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Molecular and Cellular Mechanisms of Circadian Rhythms

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 July 2017) | Viewed by 99054

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Special Issue Editor

Prof. Dr. Irina V. Zhdanova

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Guest Editor

Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, MA 02118, USA
Interests: sleep; circadian rhythm disorders; ageing; drugs of abuse; adult neurogenesis

Special Issue Information

Dear Colleagues,

In tune with the unique 24-h rhythm of our planet, a remarkable constellation of well-conserved genes provides temporal context to a variety of essential cellular, physiological and behavioral processes. The discoveries of the past few decades, outlining the molecular and cellular mechanisms of the biological clock, gave rise to the multi-disciplinary field of chronobiology. From a scientific curiosity, the clock became a focus of in-depth experimental and theoretical investigation into the role of timing in normal organismal functions. The impact of altered clock on the development or progression of major human disorders, from cancer to mental illness, is becoming increasingly evident. In spite of this outstanding progress, chronobiology remains a field full of mysteries. Why the clock is “circa-dian”? Does this reflect a nature’s error or there is a different adaptive value in having a period shorter or longer than 24h? How does the same type of clock, entrained to the same light-dark cycle defines nighttime sleep and daytime feeding in diurnal species like ourselves, and an inverse schedule in nocturnal mice? Can a timing error in one system, an organ, or even particular region of the brain through off temporal synergy of the entire organism, causing physical or mental illness? Could individualized timing of drug administration or medical procedure provide superior standard of prophylactic and therapy? The answers to these and many other questions still lie in the details of the core clock mechanisms and clock-controlled molecular networks, their inter-individual differences and sensitivity to periodically changing environment and pharmacological interventions.

This Special Issue, "Molecular and Cellular Mechanisms of Circadian Rhythms", will cover a selection of topics in the field of chronobiology, highlighting the role of the clock mechanisms in development and ageing, health and disease. Original studies, up-to-date review articles, and commentaries are all welcome.

Prof. Dr. Irina V. Zhdanova
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

circadian rhythms
suprachiasmatic nucleus (SCN)
chronobiology
clock genes
clock-controlled
chronotherapy
jet lag
shift work

Published Papers (13 papers)

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Research

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2133 KiB

Open AccessArticle

Impaired Sleep, Circadian Rhythms and Neurogenesis in Diet-Induced Premature Aging

by Alexander J. Stankiewicz, Erin M. McGowan, Lili Yu and Irina V. Zhdanova

Int. J. Mol. Sci. 2017, 18(11), 2243; https://doi.org/10.3390/ijms18112243 - 26 Oct 2017

Cited by 20 | Viewed by 7081

Abstract

Chronic high caloric intake (HCI) is a risk factor for multiple major human disorders, from diabetes to neurodegeneration. Mounting evidence suggests a significant contribution of circadian misalignment and sleep alterations to this phenomenon. An inverse temporal relationship between sleep, activity, food intake, and clock mechanisms in nocturnal and diurnal animals suggests that a search for effective therapeutic approaches can benefit from the use of diurnal animal models. Here, we show that, similar to normal aging, HCI leads to the reduction in daily amplitude of expression for core clock genes, a decline in sleep duration, an increase in scoliosis, and anxiety-like behavior. A remarkable decline in adult neurogenesis in 1-year old HCI animals, amounting to only 21% of that in age-matched Control, exceeds age-dependent decline observed in normal 3-year old zebrafish. This is associated with misalignment or reduced amplitude of daily patterns for principal cell cycle regulators, cyclins A and B, and p20, in brain tissue. Together, these data establish HCI in zebrafish as a model for metabolically induced premature aging of sleep, circadian functions, and adult neurogenesis, allowing for a high throughput approach to mechanistic studies and drug trials in a diurnal vertebrate. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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Open AccessArticle

Circadian Rhythms of Retinomotor Movement in a Marine Megapredator, the Atlantic Tarpon, Megalops atlanticus

by Kristin L. Kopperud and Michael S. Grace

Int. J. Mol. Sci. 2017, 18(10), 2068; https://doi.org/10.3390/ijms18102068 - 28 Sep 2017

Cited by 4 | Viewed by 5799

Abstract

Many ecologically and economically important marine fish species worldwide spend portions of their lives in coastal regions that are increasingly inundated by artificial light at night. However, while extensive research illustrates the harmful effects of inappropriate light exposure on biological timing in humans, rodents and birds, comparable studies on marine fish are virtually nonexistent. This study aimed to assess the effects of light on biological clock function in the marine fish retina using the Atlantic tarpon (Megalops atlanticus) as a model. Using anti-opsin immunofluorescence, we observed robust rhythms of photoreceptor outer segment position (retinomotor movement) over the course of the daily light–dark cycle: cone outer segments were contracted toward the inner retina and rods were elongated during the day; the opposite occurred at night. Phase shifting the daily light–dark cycle caused a corresponding shift of retinomotor movement timing, and cone retinomotor movement persisted in constant darkness, indicating control by a circadian clock. Constant light abolished retinomotor movements of both photoreceptor types. Thus, abnormally-timed light exposure may disrupt normal M. atlanticus clock function and harm vision, which in turn may affect prey capture and predator avoidance. These results should help inform efforts to mitigate the effects of coastal light pollution on organisms in marine ecosystems. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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2957 KiB

Open AccessArticle

Daytime-Dependent Changes of Cannabinoid Receptor Type 1 and Type 2 Expression in Rat Liver

by Ivonne Bazwinsky-Wutschke, Alexander Zipprich and Faramarz Dehghani

Int. J. Mol. Sci. 2017, 18(9), 1844; https://doi.org/10.3390/ijms18091844 - 24 Aug 2017

Cited by 12 | Viewed by 5447

Abstract

The present study was performed to investigate the diurnal expression pattern of cannabinoid receptor type 1 (CB₁) and type 2 (CB₂) in liver tissue of 12- and 51-week-old normoglycemic Wistar rats. By using real-time RT-PCR, daytime dependent changes in both age groups and, for both, hepatic Cnr1 and Cnr2 receptor mRNA levels were measured. Highest amount of mRNA was detected in the light period (ZT3, ZT6, and ZT9) while the lowest amount was measured in the dark period (ZT18 and ZT21). Diurnal transcript expression pattern was accompanied by comparable changes of protein level for CB₁, as shown by Western blotting. The current results support the conclusion that expression pattern of cannabinoid receptors are influenced by light/dark cycle and therefore seems to be under the control of a diurnal rhythm. These findings might explain the differences in the efficacy of cannabinoid receptor agonists or antagonists. In addition, investigation of liver of streptozotocin (STZ)-treated 12- and 51-week-old rats show alterations in the diurnal profile of both receptors Cnr1 and Cnr2 compared to that of normoglycemic Wistar rats. This suggests an influence of diabetic state on diurnal expression levels of cannabinoid receptors. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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Open AccessArticle

Variation within Variation: Comparison of 24-h Rhythm in Rodent Infarct Size between Ischemia Reperfusion and Permanent Ligation

by Bastiaan Du Pré, Toon Van Veen, Sandra Crnko, Marc Vos, Janine Deddens, Pieter Doevendans and Linda Van Laake

Int. J. Mol. Sci. 2017, 18(8), 1670; https://doi.org/10.3390/ijms18081670 - 01 Aug 2017

Cited by 10 | Viewed by 3657

Abstract

The detrimental effects of myocardial infarction in humans and rodents have a 24-h rhythm. In some human cohorts however, rhythmicity was absent, while the time of maximum damage differs between cohorts. We hypothesized that the type of damage influences the 24-h rhythm in infarct size. Myocardial infarction was induced in 12-week-old C57BL/six mice at four different time-points during the day using either permanent ligation (PL) or 30-min of ischemia followed by reperfusion (IR), with a control group wherein no ligation was applied. Infarct size was measured by echocardiography and histology at a 1-month follow-up. Rhythmicity in infarct size was present in the PL group at the functional and histological level, with maximal damage occurring when the infarct was induced at noon. In the IR group, no circadian rhythm was found. The time of the coronary artery ligation determines the outcome of myocardial infarction. Our data showed that in rodents, the presence of circadian rhythmicity and time of peak infarct size varies between experimental setups. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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Open AccessArticle

Entrainment of Breast Cell Lines Results in Rhythmic Fluctuations of MicroRNAs

by Rafael Chacolla-Huaringa, Jorge Moreno-Cuevas, Victor Trevino and Sean-Patrick Scott

Int. J. Mol. Sci. 2017, 18(7), 1499; https://doi.org/10.3390/ijms18071499 - 12 Jul 2017

Cited by 14 | Viewed by 5701

Abstract

Circadian rhythms are essential for temporal (~24 h) regulation of molecular processes in diverse species. Dysregulation of circadian gene expression has been implicated in the pathogenesis of various disorders, including hypertension, diabetes, depression, and cancer. Recently, microRNAs (miRNAs) have been identified as critical modulators of gene expression post-transcriptionally, and perhaps involved in circadian clock architecture or their output functions. The aim of the present study is to explore the temporal expression of miRNAs among entrained breast cell lines. For this purpose, we evaluated the temporal (28 h) expression of 2006 miRNAs in MCF-10A, MCF-7, and MDA-MB-231 cells using microarrays after serum shock entrainment. We noted hundreds of miRNAs that exhibit rhythmic fluctuations in each breast cell line, and some of them across two or three cell lines. Afterwards, we validated the rhythmic profiles exhibited by miR-141-5p, miR-1225-5p, miR-17-5p, miR-222-5p, miR-769-3p, and miR-548ay-3p in the above cell lines, as well as in ZR-7530 and HCC-1954 using RT-qPCR. Our results show that serum shock entrainment in breast cells lines induces rhythmic fluctuations of distinct sets of miRNAs, which have the potential to be related to endogenous circadian clock, but extensive investigation is required to elucidate that connection. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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1688 KiB

Open AccessArticle

Circadian Rhythm Shapes the Gut Microbiota Affecting Host Radiosensitivity

by Ming Cui, Huiwen Xiao, Dan Luo, Xin Zhang, Shuyi Zhao, Qisheng Zheng, Yuan Li, Yu Zhao, Jiali Dong, Hang Li, Haichao Wang and Saijun Fan

Int. J. Mol. Sci. 2016, 17(11), 1786; https://doi.org/10.3390/ijms17111786 - 26 Oct 2016

Cited by 61 | Viewed by 9684

Abstract

Modern lifestyles, such as shift work, nocturnal social activities, and jet lag, disturb the circadian rhythm. The interaction between mammals and the co-evolved intestinal microbiota modulates host physiopathological processes. Radiotherapy is a cornerstone of modern management of malignancies; however, it was previously unknown whether circadian rhythm disorder impairs prognosis after radiotherapy. To investigate the effect of circadian rhythm on radiotherapy, C57BL/6 mice were housed in different dark/light cycles, and their intestinal bacterial compositions were compared using high throughput sequencing. The survival rate, body weight, and food intake of mice in diverse cohorts were measured following irradiation exposure. Finally, the enteric bacterial composition of irradiated mice that experienced different dark/light cycles was assessed using 16S RNA sequencing. Intriguingly, mice housed in aberrant light cycles harbored a reduction of observed intestinal bacterial species and shifts of gut bacterial composition compared with those of the mice kept under 12 h dark/12 h light cycles, resulting in a decrease of host radioresistance. Moreover, the alteration of enteric bacterial composition of mice in different groups was dissimilar. Our findings provide novel insights into the effects of biological clocks on the gut bacterial composition, and underpin that the circadian rhythm influences the prognosis of patients after radiotherapy in a preclinical setting. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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Review

Jump to: Research

15 pages, 823 KiB

Open AccessReview

Potential Roles of Dec and Bmal1 Genes in Interconnecting Circadian Clock and Energy Metabolism

by Fuyuki Sato, Akira Kohsaka, Ujjal K. Bhawal and Yasuteru Muragaki

Int. J. Mol. Sci. 2018, 19(3), 781; https://doi.org/10.3390/ijms19030781 - 08 Mar 2018

Cited by 49 | Viewed by 8951

Abstract

The daily rhythm of mammalian energy metabolism is subject to the circadian clock system, which is made up of the molecular clock machinery residing in nearly all cells throughout the body. The clock genes have been revealed not only to form the molecular clock but also to function as a mediator that regulates both circadian and metabolic functions. While the circadian signals generated by clock genes produce metabolic rhythms, clock gene function is tightly coupled to fundamental metabolic processes such as glucose and lipid metabolism. Therefore, defects in the clock genes not only result in the dysregulation of physiological rhythms but also induce metabolic disorders including diabetes and obesity. Among the clock genes, Dec1 (Bhlhe40/Stra13/Sharp2), Dec2 (Bhlhe41/Sharp1), and Bmal1 (Mop3/Arntl) have been shown to be particularly relevant to the regulation of energy metabolism at the cellular, tissue, and organismal levels. This paper reviews our current knowledge of the roles of Dec1, Dec2, and Bmal1 in coordinating the circadian and metabolic pathways. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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21 pages, 973 KiB

Open AccessReview

Altered Circadian Timing System-Mediated Non-Dipping Pattern of Blood Pressure and Associated Cardiovascular Disorders in Metabolic and Kidney Diseases

by Asadur Rahman, Arif Ul Hasan, Akira Nishiyama and Hiroyuki Kobori

Int. J. Mol. Sci. 2018, 19(2), 400; https://doi.org/10.3390/ijms19020400 - 30 Jan 2018

Cited by 26 | Viewed by 7909

Abstract

The morning surge in blood pressure (BP) coincides with increased cardiovascular (CV) events. This strongly suggests that an altered circadian rhythm of BP plays a crucial role in the development of CV disease (CVD). A disrupted circadian rhythm of BP, such as the non-dipping type of hypertension (i.e., absence of nocturnal BP decline), is frequently observed in metabolic disorders and chronic kidney disease (CKD). The circadian timing system, controlled by the central clock in the suprachiasmatic nucleus of the hypothalamus and/or by peripheral clocks in the heart, vasculature, and kidneys, modulates the 24 h oscillation of BP. However, little information is available regarding the molecular and cellular mechanisms of an altered circadian timing system-mediated disrupted dipping pattern of BP in metabolic disorders and CKD that can lead to the development of CV events. A more thorough understanding of this pathogenesis could provide novel therapeutic strategies for the management of CVD. This short review will address our and others’ recent findings on the molecular mechanisms that may affect the dipping pattern of BP in metabolic dysfunction and kidney disease and its association with CV disorders. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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Open AccessReview

Regulation of the Rhythmic Emission of Plant Volatiles by the Circadian Clock

by Lanting Zeng, Xiaoqin Wang, Ming Kang, Fang Dong and Ziyin Yang

Int. J. Mol. Sci. 2017, 18(11), 2408; https://doi.org/10.3390/ijms18112408 - 13 Nov 2017

Cited by 18 | Viewed by 5181

Abstract

Like other organisms, plants have endogenous biological clocks that enable them to organize their metabolic, physiological, and developmental processes. The representative biological clock is the circadian system that regulates daily (24-h) rhythms. Circadian-regulated changes in growth have been observed in numerous plants. Evidence from many recent studies indicates that the circadian clock regulates a multitude of factors that affect plant metabolites, especially emitted volatiles that have important ecological functions. Here, we review recent progress in research on plant volatiles showing rhythmic emission under the regulation of the circadian clock, and on how the circadian clock controls the rhythmic emission of plant volatiles. We also discuss the potential impact of other factors on the circadian rhythmic emission of plant volatiles. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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1562 KiB

Open AccessReview

Molecular Aspects of Circadian Pharmacology and Relevance for Cancer Chronotherapy

by Narin Ozturk, Dilek Ozturk, Ibrahim Halil Kavakli and Alper Okyar

Int. J. Mol. Sci. 2017, 18(10), 2168; https://doi.org/10.3390/ijms18102168 - 17 Oct 2017

Cited by 63 | Viewed by 8026

Abstract

The circadian timing system (CTS) controls various biological functions in mammals including xenobiotic metabolism and detoxification, immune functions, cell cycle events, apoptosis and angiogenesis. Although the importance of the CTS is well known in the pharmacology of drugs, it is less appreciated at the clinical level. Genome-wide studies highlighted that the majority of drug target genes are controlled by CTS. This suggests that chronotherapeutic approaches should be taken for many drugs to enhance their effectiveness. Currently chronotherapeutic approaches are successfully applied in the treatment of different types of cancers. The chronotherapy approach has improved the tolerability and antitumor efficacy of anticancer drugs both in experimental animals and in cancer patients. Thus, chronobiological studies have been of importance in determining the most appropriate time of administration of anticancer agents to minimize their side effects or toxicity and enhance treatment efficacy, so as to optimize the therapeutic ratio. This review focuses on the underlying mechanisms of the circadian pharmacology i.e., chronopharmacokinetics and chronopharmacodynamics of anticancer agents with the molecular aspects, and provides an overview of chronotherapy in cancer and some of the recent advances in the development of chronopharmaceutics. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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1530 KiB

Open AccessReview

The Drosophila TRPA1 Channel and Neuronal Circuits Controlling Rhythmic Behaviours and Sleep in Response to Environmental Temperature

by Sanne Roessingh and Ralf Stanewsky

Int. J. Mol. Sci. 2017, 18(10), 2028; https://doi.org/10.3390/ijms18102028 - 03 Oct 2017

Cited by 15 | Viewed by 7888

Abstract

trpA1 encodes a thermosensitive transient receptor potential channel (TRP channel) that functions in selection of preferred temperatures and noxious heat avoidance. In this review, we discuss the evidence for a role of TRPA1 in the control of rhythmic behaviours in Drosophila melanogaster. Activity levels during the afternoon and rhythmic temperature preference are both regulated by TRPA1. In contrast, TRPA1 is dispensable for temperature synchronisation of circadian clocks. We discuss the neuronal basis of TRPA1-mediated temperature effects on rhythmic behaviours, and conclude that they are mediated by partly overlapping but distinct neuronal circuits. We have previously shown that TRPA1 is required to maintain siesta sleep under warm temperature cycles. Here, we present new data investigating the neuronal circuit responsible for this regulation. First, we discuss the difficulties that remain in identifying the responsible neurons. Second, we discuss the role of clock neurons (s-LNv/DN1 network) in temperature-driven regulation of siesta sleep, and highlight the role of TRPA1 therein. Finally, we discuss the sexual dimorphic nature of siesta sleep and propose that the s-LNv/DN1 clock network could play a role in the integration of environmental information, mating status and other internal drives, to appropriately drive adaptive sleep/wake behaviour. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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945 KiB

Open AccessReview

Circadian Rhythm Neuropeptides in Drosophila: Signals for Normal Circadian Function and Circadian Neurodegenerative Disease

by Qiankun He, Binbin Wu, Jeffrey L. Price and Zhangwu Zhao

Int. J. Mol. Sci. 2017, 18(4), 886; https://doi.org/10.3390/ijms18040886 - 21 Apr 2017

Cited by 19 | Viewed by 7240

Abstract

Circadian rhythm is a ubiquitous phenomenon in many organisms ranging from prokaryotes to eukaryotes. During more than four decades, the intrinsic and exogenous regulations of circadian rhythm have been studied. This review summarizes the core endogenous oscillation in Drosophila and then focuses on the neuropeptides, neurotransmitters and hormones that mediate its outputs and integration in Drosophila and the links between several of these (pigment dispersing factor (PDF) and insulin-like peptides) and neurodegenerative disease. These signaling molecules convey important network connectivity and signaling information for normal circadian function, but PDF and insulin-like peptides can also convey signals that lead to apoptosis, enhanced neurodegeneration and cognitive decline in flies carrying circadian mutations or in a senescent state. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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854 KiB

Open AccessReview

Circadian Clock, Cell Division, and Cancer: From Molecules to Organism

by Anton Shostak

Int. J. Mol. Sci. 2017, 18(4), 873; https://doi.org/10.3390/ijms18040873 - 20 Apr 2017

Cited by 122 | Viewed by 15278

Abstract

As a response to environmental changes driven by the Earth’s axial rotation, most organisms evolved an internal biological timer—the so called circadian clock—which regulates physiology and behavior in a rhythmic fashion. Emerging evidence suggests an intimate interplay between the circadian clock and another fundamental rhythmic process, the cell cycle. However, the precise mechanisms of this connection are not fully understood. Disruption of circadian rhythms has a profound impact on cell division and cancer development and, vice versa, malignant transformation causes disturbances of the circadian clock. Conventional knowledge attributes tumor suppressor properties to the circadian clock. However, this implication might be context-dependent, since, under certain conditions, the clock can also promote tumorigenesis. Therefore, a better understanding of the molecular links regulating the physiological balance between the two cycles will have potential significance for the treatment of cancer and associated disorders. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Circadian Rhythms)

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