularly to the proinflammatory cytokine TNF-α. TNF-α applied to cultures of SCN astrocytes from Per2luc knock in mice altered both the phase and amplitude of PER2 expression rhythms, in a phase dependent manner. Furthermore, conditioned media from SCN astrocytes cultures transiently challenged with TNF-α induced an increase in Per1 expression in NIH 3T3 cells, that was blocked by TNF-α antagonism. In addition, these conditioned media could induce phase shifts in SCN PER2 rhythms and, when administered intracerebroventricularly, induced phase delays in behavioral circadian rhythms and SCN activation in control mice, but not in TNF-Receptor-1 mutants. In summary, our results show that TNF-α modulates the molecular clock of SCN astrocytes in vitro and also that, in response to this molecule, SCN astrocytes can modulate clock gene expression in other cells and tissues, and induce phase shifts in a circadian behavioral output in vivo. These findings suggest a role for astroglial cells in the alteration of circadian timing by immune activation. PMID:24062487

Diurnal Cycling Transcription Factors of Pineapple Revealed by Genome-Wide Annotation and Global Transcriptomic Analysis.

PubMed

Sharma, Anupma; Wai, Ching Man; Ming, Ray; Yu, Qingyi

2017-09-01

Circadian clock provides fitness advantage by coordinating internal metabolic and physiological processes to external cyclic environments. Core clock components exhibit daily rhythmic changes in gene expression, and the majority of them are transcription factors (TFs) and transcription coregulators (TCs). We annotated 1,398 TFs from 67 TF families and 80 TCs from 20 TC families in pineapple, and analyzed their tissue-specific and diurnal expression patterns. Approximately 42% of TFs and 45% of TCs displayed diel rhythmic expression, including 177 TF/TCs cycling only in the nonphotosynthetic leaf tissue, 247 cycling only in the photosynthetic leaf tissue, and 201 cycling in both. We identified 68 TF/TCs whose cycling expression was tightly coupled between the photosynthetic and nonphotosynthetic leaf tissues. These TF/TCs likely coordinate key biological processes in pineapple as we demonstrated that this group is enriched in homologous genes that form the core circadian clock in Arabidopsis and includes a STOP1 homolog. Two lines of evidence support the important role of the STOP1 homolog in regulating CAM photosynthesis in pineapple. First, STOP1 responds to acidic pH and regulates a malate channel in multiple plant species. Second, the cycling expression pattern of the pineapple STOP1 and the diurnal pattern of malate accumulation in pineapple leaf are correlated. We further examined duplicate-gene retention and loss in major known circadian genes and refined their evolutionary relationships between pineapple and other plants. Significant variations in duplicate-gene retention and loss were observed for most clock genes in both monocots and dicots. © The Author 2017. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

Frequency Standards and Metrology

NASA Astrophysics Data System (ADS)

Maleki, Lute

2009-04-01

Preface / Lute Maleki -- Symposium history / Jacques Vanier -- Symposium photos -- pt. I. Fundamental physics. Variation of fundamental constants from the big bang to atomic clocks: theory and observations (Invited) / V. V. Flambaum and J. C. Berengut. Alpha-dot or not: comparison of two single atom optical clocks (Invited) / T. Rosenband ... [et al.]. Variation of the fine-structure constant and laser cooling of atomic dysprosium (Invited) / N. A. Leefer ... [et al.]. Measurement of short range forces using cold atoms (Invited) / F. Pereira Dos Santos ... [et al.]. Atom interferometry experiments in fundamental physics (Invited) / S. W. Chiow ... [et al.]. Space science applications of frequency standards and metrology (Invited) / M. Tinto -- pt. II. Frequency & metrology. Quantum metrology with lattice-confined ultracold Sr atoms (Invited) / A. D. Ludlow ... [et al.]. LNE-SYRTE clock ensemble: new [symbol]Rb hyperfine frequency measurement - spectroscopy of [symbol]Hg optical clock transition (Invited) / M. Petersen ... [et al.]. Precise measurements of S-wave scattering phase shifts with a juggling atomic clock (Invited) / S. Gensemer ... [et al.]. Absolute frequency measurement of the [symbol] clock transition (Invited) / M. Chwalla ... [et al.]. The semiclassical stochastic-field/atom interaction problem (Invited) / J. Camparo. Phase and frequency noise metrology (Invited) / E. Rubiola ... [et al.]. Optical spectroscopy of atomic hydrogen for an improved determination of the Rydberg constant / J. L. Flowers ... [et al.] -- pt. III. Clock applications in space. Recent progress on the ACES mission (Invited) / L. Cacciapuoti and C. Salomon. The SAGAS mission (Invited) / P. Wolf. Small mercury microwave ion clock for navigation and radioScience (Invited) / J. D. Prestage ... [et al.]. Astro-comb: revolutionizing precision spectroscopy in astrophysics (Invited) / C. E. Kramer ... [et al.]. High frequency very long baseline interferometry: frequency standards and imaging an event horizon (Invited) / S. Doeleman. Optically-pumped space cesium clock for Galileo: results of the breadboard / R. Ruffieux ... [et al.] -- pt. IV. Optical clocks I: lattice clocks. Optical lattice clock: seven years of progress and next steps (Invited) / H. Katori, M. Takamoto and T. Akatsuka. The Yb optical lattice clock (Invited) / N. D. Demke ... [et al.]. Optical Lattice clock with Sr atoms (Invited) / P. G. Westergaard ... [et al.]. Development of an optical clock based on neutral strontium atoms held in a lattice trap / E. A. Curtis ... [et al.]. Decoherence and losses by collisions in a [symbol]Sr lattice clock / J. S. R. Vellore Winfred ... [et al.]. Lattice Yb optical clock and cryogenic Cs fountain at INRIM / F. Levi ... [et al.] -- pt. V. Optical clocks II: ion clocks. [Symbol]Yb+ single-ion optical frequency standards (Invited) / Chr. Tamm ... [et al.]. An optical clock based on a single trapped [symbol]Sr+ ion (Invited) / H. S. Margolis ... [et al.]. A trapped [symbol]Yb+ ion optical frequency standard based on the [symbol] transition (Invited) / P. Gill ... [et al.]. Overview of highly accurate RF and optical frequency standards at the National Research Council of Canada (Invited) / A. A. Madej ... [et al.] -- pt. VI. Optical frequency combs. Extreme ultraviolet frequency combs for spectroscopy (Invited) / A. Ozawa ... [et al.]. Development of an optical clockwork for the single trapped strontium ion standard at 445 THz / J. E. Bernard ... [et al.]. A phase-coherent link between the visible and infrared spectral ranges using a combination of CW OPO and femtosecond laser frequency comb / E. V. Kovalchuk and A. Peters. Improvements to the robustness of a TI: sapphire-based femtosecond comb at NPL / V. Tsatourian ... [et al.] -- pt. VII. Atomic microwave standards. NIST FI and F2 (Invited) / T. P. Heavner ... [et al.]. Atomic fountains for the USNO master clock (Invited) / C. Ekstrom ... [et al.]. The transportable cesium fountain clock NIM5: its construction and performance (Invited) / T. Li ... [et al.].Compensated multi-pole mercury trapped ion frequency standard and stability evaluation of systematic effects (Invited) / E. A. Burt ... [et al.]. Research of frequency standards in SIOM - atomic frequency standards based on coherent storage (Invited) / B. Yan ... [et al.]. The PTB fountain clock ensemble preliminary characterization of the new fountain CSF2 / N. Nemitz ... [et al.]. The pulsed optically pumped clock: microwave and optical detection / S. Micalizio ... [et al.]. Research on characteristics of pulsed optically pumped rubidium frequency standard / J. Deng ... [et al.]. Status of the continuous cold fountain clocks at METAS-LTF / A. Joyet ... [et al.]. Experiments with a new [symbol]Hg+ ion clock / E. A. Burt ... [et al.]. Optimising a high-stability CW laser-pumped rubidium gas-cell frequency standard / C. Affolderbach ... [et al.]. Raman-Ramsey Cs cell atomic clock / R. Boudot ... [et al.] -- pt. VIII. Microwave resonators & oscillators. Solutions and ultimate limits in temperature compensation of metallic cylindrical microwave resonators (Invited) / A. De Marchi. Cryogenic sapphire oscillators (Invited) / J. G. Hartnett, E. N. Ivanov and M. E. Tobar. Ultra-stable optical cavity: design and experiments / J. Millo ... [et al.]. New results for whispering gallery mode cryogenic sapphire maser oscillators / K. Benmessai ... [et al.] -- pt. IX. Advanced techniques. Fundamental noise-limited optical phase locking at Femtowatt light levels (Invited) / J. Dick ... [et al.]. Microwave and optical frequency transfer via optical fibre / G. Marra ... [et al.]. Ultra-stable laser source for the [symbol]Sr+ single-ion optical frequency standard at NRC / P. Dubé, A. A. Madej and J. E. Bernard. Clock laser system for a strontium lattice clock / T. Legero ... [et al.]. Measurement noise floor for a long-distance optical carrier transmission via fiber / G. Grosche ... [et al.]. Optical frequency transfer over 172 KM of installed fiber / S. Crane -- pt. X. Miniature systems. Chip-scale atomic devices: precision atomic instruments based on MEMS (Invited) / J. Kitching ... [et al.]. CSAC - the chip-scale atomic clock (Invited) / R. Lutwak ... [et al.]. Reaching a few 10[symbol] stability level with a compact cold atom clock / F. X. Esnault ... [et al.]. Evaluation of Lin||Lin CPT for compact and high performance frequency standard / E. Breschi ... [et al.] -- pt. XI. Time scales. Atomic time scales TAI and TI(BIPM): present status and prospects (Invited) / G. Petit. Weight functions for biases in atomic frequency standards / J. H. Shirley -- pt. XII. Interferometers. Definition and construction of noise budget in atom interferometry (Invited) / E. D'Ambriosio. Characterization of a cold atom gyroscope (Invited) / A. Landragin ... [et al.]. A mobile atom interferometer for high precision measurements of local gravity / M. Schmidt ... [et al.]. Demonstration of atom interferometer comprised of geometric beam splitters / Hiromitsu Imai and Atsuo Morinaga -- pt. XIII. New directions. Active optical clocks (Invited) / J. Chen. Prospects for a nuclear optical frequency standard based on Thorium-229 (Invited) / E. Peik ... [et al.]. Whispering gallery mode oscillators and optical comb generators (Invited) / A. B. Matsko ... [et al.]. Frequency comparison using energy-time entangled photons / A. Stefanov -- List of participants.

Receiver Design, Performance Analysis, and Evaluation for Space-Borne Laser Altimeters and Space-to-Space Laser Ranging Systems

NASA Technical Reports Server (NTRS)

Davidson, Frederic M.; Sun, Xiaoli; Field, Christopher T.

1996-01-01

This progress report consists of two separate reports. The first one describes our work on the use of variable gain amplifiers to increase the receiver dynamic range of space borne laser altimeters such as NASA's Geoscience Laser Altimeter Systems (GLAS). The requirement of the receiver dynamic range was first calculated. A breadboard variable gain amplifier circuit was made and the performance was fully characterized. The circuit will also be tested in flight on board the Shuttle Laser Altimeter (SLA-02) next year. The second report describes our research on the master clock oscillator frequency calibration for space borne laser altimeter systems using global positioning system (GPS) receivers.

Effect of various features on the life cycle cost of the timing/synchronization subsystem of the DCS digital communications network

NASA Technical Reports Server (NTRS)

Kimsey, D. B.

1978-01-01

The effect on the life cycle cost of the timing subsystem was examined, when these optional features were included in various combinations. The features included mutual control, directed control, double-ended reference links, independence of clock error measurement and correction, phase reference combining, self-organization, smoothing for link and nodal dropouts, unequal reference weightings, and a master in a mutual control network. An overall design of a microprocessor-based timing subsystem was formulated. The microprocessor (8080) implements the digital filter portion of a digital phase locked loop, as well as other control functions such as organization of the network through communication with processors at neighboring nodes.

GET: A generic electronics system for TPCs and nuclear physics instrumentation

NASA Astrophysics Data System (ADS)

Pollacco, E. C.; Grinyer, G. F.; Abu-Nimeh, F.; Ahn, T.; Anvar, S.; Arokiaraj, A.; Ayyad, Y.; Baba, H.; Babo, M.; Baron, P.; Bazin, D.; Beceiro-Novo, S.; Belkhiria, C.; Blaizot, M.; Blank, B.; Bradt, J.; Cardella, G.; Carpenter, L.; Ceruti, S.; De Filippo, E.; Delagnes, E.; De Luca, S.; De Witte, H.; Druillole, F.; Duclos, B.; Favela, F.; Fritsch, A.; Giovinazzo, J.; Gueye, C.; Isobe, T.; Hellmuth, P.; Huss, C.; Lachacinski, B.; Laffoley, A. T.; Lebertre, G.; Legeard, L.; Lynch, W. G.; Marchi, T.; Martina, L.; Maugeais, C.; Mittig, W.; Nalpas, L.; Pagano, E. V.; Pancin, J.; Poleshchuk, O.; Pedroza, J. L.; Pibernat, J.; Primault, S.; Raabe, R.; Raine, B.; Rebii, A.; Renaud, M.; Roger, T.; Roussel-Chomaz, P.; Russotto, P.; Saccà, G.; Saillant, F.; Sizun, P.; Suzuki, D.; Swartz, J. A.; Tizon, A.; Usher, N.; Wittwer, G.; Yang, J. C.

2018-04-01

General Electronics for TPCs (GET) is a generic, reconfigurable and comprehensive electronics and data-acquisition system for nuclear physics instrumentation of up to 33792 channels. The system consists of a custom-designed ASIC for signal processing, front-end cards that each house 4 ASIC chips and digitize the data in parallel through 12-bit ADCs, concentration boards to read and process the digital data from up to 16 ASICs, a 3-level trigger and master clock module to trigger the system and synchronize the data, as well as all of the associated firmware, communication and data-acquisition software. An overview of the system including its specifications and measured performances are presented.

Circadian Metabolism in the Light of Evolution

PubMed Central

2015-01-01

Circadian rhythm, or daily oscillation, of behaviors and biological processes is a fundamental feature of mammalian physiology that has developed over hundreds of thousands of years under the continuous evolutionary pressure of energy conservation and efficiency. Evolution has fine-tuned the body's clock to anticipate and respond to numerous environmental cues in order to maintain homeostatic balance and promote survival. However, we now live in a society in which these classic circadian entrainment stimuli have been dramatically altered from the conditions under which the clock machinery was originally set. A bombardment of artificial lighting, heating, and cooling systems that maintain constant ambient temperature; sedentary lifestyle; and the availability of inexpensive, high-calorie foods has threatened even the most powerful and ancient circadian programming mechanisms. Such environmental changes have contributed to the recent staggering elevation in lifestyle-influenced pathologies, including cancer, cardiovascular disease, depression, obesity, and diabetes. This review scrutinizes the role of the body's internal clocks in the hard-wiring of circadian networks that have evolved to achieve energetic balance and adaptability, and it discusses potential therapeutic strategies to reset clock metabolic control to modern time for the benefit of human health. PMID:25927923

Suppressing the Neurospora crassa circadian clock while maintaining light responsiveness in continuous stirred tank reactors

PubMed Central

Cockrell, Allison L.; Pirlo, Russell K.; Babson, David M.; Cusick, Kathleen D.; Soto, Carissa M.; Petersen, Emily R.; Davis, Miah J.; Hong, Christian I.; Lee, Kwangwon; Fitzgerald, Lisa A.; Biffinger, Justin C.

2015-01-01

Neurospora crassa has been utilized as a model organism for studying biological, regulatory, and circadian rhythms for over 50 years. These circadian cycles are driven at the molecular level by gene transcription events to prepare for environmental changes. N. crassa is typically found on woody biomass and is commonly studied on agar-containing medium which mimics its natural environment. We report a novel method for disrupting circadian gene transcription while maintaining light responsiveness in N. crassa when held in a steady metabolic state using bioreactors. The arrhythmic transcription of core circadian genes and downstream clock-controlled genes was observed in constant darkness (DD) as determined by reverse transcription-quantitative PCR (RT-qPCR). Nearly all core circadian clock genes were up-regulated upon exposure to light during 11hr light/dark cycle experiments under identical conditions. Our results demonstrate that the natural timing of the robust circadian clock in N. crassa can be disrupted in the dark when maintained in a consistent metabolic state. Thus, these data lead to a path for the production of industrial scale enzymes in the model system, N. crassa, by removing the endogenous negative feedback regulation by the circadian oscillator. PMID:26031221

Scientists Weight Facts, Theories on Aging

ERIC Educational Resources Information Center

Chemical and Engineering News, 1974

1974-01-01

Discusses some of the current theories on aging, such as biological time clocks for certain cells and on-off switches for genes, that were offered as explanations at the 140th annual meeting of the American Association for the Advancement of Science (JR)

Music Education and Medicine: Music and the Neurology of Time.

ERIC Educational Resources Information Center

Wilson, Frank R.

1991-01-01

Explores how the body's biological clock affects the way musicians practice and perform. Delineates questions concerning this phenomenon. Discusses the implications for music teaching and focuses on areas for collaborative research between neurology researchers and music educators. (NL)

The relationship of chronobiology to sleep schedules and performance demands

NASA Technical Reports Server (NTRS)

Monk, T. H.

1990-01-01

This review is concerned with how chronobiological results concerning the human circadian timekeeping system ( biological clock'), its response to changes in schedule, and its influence on performance ability can be used to improve shift worker wellbeing, safety and productivity.

42 CFR 493.1411 - Standard; Technical consultant qualifications.

Code of Federal Regulations, 2014 CFR

2014-10-01

...) Hold an earned doctoral or master's degree in a chemical, physical, biological or clinical laboratory... degree in a chemical, physical or biological science or medical technology from an accredited institution... biology and additionally has documentation of 2 years of work experience performing tests of moderate...

42 CFR 493.1411 - Standard; Technical consultant qualifications.

Code of Federal Regulations, 2013 CFR

2013-10-01

...) Hold an earned doctoral or master's degree in a chemical, physical, biological or clinical laboratory... degree in a chemical, physical or biological science or medical technology from an accredited institution... biology and additionally has documentation of 2 years of work experience performing tests of moderate...

42 CFR 493.1411 - Standard; Technical consultant qualifications.

Code of Federal Regulations, 2011 CFR

2011-10-01

...) Hold an earned doctoral or master's degree in a chemical, physical, biological or clinical laboratory... degree in a chemical, physical or biological science or medical technology from an accredited institution... biology and additionally has documentation of 2 years of work experience performing tests of moderate...

42 CFR 493.1411 - Standard; Technical consultant qualifications.

Code of Federal Regulations, 2012 CFR

2012-10-01

...) Hold an earned doctoral or master's degree in a chemical, physical, biological or clinical laboratory... degree in a chemical, physical or biological science or medical technology from an accredited institution... biology and additionally has documentation of 2 years of work experience performing tests of moderate...

A systems theoretic approach to analysis and control of mammalian circadian dynamics

PubMed Central

Abel, John H.; Doyle, Francis J.

2016-01-01

The mammalian circadian clock is a complex multi-scale, multivariable biological control system. In the past two decades, methods from systems engineering have led to numerous insights into the architecture and functionality of this system. In this review, we examine the mammalian circadian system through a process systems lens. We present a mathematical framework for examining the cellular circadian oscillator, and show recent extensions for understanding population-scale dynamics. We provide an overview of the routes by which the circadian system can be systemically manipulated, and present in silico proof of concept results for phase resetting of the clock via model predictive control. PMID:28496287

True logarithmic amplification of frequency clock in SS-OCT for calibration

PubMed Central

Liu, Bin; Azimi, Ehsan; Brezinski, Mark E.

2011-01-01

With swept source optical coherence tomography (SS-OCT), imprecise signal calibration prevents optimal imaging of biological tissues such as coronary artery. This work demonstrates an approach using a true logarithmic amplifier to precondition the clock signal, with the effort to minimize the noises and phase errors for optimal calibration. This method was validated and tested with a high-speed SS-OCT. The experimental results manifest its superior ability on optimization of the calibration and improvement of the imaging performance. Particularly, this hardware-based approach is suitable for real-time calibration in a high-speed system where computation time is constrained. PMID:21698036

"Master-Slave" Biological Network Alignment

NASA Astrophysics Data System (ADS)

Ferraro, Nicola; Palopoli, Luigi; Panni, Simona; Rombo, Simona E.

Performing global alignment between protein-protein interaction (PPI) networks of different organisms is important to infer knowledge about conservation across species. Known methods that perform this task operate symmetrically, that is to say, they do not assign a distinct role to the input PPI networks. However, in most cases, the input networks are indeed distinguishable on the basis of how well the corresponding organism is biologically well-characterized. For well-characterized organisms the associated PPI network supposedly encode in a sound manner all the information about their proteins and associated interactions, which is far from being the case for not well characterized ones. Here the new idea is developed to devise a method for global alignment of PPI networks that in fact exploit differences in the characterization of organisms at hand. We assume that the PPI network (called Master) of the best characterized is used as a fingerprint to guide the alignment process to the second input network (called Slave), so that generated results preferably retain the structural characteristics of the Master (and using the Slave) network. We tested our method showing that the results it returns are biologically relevant.

Neurotransmitters of the retino-hypothalamic tract.

PubMed

Hannibal, Jens

2002-07-01

The brain's biological clock, which, in mammals, is located in the suprachiasmatic nucleus (SCN), generates circadian rhythms in behaviour and physiology. These biological rhythms are adjusted daily (entrained) to the environmental light/dark cycle via a monosynaptic retinofugal pathway, the retinohypothalamic tract (RHT). In this review, the anatomical and physiological evidence for glutamate and pituitary adenylate cyclase-activating polypeptide (PACAP) as principal transmitters of the RHT will be considered. A combination of immunohistochemistry at both the light- and electron-microscopic levels and tract-tracing studies have revealed that these two transmitters are co-stored in a subpopulation of retinal ganglion cells projecting to the retino-recipient zone of the ventral SCN. The PACAP/glutamate-containing cells, which constitute the RHT, also contain a recently identified photoreceptor protein, melanopsin, which may function as a "circadian photopigment". In vivo and in vitro studies have shown that glutamate and glutamate agonists such as N-methyl- D-aspartate mimic light-induced phase shifts and that application of glutamate antagonists blocks light-induced phase shifts at subjective night indicating that glutamate mediates light signalling to the clock. PACAP in nanomolar concentrations has similar phase-shifting capacity as light and glutamate, whereas PACAP in micromolar concentrations modulates glutamate-induced phase shifts. Possible targets for PACAP and glutamate are the recently identified clock genes Per1 and Per2, which are induced in the SCN by light, glutamate and PACAP at night.

Evolution: Understanding Life on Earth.

ERIC Educational Resources Information Center

Dybas, Cheryl Lyn

2002-01-01

Reports on presentations representing evolution at the 53rd annual meeting of the American Institute of Biological Sciences (AIBS) which was held March 22-24, 2002. Explains evolutionary patterns, phylogenetic pageantry, molecular clocks, speciation and biogeography, speciation and macroevolution, and human-induced evolution of drugs-resistant…

GPS Monitor Station Upgrade Program at the Naval Research Laboratory

NASA Technical Reports Server (NTRS)

Galysh, Ivan J.; Craig, Dwin M.

1996-01-01

One of the measurements made by the Global Positioning System (GPS) monitor stations is to measure the continuous pseudo-range of all the passing GPS satellites. The pseudo-range contains GPS and monitor station clock errors as well as GPS satellite navigation errors. Currently the time at the GPS monitor station is obtained from the GPS constellation and has an inherent inaccuracy as a result. Improved timing accuracy at the GPS monitoring stations will improve GPS performance. The US Naval Research Laboratory (NRL) is developing hardware and software for the GPS monitor station upgrade program to improve the monitor station clock accuracy. This upgrade will allow a method independent of the GPS satellite constellation of measuring and correcting monitor station time to US Naval Observatory (USNO) time. THe hardware consists of a high performance atomic cesium frequency standard (CFS) and a computer which is used to ensemble the CFS with the two CFS's currently located at the monitor station by use of a dual-mixer system. The dual-mixer system achieves phase measurements between the high-performance CFS and the existing monitor station CFS's to within 400 femtoseconds. Time transfer between USNO and a given monitor station is achieved via a two way satellite time transfer modem. The computer at the monitor station disciplines the CFS based on a comparison of one pulse per second sent from the master site at USNO. The monitor station computer is also used to perform housekeeping functions, as well as recording the health status of all three CFS's. This information is sent to the USNO through the time transfer modem. Laboratory time synchronization results in the sub nanosecond range have been observed and the ability to maintain the monitor station CFS frequency to within 3.0 x 10 (sup minus 14) of the master site at USNO.

Melatonin and the circadian system: contributions to successful female reproduction.

PubMed

Reiter, Russel J; Tamura, Hiroshi; Tan, Dun Xian; Xu, Xiao-Ying

2014-08-01

To summarize the role of melatonin and circadian rhythms in determining optimal female reproductive physiology, especially at the peripheral level. Databases were searched for the related English-language literature published up to March 1, 2014. Only papers in peer-reviewed journals are cited. Not applicable. Not applicable. Melatonin treatment, alterations of the normal light:dark cycle and light exposure at night. Melatonin levels in the blood and in the ovarian follicular fluid and melatonin synthesis, oxidative damage and circadian rhythm disturbances in peripheral reproductive organs. The central circadian regulatory system is located in the suprachiasmatic nucleus (SCN). The output of this master clock is synchronized to 24 hours by the prevailing light-dark cycle. The SCN regulates rhythms in peripheral cells via the autonomic nervous system and it sends a neural message to the pineal gland where it controls the cyclic production of melatonin; after its release, the melatonin rhythm strengthens peripheral oscillators. Melatonin is also produced in the peripheral reproductive organs, including granulosa cells, the cumulus oophorus, and the oocyte. These cells, along with the blood, may contribute melatonin to the follicular fluid, which has melatonin levels higher than those in the blood. Melatonin is a powerful free radical scavenger and protects the oocyte from oxidative stress, especially at the time of ovulation. The cyclic levels of melatonin in the blood pass through the placenta and aid in the organization of the fetal SCN. In the absence of this synchronizing effect, the offspring may exhibit neurobehavioral deficits. Also, melatonin protects the developing fetus from oxidative stress. Melatonin produced in the placenta likewise may preserve the optimal function of this organ. Both stable circadian rhythms and cyclic melatonin availability are critical for optimal ovarian physiology and placental function. Because light exposure after darkness onset at night disrupts the master circadian clock and suppresses elevated nocturnal melatonin levels, light at night should be avoided. Copyright © 2014 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Transcriptional master regulator analysis in breast cancer genetic networks.

PubMed

Tovar, Hugo; García-Herrera, Rodrigo; Espinal-Enríquez, Jesús; Hernández-Lemus, Enrique

2015-12-01

Gene regulatory networks account for the delicate mechanisms that control gene expression. Under certain circumstances, gene regulatory programs may give rise to amplification cascades. Such transcriptional cascades are events in which activation of key-responsive transcription factors called master regulators trigger a series of gene expression events. The action of transcriptional master regulators is then important for the establishment of certain programs like cell development and differentiation. However, such cascades have also been related with the onset and maintenance of cancer phenotypes. Here we present a systematic implementation of a series of algorithms aimed at the inference of a gene regulatory network and analysis of transcriptional master regulators in the context of primary breast cancer cells. Such studies were performed in a highly curated database of 880 microarray gene expression experiments on biopsy-captured tissue corresponding to primary breast cancer and healthy controls. Biological function and biochemical pathway enrichment analyses were also performed to study the role that the processes controlled - at the transcriptional level - by such master regulators may have in relation to primary breast cancer. We found that transcription factors such as AGTR2, ZNF132, TFDP3 and others are master regulators in this gene regulatory network. Sets of genes controlled by these regulators are involved in processes that are well-known hallmarks of cancer. This kind of analyses may help to understand the most upstream events in the development of phenotypes, in particular, those regarding cancer biology. Copyright © 2015 Elsevier Ltd. All rights reserved.

Redox regulation and pro-oxidant reactions in the physiology of circadian systems.

PubMed

Méndez, Isabel; Vázquez-Martínez, Olivia; Hernández-Muñoz, Rolando; Valente-Godínez, Héctor; Díaz-Muñoz, Mauricio

2016-05-01

Rhythms of approximately 24 h are pervasive in most organisms and are known as circadian. There is a molecular circadian clock in each cell sustained by a feedback system of interconnected "clock" genes and transcription factors. In mammals, the timing system is formed by a central pacemaker, the suprachiasmatic nucleus, in coordination with a collection of peripheral oscillators. Recently, an extensive interconnection has been recognized between the molecular circadian clock and the set of biochemical pathways that underlie the bioenergetics of the cell. A principle regulator of metabolic networks is the flow of electrons between electron donors and acceptors. The concomitant reduction and oxidation (redox) reactions directly influence the balance between anabolic and catabolic processes. This review summarizes and discusses recent findings concerning the mutual and dynamic interactions between the molecular circadian clock, redox reactions, and redox signaling. The scope includes the regulatory role played by redox coenzymes (NAD(P)+/NAD(P)H, GSH/GSSG), reactive oxygen species (superoxide anion, hydrogen peroxide), antioxidants (melatonin), and physiological events that modulate the redox state (feeding condition, circadian rhythms) in determining the timing capacity of the molecular circadian clock. In addition, we discuss a purely metabolic circadian clock, which is based on the redox enzymes known as peroxiredoxins and is present in mammalian red blood cells and in other biological systems. Both the timing system and the metabolic network are key to a better understanding of widespread pathological conditions such as the metabolic syndrome, obesity, and diabetes. Copyright © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

A Neural Network Underlying Circadian Entrainment and Photoperiodic Adjustment of Sleep and Activity in Drosophila.

PubMed

Schlichting, Matthias; Menegazzi, Pamela; Lelito, Katharine R; Yao, Zepeng; Buhl, Edgar; Dalla Benetta, Elena; Bahle, Andrew; Denike, Jennifer; Hodge, James John; Helfrich-Förster, Charlotte; Shafer, Orie Thomas

2016-08-31

A sensitivity of the circadian clock to light/dark cycles ensures that biological rhythms maintain optimal phase relationships with the external day. In animals, the circadian clock neuron network (CCNN) driving sleep/activity rhythms receives light input from multiple photoreceptors, but how these photoreceptors modulate CCNN components is not well understood. Here we show that the Hofbauer-Buchner eyelets differentially modulate two classes of ventral lateral neurons (LNvs) within the Drosophila CCNN. The eyelets antagonize Cryptochrome (CRY)- and compound-eye-based photoreception in the large LNvs while synergizing CRY-mediated photoreception in the small LNvs. Furthermore, we show that the large LNvs interact with subsets of "evening cells" to adjust the timing of the evening peak of activity in a day length-dependent manner. Our work identifies a peptidergic connection between the large LNvs and a group of evening cells that is critical for the seasonal adjustment of circadian rhythms. In animals, circadian clocks have evolved to orchestrate the timing of behavior and metabolism. Consistent timing requires the entrainment these clocks to the solar day, a process that is critical for an organism's health. Light cycles are the most important external cue for the entrainment of circadian clocks, and the circadian system uses multiple photoreceptors to link timekeeping to the light/dark cycle. How light information from these photorecptors is integrated into the circadian clock neuron network to support entrainment is not understood. Our results establish that input from the HB eyelets differentially impacts the physiology of neuronal subgroups. This input pathway, together with input from the compound eyes, precisely times the activity of flies under long summer days. Our results provide a mechanistic model of light transduction and integration into the circadian system, identifying new and unexpected network motifs within the circadian clock neuron network. Copyright © 2016 the authors 0270-6474/16/369084-13$15.00/0.

Light and the human circadian clock.

PubMed

Roenneberg, Till; Kantermann, Thomas; Juda, Myriam; Vetter, Céline; Allebrandt, Karla V

2013-01-01

The circadian clock can only reliably fulfil its function if it is stably entrained. Most clocks use the light-dark cycle as environmental signal (zeitgeber) for this active synchronisation. How we think about clock function and entrainment has been strongly influenced by the early concepts of the field's pioneers, and the astonishing finding that circadian rhythms continue a self-sustained oscillation in constant conditions has become central to our understanding of entrainment.Here, we argue that we have to rethink these initial circadian dogmas to fully understand the circadian programme and how it entrains. Light is also the prominent zeitgeber for the human clock, as has been shown experimentally in the laboratory and in large-scale epidemiological studies in real life, and we hypothesise that social zeitgebers act through light entrainment via behavioural feedback loops (zeitnehmer). We show that human entrainment can be investigated in detail outside of the laboratory, by using the many 'experimental' conditions provided by the real world, such as daylight savings time, the 'forced synchrony' imposed by the introduction of time zones, or the fact that humans increasingly create their own light environment. The conditions of human entrainment have changed drastically over the past 100 years and have led to an increasing discrepancy between biological and social time (social jetlag). The increasing evidence that social jetlag has detrimental consequences for health suggests that shift-work is only an extreme form of circadian misalignment, and that the majority of the population in the industrialised world suffers from a similarly 'forced synchrony'.

Unraveling the complexities of circadian and sleep interactions with memory formation through invertebrate research

PubMed Central

Michel, Maximilian; Lyons, Lisa C.

2014-01-01

Across phylogeny, the endogenous biological clock has been recognized as providing adaptive advantages to organisms through coordination of physiological and behavioral processes. Recent research has emphasized the role of circadian modulation of memory in generating peaks and troughs in cognitive performance. The circadian clock along with homeostatic processes also regulates sleep, which itself impacts the formation and consolidation of memory. Thus, the circadian clock, sleep and memory form a triad with ongoing dynamic interactions. With technological advances and the development of a global 24/7 society, understanding the mechanisms underlying these connections becomes pivotal for development of therapeutic treatments for memory disorders and to address issues in cognitive performance arising from non-traditional work schedules. Invertebrate models, such as Drosophila melanogaster and the mollusks Aplysia and Lymnaea, have proven invaluable tools for identification of highly conserved molecular processes in memory. Recent research from invertebrate systems has outlined the influence of sleep and the circadian clock upon synaptic plasticity. In this review, we discuss the effects of the circadian clock and sleep on memory formation in invertebrates drawing attention to the potential of in vivo and in vitro approaches that harness the power of simple invertebrate systems to correlate individual cellular processes with complex behaviors. In conclusion, this review highlights how studies in invertebrates with relatively simple nervous systems can provide mechanistic insights into corresponding behaviors in higher organisms and can be used to outline possible therapeutic options to guide further targeted inquiry. PMID:25136297

Human biological research since 2006 at the Christian-Albrechts-University in Kiel--aging, chronobiology, and high altitude adaptation.

PubMed

Dittmar, Manuela

2014-01-01

This article reviews the research at the Department of Human Biology at the Christian-Albrechts-University in Kiel since 2006. The research focuses on the investigation of recent human populations with respect to aging, chronobiology, and adaptation to high altitude. The research areas are outlined presenting findings, ongoing projects and future directions. Aging research examines biological changes in humans considering that aging is a multidimensional process. Changes in body composition, resting energy metabolism, oxidative stress, and sleep have been examined. The applicability of specific research methods to older people has been tested. Chronobiological research concentrates on investigating circadian rhythms of humans. The emphasis lies on the sleep-wake rhythm, body temperature rhythms, hormonal rhythms (cortisol and melatonin) and the circadian expression of so-called clock genes which are involved in the generation of circadian rhythms. Association studies examine the relationship between defined chronobiological phenotypes and clock gene polymorphisms. Genetic aspects are as well investigated within the third research area on the adaptation of native populations to life at high altitude in the South American Andes. Both candidate gene analysis and epigenetic parameters are investigated. Future research will concentrate on the aging of the circadian system.

Biological rhythms: the taste-time continuum.

PubMed

Krupp, Joshua J; Levine, Joel D

2010-02-23

The gustatory system allows the fly to assess food quality, eliciting either acceptance or avoidance behaviors. A new study demonstrates that circadian clocks in gustatory receptor neurons regulate rhythms in taste sensitivity, drive rhythms in appetitive behavior and influence feeding. Copyright 2010 Elsevier Ltd. All rights reserved.

Cross‐talk between circadian clocks, sleep‐wake cycles, and metabolic networks: Dispelling the darkness

PubMed Central

Ray, Sandipan

2016-01-01

Integration of knowledge concerning circadian rhythms, metabolic networks, and sleep‐wake cycles is imperative for unraveling the mysteries of biological cycles and their underlying mechanisms. During the last decade, enormous progress in circadian biology research has provided a plethora of new insights into the molecular architecture of circadian clocks. However, the recent identification of autonomous redox oscillations in cells has expanded our view of the clockwork beyond conventional transcription/translation feedback loop models, which have been dominant since the first circadian period mutants were identified in fruit fly. Consequently, non‐transcriptional timekeeping mechanisms have been proposed, and the antioxidant peroxiredoxin proteins have been identified as conserved markers for 24‐hour rhythms. Here, we review recent advances in our understanding of interdependencies amongst circadian rhythms, sleep homeostasis, redox cycles, and other cellular metabolic networks. We speculate that systems‐level investigations implementing integrated multi‐omics approaches could provide novel mechanistic insights into the connectivity between daily cycles and metabolic systems. PMID:26866932

Seeing the forest and trees: whole-body and whole-brain imaging for circadian biology.

PubMed

Ode, K L; Ueda, H R

2015-09-01

Recent advances in methods for making mammalian organs translucent have made possible whole-body fluorescent imaging with single-cell resolution. Because organ-clearing methods can be used to image the heterogeneous nature of cell populations, they are powerful tools to investigate the hierarchical organization of the cellular circadian clock, and how the clock synchronizes a variety of physiological activities. In particular, methods compatible with genetically encoded fluorescent reporters have the potential to detect circadian activity in different brain regions and the circadian-phase distribution across the whole body. In this review, we summarize the current methods and strategy for making organs translucent (removal of lipids, decolourization of haemoglobin and adjusting the refractive index of the specimen). We then discuss possible applications to circadian biology. For example, the coupling of circadian rhythms among different brain regions, brain activity in sleep-wake cycles and the role of migrating cells such as immune cells and cancer cells in chronopharmacology. © 2015 John Wiley & Sons Ltd.

Cross-talk between circadian clocks, sleep-wake cycles, and metabolic networks: Dispelling the darkness.

PubMed

Ray, Sandipan; Reddy, Akhilesh B

2016-04-01

Integration of knowledge concerning circadian rhythms, metabolic networks, and sleep-wake cycles is imperative for unraveling the mysteries of biological cycles and their underlying mechanisms. During the last decade, enormous progress in circadian biology research has provided a plethora of new insights into the molecular architecture of circadian clocks. However, the recent identification of autonomous redox oscillations in cells has expanded our view of the clockwork beyond conventional transcription/translation feedback loop models, which have been dominant since the first circadian period mutants were identified in fruit fly. Consequently, non-transcriptional timekeeping mechanisms have been proposed, and the antioxidant peroxiredoxin proteins have been identified as conserved markers for 24-hour rhythms. Here, we review recent advances in our understanding of interdependencies amongst circadian rhythms, sleep homeostasis, redox cycles, and other cellular metabolic networks. We speculate that systems-level investigations implementing integrated multi-omics approaches could provide novel mechanistic insights into the connectivity between daily cycles and metabolic systems. © 2016 The Authors. Bioessays published by WILEY Periodicals, Inc.

Circadian Clock Control of Endocrine Factors

PubMed Central

Gamble, Karen L.; Berry, Ryan; Frank, Stuart J.; Young, Martin E.

2015-01-01

Organisms experience dramatic fluctuations in demands/stresses over the course of the day. In order to maintain biological processes within physiologic boundaries, it is imperative that mechanisms have evolved for anticipation of, and adaptation to, these daily fluctuations. Endocrine factors undoubtedly play an integral role in homeostasis. Not only do circulating levels of various endocrine factors oscillate over the 24 period, but so too does responsiveness of target tissues to these signals/stimuli. Emerging evidence suggests that these daily oscillations do not occur solely in response to behavioral fluctuations associated with sleep/wake and feeding/fasting cycles, but are orchestrated in part by an intrinsic timekeeping mechanism known as the circadian clock. Disruption of circadian clocks, through genetic and/or environmental means, appears to precipitate numerous common disorders, including cardiometabolic diseases and cancer. Collectively, these observations, which are reviewed within the current article, have led to suggestion that strategies designed to realign normal circadian rhythmicities hold a therapeutic potential for the treatment of various endocrine-related disorders. PMID:24863387

Using the principles of circadian physiology enhances shift schedule design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Connolly, J.J.; Moore-Ede, M.C.

1987-01-01

Nuclear power plants must operate 24 h, 7 days a week. For the most part, shift schedules currently in use at nuclear power plants have been designed to meet operational needs without considering the biological clocks of the human operators. The development of schedules that also take circadian principles into account is a positive step that can be taken to improve plant safety by optimizing operator alertness. These schedules reduce the probability of human errors especially during backshifts. In addition, training programs that teach round-the-clock workers how to deal with the problems of shiftwork can help to optimize performance andmore » alertness. These programs teach shiftworkers the underlying causes of the sleep problems associated with shiftwork and also provide coping strategies for improving sleep and dealing with the transition between shifts. When these training programs are coupled with an improved schedule, the problems associated with working round-the-clock can be significantly reduced.« less

Molecular clocks and the human condition: approaching their characterization in human physiology and disease.

PubMed

Fitzgerald, G A; Yang, G; Paschos, G K; Liang, X; Skarke, C

2015-09-01

Molecular clockworks knit together diverse biological networks and compelling evidence from model systems infers their importance in metabolism, immunological and cardiovascular function. Despite this and the diurnal variation in many aspects of human physiology and the phenotypic expression of disease, our understanding of the role and importance of clock function and dysfunction in humans is modest. There are tantalizing hints of connection across the translational divide and some correlative evidence of gene variation and human disease but most of what we know derives from forced desynchrony protocols in controlled environments. We now have the ability to monitor quantitatively ex vivo or in vivo the genome, metabolome, proteome and microbiome of humans in the wild. Combining this capability, with the power of mobile telephony and the evolution of remote sensing, affords a new opportunity for deep phenotyping, including the characterization of diurnal behaviour and the assessment of the impact of the clock on approved drug function. © 2015 John Wiley & Sons Ltd.

How to fix a broken clock

PubMed Central

Schroeder, Analyne M.; Colwell, Christopher S.

2013-01-01

Fortunate are those who rise out of bed to greet the morning light well rested with the energy and enthusiasm to drive a productive day. Others however, depend on hypnotics for sleep and require stimulants to awaken lethargic bodies. Sleep/wake disruption is a common occurrence in healthy individuals throughout their lifespan and is also a comorbid condition to many diseases (neurodegenerative) and psychiatric disorders (depression and bipolar). There is growing concern that chronic disruption of the sleep/wake cycle contributes to more serious conditions including diabetes (type 2), cardiovascular disease and cancer. A poorly functioning circadian system resulting in misalignments in the timing of clocks throughout the body may be at the root of the problem for many people. In this article, we discuss environmental (light therapy) and lifestyle changes (scheduled meals, exercise and sleep) as interventions to help fix a broken clock. We also discuss the challenges and potential for future development of pharmacological treatments to manipulate this key biological system. PMID:24120229

Master in Oral Biology Program: A Path to Addressing the Need for Future Dental Educators

ERIC Educational Resources Information Center

Jergenson, Margaret A.; Barritt, Laura C.; O'Kane, Barbara J.; Norton, Neil S.

2017-01-01

In dental education, the anatomical sciences, which include gross anatomy, histology, embryology, and neuroanatomy, encompass an important component of the basic science curriculum. At Creighton University School of Dentistry, strength in anatomic science education has been coupled with a solid applicant pool to develop a novel Master of Science…

Individual differences in circadian locomotor parameters correlate with anxiety- and depression-like behavior.

PubMed

Anyan, Jeffrey; Verwey, Michael; Amir, Shimon

2017-01-01

Disrupted circadian rhythms are a core feature of mood and anxiety disorders. Circadian rhythms are coordinated by a light-entrainable master clock located in the suprachiasmatic nucleus. Animal models of mood and anxiety disorders often exhibit blunted rhythms in locomotor activity and clock gene expression. Interestingly, the changes in circadian rhythms correlate with mood-related behaviours. Although animal models of depression and anxiety exhibit aberrant circadian rhythms in physiology and behavior, it is possible that the methodology being used to induce the behavioral phenotype (e.g., brain lesions, chronic stress, global gene deletion) affect behavior independently of circadian system. This study investigates the relationship between individual differences in circadian locomotor parameters and mood-related behaviors in healthy rats. The circadian phenotype of male Lewis rats was characterized by analyzing wheel running behavior under standard 12h:12h LD conditions, constant dark, constant light, and rate of re-entrainment to a phase advance. Rats were then tested on a battery of behavioral tests: activity box, restricted feeding, elevated plus maze, forced swim test, and fear conditioning. Under 12h:12h LD conditions, percent of daily activity in the light phase and variability in activity onset were associated with longer latency to immobility in the forced swim test. Variability in onset also correlated positively with anxiety-like behavior in the elevated plus maze. Rate of re-entrainment correlated positively with measures of anxiety in the activity box and elevated plus maze. Lastly, we found that free running period under constant dark was associated with anxiety-like behaviors in the activity box and elevated plus maze. Our results provide a previously uncharacterized relationship between circadian locomotor parameters and mood-related behaviors in healthy rats and provide a basis for future examination into circadian clock functioning and mood.

Antimicrobial capacity of the freshwater planarians against S. aureus is under the control of Timeless.

PubMed

Tsoumtsa, Landry Laure; Torre, Cedric; Trouplin, Virginie; Coiffard, Benjamin; Gimenez, Gregory; Mege, Jean-Louis; Ghigo, Eric

2017-10-03

Planarians, which are non-parasitic flatworms, are highly resistant to bacterial infections. To better understand the mechanisms underlying this resistance, we investigated the role of the circadian machinery in the anti-bacterial response of the freshwater planarian Schmidtea mediterranea. We identified Smed-Tim from S. mediterranea as a homolog of the mammalian clock gene Tim. We showed via RNA interference that Smed-Tim is required for the anti-microbial activities of Schmidtea mediterranea against Staphylococcus aureus infection during the light/dark cycle. Indeed, S. aureus infection leads to the expression of Smed-Tim, which in turn promotes Smed-Traf6 and Smed-morn2, but not Smed-p38 MAPK expression, 2 master regulators of planarian anti-microbial responses.

CLOCK gene variation is associated with incidence of type-2 diabetes and cardiovascular diseases in type-2 diabetic subjects: dietary modulation in the PREDIMED randomized trial.

PubMed

Corella, Dolores; Asensio, Eva M; Coltell, Oscar; Sorlí, José V; Estruch, Ramón; Martínez-González, Miguel Ángel; Salas-Salvadó, Jordi; Castañer, Olga; Arós, Fernando; Lapetra, José; Serra-Majem, Lluís; Gómez-Gracia, Enrique; Ortega-Azorín, Carolina; Fiol, Miquel; Espino, Javier Díez; Díaz-López, Andrés; Fitó, Montserrat; Ros, Emilio; Ordovás, José M

2016-01-07

Circadian rhythms regulate key biological processes influencing metabolic pathways. Disregulation is associated with type 2 diabetes (T2D) and cardiovascular diseases (CVD). Circadian rhythms are generated by a transcriptional autoregulatory feedback loop involving core clock genes. CLOCK (circadian locomotor output cycles protein kaput), one of those core genes, is known to regulate glucose metabolism in rodent models. Cross-sectional studies in humans have reported associations between this locus and obesity, plasma glucose, hypertension and T2D prevalence, supporting its role in cardiovascular risk. However, no longitudinal study has investigated the association between CLOCK gene variation and T2D or CVD incidence. Moreover, although in a previous work we detected a gene-diet interaction between the CLOCK-rs4580704 (C > G) single nucleotide polymorphism (SNP) and monounsaturated (MUFA) intake on insulin resistance, no interventional study has analyzed gene-diet interactions on T2D or CVD outcomes. We analyzed the association between the CLOCK-rs4580704 SNP and incidence of T2D and CVD longitudinally in 7098 PREDIMED trial (ISRCTN35739639) participants after a median 4.8-year follow-up. We also examined modulation by Mediterranean diet (MedDiet) intervention (high in MUFA) on these associations. We observed a significant association between the CLOCK-rs4580704 SNP and T2D incidence in n = 3671 non-T2D PREDIMED participants, with variant allele (G) carriers showing decreased incidence (dominant model) compared with CC homozygotes (HR: 0.69; 95 % CI 0.54-0.87; P = 0.002). This protection was more significant in the MedDiet intervention group (HR: 0.58; 95 % CI 0.43-0.78; P < 0.001) than in the control group (HR: 0.95; 95 % CI 0.63-1.44; P = 0.818). Moreover, we detected a statistically significant interaction (P = 0.018) between CLOCK-rs4580704 SNP and T2D status on stroke. Thus, only in T2D subjects was CLOCK-rs4580704 SNP associated with stroke risk, G-carriers having decreased risk (HR: 0.61; 95 % CI 0.40-0.94; P = 0.024 versus CC) in the multivariable-adjusted model. In agreement with our previous results showing a protective effect of the G-allele against hyperglycemia, we extended our findings by reporting a novel association with lower T2D incidence and also suggesting a dietary modulation. Moreover, we report for the first time an association between a CLOCK polymorphism and stroke in T2D subjects, suggesting that core clock genes may significantly contribute to increased CVD risk in T2D.

Misalignment with the external light environment drives metabolic and cardiac dysfunction.

PubMed

West, Alexander C; Smith, Laura; Ray, David W; Loudon, Andrew S I; Brown, Timothy M; Bechtold, David A

2017-09-12

Most organisms use internal biological clocks to match behavioural and physiological processes to specific phases of the day-night cycle. Central to this is the synchronisation of internal processes across multiple organ systems. Environmental desynchrony (e.g. shift work) profoundly impacts human health, increasing cardiovascular disease and diabetes risk, yet the underlying mechanisms remain unclear. Here, we characterise the impact of desynchrony between the internal clock and the external light-dark (LD) cycle on mammalian physiology. We reveal that even under stable LD environments, phase misalignment has a profound effect, with decreased metabolic efficiency and disrupted cardiac function including prolonged QT interval duration. Importantly, physiological dysfunction is not driven by disrupted core clock function, nor by an internal desynchrony between organs, but rather the altered phase relationship between the internal clockwork and the external environment. We suggest phase misalignment as a major driver of pathologies associated with shift work, chronotype and social jetlag.The misalignment between internal circadian rhythm and the day-night cycle can be caused by genetic, behavioural and environmental factors, and may have a profound impact on human physiology. Here West et al. show that desynchrony between the internal clock and the external environment alter metabolic parameters and cardiac function in mice.

A Systolic Array-Based FPGA Parallel Architecture for the BLAST Algorithm

PubMed Central

Guo, Xinyu; Wang, Hong; Devabhaktuni, Vijay

2012-01-01

A design of systolic array-based Field Programmable Gate Array (FPGA) parallel architecture for Basic Local Alignment Search Tool (BLAST) Algorithm is proposed. BLAST is a heuristic biological sequence alignment algorithm which has been used by bioinformatics experts. In contrast to other designs that detect at most one hit in one-clock-cycle, our design applies a Multiple Hits Detection Module which is a pipelining systolic array to search multiple hits in a single-clock-cycle. Further, we designed a Hits Combination Block which combines overlapping hits from systolic array into one hit. These implementations completed the first and second step of BLAST architecture and achieved significant speedup comparing with previously published architectures. PMID:25969747

Daily methylphenidate and atomoxetine treatment impacts on clock gene protein expression in the mouse brain.

PubMed

Baird, Alison L; Coogan, Andrew N; Kaufling, Jennifer; Barrot, Michel; Thome, Johannes

2013-06-04

Circadian rhythms are repeating patterns of physiological and other parameters that recur with periods of approximately 24h, and are generated by an endogenous circadian timekeeping mechanism. Such circadian rhythms, and their underlying molecular mechanisms, are known to be altered by a number of central nervous system acting pharmacological compounds, as well as becoming perturbed in a number of common psychiatric and neurological conditions. The psychostimulant methylphenidate and the non-stimulant atomoxetine are used in the pharmacotherapy of attention deficit hyperactivity disorder, a common condition in which circadian rhythms have been reported to be altered. In the present study we have examined the effects of daily methylphenidate or atomoxetine treatment across 7 days on circadian clock gene product expression across numerous brain regions in the male mouse to test the potential impact of such compounds on circadian timing. We report drug, brain region and molecular specific effects of such treatments, including alterations in expression profiles in the suprachiasmatic nucleus, the master circadian pacemaker. These results indicate that drugs used in the clinical management of attention deficit hyperactivity disorder can alter molecular factors that are believed to underpin circadian timekeeping, and such effects may be of importance in both the therapeutic and side effect profiles of such drugs. Copyright © 2013 Elsevier B.V. All rights reserved.

Early development of circadian rhythmicity in the suprachiamatic nuclei and pineal gland of teleost, flounder (Paralichthys olivaeus), embryos.

PubMed

Mogi, Makoto; Uji, Susumu; Yokoi, Hayato; Suzuki, Tohru

2015-08-01

Circadian rhythms enable organisms to coordinate multiple physiological processes and behaviors with the earth's rotation. In mammals, the suprachiasmatic nuclei (SCN), the sole master circadian pacemaker, has entrainment mechanisms that set the circadian rhythm to a 24-h cycle with photic signals from retina. In contrast, the zebrafish SCN is not a circadian pacemaker, instead the pineal gland (PG) houses the major circadian oscillator. The SCN of flounder larvae, unlike that of zebrafish, however, expresses per2 with a rhythmicity of daytime/ON and nighttime/OFF. Here, we examined whether the rhythm of per2 expression in the flounder SCN represents the molecular clock. We also examined early development of the circadian rhythmicity in the SCN and PG. Our three major findings were as follows. First, rhythmic per2 expression in the SCN was maintained under 24 h dark (DD) conditions, indicating that a molecular clock exists in the flounder SCN. Second, onset of circadian rhythmicity in the SCN preceded that in the PG. Third, both 24 h light (LL) and DD conditions deeply affected the development of circadian rhythmicity in the SCN and PG. This is the first report dealing with the early development of circadian rhythmicity in the SCN in fish. © 2015 Japanese Society of Developmental Biologists.

Long Duration Exposure Facility (LDEF) attitude measurements of the interplanetary dust experiment

NASA Technical Reports Server (NTRS)

Kassel, Philip C., Jr.; Singer, S. Fred; Mulholland, J. Derral; Oliver, John P.; Weinberg, Jerry L.; Cooke, William J.; Wortman, Jim J.; Motley, William R., III

1992-01-01

The Long Duration Exposure Facility (LDEF) Interplanetary Dust Experiment (IDE) was unique in providing a time history of impacts of micron-sized particles on six orthogonal faces of LDEF during the first year in orbit. The value of this time resolved data depended on and was enhanced by the proper operation of some basic LDEF systems. Thus, the value of the data is greatly enhanced when the location and orientation of LDEF is known for each time of impact. The location and velocity of LDEF as a function of time can be calculated from the 'two-line elements' published by GSFC during the first year of the LDEF mission. The attitude of LDEF was passively stabilized in a gravity-gradient mode and a magnetically anchored viscous damper was used to dissipate roll, pitch, and yaw motions. Finally, the IDE used a standard LDEF Experiment Power and Data System (EPDS) to collect and store data and also to provide a crystal derived clock pulse (1 count every 13.1072 seconds) for all IDE time measurements. All that remained for the IDE was to provide a system to calibrate the clock, eliminating accumulative errors, and also verify the attitude of LDEF. The IDE used solar cells on six orthogonal faces to observe the LDEF sunrise and provide data about the LDEF attitude. The data was recorded by the EPDS about 10 times per day for the first 345 days of the LDEF mission. This data consist of the number of IDE counts since the last LDEF sunrise and the status of the six solar cells (light or dark) at the time of the last IDE count. The EPDS determined the time that data was recorded and includes, with each record, the master EPDS clock counter (1 count every 1.6384 seconds) that provided the range and resolution for time measurements. The IDE solar cells provided data for an excellent clock calibration, meeting their primary purpose, and the time resolved LDEF attitude measurements that can be gleaned from this data are presented.

Non-24-Hour Sleep-Wake Disorder Revisited - A Case Study.

PubMed

Garbazza, Corrado; Bromundt, Vivien; Eckert, Anne; Brunner, Daniel P; Meier, Fides; Hackethal, Sandra; Cajochen, Christian

2016-01-01

The human sleep-wake cycle is governed by two major factors: a homeostatic hourglass process (process S), which rises linearly during the day, and a circadian process C, which determines the timing of sleep in a ~24-h rhythm in accordance to the external light-dark (LD) cycle. While both individual processes are fairly well characterized, the exact nature of their interaction remains unclear. The circadian rhythm is generated by the suprachiasmatic nucleus ("master clock") of the anterior hypothalamus, through cell-autonomous feedback loops of DNA transcription and translation. While the phase length (tau) of the cycle is relatively stable and genetically determined, the phase of the clock is reset by external stimuli ("zeitgebers"), the most important being the LD cycle. Misalignments of the internal rhythm with the LD cycle can lead to various somatic complaints and to the development of circadian rhythm sleep disorders (CRSD). Non-24-hour sleep-wake disorders (N24HSWD) is a CRSD affecting up to 50% of totally blind patients and characterized by the inability to maintain a stable entrainment of the typically long circadian rhythm (tau > 24.5 h) to the LD cycle. The disease is rare in sighted individuals and the pathophysiology less well understood. Here, we present the case of a 40-year-old sighted male, who developed a misalignment of the internal clock with the external LD cycle following the treatment for Hodgkin's lymphoma (ABVD regimen, four cycles and AVD regimen, four cycles). A thorough clinical assessment, including actigraphy, melatonin profiles and polysomnography led to the diagnosis of non-24-hour sleep-wake disorders (N24HSWD) with a free-running rhythm of tau = 25.27 h. A therapeutic intervention with bright light therapy (30 min, 10,000 lux) in the morning and melatonin administration (0.5-0.75 mg) in the evening failed to entrain the free-running rhythm, although a longer treatment duration and more intense therapy might have been successful. The sudden onset and close timely connection led us to hypothesize that the chemotherapy might have caused a mutation of the molecular clock components leading to the observed elongation of the circadian period.

Lactation biology symposium: Circadian clocks and photoperiod in mammary gland development and lactation

USDA-ARS?s Scientific Manuscript database

Life on earth evolved with light-dark cycles. As a result there arose in all organisms, though probably first in photosynthetic archaebacteria, oscillatory mechanisms to time processes that were necessary for survival and reproduction. The first known account of these oscillations was given for plan...

Efficient targeted mutagenesis in the monarch butterfly using zinc-finger nucleases

PubMed Central

Merlin, Christine; Beaver, Lauren E.; Taylor, Orley R.; Wolfe, Scot A.; Reppert, Steven M.

2013-01-01

The development of reverse-genetic tools in “nonmodel” insect species with distinct biology is critical to establish them as viable model systems. The eastern North American monarch butterfly (Danaus plexippus), whose genome is sequenced, has emerged as a model to study animal clocks, navigational mechanisms, and the genetic basis of long-distance migration. Here, we developed a highly efficient gene-targeting approach in the monarch using zinc-finger nucleases (ZFNs), engineered nucleases that generate mutations at targeted genomic sequences. We focused our ZFN approach on targeting the type 2 vertebrate-like cryptochrome gene of the monarch (designated cry2), which encodes a putative transcriptional repressor of the monarch circadian clockwork. Co-injections of mRNAs encoding ZFNs targeting the second exon of monarch cry2 into “one nucleus” stage embryos led to high-frequency nonhomologous end-joining-mediated, mutagenic lesions in the germline (up to 50%). Heritable ZFN-induced lesions in two independent lines produced truncated, nonfunctional CRY2 proteins, resulting in the in vivo disruption of circadian behavior and the molecular clock mechanism. Our work genetically defines CRY2 as an essential transcriptional repressor of the monarch circadian clock and provides a proof of concept for the use of ZFNs for manipulating genes in the monarch butterfly genome. Importantly, this approach could be used in other lepidopterans and “nonmodel” insects, thus opening new avenues to decipher the molecular underpinnings of a variety of biological processes. PMID:23009861

Chronobiology of interspecific interactions in a changing world.

PubMed

Kronfeld-Schor, Noga; Visser, Marcel E; Salis, Lucia; van Gils, Jan A

2017-11-19

Animals should time activities, such as foraging, migration and reproduction, as well as seasonal physiological adaptation, in a way that maximizes fitness. The fitness outcome of such activities depends largely on their interspecific interactions; the temporal overlap with other species determines when they should be active in order to maximize their encounters with food and to minimize their encounters with predators, competitors and parasites. To cope with the constantly changing, but predictable structure of the environment, organisms have evolved internal biological clocks, which are synchronized mainly by light, the most predictable and reliable environmental cue (but which can be masked by other variables), which enable them to anticipate and prepare for predicted changes in the timing of the species they interact with, on top of responding to them directly. Here, we review examples where the internal timing system is used to predict interspecific interactions, and how these interactions affect the internal timing system and activity patterns. We then ask how plastic these mechanisms are, how this plasticity differs between and within species and how this variability in plasticity affects interspecific interactions in a changing world, in which light, the major synchronizer of the biological clock, is no longer a reliable cue owing to the rapidly changing climate, the use of artificial light and urbanization.This article is part of the themed issue 'Wild clocks: integrating chronobiology and ecology to understand timekeeping in free-living animals'. © 2017 The Author(s).

[Depression as chronobiological illness].

PubMed

Kálmán, Janos; Kálmán, Sára

2009-06-01

Chronobiological problems are always present as aetiological or pathoplastic conditions almost in all psychiatric disorders and considered as the greatest contributors to the mood and sleep disorders associated problems. The present review summarise the recent advances in the chronobiology research from the point of the clinician with particular emphasis on the psychobiology and pharmacotherapy of the depression. Human behaviour builds up from different length of circadian, ultradian and seasonal rhytms, strictly controlled by a hierarchical organisation of sub-cellullar, cellular, neuro-humoral and neuro-immunological clock systems. These internal clock systems are orchestrated at molecular level by certain clock genes and on the other hand--at neuro-humoral level--by the effect of the sleep hormone, melatonine, produced by the neurons of the suprachiasmatic nucleus (SCN). Beside the biological factors, social interactions are also considered as important regulators of the biological clock systems. The pacemaker centers of the SCN receive efferents from the serotoninergic raphe nuclei in order to regulate stress responses and neuroimmunological functions. The direction and the level of the chronobiological desynchronisation could be totally divergent in the case of the different affective disorders. Different chronobiological interventions are required therefore in the case of the advanced and delayed sleep disorders. Sleeping disorders are considered as the most recognised signs of the chronobiological desynchronisation in depression, but these symptoms are only the tip of the iceberg, since other chronobiological symptoms could be present due to the hidden physiological abnormalities. The serum melatonine profile is considered to be characteristic to age, gender and certain neuropsychiatric disorders. The natural and synthetic agonist of the melatonine receptors could be used as chronobiotics. The recently marketed agomelatine with a highly selective receptor binding profile (MT1 and MT2 agonism and 5HT2C antagonism) targets the desynchronised circadian rhytm in affective disorders and it has mainly antidepressive effect. Among the non-pharmacological chronobiological interventions, the different forms of the sleep deprivation, light and social rhytm therapies could offer alternative treatment options for the clinician.

Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms.

PubMed

Patel, Sonal A; Chaudhari, Amol; Gupta, Richa; Velingkaar, Nikkhil; Kondratov, Roman V

2016-04-01

Calorie restriction (CR) increases longevity in many species by unknown mechanisms. The circadian clock was proposed as a potential mediator of CR. Deficiency of the core component of the circadian clock-transcriptional factor BMAL1 (brain and muscle ARNT [aryl hydrocarbon receptor nuclear translocator]-like protein 1)-results in accelerated aging. Here we investigated the role of BMAL1 in mechanisms of CR. The 30% CR diet increased the life span of wild-type (WT) mice by 20% compared to mice on anad libitum(AL) diet but failed to increase life span ofBmal1(-/-)mice. BMAL1 deficiency impaired CR-mediated changes in the plasma levels of IGF-1 and insulin. We detected a statistically significantly reduction of IGF-1 in CRvs.AL by 50 to 70% in WT mice at several daily time points tested, while inBmal1(-/-)the reduction was not significant. Insulin levels in WT were reduced by 5 to 9%, whileBmal1(-/-)induced it by 10 to 35% at all time points tested. CR up-regulated the daily average expression ofBmal1(by 150%) and its downstream target genesPeriods(by 470% forPer1and by 130% forPer2). We propose that BMAL1 is an important mediator of CR, and activation of BMAL1 might link CR mechanisms with biologic clocks.-Patel, S. A., Chaudhari, A., Gupta, R., Velingkaar, N., Kondratov, R. V. Circadian clocks govern calorie restriction-mediated life span extension through BMAL1- and IGF-1-dependent mechanisms. © FASEB.

Accuracy of 3D Imaging Software in Cephalometric Analysis

DTIC Science & Technology

2013-06-21

submitted to the Faculty of the Comprehensive Dentistry Graduate Program Naval Postgraduate Dental School Uniformed Services University of the Health...Sciences in partial fulfillment of the requirements of the degree of Master of Science in Oral Biology June 2013 Naval Postgraduate Dental ...Master’s thesis of Bracken Robert Godfrey Lieutenant Commander, Dental Corps, U.S. Navy has been approved by the Examining Committee for the

A comparison of high-throughput techniques for assaying circadian rhythms in plants.

PubMed

Tindall, Andrew J; Waller, Jade; Greenwood, Mark; Gould, Peter D; Hartwell, James; Hall, Anthony

2015-01-01

Over the last two decades, the development of high-throughput techniques has enabled us to probe the plant circadian clock, a key coordinator of vital biological processes, in ways previously impossible. With the circadian clock increasingly implicated in key fitness and signalling pathways, this has opened up new avenues for understanding plant development and signalling. Our tool-kit has been constantly improving through continual development and novel techniques that increase throughput, reduce costs and allow higher resolution on the cellular and subcellular levels. With circadian assays becoming more accessible and relevant than ever to researchers, in this paper we offer a review of the techniques currently available before considering the horizons in circadian investigation at ever higher throughputs and resolutions.

The circadian coordination of cell biology.

PubMed

Chaix, Amandine; Zarrinpar, Amir; Panda, Satchidananda

2016-10-10

Circadian clocks are cell-autonomous timing mechanisms that organize cell functions in a 24-h periodicity. In mammals, the main circadian oscillator consists of transcription-translation feedback loops composed of transcriptional regulators, enzymes, and scaffolds that generate and sustain daily oscillations of their own transcript and protein levels. The clock components and their targets impart rhythmic functions to many gene products through transcriptional, posttranscriptional, translational, and posttranslational mechanisms. This, in turn, temporally coordinates many signaling pathways, metabolic activity, organelles' structure and functions, as well as the cell cycle and the tissue-specific functions of differentiated cells. When the functions of these circadian oscillators are disrupted by age, environment, or genetic mutation, the temporal coordination of cellular functions is lost, reducing organismal health and fitness. © 2016 Chaix et al.

Light-driven changes in energy metabolism directly entrain the cyanobacterial circadian oscillator

PubMed Central

Rust, Michael J.; Golden, Susan S.; O'Shea, Erin K.

2012-01-01

Circadian clocks are self-sustained biological oscillators that can be entrained by environmental cues. Though this phenomenon has been studied in many organisms, the molecular mechanisms of entrainment remain unclear. Three cyanobacterial proteins and ATP are sufficient to generate oscillations in phosphorylation in vitro. We show that changes in illumination that induce a phase shift in cultured cyanobacteria also cause changes in the ATP/ADP ratio. When these nucleotide changes are simulated in the in vitro oscillator, they cause phase shifts similar to those observed in vivo. Physiological concentrations of ADP inhibit kinase activity in the oscillator and a mathematical model constrained by data shows that this effect is sufficient to quantitatively explain entrainment of the cyanobacterial circadian clock. PMID:21233390

42 CFR 493.1405 - Standard; Laboratory director qualifications.

Code of Federal Regulations, 2010 CFR

2010-10-01

... degree in a chemical, physical, biological, or clinical laboratory science from an accredited institution... Chemistry, the American Board of Bioanalysis, or the American Board of Medical Laboratory Immunology; or (ii...) Have earned a master's degree in a chemical, physical, biological or clinical laboratory science or...

42 CFR 493.1405 - Standard; Laboratory director qualifications.

Code of Federal Regulations, 2012 CFR

2012-10-01

... degree in a chemical, physical, biological, or clinical laboratory science from an accredited institution... Chemistry, the American Board of Bioanalysis, or the American Board of Medical Laboratory Immunology; or (ii...) Have earned a master's degree in a chemical, physical, biological or clinical laboratory science or...

Vasohibin-1 is identified as a master-regulator of endothelial cell apoptosis using gene network analysis

PubMed Central

2013-01-01

Background Apoptosis is a critical process in endothelial cell (EC) biology and pathology, which has been extensively studied at protein level. Numerous gene expression studies of EC apoptosis have also been performed, however few attempts have been made to use gene expression data to identify the molecular relationships and master regulators that underlie EC apoptosis. Therefore, we sought to understand these relationships by generating a Bayesian gene regulatory network (GRN) model. Results ECs were induced to undergo apoptosis using serum withdrawal and followed over a time course in triplicate, using microarrays. When generating the GRN, this EC time course data was supplemented by a library of microarray data from EC treated with siRNAs targeting over 350 signalling molecules. The GRN model proposed Vasohibin-1 (VASH1) as one of the candidate master-regulators of EC apoptosis with numerous downstream mRNAs. To evaluate the role played by VASH1 in EC, we used siRNA to reduce the expression of VASH1. Of 10 mRNAs downstream of VASH1 in the GRN that were examined, 7 were significantly up- or down-regulated in the direction predicted by the GRN.Further supporting an important biological role of VASH1 in EC, targeted reduction of VASH1 mRNA abundance conferred resistance to serum withdrawal-induced EC death. Conclusion We have utilised Bayesian GRN modelling to identify a novel candidate master regulator of EC apoptosis. This study demonstrates how GRN technology can complement traditional methods to hypothesise the regulatory relationships that underlie important biological processes. PMID:23324451

Clocks for the city: circadian differences between forest and city songbirds.

PubMed

Dominoni, D M; Helm, B; Lehmann, M; Dowse, H B; Partecke, J

2013-07-22

To keep pace with progressing urbanization organisms must cope with extensive habitat change. Anthropogenic light and noise have modified differences between day and night, and may thereby interfere with circadian clocks. Urbanized species, such as birds, are known to advance their activity to early morning and night hours. We hypothesized that such modified activity patterns are reflected by properties of the endogenous circadian clock. Using automatic radio-telemetry, we tested this idea by comparing activity patterns of free-living forest and city European blackbirds (Turdus merula). We then recaptured the same individuals and recorded their activity under constant conditions. City birds started their activity earlier and had faster but less robust circadian oscillation of locomotor activity than forest conspecifics. Circadian period length predicted start of activity in the field, and this relationship was mainly explained by fast-paced and early-rising city birds. Although based on only two populations, our findings point to links between city life, chronotype and circadian phenotype in songbirds, and potentially in other organisms that colonize urban habitats, and highlight that urban environments can significantly modify biologically important rhythms in wild organisms.

Codon usage affects the structure and function of the Drosophila circadian clock protein PERIOD.

PubMed

Fu, Jingjing; Murphy, Katherine A; Zhou, Mian; Li, Ying H; Lam, Vu H; Tabuloc, Christine A; Chiu, Joanna C; Liu, Yi

2016-08-01

Codon usage bias is a universal feature of all genomes, but its in vivo biological functions in animal systems are not clear. To investigate the in vivo role of codon usage in animals, we took advantage of the sensitivity and robustness of the Drosophila circadian system. By codon-optimizing parts of Drosophila period (dper), a core clock gene that encodes a critical component of the circadian oscillator, we showed that dper codon usage is important for circadian clock function. Codon optimization of dper resulted in conformational changes of the dPER protein, altered dPER phosphorylation profile and stability, and impaired dPER function in the circadian negative feedback loop, which manifests into changes in molecular rhythmicity and abnormal circadian behavioral output. This study provides an in vivo example that demonstrates the role of codon usage in determining protein structure and function in an animal system. These results suggest a universal mechanism in eukaryotes that uses a codon usage "code" within genetic codons to regulate cotranslational protein folding. © 2016 Fu et al.; Published by Cold Spring Harbor Laboratory Press.

Class IIa histone deacetylases are conserved regulators of circadian function.

PubMed

Fogg, Paul C M; O'Neill, John S; Dobrzycki, Tomasz; Calvert, Shaun; Lord, Emma C; McIntosh, Rebecca L L; Elliott, Christopher J H; Sweeney, Sean T; Hastings, Michael H; Chawla, Sangeeta

2014-12-05

Class IIa histone deacetylases (HDACs) regulate the activity of many transcription factors to influence liver gluconeogenesis and the development of specialized cells, including muscle, neurons, and lymphocytes. Here, we describe a conserved role for class IIa HDACs in sustaining robust circadian behavioral rhythms in Drosophila and cellular rhythms in mammalian cells. In mouse fibroblasts, overexpression of HDAC5 severely disrupts transcriptional rhythms of core clock genes. HDAC5 overexpression decreases BMAL1 acetylation on Lys-537 and pharmacological inhibition of class IIa HDACs increases BMAL1 acetylation. Furthermore, we observe cyclical nucleocytoplasmic shuttling of HDAC5 in mouse fibroblasts that is characteristically circadian. Mutation of the Drosophila homolog HDAC4 impairs locomotor activity rhythms of flies and decreases period mRNA levels. RNAi-mediated knockdown of HDAC4 in Drosophila clock cells also dampens circadian function. Given that the localization of class IIa HDACs is signal-regulated and influenced by Ca(2+) and cAMP signals, our findings offer a mechanism by which extracellular stimuli that generate these signals can feed into the molecular clock machinery. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Effects of Chronotypes on Students' Choice, Participation, and Performance in Online Learning

ERIC Educational Resources Information Center

Luo, Yi; Pan, Rui; Choi, Jea H.; Strobel, Johannes

2018-01-01

Introducing a new theoretical framework of chronotypes (inner biological clock), this article presents a study examining students' choices, participation, and performance in two discussion-heavy online history courses. The study comprised two major parts: a repetition study and an exploratory study. The survey adopted in the repetition study…

The TICKING of the Biological and Tenure Clocks

ERIC Educational Resources Information Center

Valdata, Patricia

2005-01-01

Colleges and universities are arguably among the most enlightened and progressive institutions in America. So when it comes to maternity and career policies, one would expect that they would be at the forefront of similarly progressive accommodation practices. But in fact, colleges and universities have only recently begun to address this issue.…

Circadian clocks in symbiotic corals: the duet between Symbiodinium algae and their coral host.

PubMed

Sorek, Michal; Díaz-Almeyda, Erika M; Medina, Mónica; Levy, Oren

2014-04-01

To date, the association and synchronization between two organismal circadian clocks ticking in parallel as part of a meta-organism (termed a symbiotic association), have rarely been investigated. Reef-building corals exhibit complex rhythmic responses to diurnal, lunar, and annual changes. Understanding circadian, circatidal, and annual regulation in reef-building corals is complicated by the presence of photosynthetic endosymbionts, which have a profound physiochemical influence on the intracellular environment. How corals tune their animal-based clock machinery to respond to external cues while simultaneously responding to internal physiological changes imposed by the symbiont, is not clear. There is insufficient molecular or physiological evidence of the existence of a circadian pacemaker that controls the metabolism, photosynthesis, synchronized mass spawning, and calcification processes in symbiotic corals. In this review, we present current knowledge regarding the animal pacemaker and the symbiotic-algal pacemaker. We examine the evidence from behavioral, physiological, molecular, and evolutionary perspectives. We explain why symbiotic corals are an interesting model with which to study the complexities and evolution of the metazoan circadian clock. We also provide evidence of why the chronobiology of corals is fundamental and extremely important for explaining the biology, physiology, and metabolism of coral reefs. A deeper understanding of these complex issues can help explain coral mass spawning, one of the earth's greatest and most mysterious behavioral phenomena. Copyright © 2014 Elsevier B.V. All rights reserved.

The Circadian Clock Modulates Global Daily Cycles of mRNA Ribosome Loading[OPEN

PubMed Central

Missra, Anamika; Ernest, Ben; Jia, Qidong; Ke, Kenneth

2015-01-01

Circadian control of gene expression is well characterized at the transcriptional level, but little is known about diel or circadian control of translation. Genome-wide translation state profiling of mRNAs in Arabidopsis thaliana seedlings grown in long day was performed to estimate ribosome loading per mRNA. The experiments revealed extensive translational regulation of key biological processes. Notably, translation of mRNAs for ribosomal proteins and mitochondrial respiration peaked at night. Central clock mRNAs are among those subject to fluctuations in ribosome loading. There was no consistent phase relationship between peak translation states and peak transcript levels. The overlay of distinct transcriptional and translational cycles can be expected to alter the waveform of the protein synthesis rate. Plants that constitutively overexpress the clock gene CCA1 showed phase shifts in peak translation, with a 6-h delay from midnight to dawn or from noon to evening being particularly common. Moreover, cycles of ribosome loading that were detected under continuous light in the wild type collapsed in the CCA1 overexpressor. Finally, at the transcript level, the CCA1-ox strain adopted a global pattern of transcript abundance that was broadly correlated with the light-dark environment. Altogether, these data demonstrate that gene-specific diel cycles of ribosome loading are controlled in part by the circadian clock. PMID:26392078

FLOWERING LOCUS C Mediates Natural Variation in the High-Temperature Response of the Arabidopsis Circadian Clock[W

PubMed Central

Edwards, Kieron D.; Anderson, Paul E.; Hall, Anthony; Salathia, Neeraj S.; Locke, James C.W.; Lynn, James R.; Straume, Martin; Smith, James Q.; Millar, Andrew J.

2006-01-01

Temperature compensation contributes to the accuracy of biological timing by preventing circadian rhythms from running more quickly at high than at low temperatures. We previously identified quantitative trait loci (QTL) with temperature-specific effects on the circadian rhythm of leaf movement, including a QTL linked to the transcription factor FLOWERING LOCUS C (FLC). We have now analyzed FLC alleles in near-isogenic lines and induced mutants to eliminate other candidate genes. We showed that FLC lengthened the circadian period specifically at 27°C, contributing to temperature compensation of the circadian clock. Known upstream regulators of FLC expression in flowering time pathways similarly controlled its circadian effect. We sought to identify downstream targets of FLC regulation in the molecular mechanism of the circadian clock using genome-wide analysis to identify FLC-responsive genes and 3503 transcripts controlled by the circadian clock. A Bayesian clustering method based on Fourier coefficients allowed us to discriminate putative regulatory genes. Among rhythmic FLC-responsive genes, transcripts of the transcription factor LUX ARRHYTHMO (LUX) correlated in peak abundance with the circadian period in flc mutants. Mathematical modeling indicated that the modest change in peak LUX RNA abundance was sufficient to cause the period change due to FLC, providing a molecular target for the crosstalk between flowering time pathways and circadian regulation. PMID:16473970

Spatial and temporal transcriptome changes occurring during flower opening and senescence of the ephemeral hibiscus flower, Hibiscus rosa-sinensis.

PubMed

Trivellini, Alice; Cocetta, Giacomo; Hunter, Donald A; Vernieri, Paolo; Ferrante, Antonio

2016-10-01

Flowers are complex systems whose vegetative and sexual structures initiate and die in a synchronous manner. The rapidity of this process varies widely in flowers, with some lasting for months while others such as Hibiscus rosa-sinensis survive for only a day. The genetic regulation underlying these differences is unclear. To identify key genes and pathways that coordinate floral organ senescence of ephemeral flowers, we identified transcripts in H. rosa-sinensis floral organs by 454 sequencing. During development, 2053 transcripts increased and 2135 decreased significantly in abundance. The senescence of the flower was associated with increased abundance of many hydrolytic genes, including aspartic and cysteine proteases, vacuolar processing enzymes, and nucleases. Pathway analysis suggested that transcripts altering significantly in abundance were enriched in functions related to cell wall-, aquaporin-, light/circadian clock-, autophagy-, and calcium-related genes. Finding enrichment in light/circadian clock-related genes fits well with the observation that hibiscus floral development is highly synchronized with light and the hypothesis that ageing/senescence of the flower is orchestrated by a molecular clock. Further study of these genes will provide novel insight into how the molecular clock is able to regulate the timing of programmed cell death in tissues. © The Author 2016. Published by Oxford University Press on behalf of the Society for Experimental Biology.

Antimicrobial capacity of the freshwater planarians against S. aureus is under the control of Timeless

PubMed Central

Tsoumtsa, Landry Laure; Torre, Cedric; Trouplin, Virginie; Coiffard, Benjamin; Gimenez, Gregory; Mege, Jean-Louis; Ghigo, Eric

2017-01-01

ABSTRACT Planarians, which are non-parasitic flatworms, are highly resistant to bacterial infections. To better understand the mechanisms underlying this resistance, we investigated the role of the circadian machinery in the anti-bacterial response of the freshwater planarian Schmidtea mediterranea. We identified Smed-Tim from S. mediterranea as a homolog of the mammalian clock gene Tim. We showed via RNA interference that Smed-Tim is required for the anti-microbial activities of Schmidtea mediterranea against Staphylococcus aureus infection during the light/dark cycle. Indeed, S. aureus infection leads to the expression of Smed-Tim, which in turn promotes Smed-Traf6 and Smed-morn2, but not Smed-p38 MAPK expression, 2 master regulators of planarian anti-microbial responses. PMID:28051908

The daily timing of gene expression and physiology in mammals

PubMed Central

Schibler, Ueli

2007-01-01

Mammalian behavior and physiology undergo daily rhythms that are coordinated by an endogenous circadian timing system. This system has a hierarchical structure, in that a master pacemaker, residing in the suprachiasmatic nucleus of the ventral hypothalamus, synchronizes peripheral oscillators in virtually all body cells. While the basic molecular mechanisms generating the daily rhythms are similar in aIl cells, most clock out-puts are cell-specific. This conclusion is based on genomewide transcriptome profiling studies in several tissues that have revealed hundreds of rhythmically expressed genes. Cyclic gene expression in the various organs governs overt rhythms in behavior and physiology, encompassing sleep-wake cycles, metabolism, xenobiotic detoxification, and cellularproliferation. As a consequence, chronic perturbation of this temporal organization may lead to increased morbidity and reduced lifespan. PMID:17969863

Cell Autonomy and Synchrony of Suprachiasmatic Nucleus Circadian Oscillators

PubMed Central

Mohawk, Jennifer A.; Takahashi, Joseph S.

2013-01-01

The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of the master circadian pacemaker in mammals. The individual cells of the SCN are capable of functioning independently from one another and therefore must form a cohesive circadian network through intercellular coupling. The network properties of the SCN lead to coordination of circadian rhythms among its neurons and neuronal subpopulations. There is increasing evidence for multiple interconnected oscillators within the SCN, and in this Review, we will highlight recent advances in our understanding of the complex organization and function of the cellular and network-level SCN clock. Understanding the way in which synchrony is achieved between cells in the SCN will provide insight into the means by which this important nucleus orchestrates circadian rhythms throughout the organism. PMID:21665298

LORAN-C data reduction at the US Naval Observatory

NASA Technical Reports Server (NTRS)

Chadsey, Harold

1992-01-01

As part of its mission and in cooperation with the U.S. Coast Guard, the U.S. Naval Observatory (USNO) monitors and reports the timing of the LORAN-C chains. The procedures for monitoring and processing the reported values have evolved with advances in monitoring equipment, computer interfaces and PCs. This paper discusses the current standardized procedures used by USNO to sort the raw data according to Group Repetition Interval (GRI) rate, to fit and smooth the data points, and, for chains remotely monitored, to tie the values to the USNO Master Clock. The results of these procedures are the LORAN time of transmission values, as references to UTC(USNO) (Universal Coordinated Time) for all LORAN chains. This information is available to users via USNO publications and the USNO Automated Data Service (ADS).

Systemic Microgravity Response: Utilizing GeneLab to Develop Hypotheses for Spaceflight Risks

NASA Technical Reports Server (NTRS)

Beheshti, Afshin; Fogle, Homer; Galazka, Jonathan; Kidane, Yared; Chakravarty, Kaushik; Berrios, Daniel C.; Costes, Sylvain V.

2017-01-01

Biological risks associated with microgravity is a major concern for space travel. Although determination of risk has been a focus for NASA research, data examining systemic (i.e., multi- or pan-tissue) responses to space flight are sparse. The overall goal of our work is to identify potential master regulators responsible for such responses to microgravity conditions. To do this we utilized the NASA GeneLab database which contains a wide array of omics experiments, including data from: 1) different flight conditions (space shuttle (STS) missions vs. International Space Station (ISS); 2) different tissues; and 3) different types of assays that measure epigenetic, transcriptional, and protein expression changes. We have performed meta-analysis identifying potential master regulators involved with systemic responses to microgravity. The analysis used 7 different murine and rat data sets, examining the following tissues: liver, kidney, adrenal gland, thymus, mammary gland, skin, and skeletal muscle (soleus, extensor digitorum longus, tibialis anterior, quadriceps, and gastrocnemius). Using a systems biology approach, we were able to determine that p53 and immune related pathways appear central to pan-tissue microgravity responses. Evidence for a universal response in the form of consistency of change across tissues in regulatory pathways was observed in both STS and ISS experiments with varying durations; while degree of change in expression of these master regulators varied across species and strain, some change in these master regulators was universally observed. Interestingly, certain skeletal muscle (gastrocnemius and soleus) show an overall down-regulation in these genes, while in other types (extensor digitorum longus, tibialis anterior and quadriceps) they are up-regulated, suggesting certain muscle tissues may be compensating for atrophy responses caused by microgravity. Studying these organtissue-specific perturbations in molecular signaling networks, we demonstrate the value of GeneLab in characterizing potential master regulators associated with biological risks for spaceflight.

Control of Stochastic Master Equation Models of Genetic Regulatory Networks by Approximating Their Average Behavior

NASA Astrophysics Data System (ADS)

Umut Caglar, Mehmet; Pal, Ranadip

2010-10-01

The central dogma of molecular biology states that ``information cannot be transferred back from protein to either protein or nucleic acid.'' However, this assumption is not exactly correct in most of the cases. There are a lot of feedback loops and interactions between different levels of systems. These types of interactions are hard to analyze due to the lack of data in the cellular level and probabilistic nature of interactions. Probabilistic models like Stochastic Master Equation (SME) or deterministic models like differential equations (DE) can be used to analyze these types of interactions. SME models based on chemical master equation (CME) can provide detailed representation of genetic regulatory system, but their use is restricted by the large data requirements and computational costs of calculations. The differential equations models on the other hand, have low calculation costs and much more adequate to generate control procedures on the system; but they are not adequate to investigate the probabilistic nature of interactions. In this work the success of the mapping between SME and DE is analyzed, and the success of a control policy generated by DE model with respect to SME model is examined. Index Terms--- Stochastic Master Equation models, Differential Equation Models, Control Policy Design, Systems biology

BOTOX and our tax dollars at work

USDA-ARS?s Scientific Manuscript database

This seminar is intended for Masters level graduate students in biology at the University of the Pacific. Topics of the seminar will include information on USDA-ARS research at the Albany location and general background on botulism and neurotoxin biology. In addition, the following FCR unit botulinu...

In Vitro Bioluminescence Assay to Characterize Circadian Rhythm in Mammary Epithelial Cells.

PubMed

Fang, Mingzhu; Kang, Hwan-Goo; Park, Youngil; Estrella, Brian; Zarbl, Helmut

2017-09-28

The circadian rhythm is a fundamental physiological process present in all organisms that regulates biological processes ranging from gene expression to sleep behavior. In vertebrates, circadian rhythm is controlled by a molecular oscillator that functions in both the suprachiasmatic nucleus (SCN; central pacemaker) and individual cells comprising most peripheral tissues. More importantly, disruption of circadian rhythm by exposure to light-at-night, environmental stressors and/or toxicants is associated with increased risk of chronic diseases and aging. The ability to identify agents that can disrupt central and/or peripheral biological clocks, and agents that can prevent or mitigate the effects of circadian disruption, has significant implications for prevention of chronic diseases. Although rodent models can be used to identify exposures and agents that induce or prevent/mitigate circadian disruption, these experiments require large numbers of animals. In vivo studies also require significant resources and infrastructure, and require researchers to work all night. Thus, there is an urgent need for a cell-type appropriate in vitro system to screen for environmental circadian disruptors and enhancers in cell types from different organs and disease states. We constructed a vector that drives transcription of the destabilized luciferase in eukaryotic cells under the control of the human PERIOD 2 gene promoter. This circadian reporter construct was stably transfected into human mammary epithelial cells, and circadian responsive reporter cells were selected to develop the in vitro bioluminescence assay. Here, we present a detailed protocol to establish and validate the assay. We further provide details for proof of concept experiments demonstrating the ability of our in vitro assay to recapitulate the in vivo effects of various chemicals on the cellular biological clock. The results indicate that the assay can be adapted to a variety of cell types to screen for both environmental disruptors and chemopreventive enhancers of circadian clocks.

Circadian rhythmicity and light sensitivity of the zebrafish brain.

PubMed

Moore, Helen A; Whitmore, David

2014-01-01

Traditionally, circadian clocks have been thought of as a neurobiological phenomenon. This view changed somewhat over recent years with the discovery of peripheral tissue circadian oscillators. In mammals, however, the suprachiasmatic nucleus (SCN) in the hypothalamus still retains the critical role of a central synchronizer of biological timing. Zebrafish, in contrast, have always reflected a more highly decentralized level of clock organization, as individual cells and tissues contain directly light responsive circadian pacemakers. As a consequence, clock function in the zebrafish brain has remained largely unexplored, and the precise organization of rhythmic and light-sensitive neurons within the brain is unknown. To address this issue, we used the period3 (per3)-luciferase transgenic zebrafish to confirm that multiple brain regions contain endogenous circadian oscillators that are directly light responsive. In addition, in situ hybridization revealed localised neural expression of several rhythmic and light responsive clock genes, including per3, cryptochrome1a (cry1a) and per2. Adult brain nuclei showing significant clock gene expression include the teleost equivalent of the SCN, as well as numerous hypothalamic nuclei, the periventricular grey zone (PGZ) of the optic tectum, and granular cells of the rhombencephalon. To further investigate the light sensitive properties of neurons, expression of c-fos, a marker for neuronal activity, was examined. c-fos mRNA was upregulated in response to changing light conditions in different nuclei within the zebrafish brain. Furthermore, under constant dark (DD) conditions, c-fos shows a significant circadian oscillation. Taken together, these results show that there are numerous areas of the zebrafish central nervous system, which contain deep brain photoreceptors and directly light-entrainable circadian pacemakers. However, there are also multiple brain nuclei, which possess neither, demonstrating a degree of pacemaker complexity that was not previously appreciated.

Circadian Rhythmicity and Light Sensitivity of the Zebrafish Brain

PubMed Central

Moore, Helen A.; Whitmore, David

2014-01-01

Traditionally, circadian clocks have been thought of as a neurobiological phenomenon. This view changed somewhat over recent years with the discovery of peripheral tissue circadian oscillators. In mammals, however, the suprachiasmatic nucleus (SCN) in the hypothalamus still retains the critical role of a central synchronizer of biological timing. Zebrafish, in contrast, have always reflected a more highly decentralized level of clock organization, as individual cells and tissues contain directly light responsive circadian pacemakers. As a consequence, clock function in the zebrafish brain has remained largely unexplored, and the precise organization of rhythmic and light-sensitive neurons within the brain is unknown. To address this issue, we used the period3 (per3)-luciferase transgenic zebrafish to confirm that multiple brain regions contain endogenous circadian oscillators that are directly light responsive. In addition, in situ hybridization revealed localised neural expression of several rhythmic and light responsive clock genes, including per3, cryptochrome1a (cry1a) and per2. Adult brain nuclei showing significant clock gene expression include the teleost equivalent of the SCN, as well as numerous hypothalamic nuclei, the periventricular grey zone (PGZ) of the optic tectum, and granular cells of the rhombencephalon. To further investigate the light sensitive properties of neurons, expression of c-fos, a marker for neuronal activity, was examined. c-fos mRNA was upregulated in response to changing light conditions in different nuclei within the zebrafish brain. Furthermore, under constant dark (DD) conditions, c-fos shows a significant circadian oscillation. Taken together, these results show that there are numerous areas of the zebrafish central nervous system, which contain deep brain photoreceptors and directly light-entrainable circadian pacemakers. However, there are also multiple brain nuclei, which possess neither, demonstrating a degree of pacemaker complexity that was not previously appreciated. PMID:24465943

Modeling Pharmacological Clock and Memory Patterns of Interval Timing in a Striatal Beat-Frequency Model with Realistic, Noisy Neurons

PubMed Central

Oprisan, Sorinel A.; Buhusi, Catalin V.

2011-01-01

In most species, the capability of perceiving and using the passage of time in the seconds-to-minutes range (interval timing) is not only accurate but also scalar: errors in time estimation are linearly related to the estimated duration. The ubiquity of scalar timing extends over behavioral, lesion, and pharmacological manipulations. For example, in mammals, dopaminergic drugs induce an immediate, scalar change in the perceived time (clock pattern), whereas cholinergic drugs induce a gradual, scalar change in perceived time (memory pattern). How do these properties emerge from unreliable, noisy neurons firing in the milliseconds range? Neurobiological information relative to the brain circuits involved in interval timing provide support for an striatal beat frequency (SBF) model, in which time is coded by the coincidental activation of striatal spiny neurons by cortical neural oscillators. While biologically plausible, the impracticality of perfect oscillators, or their lack thereof, questions this mechanism in a brain with noisy neurons. We explored the computational mechanisms required for the clock and memory patterns in an SBF model with biophysically realistic and noisy Morris–Lecar neurons (SBF–ML). Under the assumption that dopaminergic drugs modulate the firing frequency of cortical oscillators, and that cholinergic drugs modulate the memory representation of the criterion time, we show that our SBF–ML model can reproduce the pharmacological clock and memory patterns observed in the literature. Numerical results also indicate that parameter variability (noise) – which is ubiquitous in the form of small fluctuations in the intrinsic frequencies of neural oscillators within and between trials, and in the errors in recording/retrieving stored information related to criterion time – seems to be critical for the time-scale invariance of the clock and memory patterns. PMID:21977014

What time is it? Deep learning approaches for circadian rhythms.

PubMed

Agostinelli, Forest; Ceglia, Nicholas; Shahbaba, Babak; Sassone-Corsi, Paolo; Baldi, Pierre

2016-06-15

Circadian rhythms date back to the origins of life, are found in virtually every species and every cell, and play fundamental roles in functions ranging from metabolism to cognition. Modern high-throughput technologies allow the measurement of concentrations of transcripts, metabolites and other species along the circadian cycle creating novel computational challenges and opportunities, including the problems of inferring whether a given species oscillate in circadian fashion or not, and inferring the time at which a set of measurements was taken. We first curate several large synthetic and biological time series datasets containing labels for both periodic and aperiodic signals. We then use deep learning methods to develop and train BIO_CYCLE, a system to robustly estimate which signals are periodic in high-throughput circadian experiments, producing estimates of amplitudes, periods, phases, as well as several statistical significance measures. Using the curated data, BIO_CYCLE is compared to other approaches and shown to achieve state-of-the-art performance across multiple metrics. We then use deep learning methods to develop and train BIO_CLOCK to robustly estimate the time at which a particular single-time-point transcriptomic experiment was carried. In most cases, BIO_CLOCK can reliably predict time, within approximately 1 h, using the expression levels of only a small number of core clock genes. BIO_CLOCK is shown to work reasonably well across tissue types, and often with only small degradation across conditions. BIO_CLOCK is used to annotate most mouse experiments found in the GEO database with an inferred time stamp. All data and software are publicly available on the CircadiOmics web portal: circadiomics.igb.uci.edu/ fagostin@uci.edu or pfbaldi@uci.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

Repeated psychosocial stress at night affects the circadian activity rhythm of male mice.

PubMed

Bartlang, Manuela S; Oster, Henrik; Helfrich-Förster, Charlotte

2015-06-01

We have recently shown that molecular rhythms in the murine suprachiasmatic nucleus (SCN) are affected by repeated social defeat (SD) during the dark/active phase (social defeat dark [SDD]), while repeated SD during the light/inactive phase (social defeat light [SDL]) had no influence on PERIOD2::LUCIFERASE explant rhythms in the SCN. Here we assessed the effects of the same stress paradigm by in vivo biotelemetry on 2 output rhythms of the circadian clock (i.e., activity and core body temperature) in wild-type (WT) and clock-deficient Period (Per)1/2 double-mutant mice during and following repeated SDL and SDD. In general, stress had more pronounced effects on activity compared to body temperature rhythms. Throughout the SD procedure, activity and body temperature were markedly increased during the 2 h of stressor exposure at zeitgeber time (ZT) 1 to ZT3 (SDL mice) and ZT13 to ZT15 (SDD mice), which was compensated by decreased activity during the remaining dark phase (SDL and SDD mice) and light phase (SDL mice) in both genotypes. Considerable differences in the activity between SDL and SDD mice were seen in the poststress period. SDD mice exhibited a reduced first activity bout at ZT13, delayed activity onset, and, consequently, a more narrow activity bandwidth compared with single-housed control (SHC) and SDL mice. Given that this effect was absent in Per1/2 mutant SDD mice and persisted under constant darkness conditions in SDD WT mice, it suggests an involvement of the endogenous clock. Taken together, the present findings demonstrate that SDD has long-lasting consequences for the functional output of the biological clock that, at least in part, appear to depend on the clock genes Per1 and Per2. © 2015 The Author(s).

What time is it? Deep learning approaches for circadian rhythms

PubMed Central

Agostinelli, Forest; Ceglia, Nicholas; Shahbaba, Babak; Sassone-Corsi, Paolo; Baldi, Pierre

2016-01-01

Motivation: Circadian rhythms date back to the origins of life, are found in virtually every species and every cell, and play fundamental roles in functions ranging from metabolism to cognition. Modern high-throughput technologies allow the measurement of concentrations of transcripts, metabolites and other species along the circadian cycle creating novel computational challenges and opportunities, including the problems of inferring whether a given species oscillate in circadian fashion or not, and inferring the time at which a set of measurements was taken. Results: We first curate several large synthetic and biological time series datasets containing labels for both periodic and aperiodic signals. We then use deep learning methods to develop and train BIO_CYCLE, a system to robustly estimate which signals are periodic in high-throughput circadian experiments, producing estimates of amplitudes, periods, phases, as well as several statistical significance measures. Using the curated data, BIO_CYCLE is compared to other approaches and shown to achieve state-of-the-art performance across multiple metrics. We then use deep learning methods to develop and train BIO_CLOCK to robustly estimate the time at which a particular single-time-point transcriptomic experiment was carried. In most cases, BIO_CLOCK can reliably predict time, within approximately 1 h, using the expression levels of only a small number of core clock genes. BIO_CLOCK is shown to work reasonably well across tissue types, and often with only small degradation across conditions. BIO_CLOCK is used to annotate most mouse experiments found in the GEO database with an inferred time stamp. Availability and Implementation: All data and software are publicly available on the CircadiOmics web portal: circadiomics.igb.uci.edu/. Contacts: fagostin@uci.edu or pfbaldi@uci.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:27307647

Versatile function of the circadian protein CIPC as a regulator of Erk activation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matsunaga, Ryota; Nishino, Tasuku; Yokoyama, Atsushi

2016-01-15

The CLOCK-interacting protein, Circadian (CIPC), has been identified as an additional negative-feedback regulator of the circadian clock. However, recent study on CIPC knockout mice has shown that CIPC is not critically required for basic circadian clock function, suggesting other unknown biological roles for CIPC. In this study, we focused on the cell cycle dependent nuclear-cytoplasmic shuttling function of CIPC and on identifying its binding proteins. Lys186 and 187 were identified as the essential amino acid residues within the nuclear localization signal (NLS) of CIPC. We identified CIPC-binding proteins such as the multifunctional enzyme CAD protein (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase,more » and dihydroorotase), which is a key enzyme for de novo pyrimidine synthesis. Compared to control cells, HEK293 cells overexpressing wild-type CIPC showed suppressed cell proliferation and retardation of cell cycle. We also found that PMA-induced Erk activation was inhibited with expression of wild-type CIPC. In contrast, the NLS mutant of CIPC, which reduced the ability of CIPC to translocate into the nucleus, did not exhibit these biological effects. Since CAD and Erk have significant roles in cell proliferation and cell cycle, CIPC may work as a cell cycle regulator by interacting with these binding proteins. - Highlights: • CIPC is a cell cycle dependent nuclear-cytoplasmic shuttling protein. • K186 and 187are the essential amino acid residues within the NLS of CIPC. • CAD was identified as a novel CIPC-binding protein. • CIPC might regulate the activity and translocation of CAD in the cells.« less

Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness

PubMed Central

Chang, Anne-Marie; Aeschbach, Daniel; Duffy, Jeanne F.; Czeisler, Charles A.

2015-01-01

In the past 50 y, there has been a decline in average sleep duration and quality, with adverse consequences on general health. A representative survey of 1,508 American adults recently revealed that 90% of Americans used some type of electronics at least a few nights per week within 1 h before bedtime. Mounting evidence from countries around the world shows the negative impact of such technology use on sleep. This negative impact on sleep may be due to the short-wavelength–enriched light emitted by these electronic devices, given that artificial-light exposure has been shown experimentally to produce alerting effects, suppress melatonin, and phase-shift the biological clock. A few reports have shown that these devices suppress melatonin levels, but little is known about the effects on circadian phase or the following sleep episode, exposing a substantial gap in our knowledge of how this increasingly popular technology affects sleep. Here we compare the biological effects of reading an electronic book on a light-emitting device (LE-eBook) with reading a printed book in the hours before bedtime. Participants reading an LE-eBook took longer to fall asleep and had reduced evening sleepiness, reduced melatonin secretion, later timing of their circadian clock, and reduced next-morning alertness than when reading a printed book. These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety. PMID:25535358

Lunar Phase Modulates Circadian Gene Expression Cycles in the Broadcast Spawning Coral Acropora millepora.

PubMed

Brady, Aisling K; Willis, Bette L; Harder, Lawrence D; Vize, Peter D

2016-04-01

Many broadcast spawning corals in multiple reef regions release their gametes with incredible temporal precision just once per year, using the lunar cycle to set the night of spawning. Moonlight, rather than tides or other lunar-regulated processes, is thought to be the proximate factor responsible for linking the night of spawning to the phase of the Moon. We compared patterns of gene expression among colonies of the broadcast spawning coral Acropora millepora at different phases of the lunar cycle, and when they were maintained under one of three experimentally simulated lunar lighting treatments: i) lunar lighting conditions matching those on the reef, or lunar patterns mimicking either ii) constant full Moon conditions, or iii) constant new Moon conditions. Normal lunar illumination was found to shift both the level and timing of clock gene transcription cycles between new and full moons, with the peak hour of expression for a number of genes occurring earlier in the evening under a new Moon when compared to a full Moon. When the normal lunar cycle is replaced with nighttime patterns equivalent to either a full Moon or a new Moon every evening, the normal monthlong changes in the level of expression are destroyed for most genes. In combination, these results indicate that daily changes in moonlight that occur over the lunar cycle are essential for maintaining normal lunar periodicity of clock gene transcription, and this may play a role in regulating spawn timing. These data also show that low levels of light pollution may have an impact on coral biological clocks. © 2016 Marine Biological Laboratory.

Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness.

PubMed

Chang, Anne-Marie; Aeschbach, Daniel; Duffy, Jeanne F; Czeisler, Charles A

2015-01-27

In the past 50 y, there has been a decline in average sleep duration and quality, with adverse consequences on general health. A representative survey of 1,508 American adults recently revealed that 90% of Americans used some type of electronics at least a few nights per week within 1 h before bedtime. Mounting evidence from countries around the world shows the negative impact of such technology use on sleep. This negative impact on sleep may be due to the short-wavelength-enriched light emitted by these electronic devices, given that artificial-light exposure has been shown experimentally to produce alerting effects, suppress melatonin, and phase-shift the biological clock. A few reports have shown that these devices suppress melatonin levels, but little is known about the effects on circadian phase or the following sleep episode, exposing a substantial gap in our knowledge of how this increasingly popular technology affects sleep. Here we compare the biological effects of reading an electronic book on a light-emitting device (LE-eBook) with reading a printed book in the hours before bedtime. Participants reading an LE-eBook took longer to fall asleep and had reduced evening sleepiness, reduced melatonin secretion, later timing of their circadian clock, and reduced next-morning alertness than when reading a printed book. These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety.

Chronobiology of deep-water decapod crustaceans on continental margins.

PubMed

Aguzzi, Jacopo; Company, Joan B

2010-01-01

Species have evolved biological rhythms in behaviour and physiology with a 24-h periodicity in order to increase their fitness, anticipating the onset of unfavourable habitat conditions. In marine organisms inhabiting deep-water continental margins (i.e. the submerged outer edges of continents), day-night activity rhythms are often referred to in three ways: vertical water column migrations (i.e. pelagic), horizontal displacements within benthic boundary layer of the continental margin, along bathymetric gradients (i.e. nektobenthic), and endobenthic movements (i.e. rhythmic emergence from the substrate). Many studies have been conducted on crustacean decapods that migrate vertically in the water column, but much less information is available for other endobenthic and nektobenthic species. Also, the types of displacement and major life habits of most marine species are still largely unknown, especially in deep-water continental margins, where steep clines in habitat factors (i.e. light intensity and its spectral quality, sediment characteristics, and hydrography) take place. This is the result of technical difficulties in performing temporally scheduled sampling and laboratory testing on living specimens. According to this scenario, there are several major issues that still need extensive research in deep-water crustacean decapods. First, the regulation of their behaviour and physiology by a biological clock is almost unknown compared to data for coastal species that are easily accessible to direct observation and sampling. Second, biological rhythms may change at different life stages (i.e. size-related variations) or at different moments of the reproductive cycle (e.g. at egg-bearing) based on different intra- and interspecific interactions. Third, there is still a major lack of knowledge on the links that exist among the observed bathymetric distributions of species and selected autoecological traits that are controlled by their biological clock, such as the diel rhythm of behaviour. Species evolved in a photically variable environment where intra- and inter-specific interactions change along with the community structure over 24 h. Accordingly, the regulation of their biology through a biological clock may be the major evolutionary constraint that is responsible for their reported bathymetric distributions. In this review, our aim is to propose a series of innovative guidelines for a discussion of the modulation of behavioural rhythms of adult decapod crustaceans, focusing on the deep waters of the continental margin areas of the Mediterranean as a paradigm for other marine zones of the world. Copyright © 2010 Elsevier Ltd. All rights reserved.

New On-board Microprocessors

NASA Astrophysics Data System (ADS)

Weigand, R.

Two new processor devices have been developed for the use on board of spacecrafts. An 8-bit 8032-microcontroller targets typical controlling applications in instruments and sub-systems, or could be used as a main processor on small satellites, whereas the LEON 32-bit SPARC processor can be used for high performance controlling and data processing tasks. The ADV80S32 is fully compliant to the Intel 80x1 architecture and instruction set, extended by additional peripherals, 512 bytes on-chip RAM and a bootstrap PROM, which allows downloading the application software using the CCSDS PacketWire pro- tocol. The memory controller provides a de-multiplexed address/data bus, and allows to access up to 16 MB data and 8 MB program RAM. The peripherals have been de- signed for the specific needs of a spacecraft, such as serial interfaces compatible to RS232, PacketWire and TTC-B-01, counters/timers for extended duration and a CRC calculation unit accelerating the CCSDS TM/TC protocol. The 0.5 um Atmel manu- facturing technology (MG2RT) provides latch-up and total dose immunity; SEU fault immunity is implemented by using SEU hardened Flip-Flops and EDAC protection of internal and external memories. The maximum clock frequency of 20 MHz allows a processing power of 3 MIPS. Engineering samples are available. For SW develop- ment, various SW packages for the 8051 architecture are on the market. The LEON processor implements a 32-bit SPARC V8 architecture, including all the multiply and divide instructions, complemented by a floating-point unit (FPU). It includes several standard peripherals, such as timers/watchdog, interrupt controller, UARTs, parallel I/Os and a memory controller, allowing to use 8, 16 and 32 bit PROM, SRAM or memory mapped I/O. With on-chip separate instruction and data caches, almost one instruction per clock cycle can be reached in some applications. A 33-MHz 32-bit PCI master/target interface and a PCI arbiter allow operating the device in a plug-in card (for SW development on PC etc.), or to consider using it as a PCI master controller in an on-board system. Advanced SEU fault tolerance is in- troduced by design, using triple modular redundancy (TMR) flip-flops for all registers and EDAC protection for all memories. The device will be manufactured in a radia- tion hard Atmel 0.25 um technology, targeting 100 MHz processor clock frequency. The non fault-tolerant LEON processor VHDL model is available as free source code, and the SPARC architecture is a well-known industry standard. Therefore, know-how, software tools and operating systems are widely available.

77 FR 22282 - Draft Guidelines on Biologics Quality Monitoring: Testing for the Detection of Mycoplasma...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-04-13

...] Draft Guidelines on Biologics Quality Monitoring: Testing for the Detection of Mycoplasma Contamination... Detection of Mycoplasma Contamination.'' This draft guideline identifies stages of manufacture where... contamination. Because the guidelines apply to final product and master seed/cell testing in veterinary vaccines...

Dim light at night disturbs the daily sleep-wake cycle in the rat.

PubMed

Stenvers, Dirk Jan; van Dorp, Rick; Foppen, Ewout; Mendoza, Jorge; Opperhuizen, Anne-Loes; Fliers, Eric; Bisschop, Peter H; Meijer, Johanna H; Kalsbeek, Andries; Deboer, Tom

2016-10-20

Exposure to light at night (LAN) is associated with insomnia in humans. Light provides the main input to the master clock in the hypothalamic suprachiasmatic nucleus (SCN) that coordinates the sleep-wake cycle. We aimed to develop a rodent model for the effects of LAN on sleep. Therefore, we exposed male Wistar rats to either a 12 h light (150-200lux):12 h dark (LD) schedule or a 12 h light (150-200 lux):12 h dim white light (5 lux) (LDim) schedule. LDim acutely decreased the amplitude of daily rhythms of REM and NREM sleep, with a further decrease over the following days. LDim diminished the rhythms of 1) the circadian 16-19 Hz frequency domain within the NREM sleep EEG, and 2) SCN clock gene expression. LDim also induced internal desynchronization in locomotor activity by introducing a free running rhythm with a period of ~25 h next to the entrained 24 h rhythm. LDim did not affect body weight or glucose tolerance. In conclusion, we introduce the first rodent model for disturbed circadian control of sleep due to LAN. We show that internal desynchronization is possible in a 24 h L:D cycle which suggests that a similar desynchronization may explain the association between LAN and human insomnia.

Dim light at night disturbs the daily sleep-wake cycle in the rat

PubMed Central

Jan Stenvers, Dirk; van Dorp, Rick; Foppen, Ewout; Mendoza, Jorge; Opperhuizen, Anne-Loes; Fliers, Eric; Bisschop, Peter H.; Meijer, Johanna H.; Kalsbeek, Andries; Deboer, Tom

2016-01-01

Exposure to light at night (LAN) is associated with insomnia in humans. Light provides the main input to the master clock in the hypothalamic suprachiasmatic nucleus (SCN) that coordinates the sleep-wake cycle. We aimed to develop a rodent model for the effects of LAN on sleep. Therefore, we exposed male Wistar rats to either a 12 h light (150–200lux):12 h dark (LD) schedule or a 12 h light (150–200 lux):12 h dim white light (5 lux) (LDim) schedule. LDim acutely decreased the amplitude of daily rhythms of REM and NREM sleep, with a further decrease over the following days. LDim diminished the rhythms of 1) the circadian 16–19 Hz frequency domain within the NREM sleep EEG, and 2) SCN clock gene expression. LDim also induced internal desynchronization in locomotor activity by introducing a free running rhythm with a period of ~25 h next to the entrained 24 h rhythm. LDim did not affect body weight or glucose tolerance. In conclusion, we introduce the first rodent model for disturbed circadian control of sleep due to LAN. We show that internal desynchronization is possible in a 24 h L:D cycle which suggests that a similar desynchronization may explain the association between LAN and human insomnia. PMID:27762290

The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity.

PubMed

Franken, P; Lopez-Molina, L; Marcacci, L; Schibler, U; Tafti, M

2000-01-15

Albumin D-binding protein (DBP) is a PAR leucine zipper transcription factor that is expressed according to a robust circadian rhythm in the suprachiasmatic nuclei, harboring the circadian master clock, and in most peripheral tissues. Mice lacking DBP display a shorter circadian period in locomotor activity and are less active. Thus, although DBP is not essential for circadian rhythm generation, it does modulate important clock outputs. We studied the role of DBP in the circadian and homeostatic aspects of sleep regulation by comparing DBP deficient mice (dbp-/-) with their isogenic controls (dbp+/+) under light-dark (LD) and constant-dark (DD) baseline conditions, as well as after sleep loss. Whereas total sleep duration was similar in both genotypes, the amplitude of the circadian modulation of sleep time, as well as the consolidation of sleep episodes, was reduced in dbp-/- under both LD and DD conditions. Quantitative EEG analysis demonstrated a marked reduction in the amplitude of the sleep-wake-dependent changes in slow-wave sleep delta power and an increase in hippocampal theta peak frequency in dbp-/- mice. The sleep deprivation-induced compensatory rebound of EEG delta power was similar in both genotypes. In contrast, the rebound in paradoxical sleep was significant in dbp+/+ mice only. It is concluded that the transcriptional regulatory protein DBP modulates circadian and homeostatic aspects of sleep regulation.

Two-Photon Excited Fluorescence from Biological Aerosol Particles

DTIC Science & Technology

2010-09-29

in material damage. We overcame these limitations by building a band-limited Yb-doped fiber laser with no dispersion compensation [9], as the master...master oscillator was an all-normal- dispersion Yb-doped fiber laser [9], followed by high- dispersion fiber for stretching the pulses, a single-mode...of ~670 fs in duration, and its expected transform-limited pulse width for a normal- dispersion laser with this spectral width would be ~454 fs [10

A novel statistical approach for identification of the master regulator transcription factor.

PubMed

Sikdar, Sinjini; Datta, Susmita

2017-02-02

Transcription factors are known to play key roles in carcinogenesis and therefore, are gaining popularity as potential therapeutic targets in drug development. A 'master regulator' transcription factor often appears to control most of the regulatory activities of the other transcription factors and the associated genes. This 'master regulator' transcription factor is at the top of the hierarchy of the transcriptomic regulation. Therefore, it is important to identify and target the master regulator transcription factor for proper understanding of the associated disease process and identifying the best therapeutic option. We present a novel two-step computational approach for identification of master regulator transcription factor in a genome. At the first step of our method we test whether there exists any master regulator transcription factor in the system. We evaluate the concordance of two ranked lists of transcription factors using a statistical measure. In case the concordance measure is statistically significant, we conclude that there is a master regulator. At the second step, our method identifies the master regulator transcription factor, if there exists one. In the simulation scenario, our method performs reasonably well in validating the existence of a master regulator when the number of subjects in each treatment group is reasonably large. In application to two real datasets, our method ensures the existence of master regulators and identifies biologically meaningful master regulators. An R code for implementing our method in a sample test data can be found in http://www.somnathdatta.org/software . We have developed a screening method of identifying the 'master regulator' transcription factor just using only the gene expression data. Understanding the regulatory structure and finding the master regulator help narrowing the search space for identifying biomarkers for complex diseases such as cancer. In addition to identifying the master regulator our method provides an overview of the regulatory structure of the transcription factors which control the global gene expression profiles and consequently the cell functioning.

Chemical chronobiology: Toward drugs manipulating time.

PubMed

Wallach, Thomas; Kramer, Achim

2015-06-22

Circadian clocks are endogenous timing systems orchestrating the daily regulation of a huge variety of physiological, metabolic and behavioral processes. These clocks are important for health - in mammals, their disruption leads to a diverse number of pathologies. While genetic and biochemical approaches largely uncovered the molecular bases of circadian rhythm generation, chemical biology strategies targeting the circadian oscillator by small chemical compounds are increasingly developed. Here, we review the recent progress in the identification of small molecules modulating circadian rhythms. We focus on high-throughput screening approaches using circadian bioluminescence reporter cell lines as well as describe alternative mechanistic screens. Furthermore, we discuss the potential for chemical optimization of small molecule ligands with regard to the recent progress in structural chronobiology. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth.

PubMed

Han, Yuyan; Meng, Fanyin; Venter, Julie; Wu, Nan; Wan, Ying; Standeford, Holly; Francis, Heather; Meininger, Cynthia; Greene, John; Trzeciakowski, Jerome P; Ehrlich, Laurent; Glaser, Shannon; Alpini, Gianfranco

2016-06-01

Disruption of circadian rhythm is associated with cancer development and progression. MicroRNAs (miRNAs) are a class of small non-coding RNAs that trigger mRNA translation inhibition. We aimed to evaluate the role of Per1 and related miRNAs in cholangiocarcinoma growth. The expression of clock genes was evaluated in human cholangiocarcinoma tissue arrays and cholangiocarcinoma lines. The rhythmic expression of clock genes was evaluated in cholangiocarcinoma cells and H69 (non-malignant cholangiocytes) by qPCR. We measured cell proliferation, cell cycle and apoptosis in Mz-ChA-1 cells after Per1 overexpression. We examined tumor growth in vivo after injection of Per1 overexpressing cells. We verified miRNAs that targets Per1. The circadian rhythm of miR-34a was evaluated in cholangiocarcinoma and H69 cells. We evaluated cell proliferation, apoptosis and invasion after inhibition of miR-34a in vitro, and the potential molecular mechanisms by mRNA profiling after overexpression of Per1. Expression of Per1 was decreased in cholangiocarcinoma. The circadian rhythm of Per1 expression was lost in cholangiocarcinoma cells. Decreased cell proliferation, lower G2/M arrest, and enhanced apoptosis were shown in Per1 overexpressing cells. An in vivo study revealed decreased tumor growth, decreased proliferation, angiogenesis and metastasis after overexpressing Per1. Per1 was verified as a target of miR-34a. miR-34a was rhythmically expressed in cholangiocarcinoma cells and H69. The inhibition of miR-34a decreased proliferation, migration and invasion in cholangiocarcinoma cells. mRNA profiling has shown that overexpression of Per1 inhibits cell growth through regulation of multiple cancer-related pathways, such as cell cycle, cell growth and apoptosis pathways. Disruption of circadian rhythms of clock genes contribute to the malignant phenotypes of human cholangiocarcinoma. The current study is about how biological clock and its regulators affect the bile duct tumor growth. The disruption of biological clock has a negative impact in different cancers. Per1 is a gene that is involved in maintaining the biological clock and show 24h oscillation. Reduced levels of Per1 and disruption of 24h circadian rhythm was found in bile duct cancer cells. Therefore, a genetic modified bile duct cancer cells was created. It has a higher level of Per1 expression and partially recovered circadian rhythm. Those genetic modified cells also displayed slower cell growth or higher rate of cell death. We also used mice model that lack of immune system to show that our genetic modified bile duct cells form smaller tumor. In addition, we tried to see how Per1 is communicating with other genes in regarding of controlling the tumor growth. We found Per1 is regulated by microRNA-34a, a small non-coding RNA that directly binds to genes and inhibit gene expression. Decreased level of miR-34a has also significantly reduced tumor growth through controlling the cell growth and cell death balance. Therefore bile duct cancer patients may be treated with miR-34a inhibitor or Per1 stimulator in the future. Published by Elsevier B.V.

Stochastic model simulation using Kronecker product analysis and Zassenhaus formula approximation.

PubMed

Caglar, Mehmet Umut; Pal, Ranadip

2013-01-01

Probabilistic Models are regularly applied in Genetic Regulatory Network modeling to capture the stochastic behavior observed in the generation of biological entities such as mRNA or proteins. Several approaches including Stochastic Master Equations and Probabilistic Boolean Networks have been proposed to model the stochastic behavior in genetic regulatory networks. It is generally accepted that Stochastic Master Equation is a fundamental model that can describe the system being investigated in fine detail, but the application of this model is computationally enormously expensive. On the other hand, Probabilistic Boolean Network captures only the coarse-scale stochastic properties of the system without modeling the detailed interactions. We propose a new approximation of the stochastic master equation model that is able to capture the finer details of the modeled system including bistabilities and oscillatory behavior, and yet has a significantly lower computational complexity. In this new method, we represent the system using tensors and derive an identity to exploit the sparse connectivity of regulatory targets for complexity reduction. The algorithm involves an approximation based on Zassenhaus formula to represent the exponential of a sum of matrices as product of matrices. We derive upper bounds on the expected error of the proposed model distribution as compared to the stochastic master equation model distribution. Simulation results of the application of the model to four different biological benchmark systems illustrate performance comparable to detailed stochastic master equation models but with considerably lower computational complexity. The results also demonstrate the reduced complexity of the new approach as compared to commonly used Stochastic Simulation Algorithm for equivalent accuracy.

Influence of simulated microgravity on clock genes expression rhythmicity and underlying blood circulating miRNAs-mRNA co-expression regulatory mechanism in C57BL/6J mice

NASA Astrophysics Data System (ADS)

Lv, Ke; Qu, Lina

Purpose: It is vital for astronauts to maintain the optimal alertness and neurobehavioral function. Among various factors that exist in the space flight and long-duration mission environment, gravity changes may probably an essential environmental factor to interfere with internal circadian rhythms homeostasis and sleep quality, but the underlying mechanism is unclear. Mammals' biological clock is controlled by the suprachiasmatic nucleus (SCN), and peripheral organs adjust their own rhythmicity with the central signals. Nevertheless the mechanism underlying this synchronizition process is still unknown. microRNAs (miRNAs) are about 19˜22nt long regulatory RNAs that serve as critical modulators of post-transcriptional gene regulation. Recently, circulating miRNAs were found to have the regulatory role between cells and peripheral tissues, besides its function inside the cells. This study aims to investigate the regulatory signal transduction role of miRNAs between SCN and peripheral biological clock effecter tissues and to further decipher the mechanism of circadian disturbance under microgravity. Method: Firstly, based on the assumption that severe alterations in the expression of genes known to be involved in circadian rhythms may affect the expression of other genes, the labeled cDNA from liver and suprachiasmatic nucleus (SCN) of clock-knockout mice and control mice in different time points were cohybridized to microarrays. The fold change exceeding 2 (FC>2) was used to identify genes with altered expression levels in the knockout mice compared with control mice. Secondly, male C57BL/6J mice at 8 weeks of age were individually caged and acclimatized to the laboratory conditions (12h light/dark cycle) before being used for continuous core body temperature and activity monitoring. The mice were individually caged and tail suspended using a strip of adhesive surgical tape attached to a chain hanging from a pulley. Peripheral blood and liver tissues collection were consecutively performed. Blood samples and liver tissues were collected from tail-suspended and control mice under LD 12:12h and DD conditions during the 12th, 13th and 14th testing days at 4h intervals. Melatonin and corticosterone in mice plasma at different time points were assayed. NIH-3T3 cells were plated in culture dish for 22h before the experiment. For ground-based simulation of weightlessness, the medium was exchanged with DMEM containing 50% horse serum to synchronization, after 2 h, this medium was replaced with DMEM and 10% FBS. Then, at various time point (0, 6, 12, 18, 24, 30, 36, 42, 48h), cells were cultured on the roating clinostat at 30r/min. Total RNA was extracted from liver and NIH-3T3 cells and subsequently reverse-transcribed. The SYBR green I real-time quantitative PCR system was conducted to examine the mRNA expression level of clock, bmal1, per1, per2, cry1 and cry2 in mice and NIH-3T3 cells, respectively. Paired comparisons of the circadian genes expression between period, peak values, amplitude and mesor (midline estimating statistic of rhythm) were examined for evidence of circadian variation using Chronos-Fit software in mice and Cosine analyses in NIH-3T3 cells. Statistical analysis: All numerical data were expressed as the mean ± standard deviation (SD). Statistical differences among groups were analyzed by one-way analysis of variance (ANOVA) to determine time points differences in the study parameters. Statistical differences between two groups were determined by the Student's t test. Results: (1) Circadian rhythm of clock and bmal1 mRNA expression was found in each testing day with similar peak phase in both tail suspension group and control group. Compared with control group, tail suspension group showed that the peak phase of clock gene mRNA level advanced approximately 4 hours and the amplitude of bmal1 gene mRNA level significantly reduced at ZT2 and ZT6. (2) The expression of circadian genes in NIH-3T3 cells demonstrated that the maximum and minimum value of mRNA relative expression levels of clock and bmal1 during clinorotation were both found approximately at the time points 6h and 18h, respectively. The period length of experimental group was about 16h longer than control group. The peak phase and peak time of clock and bmal1 with simulated weightlessness group were ahead of control group. (3) At the Zeitgeber time 2 (ZT2), we found that 23 miRNAs in the SCN and 60 miRNAs in liver were significantly altered on the basis of an adjusted FC>2 among 611 miRNAs. At the ZT14, 23 miRNAs in the SCN and 57 miRNAs in liver were altered compared with the control group (FC>2). (a) Effects of clock knock out altered expression of miRNA. We analyzed the miRNA profile in SCN and liver of clock knonck out and WT mouse at two different time points using miRNA microarray. Of these, miR-122,miR-144, miR-210 and miR-669b at ZT2, miR-200a, miR-200b, miR-429, miR-455, miR-669d and miR-96 at ZT14 were both changed in SCN and liver, respectively. Interestingly, the miR-122, a tissue specific miRNA of liver was also changed in SCN at ZT2. (b) Effects of light altered expression of miRNA: Light is an important environmental factors to regulate circadian genes expression. In clock mutant mice, all altered miRNAs except miR-144 were down-regulated in SCN while up-regulated in liver at ZT14 compared to ZT2. Interestingly, the miRNAs expression profiling in SCN and liver were opposite of WT mice at ZT14 compared to ZT2. (c) Effects of clock mutant on mRNA expression: To test whether the alteration in expression of miRNAs correlates with the gene expression pattern, cDNA microarray of SCN were assayed. The results revealed that the expression of nearly 1285 genes was altered substantially with at least 1 fold change absolute in the absence of clock. Among these altered genes, we chose the mRNAs with at least 4 fold changes to further study. Only 23 genes were altered in clock knockout compared with WT at ZT2, but 67 genes at ZT14. (d) Effects of light on mRNA expression. To evaluate the light effecting on genes expression in SCN, the cDNA microarrays in SCN at ZT2 and ZT14 were tested. 21 genes were over expression and 12 genes were down regulation ZT14 compared with ZT2 in WT. The number of altered genes in clock-/- mice was 67. (e) Direct interaction between altered miRNAs and mRNAs. To identify the interaction between regulatory miRNAs and altered mRNAs in the absence of clock, we predicted the target genes of miRNAs by TargetScan. The genes both the target genes of miRNAs and altered in cDNA microarray were unravelled. The exploration of functional interaction between miRNAs and clock genes mRNA is ongoing. Conclusion: Taken together, these results indicate that ground-based simulated weightlessness could alter the molecular biological rhythm patterns, which may preliminarily present the biological regulatory mechanism of circadian rhythm systems under spaceflight-related gravity. The potential underlying functional miRNAs could serve as targets to interfere with for interaction between central and peripheral circadian organs under simulated microgravity. This preliminary study may facilitate the exploration of circadian rhythm characteristics in space and the detailed process of signal transduction and circadian gene regulation. Key words: circadian rhythms, tail-suspension, simulated microgravity, clock genes, miRNAs Acknowledgments: This study was supported by the National Basic Research Program of China (Grant NO. 2011CB707704) and the Foundation of State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center (Grant NO. SMFA13B02, SMFA09A06 and SMFA12B05).

42 CFR 493.1406 - Standard; Laboratory director qualifications on or before February 28, 1992.

Code of Federal Regulations, 2014 CFR

2014-10-01

... American Society of Cytology to practice cytopathology or possesses qualifications that are equivalent to... biological science as a major subject and (i) Is certified by the American Board of Medical Microbiology, the... master's degree from an accredited institution with a chemical, physical, or biological science as a...

42 CFR 493.1406 - Standard; Laboratory director qualifications on or before February 28, 1992.

Code of Federal Regulations, 2010 CFR

2010-10-01

... American Society of Cytology to practice cytopathology or possesses qualifications that are equivalent to... biological science as a major subject and (i) Is certified by the American Board of Medical Microbiology, the... master's degree from an accredited institution with a chemical, physical, or biological science as a...

42 CFR 493.1406 - Standard; Laboratory director qualifications on or before February 28, 1992.

Code of Federal Regulations, 2011 CFR

2011-10-01

... American Society of Cytology to practice cytopathology or possesses qualifications that are equivalent to... biological science as a major subject and (i) Is certified by the American Board of Medical Microbiology, the... master's degree from an accredited institution with a chemical, physical, or biological science as a...

42 CFR 493.1406 - Standard; Laboratory director qualifications on or before February 28, 1992.

Code of Federal Regulations, 2013 CFR

2013-10-01

... American Society of Cytology to practice cytopathology or possesses qualifications that are equivalent to... biological science as a major subject and (i) Is certified by the American Board of Medical Microbiology, the... master's degree from an accredited institution with a chemical, physical, or biological science as a...

42 CFR 493.1406 - Standard; Laboratory director qualifications on or before February 28, 1992.

Code of Federal Regulations, 2012 CFR

2012-10-01

... American Society of Cytology to practice cytopathology or possesses qualifications that are equivalent to... biological science as a major subject and (i) Is certified by the American Board of Medical Microbiology, the... master's degree from an accredited institution with a chemical, physical, or biological science as a...

The Notion of Scientific Knowledge in Biology

ERIC Educational Resources Information Center

Morante, Silvia; Rossi, Giancarlo

2016-01-01

The purpose of this work is to reconsider and critically discuss the conceptual foundations of modern biology and bio-sciences in general, and provide an epistemological guideline to help framing the teaching of these disciplines and enhancing the quality of their presentation in High School, Master and Ph.D. courses. After discussing the…

Advanced Rotating Biological Surface Operation. Training Module 2.122.4.77.

ERIC Educational Resources Information Center

Paulson, W. L.

This document is an instructional module package prepared in objective form for use by an instructor familiar with operation and maintenance of a rotating biological surface (RBS) wastewater treatment system. Included are objectives, instructor guides, student handouts, and transparency masters. This is the third level of a three module series and…

Stroma-associated master regulators of molecular subtypes predict patient prognosis in ovarian cancer.

PubMed

Zhang, Shengzhe; Jing, Ying; Zhang, Meiying; Zhang, Zhenfeng; Ma, Pengfei; Peng, Huixin; Shi, Kaixuan; Gao, Wei-Qiang; Zhuang, Guanglei

2015-11-04

High-grade serous ovarian carcinoma (HGS-OvCa) has the lowest survival rate among all gynecologic cancers and is hallmarked by a high degree of heterogeneity. The Cancer Genome Atlas network has described a gene expression-based molecular classification of HGS-OvCa into Differentiated, Mesenchymal, Immunoreactive and Proliferative subtypes. However, the biological underpinnings and regulatory mechanisms underlying the distinct molecular subtypes are largely unknown. Here we showed that tumor-infiltrating stromal cells significantly contributed to the assignments of Mesenchymal and Immunoreactive clusters. Using reverse engineering and an unbiased interrogation of subtype regulatory networks, we identified the transcriptional modules containing master regulators that drive gene expression of Mesenchymal and Immunoreactive HGS-OvCa. Mesenchymal master regulators were associated with poor prognosis, while Immunoreactive master regulators positively correlated with overall survival. Meta-analysis of 749 HGS-OvCa expression profiles confirmed that master regulators as a prognostic signature were able to predict patient outcome. Our data unraveled master regulatory programs of HGS-OvCa subtypes with prognostic and potentially therapeutic relevance, and suggested that the unique transcriptional and clinical characteristics of ovarian Mesenchymal and Immunoreactive subtypes could be, at least partially, ascribed to tumor microenvironment.

A method for compression of intra-cortically-recorded neural signals dedicated to implantable brain-machine interfaces.

PubMed

Shaeri, Mohammad Ali; Sodagar, Amir M

2015-05-01

This paper proposes an efficient data compression technique dedicated to implantable intra-cortical neural recording devices. The proposed technique benefits from processing neural signals in the Discrete Haar Wavelet Transform space, a new spike extraction approach, and a novel data framing scheme to telemeter the recorded neural information to the outside world. Based on the proposed technique, a 64-channel neural signal processor was designed and prototyped as a part of a wireless implantable extra-cellular neural recording microsystem. Designed in a 0.13- μ m standard CMOS process, the 64-channel neural signal processor reported in this paper occupies ∼ 0.206 mm(2) of silicon area, and consumes 94.18 μW when operating under a 1.2-V supply voltage at a master clock frequency of 1.28 MHz.

Hierarchy of orofacial rhythms revealed through whisking and breathing

PubMed Central

Moore, Jeffrey D.; Deschênes, Martin; Furuta, Takahiro; Huber, Daniel; Smear, Matthew C.; Demers, Maxime; Kleinfeld, David

2014-01-01

Whisking and sniffing are predominant aspects of exploratory behavior in rodents, yet the neural mechanisms that generate their motor patterns remain largely uncharacterized. We use anatomical, behavioral, electrophysiological, and pharmacological tools to demonstrate that these patterns are coordinated by respiratory centers in the ventral medulla. We delineate a distinct region in the ventral medulla that provides rhythmic input to the facial motoneurons that drive protraction of the vibrissae. Neuronal output from this region is reset at each inspiration by direct input from the preBötzinger complex, such that high frequency sniffing has a one-to-one coordination with whisking while basal respiration is accompanied by intervening whisks that occur between breaths. We conjecture that the respiratory nuclei, which project to other premotor regions for oral and facial control, function as a master clock for behaviors that coordinate with breathing. PMID:23624373

Generalized Scaling and the Master Variable for Brownian Magnetic Nanoparticle Dynamics

PubMed Central

Reeves, Daniel B.; Shi, Yipeng; Weaver, John B.

2016-01-01

Understanding the dynamics of magnetic particles can help to advance several biomedical nanotechnologies. Previously, scaling relationships have been used in magnetic spectroscopy of nanoparticle Brownian motion (MSB) to measure biologically relevant properties (e.g., temperature, viscosity, bound state) surrounding nanoparticles in vivo. Those scaling relationships can be generalized with the introduction of a master variable found from non-dimensionalizing the dynamical Langevin equation. The variable encapsulates the dynamical variables of the surroundings and additionally includes the particles’ size distribution and moment and the applied field’s amplitude and frequency. From an applied perspective, the master variable allows tuning to an optimal MSB biosensing sensitivity range by manipulating both frequency and field amplitude. Calculation of magnetization harmonics in an oscillating applied field is also possible with an approximate closed-form solution in terms of the master variable and a single free parameter. PMID:26959493

Microbial load monitor

NASA Technical Reports Server (NTRS)

Caplin, R. S.; Royer, E. R.

1978-01-01

Attempts are made to provide a total design of a Microbial Load Monitor (MLM) system flight engineering model. Activities include assembly and testing of Sample Receiving and Card Loading Devices (SRCLDs), operator related software, and testing of biological samples in the MLM. Progress was made in assembling SRCLDs with minimal leaks and which operate reliably in the Sample Loading System. Seven operator commands are used to control various aspects of the MLM such as calibrating and reading the incubating reading head, setting the clock and reading time, and status of Card. Testing of the instrument, both in hardware and biologically, was performed. Hardware testing concentrated on SRCLDs. Biological testing covered 66 clinical and seeded samples. Tentative thresholds were set and media performance listed.

Fear Factor: How Safe Is It to Make Time for Family?

ERIC Educational Resources Information Center

Ward, Kelly; Wolf-Wendel, Lisa

2004-01-01

Biological and tenure clocks have the unfortunate tendency to tick loudly, clearly, and at the same time. The average age at which faculty earn the PhD is thirty-four, putting the tenure decision at about age forty, just when a woman's fertility is in serious decline. As more women enter the academic profession as assistant professors, more of…

Extreme Violation of Sleep Hygiene: Sleeping Against the Biological Clock During a Multiday Relay Event.

PubMed

van Maanen, Annette; Roest, Bas; Moen, Maarten; Oort, Frans; Vergouwen, Peter; Paul, Ingrid; Groenenboom, Petra; Smits, Marcel

2015-12-01

Sleep hygiene is important for sleep quality and optimal performance during the day. However, it is not always possible to follow sleep hygiene requirements. In multiday relay events, athletes have to sleep immediately after physical exertion and sometimes against their biological clock. In this pilot study we investigated the effect of having to sleep at an abnormal circadian time on sleep duration. Eight runners and two cyclists performing a 500 km relay race were followed. They were divided into two groups that took turns in running and resting. Each group ran four times for approximately five hours while the other group slept. As a result, sleep times varied between normal and abnormal times. All athletes wore actigraphs to record the duration and onset of sleep. Linear mixed model analyses showed that athletes slept on average 43 minutes longer when they slept during usual (night) times than during abnormal (day) times. In general, sleep duration decreased during the race with on average 18 minutes per period. This pilot study shows that, even under extreme violation of sleep hygiene rules, there still is an apparent effect of circadian rhythm on sleep duration in relay race athletes.

Deciphering the Duality of Clock and Growth Metabolism in a Cell Autonomous System Using NMR Profiling of the Secretome.

PubMed

Sengupta, Arjun; Krishnaiah, Saikumari Y; Rhoades, Seth; Growe, Jacqueline; Slaff, Barry; Venkataraman, Anand; Olarerin-George, Anthony O; Van Dang, Chi; Hogenesch, John B; Weljie, Aalim M

2016-07-27

Oscillations in circadian metabolism are crucial to the well being of organism. Our understanding of metabolic rhythms has been greatly enhanced by recent advances in high-throughput systems biology experimental techniques and data analysis. In an in vitro setting, metabolite rhythms can be measured by time-dependent sampling over an experimental period spanning one or more days at sufficent resolution to elucidate rhythms. We hypothesized that cellular metabolic effects over such a time course would be influenced by both oscillatory and circadian-independent cell metabolic effects. Here we use nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling of mammalian cell culture media of synchronized U2 OS cells containing an intact transcriptional clock. The experiment was conducted over 48 h, typical for circadian biology studies, and samples collected at 2 h resolution to unravel such non-oscillatory effects. Our data suggest specific metabolic activities exist that change continuously over time in this settting and we demonstrate that the non-oscillatory effects are generally monotonic and possible to model with multivariate regression. Deconvolution of such non-circadian persistent changes are of paramount importance to consider while studying circadian metabolic oscillations.

Deciphering the Duality of Clock and Growth Metabolism in a Cell Autonomous System Using NMR Profiling of the Secretome

PubMed Central

Sengupta, Arjun; Krishnaiah, Saikumari Y.; Rhoades, Seth; Growe, Jacqueline; Slaff, Barry; Venkataraman, Anand; Olarerin-George, Anthony O.; Van Dang, Chi; Hogenesch, John B.; Weljie, Aalim M.

2016-01-01

Oscillations in circadian metabolism are crucial to the well being of organism. Our understanding of metabolic rhythms has been greatly enhanced by recent advances in high-throughput systems biology experimental techniques and data analysis. In an in vitro setting, metabolite rhythms can be measured by time-dependent sampling over an experimental period spanning one or more days at sufficent resolution to elucidate rhythms. We hypothesized that cellular metabolic effects over such a time course would be influenced by both oscillatory and circadian-independent cell metabolic effects. Here we use nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling of mammalian cell culture media of synchronized U2 OS cells containing an intact transcriptional clock. The experiment was conducted over 48 h, typical for circadian biology studies, and samples collected at 2 h resolution to unravel such non-oscillatory effects. Our data suggest specific metabolic activities exist that change continuously over time in this settting and we demonstrate that the non-oscillatory effects are generally monotonic and possible to model with multivariate regression. Deconvolution of such non-circadian persistent changes are of paramount importance to consider while studying circadian metabolic oscillations. PMID:27472375

[Alteration of biological rhythms causes metabolic diseases and obesity].

PubMed

Saderi, Nadia; Escobar, Carolina; Salgado-Delgado, Roberto

2013-07-16

The incidence of obesity worldwide has become a serious, constantly growing public health issue that reaches alarming proportions in some countries. To date none of the strategies developed to combat obesity have proved to be decisive, and hence there is an urgent need to address the problem with new approaches. Today, studies in the field of chronobiology have shown that our physiology continually adapts itself to the cyclical changes in the environment, regard-less of whether they are daily or seasonal. This is possible thanks to the existence of a biological clock in our hypothalamus which regulates the expression and/or activity of enzymes and hormones involved in regulating our metabolism, as well as all the homeostatic functions. It has been observed that this clock can be upset as a result of today's modern lifestyle, which involves a drop in physical activity during the day and the abundant ingestion of food during the night, among other factors, which together promote metabolic syndrome and obesity. Hence, the aim of this review is to summarise the recent findings that show the effect that altering the circadian rhythms has on the metabolism and how this can play a part in the development of metabolic diseases.

Evolution of robust circadian clocks in Drosophila melanogaster populations reared in constant dark for over 330 generations

NASA Astrophysics Data System (ADS)

Shindey, Radhika; Varma, Vishwanath; Nikhil, K. L.; Sharma, Vijay Kumar

2016-10-01

Robustness is considered to be an important feature of biological systems which may evolve when the functionality of a trait is associated with higher fitness across multiple environmental conditions. Thus, the ability to maintain stable biological phenotypes across environments is thought to be of adaptive value. Previously, we have reported higher intrinsic activity levels (activity levels of free-running rhythm in constant darkness) and power of rhythm (as assessed by amplitude of the periodogram) in Drosophila melanogaster populations (stocks) reared in constant darkness (DD stocks) as compared to those reared in constant light (LL stocks) and 12:12-h light-dark cycles (LD stocks) for over 19 years (˜330 generations). In the current study, we intended to examine whether the enhanced levels of activity observed in DD stocks persist under various environments such as photoperiods, ambient temperatures, non-24-h light-dark (LD) cycles, and semi-natural conditions (SN). We found that DD stocks largely retain their phenotype of enhanced activity levels across most of the above-mentioned environments suggesting the evolution of robust circadian clocks in DD stocks. Furthermore, we compared the peak activity levels of the three stocks across different environmental conditions relative to their peaks in constant darkness and found that the change in peak activity levels upon entrainment was not significantly different across the three stocks for any of the examined environmental conditions. This suggests that the enhancement of activity levels in DD stocks is not due to differential sensitivity to environment. Thus, these results suggest that rearing in constant darkness (DD) leads to evolution of robust circadian clocks suggesting a possible adaptive value of possessing such rhythms under constant dark environments.

Symbols of a cosmic order

NASA Astrophysics Data System (ADS)

Madjid, F. Hadi; Myers, John M.

2016-10-01

The world runs on networks over which signals communicate sequences of symbols, e.g. numerals. Examining both engineered and natural communications networks reveals an unsuspected order that depends on contact with an unpredictable entity. This order has three roots. The first is a proof within quantum theory that no evidence can ever determine its explanation, so that an agent choosing an explanation must do so unpredictably. The second root is the showing that clocks that step computers do not "tell time" but serve as self-adjusting symbol-handling agents that regulate "logically synchronized" motion in response to unpredictable disturbances. Such a clock-agent has a certain independence as well as the capacity to communicate via unpredictable symbols with other clock-agents and to adjust its own tick rate in response to that communication. The third root is the noticing of unpredictable symbol exchange in natural systems, including the transmission of symbols found in molecular biology. We introduce a symbol-handling agent as a role played in some cases by a person, for example a physicist who chooses an explanation of given experimental outcomes, and in other cases by some other biological entity, and in still other cases by an inanimate device, such as a computer-based detector used in physical measurements. While we forbear to try to explain the propensity of agents at all levels from cells to civilizations to form and operate networks of logically synchronized symbol-handling agents, we point to this propensity as an overlooked cosmic order, an order structured by the unpredictability ensuing from the proof. Appreciating the cosmic order leads to a conception of agency that replaces volition by unpredictability and reconceives the notion of objectivity in a way that makes a place for agency in the world as described by physics. Some specific implications for physics are outlined.

Evolution of robust circadian clocks in Drosophila melanogaster populations reared in constant dark for over 330 generations.

PubMed

Shindey, Radhika; Varma, Vishwanath; Nikhil, K L; Sharma, Vijay Kumar

2016-10-01

Robustness is considered to be an important feature of biological systems which may evolve when the functionality of a trait is associated with higher fitness across multiple environmental conditions. Thus, the ability to maintain stable biological phenotypes across environments is thought to be of adaptive value. Previously, we have reported higher intrinsic activity levels (activity levels of free-running rhythm in constant darkness) and power of rhythm (as assessed by amplitude of the periodogram) in Drosophila melanogaster populations (stocks) reared in constant darkness (DD stocks) as compared to those reared in constant light (LL stocks) and 12:12-h light-dark cycles (LD stocks) for over 19 years (∼330 generations). In the current study, we intended to examine whether the enhanced levels of activity observed in DD stocks persist under various environments such as photoperiods, ambient temperatures, non-24-h light-dark (LD) cycles, and semi-natural conditions (SN). We found that DD stocks largely retain their phenotype of enhanced activity levels across most of the above-mentioned environments suggesting the evolution of robust circadian clocks in DD stocks. Furthermore, we compared the peak activity levels of the three stocks across different environmental conditions relative to their peaks in constant darkness and found that the change in peak activity levels upon entrainment was not significantly different across the three stocks for any of the examined environmental conditions. This suggests that the enhancement of activity levels in DD stocks is not due to differential sensitivity to environment. Thus, these results suggest that rearing in constant darkness (DD) leads to evolution of robust circadian clocks suggesting a possible adaptive value of possessing such rhythms under constant dark environments.

Later circadian timing of food intake is associated with increased body fat.

PubMed

McHill, Andrew W; Phillips, Andrew Jk; Czeisler, Charles A; Keating, Leigh; Yee, Karen; Barger, Laura K; Garaulet, Marta; Scheer, Frank Ajl; Klerman, Elizabeth B

2017-11-01

Background: Weight gain and obesity have reached alarming levels. Eating at a later clock hour is a newly described risk factor for adverse metabolic health; yet, how eating at a later circadian time influences body composition is unknown. Using clock hour to document eating times may be misleading owing to individual differences in circadian timing relative to clock hour. Objective: This study examined the relations between the timing of food consumption relative to clock hour and endogenous circadian time, content of food intake, and body composition. Design: We enrolled 110 participants, aged 18-22 y, in a 30-d cross-sectional study to document sleep and circadian behaviors within their regular daily routines. We used a time-stamped-picture mobile phone application to record all food intake across 7 consecutive days during a participant's regular daily routines and assessed their body composition and timing of melatonin release during an in-laboratory assessment. Results: Nonlean individuals (high body fat) consumed most of their calories 1.1 h closer to melatonin onset, which heralds the beginning of the biological night, than did lean individuals (low body fat) (log-rank P = 0.009). In contrast, there were no differences between lean and nonlean individuals in the clock hour of food consumption ( P = 0.72). Multiple regression analysis showed that the timing of food intake relative to melatonin onset was significantly associated with the percentage of body fat and body mass index (both P < 0.05) while controlling for sex, whereas no relations were found between the clock hour of food intake, caloric amount, meal macronutrient composition, activity or exercise level, or sleep duration and either of these body composition measures (all P > 0.72). Conclusions: These results provide evidence that the consumption of food during the circadian evening and/or night, independent of more traditional risk factors such as amount or content of food intake and activity level, plays an important role in body composition. This trial was registered at clinicaltrials.gov as NCT02846077. © 2017 American Society for Nutrition.

Altered energy intake and the amplitude of the body temperature rhythm are associated with changes in phase, but not amplitude, of clock gene expression in the rat suprachiasmatic nucleus in vivo.

PubMed

Goh, Grace H; Mark, Peter J; Maloney, Shane K

2016-01-01

Circadian rhythms in mammals are driven by a central clock in the suprachiasmatic nucleus (SCN). In vitro, temperature cycles within the physiological range can act as potent entraining cues for biological clocks. We altered the body temperature (Tc) rhythm in rats by manipulating energy intake (EI) to determine whether EI-induced changes in Tc oscillations are associated with changes in SCN clock gene rhythms in vivo. Male Wistar rats (n = 16 per diet) were maintained on either an ad libitum diet (CON), a high energy cafeteria diet (CAF), or a calorie restricted diet (CR), and Tc was recorded every 30 min for 6-7 weeks. SCN tissue was harvested from rats at zeitgeber time (ZT) 0, ZT6, ZT12, or ZT18. Expression of the clock genes Bmal1, Per2, Cry1, and Rev-erbα, the heat shock transcription factor Hsf1, and the heat shock protein Hsp90aa1, were determined using qPCR. The circadian profile of gene expression for each gene was characterized using cosinor analysis. Compared to the CON rats, the amplitude of Tc was decreased in CAF rats by 0.1 °C (p < 0.001), and increased in CR rats by 0.3 °C (p < 0.001). The amplitude of Hsp90aa1 expression was lowest in CAF rats and highest in CR rats (p = 0.045), but the amplitude of all of the clock genes and Hsf1 were unaffected by diet (p > 0.25). Compared to CON, phase advances of the Tc, Bmal1, and Per2 rhythms were observed with CR feeding (p < 0.05), but CAF feeding elicited no significant changes in phase. The present results indicate that in vivo, the SCN is largely resistant to entrainment by EI-induced changes in the Tc rhythm, although some phase entrainment may occur.

Green Web or megabiased clock? Plant fossils from Gondwanan Patagonia speak on evolutionary radiations.

PubMed

Wilf, Peter; Escapa, Ignacio H

2015-07-01

Evolutionary divergence-age estimates derived from molecular 'clocks' are frequently correlated with paleogeographic, paleoclimatic and extinction events. One prominent hypothesis based on molecular data states that the dominant pattern of Southern Hemisphere biogeography is post-Gondwanan clade origins and subsequent dispersal across the oceans in a metaphoric 'Green Web'. We tested this idea against well-dated Patagonian fossils of 19 plant lineages, representing organisms that actually lived on Gondwana. Most of these occurrences are substantially older than their respective, often post-Gondwanan molecular dates. The Green Web interpretation probably results from directional bias in molecular results. Gondwanan history remains fundamental to understanding Southern Hemisphere plant radiations, and we urge significantly greater caution when using molecular dating to interpret the biological impacts of geological events. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

Resynchronization of circadian oscillators and the east-west asymmetry of jet-lag

NASA Astrophysics Data System (ADS)

Lu, Zhixin; Klein-Cardeña, Kevin; Lee, Steven; Antonsen, Thomas M.; Girvan, Michelle; Ott, Edward

2016-09-01

Cells in the brain's Suprachiasmatic Nucleus (SCN) are known to regulate circadian rhythms in mammals. We model synchronization of SCN cells using the forced Kuramoto model, which consists of a large population of coupled phase oscillators (modeling individual SCN cells) with heterogeneous intrinsic frequencies and external periodic forcing. Here, the periodic forcing models diurnally varying external inputs such as sunrise, sunset, and alarm clocks. We reduce the dimensionality of the system using the ansatz of Ott and Antonsen and then study the effect of a sudden change of clock phase to simulate cross-time-zone travel. We estimate model parameters from previous biological experiments. By examining the phase space dynamics of the model, we study the mechanism leading to the difference typically experienced in the severity of jet-lag resulting from eastward and westward travel.

Faster embryonic segmentation through elevated Delta-Notch signalling

PubMed Central

Liao, Bo-Kai; Jörg, David J.; Oates, Andrew C.

2016-01-01

An important step in understanding biological rhythms is the control of period. A multicellular, rhythmic patterning system termed the segmentation clock is thought to govern the sequential production of the vertebrate embryo's body segments, the somites. Several genetic loss-of-function conditions, including the Delta-Notch intercellular signalling mutants, result in slower segmentation. Here, we generate DeltaD transgenic zebrafish lines with a range of copy numbers and correspondingly increased signalling levels, and observe faster segmentation. The highest-expressing line shows an altered oscillating gene expression wave pattern and shortened segmentation period, producing embryos with more, shorter body segments. Our results reveal surprising differences in how Notch signalling strength is quantitatively interpreted in different organ systems, and suggest a role for intercellular communication in regulating the output period of the segmentation clock by altering its spatial pattern. PMID:27302627

Activated Biological Filters (ABF Towers). Instructor's Guide. Biological Treatment Process Control.

ERIC Educational Resources Information Center

Wooley, John F.

This instructor's manual contains materials needed to teach a two-lesson unit on activated bio-filters (ABF). These materials include: (1) an overview of the two lessons; (2) lesson plans; (3) lecture outlines (keyed to a set of slides designed for use with the lessons); (4) overhead transparency masters; (5) worksheets for each lesson (with…

Reducing Unintentional Plagiarism amongst International Students in the Biological Sciences: An Embedded Academic Writing Development Programme

ERIC Educational Resources Information Center

Divan, Aysha; Bowman, Marion; Seabourne, Anna

2015-01-01

There is general agreement in the literature that international students are more likely to plagiarise compared to their native speaker peers and, in many instances, plagiarism is unintentional. In this article we describe the effectiveness of an academic writing development programme embedded into a Biological Sciences Taught Masters course…

Utility of Electromyographic Biological Feedback in Chronic Stuttering: A Clinical Study with Follow-Up.

ERIC Educational Resources Information Center

Manschreck, Theo C.; And Others

1980-01-01

Eight chronic adult stutterers underwent an electromyographic (EMG) biological feedback training program to reduce masseter muscle tension in an effort to improve fluency. All subjects mastered the program within 10 30-minute sessions. Measures of muscle tension and fluency indicated improvements that were maintained three to six months later.…

Reconciling the Tension between the Tenure and Biological Clocks to Increase the Recruitment and Retention of Women in Academia

ERIC Educational Resources Information Center

Clark, Catherine D.; Hill, Janeen M.

2010-01-01

Most women entering tenure-track positions in the sciences do so in their late twenties or early thirties after completing a graduate degree and post-doctoral training. Tenure-track positions usually span a six or seven year probationary period during which time institutions expect unlimited commitment from the tenure-track candidates to their…

Generic temperature compensation of biological clocks by autonomous regulation of catalyst concentration.

PubMed

Hatakeyama, Tetsuhiro S; Kaneko, Kunihiko

2012-05-22

Circadian clocks--ubiquitous in life forms ranging from bacteria to multicellular organisms--often exhibit intrinsic temperature compensation; the period of circadian oscillators is maintained constant over a range of physiological temperatures, despite the expected Arrhenius form for the reaction coefficient. Observations have shown that the amplitude of the oscillation depends on the temperature but the period does not; this suggests that although not every reaction step is temperature independent, the total system comprising several reactions still exhibits compensation. Here we present a general mechanism for such temperature compensation. Consider a system with multiple activation energy barriers for reactions, with a common enzyme shared across several reaction steps. The steps with the highest activation energy rate-limit the cycle when the temperature is not high. If the total abundance of the enzyme is limited, the amount of free enzyme available to catalyze a specific reaction decreases as more substrates bind to the common enzyme. We show that this change in free enzyme abundance compensates for the Arrhenius-type temperature dependence of the reaction coefficient. Taking the example of circadian clocks with cyanobacterial proteins KaiABC, consisting of several phosphorylation sites, we show that this temperature compensation mechanism is indeed valid. Specifically, if the activation energy for phosphorylation is larger than that for dephosphorylation, competition for KaiA shared among the phosphorylation reactions leads to temperature compensation. Moreover, taking a simpler model, we demonstrate the generality of the proposed compensation mechanism, suggesting relevance not only to circadian clocks but to other (bio)chemical oscillators as well.

Dissociation of Circadian and Circatidal Timekeeping in the Marine Crustacean Eurydice pulchra

PubMed Central

Zhang, Lin; Hastings, Michael H.; Green, Edward W.; Tauber, Eran; Sladek, Martin; Webster, Simon G.; Kyriacou, Charalambos P.; Wilcockson, David C.

2013-01-01

Summary Background Tidal (12.4 hr) cycles of behavior and physiology adapt intertidal organisms to temporally complex coastal environments, yet their underlying mechanism is unknown. However, the very existence of an independent “circatidal” clock has been disputed, and it has been argued that tidal rhythms arise as a submultiple of a circadian clock, operating in dual oscillators whose outputs are held in antiphase i.e., ∼12.4 hr apart. Results We demonstrate that the intertidal crustacean Eurydice pulchra (Leach) exhibits robust tidal cycles of swimming in parallel to circadian (24 hr) rhythms in behavioral, physiological and molecular phenotypes. Importantly, ∼12.4 hr cycles of swimming are sustained in constant conditions, they can be entrained by suitable stimuli, and they are temperature compensated, thereby meeting the three criteria that define a biological clock. Unexpectedly, tidal rhythms (like circadian rhythms) are sensitive to pharmacological inhibition of Casein kinase 1, suggesting the possibility of shared clock substrates. However, cloning the canonical circadian genes of E. pulchra to provide molecular markers of circadian timing and also reagents to disrupt it by RNAi revealed that environmental and molecular manipulations that confound circadian timing do not affect tidal timing. Thus, competent circadian timing is neither an inevitable nor necessary element of tidal timekeeping. Conclusions We demonstrate that tidal rhythms are driven by a dedicated circatidal pacemaker that is distinct from the circadian system of E. pulchra, thereby resolving a long-standing debate regarding the nature of the circatidal mechanism. PMID:24076244

Diurnal Cycling Transcription Factors of Pineapple Revealed by Genome-Wide Annotation and Global Transcriptomic Analysis

PubMed Central

Sharma, Anupma; Wai, Ching Man; Ming, Ray

2017-01-01

Abstract Circadian clock provides fitness advantage by coordinating internal metabolic and physiological processes to external cyclic environments. Core clock components exhibit daily rhythmic changes in gene expression, and the majority of them are transcription factors (TFs) and transcription coregulators (TCs). We annotated 1,398 TFs from 67 TF families and 80 TCs from 20 TC families in pineapple, and analyzed their tissue-specific and diurnal expression patterns. Approximately 42% of TFs and 45% of TCs displayed diel rhythmic expression, including 177 TF/TCs cycling only in the nonphotosynthetic leaf tissue, 247 cycling only in the photosynthetic leaf tissue, and 201 cycling in both. We identified 68 TF/TCs whose cycling expression was tightly coupled between the photosynthetic and nonphotosynthetic leaf tissues. These TF/TCs likely coordinate key biological processes in pineapple as we demonstrated that this group is enriched in homologous genes that form the core circadian clock in Arabidopsis and includes a STOP1 homolog. Two lines of evidence support the important role of the STOP1 homolog in regulating CAM photosynthesis in pineapple. First, STOP1 responds to acidic pH and regulates a malate channel in multiple plant species. Second, the cycling expression pattern of the pineapple STOP1 and the diurnal pattern of malate accumulation in pineapple leaf are correlated. We further examined duplicate-gene retention and loss in major known circadian genes and refined their evolutionary relationships between pineapple and other plants. Significant variations in duplicate-gene retention and loss were observed for most clock genes in both monocots and dicots. PMID:28922793

Circadian Rhythms and Sleep in Drosophila melanogaster

PubMed Central

Dubowy, Christine; Sehgal, Amita

2017-01-01

The advantages of the model organism Drosophila melanogaster, including low genetic redundancy, functional simplicity, and the ability to conduct large-scale genetic screens, have been essential for understanding the molecular nature of circadian (∼24 hr) rhythms, and continue to be valuable in discovering novel regulators of circadian rhythms and sleep. In this review, we discuss the current understanding of these interrelated biological processes in Drosophila and the wider implications of this research. Clock genes period and timeless were first discovered in large-scale Drosophila genetic screens developed in the 1970s. Feedback of period and timeless on their own transcription forms the core of the molecular clock, and accurately timed expression, localization, post-transcriptional modification, and function of these genes is thought to be critical for maintaining the circadian cycle. Regulators, including several phosphatases and kinases, act on different steps of this feedback loop to ensure strong and accurately timed rhythms. Approximately 150 neurons in the fly brain that contain the core components of the molecular clock act together to translate this intracellular cycling into rhythmic behavior. We discuss how different groups of clock neurons serve different functions in allowing clocks to entrain to environmental cues, driving behavioral outputs at different times of day, and allowing flexible behavioral responses in different environmental conditions. The neuropeptide PDF provides an important signal thought to synchronize clock neurons, although the details of how PDF accomplishes this function are still being explored. Secreted signals from clock neurons also influence rhythms in other tissues. SLEEP is, in part, regulated by the circadian clock, which ensures appropriate timing of sleep, but the amount and quality of sleep are also determined by other mechanisms that ensure a homeostatic balance between sleep and wake. Flies have been useful for identifying a large set of genes, molecules, and neuroanatomic loci important for regulating sleep amount. Conserved aspects of sleep regulation in flies and mammals include wake-promoting roles for catecholamine neurotransmitters and involvement of hypothalamus-like regions, although other neuroanatomic regions implicated in sleep in flies have less clear parallels. Sleep is also subject to regulation by factors such as food availability, stress, and social environment. We are beginning to understand how the identified molecules and neurons interact with each other, and with the environment, to regulate sleep. Drosophila researchers can also take advantage of increasing mechanistic understanding of other behaviors, such as learning and memory, courtship, and aggression, to understand how sleep loss impacts these behaviors. Flies thus remain a valuable tool for both discovery of novel molecules and deep mechanistic understanding of sleep and circadian rhythms. PMID:28360128

Artifacts in Digital Coincidence Timing

PubMed Central

Moses, W. W.; Peng, Q.

2014-01-01

Digital methods are becoming increasingly popular for measuring time differences, and are the de facto standard in PET cameras. These methods usually include a master system clock and a (digital) arrival time estimate for each detector that is obtained by comparing the detector output signal to some reference portion of this clock (such as the rising edge). Time differences between detector signals are then obtained by subtracting the digitized estimates from a detector pair. A number of different methods can be used to generate the digitized arrival time of the detector output, such as sending a discriminator output into a time to digital converter (TDC) or digitizing the waveform and applying a more sophisticated algorithm to extract a timing estimator. All measurement methods are subject to error, and one generally wants to minimize these errors and so optimize the timing resolution. A common method for optimizing timing methods is to measure the coincidence timing resolution between two timing signals whose time difference should be constant (such as detecting gammas from positron annihilation) and selecting the method that minimizes the width of the distribution (i.e., the timing resolution). Unfortunately, a common form of error (a nonlinear transfer function) leads to artifacts that artificially narrow this resolution, which can lead to erroneous selection of the “optimal” method. The purpose of this note is to demonstrate the origin of this artifact and suggest that caution should be used when optimizing time digitization systems solely on timing resolution minimization. PMID:25321885

Artifacts in digital coincidence timing

DOE PAGES

Moses, W. W.; Peng, Q.

2014-10-16

Digital methods are becoming increasingly popular for measuring time differences, and are the de facto standard in PET cameras. These methods usually include a master system clock and a (digital) arrival time estimate for each detector that is obtained by comparing the detector output signal to some reference portion of this clock (such as the rising edge). Time differences between detector signals are then obtained by subtracting the digitized estimates from a detector pair. A number of different methods can be used to generate the digitized arrival time of the detector output, such as sending a discriminator output into amore » time to digital converter (TDC) or digitizing the waveform and applying a more sophisticated algorithm to extract a timing estimator.All measurement methods are subject to error, and one generally wants to minimize these errors and so optimize the timing resolution. A common method for optimizing timing methods is to measure the coincidence timing resolution between two timing signals whose time difference should be constant (such as detecting gammas from positron annihilation) and selecting the method that minimizes the width of the distribution (i.e. the timing resolution). Unfortunately, a common form of error (a nonlinear transfer function) leads to artifacts that artificially narrow this resolution, which can lead to erroneous selection of the 'optimal' method. In conclusion, the purpose of this note is to demonstrate the origin of this artifact and suggest that caution should be used when optimizing time digitization systems solely on timing resolution minimization.« less

Artifacts in digital coincidence timing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moses, W. W.; Peng, Q.

Digital methods are becoming increasingly popular for measuring time differences, and are the de facto standard in PET cameras. These methods usually include a master system clock and a (digital) arrival time estimate for each detector that is obtained by comparing the detector output signal to some reference portion of this clock (such as the rising edge). Time differences between detector signals are then obtained by subtracting the digitized estimates from a detector pair. A number of different methods can be used to generate the digitized arrival time of the detector output, such as sending a discriminator output into amore » time to digital converter (TDC) or digitizing the waveform and applying a more sophisticated algorithm to extract a timing estimator.All measurement methods are subject to error, and one generally wants to minimize these errors and so optimize the timing resolution. A common method for optimizing timing methods is to measure the coincidence timing resolution between two timing signals whose time difference should be constant (such as detecting gammas from positron annihilation) and selecting the method that minimizes the width of the distribution (i.e. the timing resolution). Unfortunately, a common form of error (a nonlinear transfer function) leads to artifacts that artificially narrow this resolution, which can lead to erroneous selection of the 'optimal' method. In conclusion, the purpose of this note is to demonstrate the origin of this artifact and suggest that caution should be used when optimizing time digitization systems solely on timing resolution minimization.« less

Global synchronization of parallel processors using clock pulse width modulation

DOEpatents

Chen, Dong; Ellavsky, Matthew R.; Franke, Ross L.; Gara, Alan; Gooding, Thomas M.; Haring, Rudolf A.; Jeanson, Mark J.; Kopcsay, Gerard V.; Liebsch, Thomas A.; Littrell, Daniel; Ohmacht, Martin; Reed, Don D.; Schenck, Brandon E.; Swetz, Richard A.

2013-04-02

A circuit generates a global clock signal with a pulse width modification to synchronize processors in a parallel computing system. The circuit may include a hardware module and a clock splitter. The hardware module may generate a clock signal and performs a pulse width modification on the clock signal. The pulse width modification changes a pulse width within a clock period in the clock signal. The clock splitter may distribute the pulse width modified clock signal to a plurality of processors in the parallel computing system.

Central and peripheral clocks are coupled by a neuropeptide pathway in Drosophila

PubMed Central

Selcho, Mareike; Millán, Carola; Palacios-Muñoz, Angelina; Ruf, Franziska; Ubillo, Lilian; Chen, Jiangtian; Bergmann, Gregor; Ito, Chihiro; Silva, Valeria; Wegener, Christian; Ewer, John

2017-01-01

Animal circadian clocks consist of central and peripheral pacemakers, which are coordinated to produce daily rhythms in physiology and behaviour. Despite its importance for optimal performance and health, the mechanism of clock coordination is poorly understood. Here we dissect the pathway through which the circadian clock of Drosophila imposes daily rhythmicity to the pattern of adult emergence. Rhythmicity depends on the coupling between the brain clock and a peripheral clock in the prothoracic gland (PG), which produces the steroid hormone, ecdysone. Time information from the central clock is transmitted via the neuropeptide, sNPF, to non-clock neurons that produce the neuropeptide, PTTH. These secretory neurons then forward time information to the PG clock. We also show that the central clock exerts a dominant role on the peripheral clock. This use of two coupled clocks could serve as a paradigm to understand how daily steroid hormone rhythms are generated in animals. PMID:28555616

The Drosophila Clock Neuron Network Features Diverse Coupling Modes and Requires Network-wide Coherence for Robust Circadian Rhythms.

PubMed

Yao, Zepeng; Bennett, Amelia J; Clem, Jenna L; Shafer, Orie T

2016-12-13

In animals, networks of clock neurons containing molecular clocks orchestrate daily rhythms in physiology and behavior. However, how various types of clock neurons communicate and coordinate with one another to produce coherent circadian rhythms is not well understood. Here, we investigate clock neuron coupling in the brain of Drosophila and demonstrate that the fly's various groups of clock neurons display unique and complex coupling relationships to core pacemaker neurons. Furthermore, we find that coordinated free-running rhythms require molecular clock synchrony not only within the well-characterized lateral clock neuron classes but also between lateral clock neurons and dorsal clock neurons. These results uncover unexpected patterns of coupling in the clock neuron network and reveal that robust free-running behavioral rhythms require a coherence of molecular oscillations across most of the fly's clock neuron network. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

ABC Assay: Method Development and Application to Quantify the Role of Three DWV Master Variants in Overwinter Colony Losses of European Honey Bees.

PubMed

Kevill, Jessica L; Highfield, Andrea; Mordecai, Gideon J; Martin, Stephen J; Schroeder, Declan C

2017-10-27

Deformed wing virus (DWV) is one of the most prevalent honey bee viral pathogens in the world. Typical of many RNA viruses, DWV is a quasi-species, which is comprised of a large number of different variants, currently consisting of three master variants: Type A, B, and C. Little is known about the impact of each variant or combinations of variants upon the biology of individual hosts. Therefore, we have developed a new set of master variant-specific DWV primers and a set of standards that allow for the quantification of each of the master variants. Competitive reverse transcriptase polymerase chain reaction (RT-PCR) experimental design confirms that each new DWV primer set is specific to the retrospective master variant. The sensitivity of the ABC assay is dependent on whether DNA or RNA is used as the template and whether other master variants are present in the sample. Comparison of the overall proportions of each master variant within a sample of known diversity, as confirmed by next-generation sequence (NGS) data, validates the efficiency of the ABC assay. The ABC assay was used on archived material from a Devon overwintering colony loss (OCL) 2006-2007 study; further implicating DWV type A and, for the first time, possibly C in the untimely collapse of honey bee colonies. Moreover, in this study DWV type B was not associated with OCL. The use of the ABC assay will allow researchers to quickly and cost effectively pre-screen for the presence of DWV master variants in honey bees.

An immune clock of human pregnancy

PubMed Central

Aghaeepour, Nima; Ganio, Edward A.; Mcilwain, David; Tsai, Amy S.; Tingle, Martha; Van Gassen, Sofie; Gaudilliere, Dyani K.; Baca, Quentin; McNeil, Leslie; Okada, Robin; Ghaemi, Mohammad S.; Furman, David; Wong, Ronald J.; Winn, Virginia D.; Druzin, Maurice L.; El-Sayed, Yaser Y.; Quaintance, Cecele; Gibbs, Ronald; Darmstadt, Gary L.; Shaw, Gary M.; Stevenson, David K.; Tibshirani, Robert; Nolan, Garry P.; Lewis, David B.; Angst, Martin S.; Gaudilliere, Brice

2017-01-01

The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling–based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2–dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies. PMID:28864494