Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Biological Clocks”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 541 records · Page 30Linked to original sources

Nonlinear systems theory in medical care management.

Health care is provided to biological, not mechanical systems. The focus of attention is a human being, not an automobile or clock. Biological systems are highly complex and their behavior can be nonlinear. By understanding this difference, we can begin to answer the question of how can we deliver efficient and effective clinical care, while controlling spiraling costs. This article describes the behavior of complex systems and explores what has been learned about managing such systems in non health care fields. The author translates that learning into the health care setting and proposes a new model for the health care environment, based on the principles of complex adaptive systems. The approach advocated is to design models that can learn and adapt, and then to implement them with skill. Such models should include the elements of roadmaps, decision aids, and continuous improvement.

Decision Making, Organizational↗

Predicted 3D-structure of melanopsin, the non-rod, non-cone photopigment of the mammalian circadian clock, from Djungarian hamsters (Phodopus sungorus).

Melanopsin is the photopigment of the retinal ganglion cells, which are involved in the synchronization of the biological clock in the suprachiasmatic nucleus (SCN) of mammals with the exogenous photoperiod. So far, no information about the three-dimensional (3D) structure of melanopsin is available. Here we report the predicted structure based on the protein-coding region of the nucleotide sequence of the gene for melanopsin, originating from isolated mRNA from the eyes of Djungarian hamsters (Phodopus sungorus). The nucleotide sequence shares the largest homologies with melanopsin of mice and rats (each 89%) and humans (84%). Based on the amino-acid sequence, and in comparison with the known structure of bovine rhodopsin, the three-dimensional melanopsin protein structure was modeled by using automated homology modeling approaches that were subsequently refined. Melanopsin consists of highly conserved seven-transmembrane domains and a long cytoplasmatic tail with multiple putative phosphorylation sites. In the binding site of the chromophore, a 11-cis-retinal is likely to be bound to lysine at position 336 as Schiff's base. The modeling results may indicate different photoisomerization within the melanopsin molecule compared with bovine rhodopsin.

Amino Acid Sequence↗

[Reliability of enzyme systems and molecular mechanisms of aging].

A stochastic model of animal mortality and ageing is proposed. In a living being there is a "biological clock", constructed from Q kinds of functional elements (genes), The reliability of functioning of these genes determines the biological age of the being. Oxidative processes in the cells are accompanied by random failures of electron transfer enzyme systems, which result in appearance of free superoxide radicals. Failures of electron transfer enzymes and of defence enzymes lead to accumulation of functional damages in the genes of the "clock". In terms of the model experimental data of gerontology (Gompertz's law, Strehler-Mildvan's compensation effect, etc) are easily explained. The value of Q for the man is estimated to be of the order of 10. Some possible mechanisms of action of "geroprotectors" have been discussed.

Aging↗

Modulation of the rat suprachiasmatic circadian clock by melatonin in vitro.

The pineal hormone melatonin regulates daily and seasonal rhythms, at least in part through an action on the mammalian biological clock in the suprachiasmatic nuclei (SCN). Melatonin was tested in vitro (10(-15)-10(-6) M; ZT9.5-10.5) for its effect on the circadian peak in neuronal firing rate in the rat SCN slice. It produced a concentration-related phase advance (maximum advance = 3 +/- 0.3 h at 10(-9) M, n = 3; minimum effective concentration = 10(-13) M; EC50 = 1.2 x 10(-12) M). The melatonin receptor antagonist luzindole (10(-5) M) blocked the phase-advance produced by melatonin (10(-9) M), whilst having no effect on its own. These data show that the effect of melatonin on the SCN clock, measured via the circadian rhythm of neuronal firing rate in the nuclei, is consistent with a concentration-dependent action via a high affinity melatonin receptor.

Action Potentials↗

Circadian gene expression of clock genes and plasminogen activator inhibitor-1 in heart and aorta of spontaneously hypertensive and Wistar-Kyoto rats.

OBJECTIVE: Heart and aorta possess biologic clocks, but their involvement in genetic hypertension has been unknown. Plasminogen activator inhibitor-1 (PAI-1) expression is directly regulated by clock genes, while angiotensin II modulates both PAI-1 and clock gene expression. We therefore examined circadian expression of PAI-1 and clock genes, and effects of angiotensin type 1 (AT1) receptor antagonism, in heart and aorta of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. METHODS: We examined cardiac and aortic mRNA expression for PAI-1 and clock genes (Per2, Bmal1, Clock, and Dbp) every 4 h throughout the day by quantitative reverse transcription-polymerase chain reaction, and intervention with the AT1 receptor antagonist candesartan and equihypotensive hydralazine. RESULTS: Cardiac PAI-1 expression was high in the dark, while aortic PAI-1 expression was high in the light. Both cardiac and aortic PAI-1 expression were greater in SHR than in WKY rats. Candesartan treatment decreased cardiac PAI-1 expression only in the dark in WKY rats but throughout the day in SHR. Candesartan but not hydralazine strongly attenuated circadian fluctuation of aortic PAI-1 mRNA in SHR and WKY rats. Clock genes oscillated synchronously in heart and aorta of SHR and WKY rats. Clock gene expression was increased in heart but not aorta of SHR. Candesartan did not affect clock gene expression. CONCLUSIONS: Enhanced expression of clock genes may increase PAI-1 expression in concert with activated renin-angiotensin system in SHR heart. Rather than clock genes, the renin-angiotensin system induces daily fluctuation and increased expression of aortic PAI-1 mRNA in SHR.

ARNTL Transcription Factors↗

Chronobiological analysis and mass spectrometric characterization of pigment-dispersing factor in the cockroach Leucophaea maderae.

Pigment-dispersing factor (PDF) is a neuropeptide that plays a prominent role in the circadian clock of several insects. The cockroach Leucophaea maderae was the first animal where the site of a biological clock could be located, and still is a focal point of circadian research. Although detailed studies on the action of pigment-dispersing factor and the distribution of PDF-like immunoreactivity in the L. maderae brain exist, a native pigment-dispersing factor of this species has not been characterized so far. The authentic Lem-PDF was isolated from L. maderae by a combination of high performance liquid chromatography, crab pigment-dispersion bioassay and an immunosorbent assay. Mass spectrometric characterization and the conserved sequence of pigment-dispersing factor in orthopteromorphan insects suggest that Lem-PDF has the sequence NSEXINSLLGLPKVLNDAa (where X= I or L). Lem-PDF is thus identical to either Periplaneta americana PDF or Acheta domesticus PDF. Detailed analysis of PDF-like immunofluorescence in different regions of the brain suggests that there are no drastic daily changes in the amount of pigment-dispersing factor as occur in Drosophila melanogaster, which might be explained by a lack of circadian pigment-dispersing factor release and production, or by phase differences between the pigment-dispersing factor neurons.

Amino Acid Sequence↗

[Physiologic rhythm of sleep and waking].

The sleep-wake cycle is one of the endogenous rhythm of the body that become entrained to the day/night cycle. Light serves as a Zeitgeber, a stimulus that entrains an endogenous rhythm to the circadian clock. A direct retinohypothalamic tract (RHT) conveyed information about light to the internal circadian pacemaker. The primary biological clock is located in the suprachiasmatic nucleus (SCN). The RHT may serve to couple the circadian system to the external light/dark cycle.

Circadian Rhythm↗

Adenosine A1 receptors regulate the response of the hamster circadian clock to light.

Circadian rhythms are synchronized to the environmental light-dark cycle by daily, light-induced adjustments in the phase of a biological clock located in the suprachiasmatic nucleus. Ambient light alters the phase of the clock via a direct, glutamatergic projection from retinal ganglion cells. We investigated the hypothesis that adenosine A1 receptors modulate the phase adjusting effect of light on the circadian clock. Systemic administration of the selective adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA), significantly (p<0.05) attenuated light-induced phase delays and advances of the circadian activity rhythm. Selective agonists for the adenosine A2A and adenosine A3 receptors were without effect. The inhibitory effect of CHA on light-induced phase advances was dose-dependent (0.025-1.0 mg/kg, ED(50)=0.3 mg/kg), and this effect was blocked in a dose-dependent (0.005-1.0 mg/kg) manner by the adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Injection of CHA (10 microM) into the region of the suprachiasmatic nucleus significantly attenuated light-induced phase advances, and this effect was also blocked by DPCPX (100 microM). The results suggest that adenosine A1 receptors located in the region of the suprachiasmatic nucleus regulate the response of the circadian clock to the phase-adjusting effects of light.

Adenosine↗

The influence of isolation on psychological and physiological variables.

BACKGROUND: Human behavior is temporally organized by an endogenous "biological clock," and the alternation between activity and rest is an integral part of this system. Like all other biological functions, the system is only capable of adapting to external stimuli to a limited (and recognizable) extent. HYPOTHESIS: In space, astronauts are kept in a relatively isolated and extreme environment. Under these conditions the circadian system is disturbed and specific countermeasures must be invoked in order to avoid negative consequences on sleep, mood and performance. METHOD: The results of isolation experiments will be compared with studies in space focusing on the circadian course of variables such as body core temperature, sleep-wake patterns, mood, and performance. RESULTS: Subjects in isolation can show disturbances of sleep, mood and vigilance if their biological rhythms run "out of phase." CONCLUSIONS: A strict 24-h time schedule should be kept with regard to environmental, as well as behavioral influences to insure adequate and restful sleep and optimal levels of waking performance and psychological well-being.

Adaptation, Psychological↗

Neurotransmitters of the retino-hypothalamic tract.

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.

Animals↗

Precise circadian clocks in prokaryotic cyanobacteria.

Prokaryotic cyanobacteria express robust circadian (daily) rhythms under the control of a timing mechanism that is independent of the cell division cycle. This biological clock orchestrates global regulation of gene expression and controls the timing of cell division. Proteins that may be involved in input pathways have been identified. Mutational screening has identified three clock genes that are organized as a gene cluster. The structure of cyanobacterial clock proteins, their phosphorylation, and regulation is described. A new model for the core clockwork in cyanobacteria proposes that rhythmic changes in the status of the chromosome underlie the rhythms of gene expression. Mixed-strain experiments demonstrate that this timekeeper confers adaptive value when different strains compete against each other.

Bacterial Proteins↗

Long-term constant light induces constitutive elevated expression of mPER2 protein in the murine SCN: a molecular basis for Aschoff's rule?

Circadian rhythms in behavior, metabolism, and physiology are based upon transcriptional/translational feedback loops involving a core set of clock genes that interact to regulate their own expression. In mammals, the SCN is the site of a master biological clock regulating circadian locomotor rhythms. The products of the clock genes mPer1, mPer2, mCry1, and mCry2 form essential components of both negative and positive elements within the SCN oscillator. The primary aims of this study were to examine clock gene abundance under longterm LL in an attempt to provide molecular correlates of the lengthened tau and daily phase delays described by Aschoff's rule. Wheel-running behavior was recorded from mice maintained in either DD or LL for 50 days. The abundance of the clock genes mPer1, mPer2, mCry1, and mCry2 and their protein products was then examined (every approximately 4 h) within the SCN using in situ hybridization and immunocytochemistry. Under LL conditions, mPer1, mPer2, mCry1, and mCry2 messages remained rhythmic, although the waveform of mCry2 was altered compared to DD. In LL, mPER1, mCRY1, and mCRY2 protein levels were also rhythmic and comparable to the patterns observed in DD. However, mPER2 is elevated and constitutively expressed under LL. Thus, rhythmic expression of these clock genes is not dependent on the rhythmic production of mPER2, and the acute up-regulation of mPer1 and mPer2 described for short (nonparametric) light pulses is not sustained under LL conditions. These findings suggest that mPER2 is important for the generation of phase delays in the molecular clockwork, providing a possible molecular explanation for Aschoff's rule: LL lengthens the circadian period by inhibiting the degeneration of mPER2, and constitutively elevated levels of mPER2 enhance the phase-delaying limb of the molecular oscillator.

Animals↗

Biological perspectives on circadian cancer therapy.

Temporal coordination of biologic processes with an approximately 24-hour cycle (circadian) is ubiquitous throughout the animal and plant kingdoms. In each organism studied, the capability to keep biologic time is an inherited characteristic. These biological clocks anticipate, get the organism ready for, regular environmental changes. The immense selective environmental pressure to keep time accurately is reflected in the parallel evolution of different molecular strategies for biologic timekeeping that have apparently arisen independently several times throughout evolution. The anatomic, biochemical, and molecular mechanisms of the clock are currently being defined. Circadian temporal organization at the cellular, organ, and organismic levels results in predictable differences in the capacity of plants, animals, and human beings to respond to therapeutic interventions administered at different times throughout this daily cycle. The biologic basis for these time-of-day differences in therapeutic outcome derive from the circadian dependence of drug pharmacology and the circadian physiology of both normal and malignant tissues. In the treatment of cancer, circadian timing of anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, enhanced tumor control, and improved host survival. The routine clinical application of such principles is facilitated by the availability of programmable drug delivery devices.

Antineoplastic Agents↗

Circadian rhythms and cancer chemotherapy.

Temporal coordination of biologic processes with an approximately 24-h cycle (circadian) is common throughout the animal and plant kingdom and even in some prokaryotic organisms. In all organisms studied, the capability to keep biologic time is an inherited characteristic located intracellularly. These biological clocks anticipate and get the organism ready for regular environmental changes. This indicates both the ubiquity and the weight of the selective environmental pressure to keep time accurately. Several molecular strategies for biologic time keeping have apparently arisen independently several times throughout evolution. The anatomic, biochemical, and molecular mechanisms of the clock are in the process of being defined. This temporal organization at the cellular, organ, and organismic levels results in predictable differences in the capacity of plants, animals, and human beings to respond to therapeutic interventions administered at different times throughout important biologic cycles (e.g., circadian timed therapy). In the treatment of the cancer bearing host, circadian timing of surgery, anticancer drugs, radiation therapy, and biologic agents can result in improved toxicity profiles, enhanced tumor control, and improved host survival. The routine clinical application of such principles is facilitated by the availability of programmable drug delivery devices. Rhythm frequency ranges other than 24-h (e.g., low frequency: menstrual; high frequency: 10 to 120 min) may also be important to understanding health and disease and to designing successful therapy in diseases as diverse as cancer, infertility, and diabetes.

Animals↗

Circadian rhythms in rat brain neurotransmitter receptors.

In the rat brain there are daily rhythms in the number of alpha- and beta-adrenergic, muscarinic cholinergic, dopamine, opiate, and benzodiazepine receptors. The rhythms are circadian, i.e., with periods of approximately 24 h and endogenously generated. The characteristics of the circadian rhythms change over the year. Ablation of the suprachiasmatic nuclei, believed to act as a biological clock, abolishes the circadian rhythms. In the cerebral cortex the circadian rhythm in norepinephrine-stimulated cyclic AMP production is a biological response to the circadian rhythms in alpha- and beta-adrenergic receptors. The effects on neurotransmitter receptor rhythms of treatments that are antidepressant in humans were studied. Chronic administration of the antidepressant drugs imipramine and clorgyline delays the timing of the peak number of many receptors. Chronic administration of the antidepressant, antimanic drug lithium carbonate delays the timing of the peak number of some receptors and abolishes the rhythms in several others. Twenty-four hours of sleep deprivation is almost without effect on the rhythms. Fluphenazine and lithium, both antimanic in humans, increase the 24-h mean number of most receptors. Circadian receptor rhythms evoking intracellular circadian biological responses may modulate brain neurotransmission, coordinating internal physiological processes, and synchronizing them to environmental events. Alterations in circadian receptor rhythms with chronic psychoactive drug administration may play a role in the therapeutic actions of these drugs.

Animals↗

An opposite role for tau in circadian rhythms revealed by mathematical modeling.

Biological clocks with a period of approximately 24 h (circadian) exist in most organisms and time a variety of functions, including sleep-wake cycles, hormone release, bioluminescence, and core body temperature fluctuations. Much of our understanding of the clock mechanism comes from the identification of specific mutations that affect circadian behavior. A widely studied mutation in casein kinase I (CKI), the CKIepsilon(tau) mutant, has been shown to cause a loss of kinase function in vitro, but it has been difficult to reconcile this loss of function with the current model of circadian clock function. Here we show that mathematical modeling predicts the opposite, that the kinase mutant CKIepsilon(tau) increases kinase activity, and we verify this prediction experimentally. CKIepsilon(tau) is a highly specific gain-of-function mutation that increases the in vivo phosphorylation and degradation of the circadian regulators PER1 and PER2. These findings experimentally validate a mathematical modeling approach to a complex biological function, clarify the role of CKI in the clock, and demonstrate that a specific mutation can be both a gain and a loss of function depending on the substrate.

Animals↗

Expression of the transcriptional coactivators CBP and p300 in the hamster suprachiasmatic nucleus: possible molecular components of the mammalian circadian clock.

Immediate early genes are expressed in the mammalian suprachiasmatic nucleus in response to photic information arriving from the retina at restricted times of the day, therefore their expression is regulated by the circadian biological clock. These light-induced genes are also activated by the phosphorylated form of CREB (pCREB) that binds to a cAMP response element upstream of the genes. The nuclear proteins CBP and p300 are known to be coactivators with pCREB in certain cell types, but their identification within the rodent SCN has not been reported. Therefore, in this study we examined the distribution of both CBP and p300 in the hamster suprachiasmatic nucleus. CBP and p300 immunoreactivity is detected in cells throughout the suprachiasmatic nucleus, and the pattern of staining within cells is indicative of a nuclear location for these proteins. The number of cells immunoreactive for both CBP and p300 significantly decreases at mid-night circadian times with respect to mid-day circadian times, although the reduction is less than 20%. Neither CBP nor p300 expression is affected by a circadian phase-resetting light pulse given late in the night. The ability of CBP and p300 to interact with pCREB as well as with the clock gene BMAL1 is discussed, and we propose that CBP and p300 may interact with, and link, both clock genes and clock-controlled genes in the generation of circadian rhythms in mammals. We further suggest that there will be a general importance for the role of transcriptional coactivators such as CBP and p300 in many of the molecular pathways related to the mammalian circadian clock.

ARNTL Transcription Factors↗

The effects of altering extracellular potassium ion concentration on the membrane potential and circadian clock of Paramecium bursaria.

In some neural models of circadian rhythmicity, membrane potential and transmembrane flux of potassium and calcium ions appear to play important roles in the entrainment and central mechanisms of the biological clock. We wondered whether these cellular variables might be generally involved in circadian clocks, even non-neural clocks. Therefore, we tested the impact of changing extracellular potassium level on the circadian rhythm of photoaccumulation of Paramecium cells, whose membrane potential responds to changes of extracellular potassium in a manner similar to that of neurones. We found that pulse or step changes of extracellular potassium concentration did not phase-shift the circadian clock of P. bursaria cells in a phase-specific manner. Furthermore, modifying the extracellular concentration of calcium did not affect the magnitude of light-induced phase resetting. Therefore, while membrane potential and calcium fluxes may be crucial components of the circadian clock system in some organisms, especially in neural systems that involve intercellular communication, the P. bursaria data indicate that membrane potential changes are not necessarily an intrinsic component of circadian organization at the cellular level.

Animals↗