Effects of reserpine on biological clocks for metabolic fuels during starvation in man.
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Adolescent↗
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Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis.
Human cyclic haematopoiesis (cyclic neutropenia, MIM 162800) is an autosomal dominant disease in which blood-cell production from the bone marrow oscillates with 21-day periodicity. Circulating neutrophils vary between almost normal numbers and zero. During intervals of neutropenia, affected individuals are at risk for opportunistic infection. Monocytes, platelets, lymphocytes and reticulocytes also cycle with the same frequency. Here we use a genome-wide screen and positional cloning to map the locus to chromosome 19p13.3. We identified 7 different single-base substitutions in the gene (ELA2) encoding neutrophil elastase (EC 3. 4.21.37, also known as leukocyte elastase, elastase 2 and medullasin), a serine protease of neutrophil and monocyte granules, on unique haplotypes in 13 of 13 families as well as a new mutation in a sporadic case. Neutrophil elastase (a 240-aa mature protein predominantly found in neutrophil granules) is the target for protease inhibition by alpha1-antitrypsin, and its unopposed release destroys tissue at sites of inflammation. We hypothesize that a perturbed interaction between neutrophil elastase and serpins or other substrates may regulate mechanisms governing the clock-like timing of haematopoiesis.
Base Sequence↗
Action potential mutations stop a biological clock in Drosophila.
The Drosophila melanogaster male produces a species-specific courtship song by wing vibration. The most conspicuous feature of the song is a series of pulses with a 30-40-ms interpulse interval (IPI) which oscillate in wild-type males with a period of 50-60 s. This short-term biological rhythm in IPI is influenced by several gene mutations at the period (per) locus, which alter the normal 24-h free-running period of the circadian clock and have corresponding effects on the song cycle. The present study reveals that, under restrictive conditions, temperature-sensitive mutations which affect neuronal membrane excitability seem to stop the biological clock underlying the fruitfly's song rhythm.
Action Potentials↗
Two components model for the biological clock and its evaluation by computer.
Two component interaction model for the circadian clock oscillator can easily explain the temperature independence. To verify this model, we successfully carried out Q10 calculation of each component and oscillator.
Biological Clocks↗
Neuronal input pathways to the brain's biological clock and their functional significance.
Circadian rhythms are entrained daily by environmental photic and non-photic cues. The present review describes the anatomy and functional characteristics of the three major input pathways to the circadian clock mediating entrainment: the retino-hypothalamic tract, the geniculo-hypothalamic tract and the midbrain raphe projection.
Afferent Pathways↗
[Advances in studies of biological clock gene].
The circadian clock genes, which generate and control the running of the circadian rhythms, exist in organisms ranging from prokaryotes to mammals. The oscillator genes and its coding proteins compose the feedback loops of circadian system. The kind, number and regulating route of clock genes are characterized by living things at different evolution levels. The molecular mechanism of the run of circadian clock genes in cyanobacteria, neurospore, fruit fly, mouse and human being is introduced in this article.
Animals↗
Tripping along the trail to the molecular mechanisms of biological clocks.
Solving the mechanism of circadian clocks has become an important goal, in part because daily rhythms are running in such a wide variety of organisms, and contribute to many aspects of their well being. Systematic genetic approaches to studying 'the clock' were initiated in fruitflies more than 20 years ago as a novel means by which neural-pacemaking mysteries might be solved. Such chronogenetic investigations gained momentum when they spread to other species, and became molecular. However, the molecular studies were misleading, that is, until some elementary neuro-anatomical observations, involving the expression of a 'clock gene' in Drosophila, gave the experiments in this molecular-neurogenetic area of chronobiology a new direction. The initially neuro-descriptive studies led to the current investigations that involve negatively acting transcription factors and other clock molecules that are presumed to interact with them. In addition, new mutants and clones have been isolated in a timely manner. These mutations and molecules should permit chronogeneticists, working on a wide variety of organisms, to unravel further details of how the clock works, how environmental information finds its way to it, and how it sends information out into the organism's physiology, biochemistry and behavior.
Animals↗
Norepinephrine release in the rat pineal gland: the input from the biological clock measured by in vivo microdialysis.
The sympathetic innervation of the rat pineal gland was investigated, measuring the norepinephrine (NE) release by on-line in vivo microdialysis. NE was assayed using an HPLC method with precolumn derivatization and fluorescence detection. Its high sensitivity and reliability made it very suitable to monitor the low levels of NE in the dialysates (12.5 fmol during nighttime, 3 fmol during daytime). To increase NE levels, the monoamine reuptake inhibitor cocaine was added to Ringer's solution at concentrations of 10(-6) and 10(-5) M. This resulted in increases of neurotransmitter output of 167 and 219%, respectively, but did not change the qualitative and/or quantitative outcome of other experiments. Perfusion with 10(-6) M tetrodotoxin for 1 h resulted in a decrease of the NE release by >80%, whereas perfusion with the alpha 2-receptor antagonist yohimbine caused a twofold increase. These results indicate that the NE release in the rat pineal was of neuronal origin and regulated by a negative feedback mechanism involving inhibitory presynaptic alpha 2-receptors. Long-term (i.e., 16 h) measurements are described, showing the circadian properties of NE release. A pronounced rhythm is reported, showing extremely sharp transitions between low daytime and high nighttime values. Increases and decreases are reported to occur within the duration of collecting one sample (20 min). For comparison, the rhythm of melatonin release was also recorded. The on and off switches of the sympathetic input correlated well with the circadian rhythm of melatonin release and can thus be considered as the primary clock signal, inducing the nightly production of melatonin.
Adrenergic alpha-Antagonists↗
Circadian oscillations of neuropeptide expression in the human biological clock.
The mammalian suprachiasmatic nucleus is the principal component of a neural timing system implicated in the temporal organization of circadian and seasonal processes. The present study was performed to analyze the circadian profiles of two major neuropeptidergic cell groups in the human suprachiasmatic nucleus. To that end the brains of 40 human subjects collected at autopsy were investigated. The populations of arginine vasopressin- and vasoactive intestinal polypeptide-expressing neurons, located in the shell and core of the suprachiasmatic nucleus, respectively, showed marked circadian rhythms with an asymmetrical, bimodal waveform. Time series analysis revealed that these circadian cycles in neuronal activity could be described by a composite model consisting of a nonlinear periodic function, with mono- and diphasic cycles. The findings suggest that the 24-h biosynthesis of neuropeptides in the human suprachiasmatic nucleus, being part of the neural output pathway of the clock, is driven by a complex pacemaker system consisting of coupled nonlinear oscillators, in accordance with a multioscillator model of circadian timekeeping.
Adolescent↗
[Molecular mechanism of biological clock: for chronobiological approach to stress].
Recent progress in molecular chronobiology revealed that the clock genes control intracellular feedback loops. CLOCK protein and BMAL1 protein, first discovered as components of the circadian clock in mammals, are known to function as transcriptional activators in the circadian feedback loop of drosophila. PERIOD and TIMELESS proteins work as inhibitors for these activators in drosophila and possibly in mammals. The clock genes described above are also expressed in peripheral tissues with circadian rhythmicity. Cultured rat-1 fibroblast shows circadian expression of clock genes after serum shock or forskolin stimulation. These results indicate that the clock genes function not only as components of the endogenous clock, but also as a coordinator of the circadian activity of peripheral tissues. It will be important to study stress from the aspect of circadian rhythm.
ARNTL Transcription Factors↗
Watching the hands of the Arabidopsis biological clock.
Oligonucleotide and cDNA microarrays have been used to analyse the mRNA levels of 8,000 genes in Arabidopsis thaliana throughout the day/night cycle. Genes involved in signal transduction and in various metabolic pathways were found to be coordinately regulated by circadian rhythms and/or by light.
Arabidopsis↗
How similar are daily and seasonal biological clocks?
Daily and seasonal timing systems in insects have usually been supposed to share similar mechanisms, because both rely in large measure on information from the daily light-dark cycle: daily clocks can ensure that activity coincides with the appropriate time of day, and seasonal time is indicated most reliably by daylength. However, several lines of evidence suggest that the systems are different. For example, receptor features, photosensitive pigments, clocks, and the effectors that mediate responses to information derived from the clock may have different daily, seasonal and general functions and properties, and several different systems are known. There are many different additional elements in the seasonal response. Therefore, these responses may not rely on similar timing mechanisms, despite the long-standing belief that the seasonal clock has circadian components. Such a difference would be consistent with the fact that temporal responses serve a very wide range of purposes, meeting many different ecological needs on different time frames. Consequently, understanding the seasonal relevance of the photoperiodic responses is more important than revealing any possible involvement with circadian systems.
Animals↗
Comparison between some biological clocks regulating sensory and psychomotor aspects of perception in man.
Regular repetition of one monitor of sensory perception and another of psychomotor perception revealed similar frequency and amplitude aspects of spontaneous endogenous free-running cycles of perception and others of vigilance. The ultradian periodicities of these cycles distinguish between persons with intact nervous systems and those with brain damage.
Adult↗
[A problem of biological clocks. New data on the circadian rhythm of the changes in the state of the human body].
Analysis of time-dependent development of various events in man's life (diseases, traumas traffic accidents, normal delivery, death because of diseases) and physiological processes allowed to reveal the presence of intradian cycle in their dynamics with the period about 4-6 hs. At present possible mechanism(s) of this phenomenon is being discussed.
Biological Clocks↗
[Role of biological clocks in normal conditions, pathology, and in therapy. 2. Clinical chronoradiotherapy of lung cancer].
The present study tests whether body core temperature can serve as a marker rhythm for guiding the timing of the radiotherapy of lung cancer. It was shown that the treatment by radiation at the time of peak core temperature has more effectively then treatment at other circadian stages here investigated.
Biological Clocks↗
[The role of biological clocks in formation of standards, pathology, and in therapy. 1. Chronobiological aspects of formation of blood pressure in children with positive and negative family history of relatively high blood pressure].
There are a difference in average values and in amplitudes of about-7 and monthly rhythms of infants' blood pressure with positive and negative family history to the hypertension. Chronobiological approach to these problem can reveal hypertension risk at the early stage of life.
Biological Clocks↗
Biological clock in total darkness: the Clock/MOP3 circadian system of the blind subterranean mole rat.
Blind subterranean mole rats retain a degenerated, subcutaneous, visually blind but functionally circadian eye involved in photoperiodic perception. Here we describe the cloning, sequence, and expression of the circadian Clock and MOP3 cDNAs of the Spalax ehrenbergi superspecies in Israel. Both genes are relatively conserved, although characterized by a significant number of amino acid substitutions. The glutamine-rich area of Clock, which is assumed to function in circadian rhythmicity, is expanded in Spalax compared with that of humans and mice, and is different in amino acid composition from that of rats. We also show that MOP3 is a bona fide partner of Spalax Clock and that the Spalax Clock/MOP3 dimer is less potent than its human counterpart in driving transcription. We suggest that this reduction in transcriptional activity may be attributed to the Spalax Clock glutamine-rich domain, which is unique in its amino acid composition compared with other studied mammalian species. Understanding Clock/MOP3 function could highlight circadian mechanisms in blind mammals and their unique pattern as a result of adapting to life underground.
ARNTL Transcription Factors↗
Circadian rhythms of cyanobacteria: monitoring the biological clocks of individual colonies by bioluminescence.
Reproducible circadian rhythms of bioluminescence from individual colonies of cyanobacteria (Synechococcus sp. strain PCC 7942) has been observed. Phenotypic monitoring of colonies on agar plates will enable us to genetically analyze the molecular mechanism of the circadian clock of cyanobacteria by screening for clock mutants. By the introduction of a bacterial luciferase gene, we previously developed a transformed cyanobacterial strain (AMC149) that expresses luciferase as a bioluminescent reporter of the circadian clock. In liquid culture, AMC149 expresses a rhythm of bioluminescence that displays the same behavior as circadian rhythms in higher eukaryotes. Improvements in the technique for administering the reporter enzyme's substrate (decanal) and a highly sensitive photon-counting camera allow monitoring the bioluminescence of single colonies. Individual colonies on agar plates displayed a rhythmicity which is essentially the same as that previously reported for liquid cultures.
Biological Clocks↗