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PubMed2006

The expression of the clock protein PER2 in the limbic forebrain is modulated by the estrous cycle.

Daily behavioral and physiological rhythms are linked to circadian oscillations of clock genes in the brain and periphery that are synchronized by the master clock in the suprachiasmatic nucleus. In addition, there are a number of inputs that can influence circadian oscillations in clock gene expression in a tissue-specific manner. Here we identify an influence on the circadian oscillation of the clock protein PER2, endogenous changes in ovarian steroids, within two nuclei of the limbic forebrain: the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala. We show that the daily rhythm of PER2 expression within these nuclei but not in the suprachiasmatic nucleus, dentate gyrus, or basolateral amygdala is blunted in the metestrus and diestrus phases of the estrus cycle. The blunting of the PER2 rhythm at these phases of the cycle is abolished by ovariectomy and restored by phasic estrogen replacement suggesting that fluctuations in estrogen levels or their sequelae are necessary to produce these effects. The finding that fluctuations in ovarian hormones have area-specific effects on clock gene expression in the brain introduces a new level of organizational complexity in the control of circadian rhythms of behavior and physiology.

Animals↗
PubMed2006

Veela defines a molecular link between Cryptochrome and Timeless in the light-input pathway to Drosophila's circadian clock.

Organisms use the daily cycles of light and darkness to synchronize their internal circadian clocks with the environment. Because they optimize physiological processes and behavior, properly synchronized circadian clocks are thought to be important for the overall fitness. In Drosophila melanogaster, the circadian clock is synchronized with the natural environment by light-dependent degradation of the clock protein Timeless, mediated by the blue-light photoreceptor Cryptochrome (Cry). Here we report identification of a genetic variant, Veela, which severely disrupts this process, because these genetically altered flies maintain behavioral and molecular rhythmicity under constant-light conditions that usually stop the clock. We show that the Veela strain carries a natural timeless allele (ls-tim), which encodes a less-light-sensitive form of Timeless in combination with a mutant variant of the F-box protein Jetlag. However, neither the ls-tim nor the jetlag genetic variant alone is sufficient to disrupt light input into the central pacemaker. We show a strong interaction between Veela and cryptochrome genetic variants, demonstrating that the Jetlag, Timeless, and Cry proteins function in the same pathway. Veela also reveals a function for the two natural variants of timeless, which differ in their sensitivity to light. In combination with the complex array of retinal and extraretinal photoreceptors known to signal light to the pacemaker, this previously undescribed molecular component of photic sensitivity mediated by the two Timeless proteins reveals that an unexpectedly rich complexity underlies modulation of this process.

Alleles↗
PubMed2001

A cell-based system that recapitulates the dynamic light-dependent regulation of the vertebrate clock.

The primary hallmark of circadian clocks is their ability to entrain to environmental stimuli. The dominant, and therefore most physiologically important, entraining stimulus comes from environmental light cycles. Here we describe the establishment and characterization of a new cell line, designated Z3, which derives from zebrafish embryos and contains an independent, light-entrainable circadian oscillator. Using this system, we show distinct and differential light-dependent gene activation for several central clock components. In particular, activation of Per2 expression is shown to be strictly regulated and dependent on light. Furthermore, we demonstrate that Per1, Per2, and Per3 all have distinct responses to light-dark (LD) cycles and light-pulse treatments. We also show that Clock, Bmal1, and Bmal2 all oscillate under LD and dark-dark conditions with similar kinetics, but only Clock is significantly induced while initiating a light-induced circadian oscillation in Z3 cells that have never been exposed to a LD cycle. Finally, our results suggest that Per2 is responsible for establishing the phase of a circadian rhythm entraining to an alternate LD cycle. These findings not only underscore the complexity by which central clock genes are regulated, but also establishes the Z3 cells as an invaluable system for investigating the links between light-dependent gene activation and the signaling pathways responsible for vertebrate circadian rhythms.

Animals↗
PubMed1988

On the role of protein synthesis in the circadian clock of Neurospora crassa.

Inhibitors of protein synthesis reset the biological clocks of many organisms. This has been interpreted to mean either that the synthesis per se of proteins is a step in the oscillatory feedback loop or merely that certain unstable protein(s) are required at certain times of the cycle to complete the feedback loop. We report here that Neurospora strains bearing the clock mutation frq-7 are relatively insensitive to the resetting action of the protein-synthesis-inhibitor cycloheximide. Protein synthesis itself in this mutant is inhibited by the drug to the same extent as in wild type. Since the clock of frq-7 continues to run relatively unimpeded even in the virtual absence of protein synthesis, it is unlikely that synthesis per se can be a part of the feedback cycle. Rather, we suggest that for normal operation of the Neurospora clock, certain protein(s) with a high turnover rate are required daily and, thus, must be resynthesized each day (at least) during discrete times in the cycle. The frq-7 mutation simultaneously alters several distinct clock characteristics--period length, temperature compensation, and resetting by cycloheximide. A model is presented to unify these observations.

Circadian Rhythm↗
PubMed1994

The superoxide dismutase molecular clock revisited.

The Cu,Zn superoxide dismutase (SOD) was examined earlier and found to behave in a very unclock-like manner despite (accepted point mutation, or PAM) corrections for multiple replacements per site. Depending upon the time span involved, rates could differ 5-fold. We have sought to determine whether the data might be clock-like if a covarion model were used. We first determined that the number of concomitantly variable codons (covarions) in SOD is 28. With that value fixed we found that the observations for SOD could fit reasonably well a molecular clock if, given 28 covarions, (i) there are approximately six replacements every 10 million years, (ii) the total number of codons is 162, (iii) the number of codons that are permanently invariable across the range of taxa from fungi to mammals is 44, and (iv) the persistence of variability is quite low (0.01). Thus, the inconsistent number of amino acid differences between various pairs of descendent sequences could well be the result of a fairly accurate molecular clock. The general conclusion has two sides: (i) the inference that a given gene is a bad clock may sometimes arise through a failure to take all the relevant biology into account and (ii) one should examine the possibility that different subsets of amino acids are evolving at different rates, because otherwise the assumption of a clock may yield erroneous estimates of divergence times on the basis of the observed number of amino acid differences.

Animals↗
PubMed1995

Functional dissection of circadian clock- and phytochrome-regulated transcription of the Arabidopsis CAB2 gene.

Both the circadian clock and phytochrome regulate expression of the Arabidopsis genes encoding the light-harvesting chlorophyll a/b-binding proteins (CAB genes). Phytochrome activates CAB transcription, and it has been proposed that the circadian clock negatively regulates CAB transcription. The tobacco nuclear proteins CUF-1 (CAB upstream factor 1) and CGF-1 (CAB GATA factor 1) bind the Arabidopsis CAB2 promoter, and the CGF-1 binding site is contained within a minimal clock- and phytochrome-regulated region of the promoter. We have used in vivo cab2::luciferase gene bioluminescence markers containing site-directed mutations in the CUF-1 and CGF-1 binding sites to define the role of these proteins in CAB2 regulation and to further delineate the terminal genomic targets of the phytochrome and circadian clock signal transduction pathways. Results from these studies confirm that CUF-1 is not required to generate the circadian clock- or phytochrome-responsive CAB2 expression pattern but rather functions as a positive factor to increase CAB2 expression levels. CGF-1 interaction with the CAB2 promoter mediates the acute increase in CAB2 expression in response to phytochrome activation and contributes to the light-induced high-amplitude circadian oscillation in CAB2 expression.

Arabidopsis↗
PubMed1999

The circadian clock controls the expression pattern of the circadian input photoreceptor, phytochrome B.

Developmental and physiological responses are regulated by light throughout the entire life cycle of higher plants. To sense changes in the light environment, plants have developed various photoreceptors, including the red/far-red light-absorbing phytochromes and blue light-absorbing cryptochromes. A wide variety of physiological responses, including most light responses, also are modulated by circadian rhythms that are generated by an endogenous oscillator, the circadian clock. To provide information on local time, circadian clocks are synchronized and entrained by environmental time cues, of which light is among the most important. Light-driven entrainment of the Arabidopsis circadian clock has been shown to be mediated by phytochrome A (phyA), phytochrome B (phyB), and cryptochromes 1 and 2, thus affirming the roles of these photoreceptors as input regulators to the plant circadian clock. Here we show that the expression of PHYB::LUC reporter genes containing the promoter and 5' untranslated region of the tobacco NtPHYB1 or Arabidopsis AtPHYB genes fused to the luciferase (LUC) gene exhibit robust circadian oscillations in transgenic plants. We demonstrate that the abundance of PHYB RNA retains this circadian regulation and use a PHYB::Luc fusion protein to show that the rate of PHYB synthesis is also rhythmic. The abundance of bulk PHYB protein, however, exhibits only weak circadian rhythmicity, if any. These data suggest that photoreceptor gene expression patterns may be significant in the daily regulation of plant physiology and indicate an unexpectedly intimate relationship between the components of the input pathway and the putative circadian clock mechanism in higher plants.

Circadian Rhythm↗
PubMed2002

The circadian clock as a molecular calendar.

There are two dominant environmental oscillators shaping the living conditions of our world: the day-night cycle and the succession of the seasons. Organisms have adapted to these by evolving internal clocks to anticipate these variations. An orchestra of finely tuned peripheral clocks slaved to the master pacemaker of the suprachiasmatic nuclei (SCN) synchronizes the body to the daily 24h cycle. However, this circadian clockwork closely interacts with the seasonal time-teller. Recent experiments indeed show that photoperiod--the dominant Zeitgeber of the circannual clock--might be deciphered by the organism using the tools of the circadian clock itself. From the SCN, the photoperiodic signal is transferred to the pineal where it is decoded as a varying secretion of melatonin. Different models have been proposed to explain the mechanism by which the circadian clock measures day-length. Recent work using mutant mice suggests a set of two molecular oscillators tracking dusk and dawn, respectively, thereby translating day-length to the body. However, not every aspect of photoperiodism is covered by this theory and majoradjustments will need tobe made toestablish a widely acceptable uniform model of circadian/circannual timekeeping.

Animals↗
PubMed2006

Maximum likelihood molecular clock comb: analytic solutions.

Maximum likelihood (ML) is increasingly used as an optimality criterion for selecting evolutionary trees, but finding the global optimum is a hard computational task. Because no general analytic solution is known, numeric techniques such as hill climbing or expectation maximization (EM), are used in order to find optimal parameters for a given tree. So far, analytic solutions were derived only for the simplest model--three taxa, two state characters, under a molecular clock. Four taxa rooted trees have two topologies--the fork (two subtrees with two leaves each) and the comb (one subtree with three leaves, the other with a single leaf). In a previous work, we devised a closed form analytic solution for the ML molecular clock fork. In this work, we extend the state of the art in the area of analytic solutions ML trees to the family of all four taxa trees under the molecular clock assumption. The change from the fork topology to the comb incurs a major increase in the complexity of the underlying algebraic system and requires novel techniques and approaches. We combine the ultrametric properties of molecular clock trees with the Hadamard conjugation to derive a number of topology dependent identities. Employing these identities, we substantially simplify the system of polynomial equations. We finally use tools from algebraic geometry (e.g., Gröbner bases, ideal saturation, resultants) and employ symbolic algebra software to obtain analytic solutions for the comb. We show that in contrast to the fork, the comb has no closed form solutions (expressed by radicals in the input data). In general, four taxa trees can have multiple ML points. In contrast, we can now prove that under the molecular clock assumption, the comb has a unique (local and global) ML point. (Such uniqueness was previously shown for the fork.).

Evolution, Molecular↗
PubMed1991

Clock drawing in acute stroke.

We studied 118 elderly subjects with first-ever stroke free of severe cognitive impairment and able to write. Within 14 days of stroke we measured clock drawing, ability to copy drawings of dual pentagons and a house, line bisection, Mini-Mental State score, homonymous hemianopia and visual and tactile extinction. Thirty subjects had impaired clock drawing. When compared with the remaining 88 subjects with normal clock drawing the impaired group had similar pre-stroke characteristics but had significantly more severe stroke deficits. Hospital stay was significantly longer in the impaired group and a much greater proportion of subjects were discharged to long-term hospitals rather than home. Barthel ADL scores at days 7, 30, 60 and maximal recovery were significantly lower. Using a multivariate generalized linear model, clock drawing was a significant independent predictor of maximal Barthel ADL after accounting for other significant predictors such as Barthel score at day 7, limb power, visual extinction, line bisection error and Mini-Mental State score. Impaired clock drawing can reflect either cognitive impairment or spatial neglect.

Acute Disease↗
PubMed2026

Assessing the influence of different alignment tools on the accuracy of a forensic epigenetic clock.

MOTIVATION: DNA methylation (DNAm) has long been a commonly investigated biomarker in biomedical research. The current gold standard for DNAm detection is bisulfite sequencing which requires dedicated alignment tools that can handle reduced sequence complexity. One commonly used application of DNAm are epigenetic clock measurements. These clocks have been adapted by many fields for their specific needs, including forensic genetics. Here, epigenetic clocks were designed to help estimate the chronological age of a biological stain donor for investigative purposes. RESULTS: In this study, data generated with a well-established forensic epigenetic clock is aligned with four different bisulfite-specific alignment tools: "Bwa-meth," "Abismal," "Bismark," and "BS-Seeker2." For each tool, we tested up to six different settings, altering parameters such as the maximum number of mismatches or the score function setting. The goal was to investigate whether the final predicted ages differed considerably between the tested alignment tools and settings. Quality controls such as read depth, precision, recall, F1 score, and alignment run time were also assessed. To allow other researchers to easily perform such methylation comparison analyses on their own data, a Shiny app called "MethylAge Explorer" was developed within this study. None of the tested settings for the three alignment tools "Abismal," "Bismark," and "BS-Seeker2" outperformed the originally used alignment tool "Bwa-meth" in terms of age prediction accuracy. However, differences in final age predictions were observed between the different alignment tools. Therefore, it is necessary to be aware of which alignment tool to use for particular epigenetic clocks. AVAILABILITY AND IMPLEMENTATION: The data underlying this article and the code for the shiny app are available on GitHub (https://github.com/charlsut/methylage_explorer).

DNA Methylation↗
PubMed2001

Epistatic and synergistic interactions between circadian clock mutations in Neurospora crassa.

We identified a series of epistatic and synergistic interactions among the circadian clock mutations of Neurospora crassa that indicate possible physical interactions among the various clock components encoded by these genes. The period-6 (prd-6) mutation, a short-period temperature-sensitive clock mutation, is epistatic to both the prd-2 and prd-3 mutations. The prd-2 and prd-3 long-period mutations show a synergistic interaction in that the period length of the double mutant strain is considerably longer than predicted. In addition, the prd-2 prd-3 double mutant strain also exhibits overcompensation to changes in ambient temperature, suggesting a role in the temperature compensation machinery of the clock. The prd-2, prd-3, and prd-6 mutations also show significant interactions with the frq(7) long-period mutation. These results suggest that the gene products of prd-2, prd-3, and prd-6 play an important role in both the timing and temperature compensation mechanisms of the circadian clock and may interact with the FRQ protein.

Alleles↗
PubMed2002

An insect molecular clock dates the origin of the insects and accords with palaeontological and biogeographic landmarks.

A unified understanding of >390 Myr of insect evolution requires insight into their origin. Molecular clocks are widely applied for evolutionary dating, but clocks for the class Insecta have remained elusive. We now define a robust nucleotide and amino acid mitochondrial molecular clock encompassing five insect orders, including the Blattaria (cockroaches), Orthoptera (crickets and locusts), Hemiptera (true bugs), Diptera, and Lepidoptera (butterflies and moths). Calibration of the clock using one of the earliest, most extensive fossil records for insects (the early ancestors of extant Blattaria) was congruent with all available insect fossils, with biogeographic history, with the Cambrian explosion, and with independent dating estimates from Lepidopteran families. In addition, dates obtained from both nucleotide and amino acid clocks were congruent with each other. Of particular interest to vector biology is the early date of the emergence of triatomine bugs (99.8-93.5 MYA), coincident with the formation of the South American continent during the breakup of Gondwanaland. More generally, we reveal the insects arising from a common ancestor with the Anostraca (fairy shrimps) at around the Silurian-Ordovician boundary (434.2-421.1 MYA) coinciding with the earliest plant megafossil. We explore Tilyard's theory proposing that the terrestrial transition of the aquatic arthropod ancestor to the insects is associated with a particular plant group (early vascular plants). The major output of the study is a comprehensive series of dates for deep-branching points within insect evolution that can act as calibration points for further dating studies within insect families and genera.

Animals↗
PubMed2006

Circadian clock gene expression in the ovary: Effects of luteinizing hormone.

A molecular device that measures time on a daily, or circadian, scale is a nearly ubiquitous feature of eukaryotic organisms. A core group of clock genes, whose coordinated function is required for this timekeeping, is expressed both in the central clock and within numerous peripheral organs. We examined expression of clock genes in the rat ovary. Transcripts for core oscillator elements (Arntl, Clock, Per1, Per2, and Cry1) were present in the ovary as indicated by quantitative real-time RT-PCR. Rhythmic expression patterns of Arntl and Per2 transcripts and protein products were out of phase with respect to the central oscillator and in complete antiphase to each other. Expression of Arntl was significantly elevated after the LH surge on the day of proestrus. Finally, hCG treatment induced cyclic expression of both Arntl and Per2 gene products in hypophysectomized, immature rats primed with eCG. Collectively, these data suggest that the core underpinnings of the transcriptional/translational feedback loop that drives circadian rhythmicity is present in the rat ovary. Furthermore, the study identifies LH as a potential regulator of circadian clock gene rhythms in the ovary.

ARNTL Transcription Factors↗
PubMed2001

Picking out parallels: plant circadian clocks in context.

Molecular models have been described for the circadian clocks of representatives of several different taxa. Much of the work on the plant circadian system has been carried out using the thale cress, Arabidopsis thaliana, as a model. We discuss the roles of genes implicated in the plant circadian system, with special emphasis on Arabidopsis. Plants have an endogenous clock that regulates many aspects of circadian and photoperiodic behaviour. Despite the discovery of components that resemble those involved in the clocks of animals or fungi, no coherent model of the plant clock has yet been proposed. In this review, we aim to provide an overview of studies of the Arabidopsis circadian system. We shall compare these with results from different taxa and discuss them in the context of what is known about clocks in other organisms.

Animals↗
PubMed2004

Realistic clocks, universal decoherence, and the black hole information paradox.

Ordinary quantum mechanics is formulated on the basis of the existence of an ideal classical clock external to the system under study. This is clearly an idealization. As emphasized originally by Salecker and Wigner and more recently by others, there exist limits in nature to how "classical" even the best possible clock can be. With realistic clocks, quantum mechanics ceases to be unitary and a fundamental mechanism of decoherence of quantum states arises. We estimate the rate of the universal loss of unitarity using optimal realistic clocks. In particular, we observe that the rate is rapid enough to eliminate the black hole information puzzle: all information is lost through the fundamental decoherence before the black hole can evaporate. This improves on a previous calculation we presented with a suboptimal clock in which only part of the information was lost by the time of evaporation.

Journal Article↗
PubMed2006

Magnetic field-induced spectroscopy of forbidden optical transitions with application to lattice-based optical atomic clocks.

We develop a method of spectroscopy that uses a weak static magnetic field to enable direct optical excitation of forbidden electric-dipole transitions that are otherwise prohibitively weak. The power of this scheme is demonstrated using the important application of optical atomic clocks based on neutral atoms confined to an optical lattice. The simple experimental implementation of this method--a single clock laser combined with a dc magnetic field--relaxes stringent requirements in current lattice-based clocks (e.g., magnetic field shielding and light polarization), and could therefore expedite the realization of the extraordinary performance level predicted for these clocks. We estimate that a clock using alkaline-earth-like atoms such as Yb could achieve a fractional frequency uncertainty of well below 10(-17) for the metrologically preferred even isotopes.

Journal Article↗
PubMed2001

Circadian clock-regulated expression of phytochrome and cryptochrome genes in Arabidopsis.

Many physiological and biochemical processes in plants exhibit endogenous rhythms with a period of about 24 h. Endogenous oscillators called circadian clocks regulate these rhythms. The circadian clocks are synchronized to the periodic environmental changes (e.g. day/night cycles) by specific stimuli; among these, the most important is the light. Photoreceptors, phytochromes, and cryptochromes are involved in setting the clock by transducing the light signal to the central oscillator. In this work, we analyzed the spatial, temporal, and long-term light-regulated expression patterns of the Arabidopsis phytochrome (PHYA to PHYE) and cryptochrome (CRY1 and CRY2) promoters fused to the luciferase (LUC(+)) reporter gene. The results revealed new details of the tissue-specific expression and light regulation of the PHYC and CRY1 and 2 promoters. More importantly, the data obtained demonstrate that the activities of the promoter::LUC(+) constructs, with the exception of PHYC::LUC(+), display circadian oscillations under constant conditions. In addition, it is shown by measuring the mRNA abundance of PHY and CRY genes under constant light conditions that the circadian control is also maintained at the level of mRNA accumulation. These observations indicate that the plant circadian clock controls the expression of these photoreceptors, revealing the formation of a new regulatory loop that could modulate gating and resetting of the circadian clock.

Arabidopsis↗