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      Episodic Ultradian Events—Ultradian Rhythms

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          Abstract

          In the fast lane of chronobiology, ultradian events are short-term rhythms that have been observed since the beginning of modern biology and were quantified about a century ago. They are ubiquitous in all biological systems and found in all organisms, from unicellular organisms to mammals, and from single cells to complex biological functions in multicellular animals. Since these events are aperiodic and last for a few minutes to a few hours, they are better classified as episodic ultradian events (EUEs). Their origin is unclear. However, they could have a molecular basis and could be controlled by hormonal inputs—in vertebrates, they originate from the activity of the central nervous system. EUEs are receiving increasing attention but their aperiodic nature requires specific sampling and analytic tools. While longer scale rhythms are adaptations to predictable changes in the environment, in theory, EUEs could contribute to adaptation by preparing organisms and biological functions for unpredictability.

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          Most cited references104

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          Thyroid hormone regulation of metabolism.

          Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5'-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.
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            Interacting molecular loops in the mammalian circadian clock.

            We show that, in the mouse, the core mechanism for the master circadian clock consists of interacting positive and negative transcription and translation feedback loops. Analysis of Clock/Clock mutant mice, homozygous Period2(Brdm1) mutants, and Cryptochrome-deficient mice reveals substantially altered Bmal1 rhythms, consistent with a dominant role of PERIOD2 in the positive regulation of the Bmal1 loop. In vitro analysis of CRYPTOCHROME inhibition of CLOCK: BMAL1-mediated transcription shows that the inhibition is through direct protein:protein interactions, independent of the PERIOD and TIMELESS proteins. PERIOD2 is a positive regulator of the Bmal1 loop, and CRYPTOCHROMES are the negative regulators of the Period and Cryptochrome cycles.
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              Dynamics of the p53-Mdm2 feedback loop in individual cells.

              The tumor suppressor p53, one of the most intensely investigated proteins, is usually studied by experiments that are averaged over cell populations, potentially masking the dynamic behavior in individual cells. We present a system for following, in individual living cells, the dynamics of p53 and its negative regulator Mdm2 (refs. 1,4-7): this system uses functional p53-CFP and Mdm2-YFP fusion proteins and time-lapse fluorescence microscopy. We found that p53 was expressed in a series of discrete pulses after DNA damage. Genetically identical cells had different numbers of pulses: zero, one, two or more. The mean height and duration of each pulse were fixed and did not depend on the amount of DNA damage. The mean number of pulses, however, increased with DNA damage. This approach can be used to study other signaling systems and suggests that the p53-Mdm2 feedback loop generates a 'digital' clock that releases well-timed quanta of p53 until damage is repaired or the cell dies.
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                Author and article information

                Journal
                Biology (Basel)
                Biology (Basel)
                biology
                Biology
                MDPI
                2079-7737
                14 March 2019
                March 2019
                : 8
                : 1
                : 15
                Affiliations
                [1 ]School of Human Sciences, Faculty of Science, The University of Western Australia, 35 Stirling Highway, Crawley 6009, Western Australia, Australia; grace.goh@ 123456uwa.edu.au (G.H.G.); shane.maloney@ 123456uwa.edu.au (S.K.M.) peter.mark@ 123456uwa.edu.au (P.J.M.)
                [2 ]School of Agriculture and Environment and UWA Institute of Agriculture, Faculty of Science, The University of Western Australia, 35 Stirling Highway, Crawley 6009, Western Australia, Australia
                Author notes
                Author information
                https://orcid.org/0000-0001-5431-9939
                https://orcid.org/0000-0002-5878-2266
                https://orcid.org/0000-0003-3476-3068
                Article
                biology-08-00015
                10.3390/biology8010015
                6466064
                30875767
                dbf548c8-a6ca-414a-a1ae-b88b57e3b92f
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 January 2019
                : 09 March 2019
                Categories
                Review

                short-term rhythms,temperature,gene,central nervous system,methodology

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