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PubMed2003

Modeling of a bipedal locomotor using coupled nonlinear oscillators of Van der Pol.

Research to date points to an understanding of human biped locomotion that has been primarily experimental in nature largely due to the complexity of the process. In view of the new, exciting possibilities of programmed electrostimulation of artificial muscles to generate motion (locomotion), a critical study at the theoretical level is greatly warranted. There is strong evidence that many biological clocks consist of a population of mutually coupled oscillators [Pavlidis T (1973) Biological oscillators, Academic; Johnsson A (1978) Zur Biophysik biologischer Oszillatoren. In: Biophisik, Springer]. In this work, a form of bipedal locomotion is simulated by using mutually coupled nonlinear oscillators. A planar model, which includes three out of the six determinants of gait that characterize the human locomotion, was adopted.

Algorithms↗

PubMed2002

Molecular machinery of the circadian clock in mammals.

The discovery of clock genes and the general principle of their oscillation has stimulated research on biological clocks and this research has had a major impact on the field of life sciences. The mammalian circadian core oscillator is thought to be composed of an autoregulatory transcription-(post)translation-based feedback loop involving a set of clock genes. The real time monitoring of clock gene oscillation at the levels of genes, cells, tissues, and systems will clarify the issue of how the time signal is born and how it is integrated into the organismic level. Investigations of circadian systems in various organisms employ multiple methods including ethology, physiology, neuroscience, molecular biology, cell biology and genetics. The circadian system has thus become a unique example in the elucidation of the general principles of how genes control cellular, systemic and behavioral functions.

Animals↗

PubMed2003

Acetylcholine increases intracellular Ca2+ via nicotinic receptors in cultured PDF-containing clock neurons of Drosophila.

Light entrains the biological clock both in adult and larval Drosophila melanogaster. The Bolwig organ photoreceptors most likely constitute one substrate for this light entrainment in larvae. Acetylcholine (ACh) has been suggested as the neurotransmitter in these photoreceptors, but there is no evidence that ACh signaling is involved in photic input onto circadian pacemaker neurons. Here we demonstrate that the putative targets of the Bolwig photoreceptors, the PDF-containing clock neurons (LNs), in the larval brain express functional ACh receptors (AChRs). With the use of GAL4-UAS-driven expression of green fluorescent protein (GFP), we were able to identify LNs in dissociated cell culture. After loading with the Ca(2+)-sensitive dye fura-2, we monitored changes in intracellular Ca(2+) levels ([Ca(2+)](i)) in GFP-marked LNs while applying candidate neurotransmitters. ACh induced transient increases in [Ca(2+)](i) at physiological concentrations. These increases were dependent on extracellular Ca(2+) and Na(+) and were likely caused by activation of voltage-dependent Ca(2+) channels. Application of nicotinic and muscarinic agonists and antagonists showed that the AChRs on cultured LNs have a nicotinic pharmacology. Antibodies to several subunits of nicotinic AChRs (nAChRs) labeled the putative contact site of the Bolwig organ axon terminals with the dendrites of LNs, as well as dissociated LNs in culture. Our findings support a role of ACh as input factor onto the LNs and suggest that Ca(2+) is used as a second messenger mediating cholinergic input within the LNs. Experiments using a more general GAL4-UAS-driven expression of GFP showed that functional expression of nAChRs is a widespread phenomenon in peptidergic neurons.

Acetylcholine↗

PubMed2000

Correlative association between N-methyl-D-aspartate receptor-mediated expression of period genes in the suprachiasmatic nucleus and phase shifts in behavior with photic entrainment of clock in hamsters.

Because the rapid induction of Period (Per) genes is associated with the photic entrainment of the biological clock, we examined whether N-methyl-D-aspartate (NMDA) receptors were involved in the photic induction of Per genes in the hamster suprachiasmatic nucleus (SCN). In situ hybridization observation revealed that light during the early subjective night [circadian time (CT) 13.5] or the late subjective night (CT20) caused an induction of Per1 and Per2 but not Per3 mRNA in the SCN. Photic induction of Per mRNA at CT13.5 was observed especially in the ventrolateral SCN, whereas that at CT20 was more widespread from the ventrolateral to the dorsal SCN. A noncompetitive NMDA receptor antagonist, +MK801, dose-dependently (0. 1-5.0 mg/kg) suppressed only the ventrolateral part of Per1 and Per2 mRNA induction by light at CT13.5 or CT20 in the SCN. The suppressive effects of +MK801 on Per mRNA strongly correlated with the attenuating action of this compound on phase shifts by light at both CT13.5 and CT20. A competitive NMDA receptor antagonist, D-2-amino-5-phosphonovalerate (D-APV), also exhibited inhibitory actions on light (CT20)-induced Per1 and Per2 mRNA expression in the ventrolateral SCN. Furthermore, local injection of NMDA into the SCN resulted in the induction of Per1 and Per2 mRNA in the SCN. Among NMDA receptors, NR2B and NR2C mRNA were expressed in the ventrolateral and dorsal SCN, respectively. These results suggest that the activation of NMDA receptor is a critical step for photic induction of Per1 and Per2 transcripts in the SCN, which are linked to a photic behavioral entrainment.

Analysis of Variance↗

PubMed2024

CLOCK gene 3'UTR and exon 9 polymorphisms show a strong association with essential hypertension in a North Indian population.

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

Humans↗

PubMed2005

Modeling the VPAC2-activated cAMP/PKA signaling pathway: from receptor to circadian clock gene induction.

Increasing evidence suggests an important role for VPAC2-activated signal transduction pathways in maintaining a synchronized biological clock in the suprachiasmatic nucleus (SCN). Activation of the VPAC2 signaling pathway induces per1 gene expression in the SCN and phase-shifts the circadian clock. Mice without the VPAC2 receptor lack an overt, coherent circadian rhythm in clock gene expression, SCN neuron firing rate, and locomotor behavior. Using a systems approach, we have developed a kinetic model integrating VPAC2 signaling mediated by the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and leading to induced circadian clock gene expression. We fit the model to experimental data from the literature for cAMP accumulation, PKA activation, cAMP-response element binding protein phosphorylation, and per1 induction. By linking the VPAC2 model to a published circadian clock model, we also simulated clock phase shifts induced by vasoactive intestinal polypeptide (VIP) and matched experimental data for the VIP response. The simulated phase response curve resembled the hamster response to a related neuropeptide, GRP1-27, and light. Simulations using pulses of VIP revealed that the system response is extraordinarily robust to input signal duration, a result with physiologically relevant consequences. Lastly, simulations using varied receptor levels matched literature experimental data from animals overexpressing VPAC2 receptors.

Animals↗

PubMed2006

Circadian control of the sleep-wake cycle.

It is beyond doubt that the timing of sleep is under control of the circadian pacemaker. Humans are a diurnal species; they sleep mostly at night, and they do so at approximately 24-h intervals. If they do not adhere to this general pattern, for instance when working night shifts or when travelling across time zones, they experience the stubborn influence of their circadian clock. In recent years much has been discovered about the organisation of the circadian clock. New photoreceptor cells in the retina have been found to influence the input to the clock, and much of the molecular machinery of the clock has been unravelled. It is now known that the circadian rhythm of sleep and wakefulness is only loosely coupled to the circadian rhythm of the pacemaker. New theories have been proposed for the functions of sleep and the sites at which those functions are executed. In spite of this rapid increase in knowledge of the circadian clock and of sleep regulatory processes, much remains to be discovered concerning the precise interaction between the biological clock and sleep timing. This is particularly unfortunate in view of the 24-h demands of our society for 7 days a week. Too little is known about the negative consequences of the societal pressures on well-being and performance.

Animals↗

PubMed2004

The adaptive value of circadian clocks: an experimental assessment in cyanobacteria.

Circadian clocks are thought to enhance the fitness of organisms by improving their ability to adapt to extrinsic influences, specifically daily changes in environmental factors such as light, temperature, and humidity. Some investigators have proposed that circadian clocks provide an additional "intrinsic adaptive value," that is, the circadian clock that regulates the timing of internal events has evolved to be such an integral part of the temporal regulation that it is useful in all conditions, even in constant environments. There have been practically no rigorous tests of either of these propositions. Using cyanobacterial strains with different clock properties growing in competition with each other, we found that strains with a functioning biological clock defeat clock-disrupted strains in rhythmic environments. In contrast to the expectations of the "intrinsic value model," this competitive advantage disappears in constant environments. In addition, competition experiments using strains with different circadian periods showed that cyanobacterial strains compete most effectively in a rhythmic environment when the frequency of their internal biological oscillator and that of the environmental cycle are similar. Together, these studies demonstrate the adaptive value of circadian temporal programming in cyanobacteria but indicate that this adaptive value is only fulfilled in cyclic environments.

Adaptation, Physiological↗

PubMed2006

SCN outputs and the hypothalamic balance of life.

The circadian clock in the suprachiasmatic nucleus (SCN) is composed of thousands of oscillator neurons, each dependent on the cell-autonomous action of a defined set of circadian clock genes. Still, the major question remains how these individual oscillators are organized into a biological clock producing a coherent output able to time all the different daily changes in behavior and physiology. In the present review, the authors discuss the anatomical connections and neurotransmitters used by the SCN to control the daily rhythms in hormone release. The efferent SCN projections mainly target neurons in the medial hypothalamus surrounding the SCN. The activity of these preautonomic and neuroendocrine target neurons is controlled by differentially timed waves of, among others, vasopressin, GABA, and glutamate release from SCN terminals. Together, the data on the SCN control of neuroendocrine rhythms provide clear evidence not only that the SCN consists of phenotypically (i.e., according to neurotransmitter content) different subpopulations of neurons but also that subpopulations should be distinguished (within phenotypically similar groups of neurons) based on the acrophase of their (electrical) activity. Moreover, the specialization of the SCN may go as far as a single body structure, that is, the SCN seems to contain neurons that specifically target the liver, pineal, and adrenal.

Animals↗

PubMed2005

Importin alpha/beta mediates nuclear transport of a mammalian circadian clock component, mCRY2, together with mPER2, through a bipartite nuclear localization signal.

Circadian rhythms, which period is approximately one day, are generated by endogenous biological clocks. These clocks are found throughout the animal kingdom, as well as in plants and even in prokaryotes. Molecular mechanisms for circadian rhythms are based on transcriptional oscillation of clock component genes, consisting of interwoven autoregulatory feedback loops. Among the loops, the nuclear transport of clock proteins is a crucial step for transcriptional regulation. In the present study, we showed that the nuclear entry of mCRY2, a mammalian clock component, is mediated by the importin alpha/beta system through a bipartite nuclear localization signal in its carboxyl end. In vitro transport assay using digitonin-permeabilized cells demonstrated that all three importin alphas, alpha1 (Rch1), alpha3 (Qip-1), and alpha7 (NPI-2), can mediate mCRY2 import. mCRY2 with the mutant nuclear localization signal failed to transport mPER2 into the nucleus of mammalian cultured cells, indicating that the nuclear localization signal identified in mCRY2 is physiologically significant. These results suggest that the importin alpha/beta system is involved in nuclear entry of mammalian clock components, which is indispensable to transcriptional oscillation of clock genes.

Active Transport, Cell Nucleus↗

PubMed2004

Glutamatergic clock output stimulates melatonin synthesis at night.

The rhythm of melatonin synthesis in the rat pineal gland is under the control of the biological clock, which is located in the suprachiasmatic nucleus of the hypothalamus (SCN). Previous studies demonstrated a daytime inhibitory influence of the SCN on melatonin synthesis, by using gamma-aminobutyric acid input to the paraventricular nucleus of the hypothalamus (PVN). Nevertheless, a recent lesion study suggested the presence of a stimulatory clock output in the control of the melatonin rhythm as well. In order to further investigate this output in acute in vivo conditions, we first measured the release of melatonin in the pineal gland before, during and after a temporary shutdown of either SCN or PVN neuronal activity, using multiple microdialysis. For both targets, SCN and PVN, the application of tetrodotoxin by reverse dialysis in the middle of the night decreased melatonin levels. Due to recent evidence of the existence of glutamatergic clock output, we then studied the effect on melatonin release of glutamate antagonist application within the PVN in the middle of the night. Blockade of the glutamatergic input to the PVN significantly decreased melatonin release. These results demonstrate that (i) neuronal activity of both PVN and SCN is necessary to stimulate melatonin synthesis during the dark period and (ii) glutamatergic signalling within the PVN plays an important role in melatonin synthesis.

Animals↗

PubMed1992

Molecular analysis of the Neurospora clock: cloning and characterization of the frequency and period-4 genes.

Genetic analysis of Neurospora crassa has identified many mutants that affect the biological clock. In this article we review the cloning of two of these genes, frq and prd-4. Both genes were isolated using a chromosome walk technique. Subcloning experiments and subsequent Northern analysis of frq implicate the importance of two transcripts that emanate from this locus. In preliminary data, no protein-coding region is evident in the smaller transcript; the larger transcript contains a 962-amino acid open reading frame. The open reading frame shows limited homology to per, a clock gene identified in Drosophila. Sequence analysis of all existing frq alleles suggests that the defect in each case lies within the open reading frame. Successful cloning of the prd-4 gene required walking a distance of greater than 40 kb. A physical map of this region has been constructed using restriction analysis. The dominance-recessive relationship of prd-4 and prd-4+ was established by examining the period lengths of strains harboring a wide range of prd-4/prd-4+ nuclear ratios.

Amino Acid Sequence↗

PubMed2000

Biological time and in vivo research: a field guide to pitfalls.

Biological rhythmicity is a fundamental characteristic of all life forms, from primitive bacteria to man. The molecular biology, genetics, and the neurobiology of the biological clock(s) are being elucidated. Daily (circadian) statistically significant fluctuations occur in all of the normal biological variables studied in the experimental animal and the human. Many researchers, however, are not aware of the negative impact biological rhythmicity can have on experimental design and/or data interpretation. This article serves not as a review, but as a "field guide" to the pitfalls that can occur when research is performed in the absence of an understanding of biological rhythmicity. The major topics discussed are: 1) data transfer from the diurnally in-active/resting/sleeping lab animal to the diurnally active human, 2) frequency of sampling, 3) free-running vs. synchronization, 4) alternating periods of resistance and susceptibility, 5) phase shifting of a rhythm, 6) the assumption that one mean +/- S.E. from control animals can be "stretched" across an experimental time span, and 7) plotting data on an "hours after treatment" format vs. a "time of day" format. The hope is that by avoiding the pitfalls, biological time will become an ally in the endeavor to understand human biology.

Animals↗

PubMed1994

Intergeneric complementation of a circadian rhythmicity defect: phylogenetic conservation of structure and function of the clock gene frequency.

The Neurospora crassa frequency locus encodes a 989 amino acid protein that is a central component, a state variable, of the circadian biological clock. We have determined the sequence of all or part of this protein and surrounding regulatory regions from additional fungi representing three genera and report that there is distinct, preferential conservation of the frequency open reading frame (ORF) as compared with non-coding sequences. Within the coding region, many of the domain hallmarks of the N. crassa protein are highly conserved, especially an internal region bearing the causative mutations in frq1 and frq7, the most extreme alleles in the frequency allelic series. Despite considerable diversity among the strains analyzed in terms of morphology, growth, circadian clock output and frq sequence, the ORF from the most distantly related fungus included in this study (Sordaria fimicola) rescues rhythmicity in a N.crassa frequency null strain. Both sequence conservation, and the ability of frequency from a genus displaying one developmental program to complement circadian defects in a separate genus with a distinct, clock-regulated developmental program, are consistent with a central role of the frequency gene product in a general circadian oscillator capable of controlling diverse outputs in a variety of systems.

Amino Acid Sequence↗

PubMed2004

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

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.

Bacterial Proteins↗

PubMed1993

The melatonin rhythm: both a clock and a calendar.

The paper briefly reviews the data which shows that the circadian production and secretion of melatonin by the pineal gland can impart both daily, i.e., clock, and seasonal, i.e., calendar, information to the organism. The paper summarizes the 3 patterns of nocturnal melatonin production that have been described. Clearly, regardless of the pattern of nocturnal melatonin production a particular species normally displays, the duration of nightime elevated melatonin is proportional to the duration of the night length. Since daylength under natural conditions changes daily the melatonin rhythm, which adjusts to the photoperiod sends time of year information to the organism. The melatonin receptors which subserve the clock message sent by the pineal gland in the form of a melatonin cycle may reside in the biological clock itself, namely, the suprachiasmatic nuclei (SCN). The melatonin receptors that mediate seasonal changes in reproductive physiology are presumably those that are located on the pars tuberalis cells of the anterior pituitary gland. Besides these receptors which likely mediate clock and calendar information, melatonin receptors have been described in other organs. Interestingly, the distribution of melatonin receptors is highly species-specific. Whereas the clock and calendar information that the melatonin cycle imparts to the organism relies on cell membrane receptors, a fact that is of some interest considering the high lipophilicity of melatonin, recent studies indicate that other functions of melatonin may require no receptor whatsoever.

Animals↗

PubMed2004

[Health problems due to night shift work and jetlag].

Technical demands, economic considerations and allocation of services around the clock bring about, that night work constantly represents a portion of 12-15% in Germany. Work against the biologic clock increases the risks for accidents and may produce health risks as sleeping or gastro-intestinal disorders, depression, cardio-vascular diseases, overweight, and a disturbed sexual activity and fertility. Adaptation to an altered day/night rhythm during night shift work takes more than a week, and even then the time shift is rarely complete. In contrast the duration of time shift is much shorter during a jetlag and is mostly completed after 2-3 days. Therefore, much less health risk is to be expected from jetlag as compared to night shift work. About 15% of all healthy adults are insufficiently adaptable to night shift work. These individuals carry a particularly high health risk, if regularly participating in night shift work.

Accidents, Occupational↗

PubMed2000

Circadian waves of expression of the APRR1/TOC1 family of pseudo-response regulators in Arabidopsis thaliana: insight into the plant circadian clock.

The Arabidopsis pseudo-response regulator, APRR1, has a unique structural design containing a pseudo-receiver domain and a C-terminal CONSTANS motif. This protein was originally characterized as a presumed component of the His-to-Asp phosphorelay systems in Arabidopsis thaliana. Recently, it was reported that APRR1 is identical to the TOC1 gene product, a mutational lesion of which affects the periods of many circadian rhythms in Arabidopsis plants. TOC1 is believed to be a component of the presumed circadian clock (or central oscillator). Based on these facts, in this study four more genes, each encoding a member of the APRR1/TOC1 family of pseudo-response regulators were identified and characterized with special reference to circadian rhythms. It was found that all these members of the APRR1/TOC1 family (APRR1, APRR3, APRR5, APRR7, and APRR9) are subjected to a circadian rhythm at the level of transcription. Furthermore, in a given 24 h period, the APRR-mRNAs started accumulating sequentially after dawn with 2-3 h intervals in the order of APRR9-->APRR7-->APRR5-->APRR3-->APRR1. These sequential events of transcription, termed 'circadian waves of APRR1/TOCI', were not significantly affected by the photoperiod conditions, if any (e.g. both long and short days), and the expression of APRR9 was first boosted always after dawn. Among these APRRs, in fact, only the expression of APRR9 was rapidly and transiently induced also by white light, whereas such light responses of others were very dull, if any. These results collectively support the view that these members of the APRR1/TOC1 family are together all involved in an as yet unknown mechanism underlying the Arabidopsis circadian clock. Here we propose that the circadian waves of the APRR1/TOC1 family members are most likely a molecular basis of such a biological clock in higher plants.

Amino Acid Sequence↗