DISRUPTED DAILY OSCILLATIONS OF CLOCK GENES EXPRESSION AND CLOCK PROTEINS CONTENT IN TUMORS AND DISTANT TISSUES IN HER2/NEU TRANSGENIC MICE

The connection between circadian rhythms and cancer is bilateral at the body and cellular level. Negative impact of tumor development on circadian rhythms represents one of its aspects. Materials and methods. 16 FVB/N and 16 FVB/N transgenic HER2/neu female mice were used in the experiment. 4 mice of each line were euthanized at ZT0 (light switch-on time), ZT6, ZT12 and ZT18. Bmal1, Clock and Cry1 gene expression was evaluated in the suprachiasmatic nucleus, liver, mammary tissue and tumors by real-time PCR. Content of BMAL1 and CLOCK proteins in mammary tissue and tumors was evaluated by immunohistochemistry. Results. Absence of clock genes expression and clock proteins content daily oscillations was observed in spontaneous mammary adenocarcinomas of HER2/neu transgenic mice. We also revealed decrease in peak values of clock genes expression in the suprachiasmatic nucleus, liver and mammary gland in tumor- bearing animals. Conclusions. The obtained data confirm the hypothesis about disruption of circadian rhythms in breast tumors and negative influence of tumors on the rhythms of the whole organism.

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Suprachiasmatic Nucleus Anatomy, Physiology, and Neurochemistry

Oxford Research Encyclopedia of Neuroscience ◽

10.1093/acrefore/9780190264086.013.27 ◽

2018 ◽

Cited By ~ 2

Author(s):

Rae Silver

Keyword(s):

Gene Expression ◽

Circadian Rhythms ◽

Electrical Activity ◽

Suprachiasmatic Nucleus ◽

Clock Gene ◽

Clock Genes ◽

Transgenic Animals ◽

The Body ◽

Network Activity ◽

Over Time

We live in an approximately 24-hour world and circadian rhythms have evolved to adapt organisms to the opportunities presented by Earth’s 24-hour cycle of light and dark. A “master clock” located in the suprachiasmatic nucleus (SCN) of the brain orchestrates daily rhythms in all manner of behavioral, endocrine, metabolic, autonomic, and homeostatic systems in our bodies. The SCN is comprised of about 20,000 neurons and about one third as many astroglia. How can so few neurons and astroglia guide so many rhythms? How do neurons time out an interval as long as a day? The answers are a case study in understanding how genes within cells, and cells within circuits, function together to perform complex activities and optimize bodily functions. While individual clock cells are found in virtually all bodily tissues, the unique connectome of the SCN, its specialized afferent inputs from the retinohypothalamic tract, and its neural and humoral outputs enable its “babel” of neuronal types to synchronize their activity and signal time to the rest of the body. At the molecular-cellular level, circadian rhythms are regulated by a 24-hour transcriptional–translational feedback loop. At the SCN tissue level, individual SCN neurons coordinate their gene expression and electrical activity, working together in circuits that sustain coherent rhythms. The SCN has many distinct cell types based on their neurotransmitters, neuropeptides, and afferent and efferent connections. There has been much progress in unraveling the dynamic network organization that underlies the SCN network’s communications. Though the precise anatomical connections underlying interneuronal communication in the SCN are not completely understood, key signaling mechanisms that sustain the SCN’s intrinsic rhythmicity have been tackled using intersectional genomic tools. Transgenic animals that permit the visualization of clock gene–protein expression have enabled analysis of SCN network activity over time. Availability of animals bearing mutations in clock genes or proteins enable the determination of changes within neurons, among neurons in networks, and their impact on behavior. The use of continuous readouts of circadian activity that track behavior, or clock gene expression, or electrical activity changes over time, within an SCN or a single neuron, leads the way to unraveling mechanisms sustaining the circadian timing system. Because the results of circadian studies generate huge amounts of data, the entry of mathematical modelers and statisticians into the field has begun to yield useful and testable predictions on how these multiplexed systems work to adapt to our 24-hour world.

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Musculoskeletal disorders among robotic surgeons: A questionnaire analysis

Archivio Italiano di Urologia e Andrologia ◽

10.4081/aiua.2014.2.95 ◽

2014 ◽

Vol 86 (2) ◽

pp. 95 ◽

Cited By ~ 17

Author(s):

Claudio Giberti ◽

Fabrizio Gallo ◽

Luca Francini ◽

Alessio Signori ◽

Marco Testa

Keyword(s):

Musculoskeletal Disorders ◽

Surgical Outcomes ◽

Negative Impact ◽

Negative Influence ◽

The Body ◽

Sitting Position ◽

Body Parts ◽

Upper Limbs ◽

Fixed Position ◽

Prolonged Sitting

Objective: Robotic surgical systems offer better workplace in order to relieve surgeons from prolonged physical efforts and improve their surgical outcomes. However, robotic surgery could produce musculoskeletal disorders due to the prolonged sitting position of the operator, the fixed position of the console viewer and the movements of the limbs. Until today, no one study has been reported concerning the association between robotics and musculoskeletal pain. The aim of this work was verify the prevalence of musculoskeletal disorders among Italian robotic surgeons. Material and methods: Between July 2011 and April 2012 a modified Standardized Nordic Questionnaire was delivered to thirty-nine Italian robotic centres. Twentytwo surgeons (56%) returned the questionnaires but only seventeen questionnaires (43.5%) were evaluable. Results: Seven surgeons (41.2%) reported musculoskeletal disorders, by since their first use of the robot which significantly persisted during the daily surgical activity (P < 0.001). Regarding the body parts affected, musculoskeletal disorders were mainly reported in the cervical spine (29.4%) and in the upper limbs (23.5%). Six surgeons (35.3%) defined the robotic console as less comfortable or neither comfortable/uncomfortable with a negative influence on their surgical procedures. Conclusions: In spite of some important limitations, our data showed musculoskeletal disorders due to posture discomfort with negative impact on daily surgical activity among robotic surgeons. These aspects could be due to the lack of ergonomic seat and to the fixed position of the console viewer which could have produced an inadequate spinal posture. The evaluation of these postural factors, in particular the development of an integrated and more ergonomic chair, could further improve the comfort feeling of the surgeon at the console and probably his surgical outcomes.

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Abolished Daily Expression Patterns of SIRT1, SIRT2, and SIRT5 in Human Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v120.21.4613.4613 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4613-4613

Author(s):

Ming-Yu Yang ◽

Pai-Mei Lin ◽

Jui-Feng Hsu ◽

Wen-Chi Yang ◽

Yi-Chang Liu ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Circadian Rhythms ◽

Circadian Clock ◽

Myeloid Leukemia ◽

Clock Genes ◽

Expression Patterns ◽

Healthy Individuals ◽

Daily Pattern ◽

Genes Expression ◽

Circadian Clock Genes

Abstract Abstract 4613 Circadian rhythms regulate various functions of human body and disruption of circadian rhythm has been associated with cancer development and tumor progression. Circadian clock genes use transcriptional-translational feedback loops to control circadian rhythms. Many transcriptional regulators are histone acetyltransferases (HAT) or histone deacetylases (HDAC). As clock function and integration of inputs rely on transcriptional regulation, it is possible that chromatin is remodeled during circadian cycles and in response to signals that regulate the clock. SIRT1 (sirtuin 1) is a HDAC that has recently been identified as a crucial modulator of the circadian clock machinery. To date, at least 7 SIRT genes (SIRT1–7) have been identified. In our previous report we have demonstrated the daily expression patterns of PER1, PER2, PER3, CRY1, CRY2, and CKIe in peripheral blood (PB) of healthy individuals were abolished in chronic myeloid leukemia (CML) patients and partial recoveries of daily patterns were observed in CML patients with complete cytogenetic response (CCyR) and major molecular response (MMR) post-imatinib treatment [J Biol Rhythms 2011]. In this study we further investigated the expression profiles of the 7 SIRT genes (SIRT1–7) in PB total leukocytes from 49 CML and 22 healthy volunteers. Collection of PB was carried out at four time points: 2000 h, 0200 h, 0800 h, and 1400 h, respectively. In PB total leukocytes of healthy individuals, the daily pattern of SIRT1 (p < 0.01) and SIRT5 (p < 0.05) expression level peaked at 0200 h, and SIRT2 (p < 0.01) peaked at 0800 h. Daily pattern expression of these 3 genes was abolished in newly diagnosed pre-imatinib mesylate treated and blast crisis-phase CML patients. Partial daily patterns of gene expression recoveries were observed in CML patients with CCyR and MMR. In some serial monitored individual patients, the recoveries of oscillations of SIRT1, 2, and 5 genes expression accompanied with the disappearance of BCR-ABL transcripts were also noted. The expression of SIRT3, 6, and 7 did not show a time-dependent variation among the healthy and CML patients. SIRT4 expression was undetectable both in the healthy and CML patients. Updated in vitro study results of the regulation of SIRT1, 2, and 5 genes on circadian clock genes expression will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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The Influence of Cold Atmospheric Air on the Environmental Health of Sportsman

Man and Environment. Issues of Neoecology ◽

10.26565/1992-4224-2018-30-14 ◽

2018 ◽

Keyword(s):

Respiratory Tract ◽

Natural Environment ◽

Negative Impact ◽

Negative Influence ◽

Modern Human ◽

The Body ◽

Sporting Events ◽

Cold Environment ◽

Ecological Health ◽

Atmospheric Air

On the basis of a systematic analysis of the scientific literature, it was found that the increased sensitivity of a modern human being to the negative effects of the cold natural environment is due to its passage from the shrouds of East Africa with characteristic high ambient temperatures, primarily atmospheric air. At the same time, in comparative terms, the extinct Neanderthal, with his Eurasian apprehension in the conditions of glacial periods, was on the contrary sufficiently well adapted to the cold environment. The subsequent adaptation of a modern human type at the genetic level with the formation of the main races (Caucasoid, Negroid, Mongoloid) could not sufficiently compensate for its insufficient resistance to the cold environment. According to the results of the research, the main ways of solving the problem of the negative influence of the cold natural environment on the ecological health of athletes were determined: the rationing of the order of sporting activities of athletes depending on the degree of low-temperature environment, diagnosing the athletes' hypersensitivity of the respiratory tract to cold atmospheric air, degree of tension of the processes of thermoregulation of the body. The conclusions are drawn according to which the prevention of the negative impact of extreme conditions of the cold environment (primarily cold atmospheric air) on the ecological health of athletes should be systemic, integrated. The system of preventive measures should include an early diagnosis of the development of airway hyperresponsiveness of athletes to the effects of cold atmospheric air, as well as an assessment of the degree of tension of the body's thermoregulatory system to the effect of cold. In the system of preventing the negative impact of the cold environment on the body of athletes engaged in winter sports in the open space, it is necessary to include regulation (normalization) of the temperature regime of cold atmospheric air when determining the possibility of holding sporting events. If necessary (the presence of hypersensitivity of the airways to the action of cold atmospheric air), it is advisable to use special means of protecting the respiratory tract of athletes from the negative influence of cold atmospheric air.

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Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms

10.1101/2020.10.09.333732 ◽

2020 ◽

Author(s):

Yangbo Xiao ◽

Ye Yuan ◽

Mariana Jimenez ◽

Neeraj Soni ◽

Swathi Yadlapalli

Keyword(s):

Gene Expression ◽

Circadian Rhythms ◽

Nuclear Envelope ◽

Circadian Clock ◽

Clock Genes ◽

Circadian Clocks ◽

Spatiotemporal Organization ◽

Clock Proteins ◽

Expression Behavior ◽

Clock Protein

ABSTRACTCircadian clocks regulate ∼24 hour oscillations in gene expression, behavior, and physiology. While the molecular and neural mechanisms of circadian rhythms are well characterized, how cellular organization of clock components controls circadian clock regulation remains poorly understood. Here, we elucidate how clock proteins regulate circadian rhythms by controlling the spatiotemporal organization of clock genes. Using high-resolution live imaging techniques we demonstrate that Drosophila clock proteins are concentrated in a few discrete foci and are organized at the nuclear envelope; these results are in contrast to longstanding expectations that clock proteins are diffusely distributed in the nucleus. We also show that clock protein foci are highly dynamic and change in number, size, and localization over the circadian cycle. Further, we demonstrate that clock genes are positioned at the nuclear periphery by the clock proteins precisely during the circadian repression phase, suggesting that subnuclear localization of clock genes plays an important role in the control of rhythmic gene expression. Finally, we show that Lamin B receptor, a nuclear envelope protein, is required for peripheral localization of clock protein foci and clock genes and for normal circadian rhythms. These results reveal that clock proteins form dynamic nuclear foci and play a hitherto unexpected role in the subnuclear reorganization of clock genes to control circadian rhythms, identifying a novel mechanism of circadian regulation. Our results further suggest a new role for clock protein foci in the clustering of clock-regulated genes during the repression phase to control gene co-regulation and circadian rhythms.SIGNIFICANCEAlmost all living organisms have evolved circadian clocks to tell time. Circadian clocks regulate ∼24-hour oscillations in gene expression, behavior and physiology. Here, we reveal the surprisingly sophisticated spatiotemporal organization of clock proteins and clock genes and its critical role in circadian clock function. We show, in contrast to current expectations, that clock proteins are concentrated in a few discrete, dynamic nuclear foci at the nuclear envelope during the repression phase. Further, we uncovered several unexpected features of clock protein foci, including their role in positioning the clock genes at the nuclear envelope precisely during the repression phase to enable circadian rhythms. These studies provide fundamental new insights into the cellular mechanisms of circadian rhythms and establish direct links between nuclear organization and circadian clocks.

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Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2019756118 ◽

2021 ◽

Vol 118 (28) ◽

pp. e2019756118

Author(s):

Yangbo Xiao ◽

Ye Yuan ◽

Mariana Jimenez ◽

Neeraj Soni ◽

Swathi Yadlapalli

Keyword(s):

Gene Expression ◽

Circadian Rhythms ◽

Nuclear Envelope ◽

Molecular Mechanisms ◽

Clock Genes ◽

Nuclear Periphery ◽

Spatiotemporal Organization ◽

Subnuclear Localization ◽

Clock Proteins ◽

Spatial Reorganization

Circadian clocks regulate ∼24-h oscillations in gene expression, behavior, and physiology. While the genetic and molecular mechanisms of circadian rhythms are well characterized, what remains poorly understood are the intracellular dynamics of circadian clock components and how they affect circadian rhythms. Here, we elucidate how spatiotemporal organization and dynamics of core clock proteins and genes affect circadian rhythms in Drosophila clock neurons. Using high-resolution imaging and DNA-fluorescence in situ hybridization techniques, we demonstrate that Drosophila clock proteins (PERIOD and CLOCK) are organized into a few discrete foci at the nuclear envelope during the circadian repression phase and play an important role in the subnuclear localization of core clock genes to control circadian rhythms. Specifically, we show that core clock genes, period and timeless, are positioned close to the nuclear periphery by the PERIOD protein specifically during the repression phase, suggesting that subnuclear localization of core clock genes might play a key role in their rhythmic gene expression. Finally, we show that loss of Lamin B receptor, a nuclear envelope protein, leads to disruption of PER foci and per gene peripheral localization and results in circadian rhythm defects. These results demonstrate that clock proteins play a hitherto unexpected role in the subnuclear reorganization of core clock genes to control circadian rhythms, revealing how clocks function at the subcellular level. Our results further suggest that clock protein foci might regulate dynamic clustering and spatial reorganization of clock-regulated genes over the repression phase to control circadian rhythms in behavior and physiology.

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Circadian rhythms of locomotor activity and hippocampal clock genes expression are dampened in vitamin A–deficient rats

Nutrition Research ◽

10.1016/j.nutres.2014.02.002 ◽

2014 ◽

Vol 34 (4) ◽

pp. 326-335 ◽

Cited By ~ 9

Author(s):

Lorena S. Navigatore-Fonzo ◽

Silvia M. Delgado ◽

Rebeca S. Golini ◽

Ana C. Anzulovich

Keyword(s):

Locomotor Activity ◽

Circadian Rhythms ◽

Vitamin A ◽

Clock Genes ◽

Genes Expression

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Photoperiod differentially regulates clock genes expression in the suprachiasmatic nucleus of Syrian hamster

10.1240/sav_gbm_2003_m_000380 ◽

2003 ◽

Vol 2003 (Spring) ◽

Author(s):

Benjamin B Tournier ◽

Jérôme S Menet ◽

Hugues Dardente ◽

Vincent Joseph Poirel ◽

André Malan ◽

...

Keyword(s):

Suprachiasmatic Nucleus ◽

Syrian Hamster ◽

Clock Genes ◽

Genes Expression

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Dissociation of Per1 and Bmal1 circadian rhythms in the suprachiasmatic nucleus in parallel with behavioral outputs

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1613374114 ◽

2017 ◽

Vol 114 (18) ◽

pp. E3699-E3708 ◽

Cited By ~ 34

Author(s):

Daisuke Ono ◽

Sato Honma ◽

Yoshihiro Nakajima ◽

Shigeru Kuroda ◽

Ryosuke Enoki ◽

...

Keyword(s):

Circadian Rhythms ◽

Suprachiasmatic Nucleus ◽

Clock Genes ◽

Behavioral Rhythm ◽

Calcium Indicator ◽

Intracellular Ca ◽

Regional Specificity ◽

Free Running ◽

Activity Onset ◽

And Behavior

The temporal order of physiology and behavior in mammals is primarily regulated by the circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). Taking advantage of bioluminescence reporters, we monitored the circadian rhythms of the expression of clock genes Per1 and Bmal1 in the SCN of freely moving mice and found that the rate of phase shifts induced by a single light pulse was different in the two rhythms. The Per1-luc rhythm was phase-delayed instantaneously by the light presented at the subjective evening in parallel with the activity onset of behavioral rhythm, whereas the Bmal1-ELuc rhythm was phase-delayed gradually, similar to the activity offset. The dissociation was confirmed in cultured SCN slices of mice carrying both Per1-luc and Bmal1-ELuc reporters. The two rhythms in a single SCN slice showed significantly different periods in a long-term (3 wk) culture and were internally desynchronized. Regional specificity in the SCN was not detected for the period of Per1-luc and Bmal1-ELuc rhythms. Furthermore, neither is synchronized with circadian intracellular Ca2+ rhythms monitored by a calcium indicator, GCaMP6s, or with firing rhythms monitored on a multielectrode array dish, although the coupling between the circadian firing and Ca2+ rhythms persisted during culture. These findings indicate that the expressions of two key clock genes, Per1 and Bmal1, in the SCN are regulated in such a way that they may adopt different phases and free-running periods relative to each other and are respectively associated with the expression of activity onset and offset.

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