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1
Wood, Kieran, Paul M. Saffin, and Anastasios Avgoustidis. "Clockwork cosmology." Journal of Cosmology and Astroparticle Physics 2023, no. 07 (July 1, 2023): 062. http://dx.doi.org/10.1088/1475-7516/2023/07/062.
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Abstract The higher order generalisation of the clockwork mechanism to gravitational interactions provides a means to generate an exponentially suppressed coupling to matter from a fundamental theory of multiple interacting gravitons, without introducing large hierarchies in the underlying potential and without the need for a dilaton, suggesting a possible application to the hierarchy problem. We work in the framework of ghost free multi-gravity with “nearest-neighbour” interactions, and present a formalism by which one is able to construct potentials such that the theory will always exhibit this clockwork effect. We also consider cosmological solutions to the general theory, where all metrics are of FRW form, with site-dependent scale factors/lapses. We demonstrate the existence of multiple deSitter vacua where all metrics share the same Hubble parameter, and we solve the modified Einstein equations numerically for an example clockwork model constructed using our formalism, finding that the evolution of the metric that matter couples to is essentially equivalent to that of general relativity at the modified Planck scale. It is important to stress that while we focus on the application to clockwork theories, our work is entirely general and facilitates finding cosmological solutions to any ghost free multi-gravity theory with “nearest-neighbour” interactions. Moreover, we clarify previous work on the continuum limit of the theory, which is generically a scalar-tensor braneworld, using the Randall-Sundrum model as a special case and showing how the discrete-clockwork cosmological results map to the continuum results in the appropriate limit.
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Bai, Long, Fan Zheng, Xiaohong Chen, Yuanxi Sun, and Junzhan Hou. "Design and Experimental Evaluation of a Single-Actuator Continuous Hopping Robot Using the Geared Symmetric Multi-Bar Mechanism." Applied Sciences 9, no. 1 (December 20, 2018): 13. http://dx.doi.org/10.3390/app9010013.
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This paper proposes the design and performance evaluation of a miniaturized continuous hopping robot RHop for unstructured terrain. The hopping mechanism of RHop is realized by an optimized geared symmetric closed-chain multi-bar mechanism that is transformed from the eight-bar mechanism, and the actuator of RHop is realized by a servo motor and the clockwork spring, thereby enabling RHop to realize continuous hopping while its motor rotates continuously only in one direction. Comparative simulations and experiments are conducted for RHop. The results show that RHop can realize better continuous hopping performance, as well as the improvement of energy conversion efficiency from 70.98% to 76.29% when the clockwork spring is applied in the actuator. In addition, comparisons with some state-of-the-art hopping robots are conducted, and the normalized results show that RHop has a better energy storage speed.
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Banerjee, I., T. Salih, H. Ramachandraiah, J. Erlandsson, T. Pettersson, A. C. Araújo, M. Karlsson, and A. Russom. "Slipdisc: a versatile sample preparation platform for point of care diagnostics." RSC Advances 7, no. 56 (2017): 35048–54. http://dx.doi.org/10.1039/c7ra05209j.
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A novel POC sample preparation technology, “Slipdisc”, based rotational slipchip technology is presented. In operation, the hand-winded slipdisc platform uses a unique clockwork mechanism to manipulate minute amount of liquids.
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Bennet-Clark, H. C., and Winston J. Bailey. "Ticking of the clockwork cricket: the role of the escapement mechanism." Journal of Experimental Biology 205, no. 5 (March 1, 2002): 613–25. http://dx.doi.org/10.1242/jeb.205.5.613.
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SUMMARYThe ‘clockwork cricket’ model for cricket sound production suggests that the catch-and-release of the file of one forewing by the plectrum on the opposite wing act as an ‘escapement’ to provide the phasic impulses that initiate and sustain the vibration of the resonant regions of the wings from which the sounds are produced. The action of the escapement produces the familiar ticking sound of clocks.The higher-frequency components of the songs of twelve species of cricket were analysed after removing the dominant low-frequency components and amplifying the remaining higher-frequency components. In normal song pulses of all species, the higher-frequency components showed a close phase-locking to the waveform of the dominant frequency, but the amplitude of the higher-frequency components did not correlate with that at the dominant frequency.Anomalous pulses occurred spontaneously in the songs of several species: multimodal, interrupted or curtailed pulses are described. In all of these, the anomalous pulse envelope was associated with changes in the amplitude and/or instantaneous frequency of the higher-frequency components of the sound.A model of the escapement suggests that the frequency of the residual components of the song depends on the symmetry of action of the plectrum on the teeth of the file.
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Chrysoula Markou. "The Linear Dilaton: from the Clockwork Mechanism to Its Supergravity Embedding." Physics of Particles and Nuclei Letters 17, no. 5 (September 2020): 660–62. http://dx.doi.org/10.1134/s1547477120050271.
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Herzog, Erik D., and William J. Schwartz. "Invited Review: A neural clockwork for encoding circadian time." Journal of Applied Physiology 92, no. 1 (January 1, 2002): 401–8. http://dx.doi.org/10.1152/japplphysiol.00836.2001.
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10.1152/japplphysiol.00836.2001.—Many daily biological rhythms are governed by an innate timekeeping mechanism or clock. Endogenous, temperature-compensated circadian clocks have been localized to discrete sites within the nervous systems of a number of organisms. In mammals, the master circadian pacemaker is the bilaterally paired suprachiasmatic nucleus (SCN) in the anterior hypothalamus. The SCN is composed of multiple single cell oscillators that must synchronize to each other and the environmental light schedule. Other tissues, including those outside the nervous system, have also been shown to express autonomous circadian periodicities. This review examines 1) how intracellular regulatory molecules function in the oscillatory mechanism and in its entrainment to environmental cycles; 2) how individual SCN cells interact to create an integrated tissue pacemaker with coherent metabolic, electrical, and secretory rhythms; and 3) how such clock outputs are converted into temporal programs for the whole organism.
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Cattenoz, Pierre B., and Angela Giangrande. "New insights in the clockwork mechanism regulating lineage specification: Lessons from theDrosophilanervous system." Developmental Dynamics 244, no. 3 (December 11, 2014): 332–41. http://dx.doi.org/10.1002/dvdy.24228.
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Pacelli, Consiglia, Giovannina Rotundo, Lucia Lecce, Marta Menga, Eris Bidollari, Rosella Scrima, Olga Cela, et al. "Parkin Mutation Affects Clock Gene-Dependent Energy Metabolism." International Journal of Molecular Sciences 20, no. 11 (June 5, 2019): 2772. http://dx.doi.org/10.3390/ijms20112772.
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Growing evidence highlights a tight connection between circadian rhythms, molecular clockworks, and mitochondrial function. In particular, mitochondrial quality control and bioenergetics have been proven to undergo circadian oscillations driven by core clock genes. Parkinson’s disease (PD) is a chronic neurodegenerative disease characterized by a selective loss of dopaminergic neurons. Almost half of the autosomal recessive forms of juvenile parkinsonism have been associated with mutations in the PARK2 gene coding for parkin, shown to be involved in mitophagy-mediated mitochondrial quality control. The aim of this study was to investigate, in fibroblasts from genetic PD patients carrying parkin mutations, the interplay between mitochondrial bioenergetics and the cell autonomous circadian clock. Using two different in vitro synchronization protocols, we demonstrated that normal fibroblasts displayed rhythmic oscillations of both mitochondrial respiration and glycolytic activity. Conversely, in fibroblasts obtained from PD patients, a severe damping of the bioenergetic oscillatory patterns was observed. Analysis of the core clock genes showed deregulation of their expression patterns in PD fibroblasts, which was confirmed in induced pluripotent stem cells (iPSCs) and induced neural stem cells (iNSCs) derived thereof. The results from this study support a reciprocal interplay between the clockwork machinery and mitochondrial energy metabolism, point to a parkin-dependent mechanism of regulation, and unveil a hitherto unappreciated level of complexity in the pathophysiology of PD and eventually other neurodegenerative diseases.
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Imamura, Kiyomichi, Hikari Yoshitane, Kazuki Hattori, Mitsuo Yamaguchi, Kento Yoshida, Takenori Okubo, Isao Naguro, Hidenori Ichijo, and Yoshitaka Fukada. "ASK family kinases mediate cellular stress and redox signaling to circadian clock." Proceedings of the National Academy of Sciences 115, no. 14 (March 19, 2018): 3646–51. http://dx.doi.org/10.1073/pnas.1719298115.
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Daily rhythms of behaviors and physiologies are generated by the circadian clock, which is composed of clock genes and the encoded proteins forming transcriptional/translational feedback loops (TTFLs). The circadian clock is a self-sustained oscillator and flexibly responds to various time cues to synchronize with environmental 24-h cycles. However, the key molecule that transmits cellular stress to the circadian clockwork is unknown. Here we identified apoptosis signal-regulating kinase (ASK), a member of the MAPKKK family, as an essential mediator determining the circadian period and phase of cultured cells in response to osmotic changes of the medium. The physiological impact of ASK signaling was demonstrated by a response of the clock to changes in intracellular redox states. Intriguingly, the TTFLs drive rhythmic expression of Ask genes, indicating ASK-mediated association of the TTFLs with intracellular redox. In behavioral analysis, Ask1, Ask2, and Ask3 triple-KO mice exhibited compromised light responses of the circadian period and phase in their activity rhythms. LC-MS/MS–based proteomic analysis identified a series of ASK-dependent and osmotic stress-responsive phosphorylations of proteins, among which CLOCK, a key component of the molecular clockwork, was phosphorylated at Thr843 or Ser845 in the carboxyl-terminal region. These findings reveal the ASK-dependent stress response as an underlying mechanism of circadian clock flexibility.
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Shi, Yuxuan, Yanyu Wang, and Haoran Zheng. "Wind Speed Prediction for Offshore Sites Using a Clockwork Recurrent Network." Energies 15, no. 3 (January 20, 2022): 751. http://dx.doi.org/10.3390/en15030751.
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Offshore sites show greater potential for wind energy utilization than most onshore sites. When planning an offshore wind power farm, the speed of offshore wind is used to estimate various operation parameters, such as the power output, extreme wind load, and fatigue load. Accurate speed prediction is crucial to the running of wind power farms and the security of smart grids. Unlike onshore wind, offshore wind has the characteristics of random, intermittent, and chaotic, which will cause the time series of wind speeds to have strong nonlinearity. It will bring greater difficulties to offshore wind speed predictions, which traditional recurrent neural networks cannot deal with for lacking in long-term dependency. An offshore wind speed prediction method is proposed by using a clockwork recurrent network (CWRNN). In a CWRNN model, the hidden layer is subdivided into several parts and each part is allocated a different clock speed. Under the mechanism, the long-term dependency of the recurrent neural network can be easily addressed, which can furthermore effectively solve the problem of strong nonlinearity in offshore speed winds. The experiments are performed by using the actual data of two different offshore sites located in the Caribbean Sea and one onshore site located in the interior of the United States, to verify the performance of the model. The results show that the prediction model achieves significant accuracy improvement.
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Kádár, Zoltán. "Civilization Critical Investigation on the „Clockwork Condition” described by Anthony Burgess." Belvedere Meridionale 33, no. 3 (2021): 90–96. http://dx.doi.org/10.14232/belv.2021.3.5.
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The negative effects of the civilized lifestyle are widely discussed by many authors (for example Marx, Wells, or Max Nordau) in the nineteenth century, showing that industrial society and its mechanic requirements make a hard mental and physical impact on people who build and constantly change the modern world. In the twentieth century, many authors also dealt with the problem of adaptation to technology – a process that deeply changes people – that pushes them to a direction that leads towards an obedient, man-machine condition of life. Taylorism and its heritage, plus the culture, sport, sex, etc. industries and above all politics with its satellite media determine people how to live their lives. This makes a lifelong discomfort for those who want some autonomy but gives redemption for others who flee from constant decision-making. Burgess’s „clockwork condition” is a great depiction of the (post)modern man whose actions are mostly mere responses to a mechanic milieu created by „the state” that uses people as tools. Even democracy can turn into a spiritless, alienated sequence impregnated with boring or obviously mad plans of a governing minority if citizens forget how to be conscious, creative, and responsible when they make decisions. Beyond the topic of the novel A Clockwork Orange the problem is general: do we choose the „forced marriage of an organism to a mechanism” and follow the given patterns, let the conditioning happen, or insist on being imperfect, but capable of making decisions, even if many of them are bad.
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Sládek, Martin, Zuzana Jindráková, Zdenka Bendová, and Alena Sumová. "Postnatal ontogenesis of the circadian clock within the rat liver." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 292, no. 3 (March 2007): R1224—R1229. http://dx.doi.org/10.1152/ajpregu.00184.2006.
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In mammals, the circadian oscillator within the suprachiasmatic nuclei (SCN) entrains circadian clocks in numerous peripheral tissues. Central and peripheral clocks share a molecular core clock mechanism governing daily time measurement. In the rat SCN, the molecular clockwork develops gradually during postnatal ontogenesis. The aim of the present work was to elucidate when during ontogenesis the expression of clock genes in the rat liver starts to be rhythmic. Daily profiles of mRNA expression of clock genes Per1, Per2, Cry1, Clock, Rev-Erbα, and Bmal1 were analyzed in the liver of fetuses at embryonic day 20 (E20) or pups at postnatal age 2 (P2), P10, P20, P30, and in adults by real-time RT-PCR. At E20, only a high-amplitude rhythm in Rev-Erbα and a low-amplitude variation in Cry1 but no clear circadian rhythms in expression of other clock genes were detectable. At P2, a high-amplitude rhythm in Rev-Erbα and a low-amplitude variation in Bmal1 but no rhythms in expression of other genes were detected. At P10, significant rhythms only in Per1 and Rev-Erbα expression were present. At P20, clear circadian rhythms in the expression of Per1, Per2, Rev-Erbα, and Bmal1, but not yet of Cry1 and Clock, were detected. At P30, all clock genes were expressed rhythmically. The phase of the rhythms shifted between all studied developmental periods until the adult stage was achieved. The data indicate that the development of the molecular clockwork in the rat liver proceeds gradually and is roughly completed by 30 days after birth.
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Gu, Hai-Feng, Jin-Hua Xiao, Derek W. Dunn, Li-Ming Niu, Bo Wang, Ling-Yi Jia, and Da-Wei Huang. "Evidence for the circadian gene period as a proximate mechanism of protandry in a pollinating fig wasp." Biology Letters 10, no. 3 (March 2014): 20130914. http://dx.doi.org/10.1098/rsbl.2013.0914.
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Protandry in insects is the tendency for adult males to emerge before females and usually results from intra-sexual selection. However, the genetic basis of this common phenomenon is poorly understood. Pollinating fig wasp (Agaonidae) larvae develop in galled flowers within the enclosed inflorescences (‘figs’) of fig trees. Upon emergence, males locate and mate with the still galled females. After mating, males release females from their galls to enable dispersal. Females cannot exit galls or disperse from a fig without male assistance. We sampled male and female Ceratosolen solmsi (the pollinator of Ficus hispida ) every 3 h over a 24 h emergence period, and then measured the expression of five circadian genes: period ( per ), clock ( clk ), cycle ( cyc ), pigment-dispersing factor ( pdf ) and clockwork orange ( cwo ). We found significant male-biased sexual dimorphism in the expression of all five genes. per showed the greatest divergence between the sexes and was the only gene rhythmically expressed. Expression of per correlated closely with emergence rates at specific time intervals in both male and female wasps. We suggest that this rhythmical expression of per may be a proximate mechanism of protandry in this species.
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Kurabayashi, Nobuhiro, Tsuyoshi Hirota, Mihoko Sakai, Kamon Sanada, and Yoshitaka Fukada. "DYRK1A and Glycogen Synthase Kinase 3β, a Dual-Kinase Mechanism Directing Proteasomal Degradation of CRY2 for Circadian Timekeeping." Molecular and Cellular Biology 30, no. 7 (February 1, 2010): 1757–68. http://dx.doi.org/10.1128/mcb.01047-09.
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ABSTRACT Circadian molecular oscillation is generated by a transcription/translation-based feedback loop in which CRY proteins play critical roles as potent inhibitors for E-box-dependent clock gene expression. Although CRY2 undergoes rhythmic phosphorylation in its C-terminal tail, structurally distinct from the CRY1 tail, little is understood about how protein kinase(s) controls the CRY2-specific phosphorylation and contributes to the molecular clockwork. Here we found that Ser557 in the C-terminal tail of CRY2 is phosphorylated by DYRK1A as a priming kinase for subsequent GSK-3β (glycogen synthase kinase 3β)-mediated phosphorylation of Ser553, which leads to proteasomal degradation of CRY2. In the mouse liver, DYRK1A kinase activity toward Ser557 of CRY2 showed circadian variation, with its peak in the accumulating phase of CRY2 protein. Knockdown of Dyrk1a caused abnormal accumulation of cytosolic CRY2, advancing the timing of a nuclear increase of CRY2, and shortened the period length of the cellular circadian rhythm. Expression of an S557A/S553A mutant of CRY2 phenocopied the effect of Dyrk1a knockdown in terms of the circadian period length of the cellular clock. DYRK1A is a novel clock component cooperating with GSK-3β and governs the Ser557 phosphorylation-triggered degradation of CRY2.
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Kann, Oliver, Ismini E. Papageorgiou, and Andreas Draguhn. "Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks." Journal of Cerebral Blood Flow & Metabolism 34, no. 8 (June 4, 2014): 1270–82. http://dx.doi.org/10.1038/jcbfm.2014.104.
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Gamma oscillations (~30 to 100 Hz) provide a fundamental mechanism of information processing during sensory perception, motor behavior, and memory formation by coordination of neuronal activity in networks of the hippocampus and neocortex. We review the cellular mechanisms of gamma oscillations about the underlying neuroenergetics, i.e., high oxygen consumption rate and exquisite sensitivity to metabolic stress during hypoxia or poisoning of mitochondrial oxidative phosphorylation. Gamma oscillations emerge from the precise synaptic interactions of excitatory pyramidal cells and inhibitory GABAergic interneurons. In particular, specialized interneurons such as parvalbumin-positive basket cells generate action potentials at high frequency (‘fast-spiking’) and synchronize the activity of numerous pyramidal cells by rhythmic inhibition (‘clockwork’). As prerequisites, fast-spiking interneurons have unique electrophysiological properties and particularly high energy utilization, which is reflected in the ultrastructure by enrichment with mitochondria and cytochrome c oxidase, most likely needed for extensive membrane ion transport and γ-aminobutyric acid metabolism. This supports the hypothesis that highly energized fast-spiking interneurons are a central element for cortical information processing and may be critical for cognitive decline when energy supply becomes limited (‘interneuron energy hypothesis’). As a clinical perspective, we discuss the functional consequences of metabolic and oxidative stress in fast-spiking interneurons in aging, ischemia, Alzheimer's disease, and schizophrenia.
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Teboul, Michèle, Aline Gréchez-Cassiau, Fabienne Guillaumond, and Franck Delaunay. "How nuclear receptors tell time." Journal of Applied Physiology 107, no. 6 (December 2009): 1965–71. http://dx.doi.org/10.1152/japplphysiol.00515.2009.
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Most organisms adapt their behavior and physiology to the daily changes in their environment through internal (∼24 h) circadian clocks. In mammals, this time-keeping system is organized hierarchically, with a master clock located in the suprachiasmatic nuclei of the hypothalamus that is reset by light, and that, in turn, coordinates the oscillation of local clocks found in all cells. Central and peripheral clocks control, in a highly tissue-specific manner, hundreds of target genes, resulting in the circadian regulation of most physiological processes. A great deal of knowledge has accumulated during the last decade regarding the molecular basis of mammalian circadian clocks. These studies have collectively demonstrated how a set of clock genes and their protein products interact together in complex feedback transcriptional/translational loops to generate 24-h oscillations at the molecular, cellular, and organism levels. In recent years, a number of nuclear receptors (NRs) have been implicated as important regulators of the mammalian clock mechanism. REV-ERB and retinoid-related orphan receptor NRs regulate directly the core feedback loop and increase its robustness. The glucocorticoid receptor mediates the synchronizing effect of glucocorticoid hormones on peripheral clocks. Other NR family members, including the orphan NR EAR2, peroxisome proliferator activated receptors-α/γ, estrogen receptor-α, and retinoic acid receptors, are also linked to the clockwork mechanism. These findings together establish nuclear hormone receptor signaling as an integral part of the circadian timing system.
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Putilov, Arcady A., Elena V. Budkevich, and Roman O. Budkevich. "A Review of Evidence for the Involvement of the Circadian Clock Genes into Malignant Transformation of Thyroid Tissue." Clocks & Sleep 5, no. 3 (July 13, 2023): 384–98. http://dx.doi.org/10.3390/clockssleep5030029.
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(1) Background: In 2013, the results of a pioneer study on abnormalities in the levels and circadian rhythmicity of expression of circadian clock genes in cancerous thyroid nodules was published. In the following years, new findings suggesting the involvement of circadian clockwork dysfunction into malignant transformation of thyroid tissue were gradually accumulating. This systematic review provides an update on existing evidence regarding the association of these genes with thyroid tumorigenesis. (2) Methods: Two bibliographic databases (Scopus and PubMed) were searched for articles from inception to 20 March 2023. The reference lists of previously published (nonsystematic) reviews were also hand-searched for additional relevant studies. (3) Results: Nine studies published between 2013 and 2022 were selected. In total, 9 of 12 tested genes were found to be either up- or downregulated. The list of such genes includes all families of core circadian clock genes that are the key components of three transcriptional–translational feedback loops of the circadian clock mechanism (BMAL1, CLOCK, NPAS2, RORα, REV-ERBα, PERs, CRYs, and DECs). (4) Conclusions: Examination of abnormalities in the levels and circadian rhythmicity of expression of circadian clock genes in thyroid tissue can help to reduce the rate of inadequate differential preoperative diagnosis for thyroid carcinoma.
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Isla, Enrique. "Animal–Energy Relationships in a Changing Ocean: The Case of Continental Shelf Macrobenthic Communities on the Weddell Sea and the Vicinity of the Antarctic Peninsula." Biology 12, no. 5 (April 27, 2023): 659. http://dx.doi.org/10.3390/biology12050659.
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The continental shelves of the Weddell Sea and the Antarctic Peninsula vicinity host abundant macrobenthic communities, and the persistence of which is facing serious global change threats. The current relationship among pelagic energy production, its distribution over the shelf, and macrobenthic consumption is a “clockwork” mechanism that has evolved over thousands of years. Together with biological processes such as production, consumption, reproduction, and competence, it also involves ice (e.g., sea ice, ice shelves, and icebergs), wind, and water currents, among the most important physical controls. This bio-physical machinery undergoes environmental changes that most likely will compromise the persistence of the valuable biodiversity pool that Antarctic macrobenthic communities host. Scientific evidence shows that ongoing environmental change leads to primary production increases and also suggests that, in contrast, macrobenthic biomass and the organic carbon concentration in the sediment may decrease. Warming and acidification may affect the existence of the current Weddell Sea and Antarctic Peninsula shelf macrobenthic communities earlier than other global change agents. Species with the ability to cope with warmer water may have a greater chance of persisting together with allochthonous colonizers. The Antarctic macrobenthos biodiversity pool is a valuable ecosystem service that is under serious threat, and establishing marine protected areas may not be sufficient to preserve it.
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Chuffa, Luiz Gustavo de Almeida, Fábio Rodrigues Ferreira Seiva, Maira Smaniotto Cucielo, Henrique Spaulonci Silveira, Russel J. Reiter, and Luiz Antonio Lupi. "Clock genes and the role of melatonin in cancer cells: an overview." Melatonin Research 2, no. 2 (June 12, 2019): 133–57. http://dx.doi.org/10.32794/mr11250026.
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Circadian rhythms control most biological processes in every organism and their disruption or an aberrant function in the expression of clock genes are associated with a number of cancers including some hormone-dependent and independent cancers. The processes involved in carcinogenesis and tumor progression are complex, but understanding the daily profiles of the core clock genes and their clock-controlled genes is essential to evaluate specifically the molecular program of the cancer phenotype; this may be helpful in providing a more realistic strategy for both diagnosis and treatment during the course of the disease. Because melatonin production and secretion oscillates rhythmically through the light:dark cycle and is related to the circadian machinery genes (Clock, Bmal1, Periods, and Cryptochromes), its regulatory role on clock genes in cancer cells may bring additional evidence regarding the mechanism(s) by which melatonin is involved. Mechanistically, melatonin acts via proteasome inhibition and sirtuins to indirectly modulate clock genes in cancer; however, melatonin seems to be capable of directly altering the expression of clock genes to affect cancer development. Depending on cancer cell type, melatonin might up or downregulate specific clock genes to control cell cycle, survival, repair mechanisms, etc. In parallel, melatonin exerts pro-apoptotic, anti-proliferative and pro-oxidative effects, metabolic shifting, reduction in neovasculogenesis and inflammation, and restores chemosensitivity of cancer cells. Finally, melatonin improves the life quality of patients. This review focuses on the main functions of melatonin on clock genes, and reviews, from a clinical and experimental standpoint, how melatonin regulates the expression of clock genes in some prevalent cancer types such as breast, prostate, liver, and colon cancers, leukemia and melanoma. We further emphasized possible signaling mechanisms whereby melatonin interferes with clockwork genes and circadian-controlled genes within cancer cells.
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Park, Seong Chan, and Chang Sub Shin. "Clockwork seesaw mechanisms." Physics Letters B 776 (January 2018): 222–26. http://dx.doi.org/10.1016/j.physletb.2017.11.057.
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Dmitriev, Igor. "“They are Faithful, Precise, Relentless”. Clock Metaphor in Modern European Thought." Philosophy. Journal of the Higher School of Economics VII, no. 1 (March 31, 2023): 243–78. http://dx.doi.org/10.17323/2587-8719-2023-1-243-278.
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The clock metaphor, which began to spread in European literature in the fourteenth century, at first became an expression of certain Christian virtues, most notably temperantia. By the turn of the fifteenth and sixteenth centuries, the function of this metaphor had expanded considerably, and the mechanical clock also became a symbol of the orderliness and harmony of the Universe, the wisdom of the Creator, and the image of an ideal monarchical state. In early modern times, the metaphor of the clock was associated with mechanical philosophy, most prominently in the writings of R. Boyle and R. Descartes. A distinctive feature of the new natural philosophy was its approach to understanding natural phenomena as if they were the result of the action of machines, and the mechanical clock was most often chosen as the machine-analog of the world. The structure and functioning of the clock mechanism served as an analogue of the structure and functioning not only of the Universe, but also of an ideal state in which everything emanated from a single center. The political connotations of chorological metaphors clearly correlated with the idea of a strong central authority with its desire for all-encompassing control and a unidirectional (top-down, no feedback) system of communication with non-central elements. In the eighteenth and early nineteenth centuries, the metaphor of the clock gradually lost its popularity, especially in England. By the end of the Age of Enlightenment, the relationship between the laws of nature, rather than the coherence of the wheels of a clockwork mechanism, was seen as the best evidence in favor of a Higher Intelligence behind the “system of the world”. Clocks, on the other hand, have come to symbolize regimentation and oppression, an unfree, dull, repetitive mode of operation, rigid determinism, and the denial of free will (including the will of God). The mechanical clock, itself a worthy and useful device, symbolized all that was rejected by English intellectuals of the second half of the seventeenth and eighteenth centuries, primarily in the subjects of theology and politics.
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Robinson, I., and A. B. Reddy. "Molecular mechanisms of the circadian clockwork in mammals." FEBS Letters 588, no. 15 (June 6, 2014): 2477–83. http://dx.doi.org/10.1016/j.febslet.2014.06.005.
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Keil, Frank C., and Kristi L. Lockhart. "Beyond Cause: The Development of Clockwork Cognition." Current Directions in Psychological Science 30, no. 2 (April 2021): 167–73. http://dx.doi.org/10.1177/0963721421992341.
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Thinking of the world in mechanistic terms—how things work—is both cognitively natural and motivating for humans from the preschool years onward. Mechanisms have distinct structural properties that go far beyond mere causal facts. They typically contain layers of causal clusters and the systematic interactions between those clusters that give rise to the next level up. Following developments in the philosophy of science and studies on children’s questioning behaviors, recent research shows that, from an early age, people appreciate the informational and inductive potential of mechanistic information. People selectively notice and choose mechanistic explanations as especially useful opportunities for learning; but they also soon forget the details of what they encounter. We argue that enduring cognitive abstractions from such details provide powerful ways of accessing and evaluating expertise in other people.
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Chowdhury, Debajyoti, Chao Wang, Ai-Ping Lu, and Hai-Long Zhu. "Understanding Quantitative Circadian Regulations Are Crucial Towards Advancing Chronotherapy." Cells 8, no. 8 (August 13, 2019): 883. http://dx.doi.org/10.3390/cells8080883.
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Circadian rhythms have a deep impact on most aspects of physiology. In most organisms, especially mammals, the biological rhythms are maintained by the indigenous circadian clockwork around geophysical time (~24-h). These rhythms originate inside cells. Several core components are interconnected through transcriptional/translational feedback loops to generate molecular oscillations. They are tightly controlled over time. Also, they exert temporal controls over many fundamental physiological activities. This helps in coordinating the body’s internal time with the external environments. The mammalian circadian clockwork is composed of a hierarchy of oscillators, which play roles at molecular, cellular, and higher levels. The master oscillation has been found to be developed at the hypothalamic suprachiasmatic nucleus in the brain. It acts as the core pacemaker and drives the transmission of the oscillation signals. These signals are distributed across different peripheral tissues through humoral and neural connections. The synchronization among the master oscillator and tissue-specific oscillators offer overall temporal stability to mammals. Recent technological advancements help us to study the circadian rhythms at dynamic scale and systems level. Here, we outline the current understanding of circadian clockwork in terms of molecular mechanisms and interdisciplinary concepts. We have also focused on the importance of the integrative approach to decode several crucial intricacies. This review indicates the emergence of such a comprehensive approach. It will essentially accelerate the circadian research with more innovative strategies, such as developing evidence-based chronotherapeutics to restore de-synchronized circadian rhythms.
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Cvitanović, Predrag. "Recurrent flows: the clockwork behind turbulence." Journal of Fluid Mechanics 726 (June 6, 2013): 1–4. http://dx.doi.org/10.1017/jfm.2013.198.
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AbstractThe understanding of chaotic dynamics in high-dimensional systems that has emerged in the last decade offers a promising dynamical framework to study turbulence. Here turbulence is viewed as a walk through a forest of exact solutions in the infinite-dimensional state space of the governing equations. Recently, Chandler & Kerswell (J. Fluid Mech., vol. 722, 2013, pp. 554–595) carry out the most exhaustive study of this programme undertaken so far in fluid dynamics, a feat that requires every tool in the dynamicist’s toolbox: numerical searches for recurrent flows, computation of their stability, their symmetry classification, and estimating from these solutions statistical averages over the turbulent flow. In the long run this research promises to develop a quantitative, predictive description of moderate-Reynolds-number turbulence, and to use this description to control flows and explain their statistics.
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Maywood, Elizabeth S., John S. O’Neill, Johanna E. Chesham, and Michael H. Hastings. "Minireview: The Circadian Clockwork of the Suprachiasmatic Nuclei—Analysis of a Cellular Oscillator that Drives Endocrine Rhythms." Endocrinology 148, no. 12 (December 1, 2007): 5624–34. http://dx.doi.org/10.1210/en.2007-0660.
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The secretion of hormones is temporally precise and periodic, oscillating over hours, days, and months. The circadian timekeeper within the suprachiasmatic nuclei (SCN) is central to this coordination, modulating the frequency of pulsatile release, maintaining daily cycles of secretion, and defining the time base for longer-term rhythms. This central clock is driven by cell-autonomous, transcriptional/posttranslational feedback loops incorporating Period (Per) and other clock genes. SCN neurons exist, however, within neural circuits, and an unresolved question is how SCN clock cells interact. By monitoring the SCN molecular clockwork using fluorescence and bioluminescence videomicroscopy of organotypic slices from mPer1::GFP and mPer1::luciferase transgenic mice, we show that interneuronal neuropeptidergic signaling via the vasoactive intestinal peptide (VIP)/PACAP2 (VPAC2) receptor for VIP (an abundant SCN neuropeptide) is necessary to maintain both the amplitude and the synchrony of clock cells in the SCN. Acute induction of mPer1 by light is, however, independent of VIP/VPAC2 signaling, demonstrating dissociation between cellular mechanisms mediating circadian control of the clockwork and those mediating its retinally dependent entrainment to the light/dark cycle. The latter likely involves the Ca2+/cAMP response elements of mPer genes, triggered by a MAPK cascade activated by retinal afferents to the SCN. In the absence of VPAC2 signaling, however, this cascade is inappropriately responsive to light during circadian daytime. Hence VPAC2-mediated signaling sustains the SCN cellular clockwork and is necessary both for interneuronal synchronization and appropriate entrainment to the light/dark cycle. In its absence, behavioral and endocrine rhythms are severely compromised.
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Schmelling, Nicolas M., and Ilka M. Axmann. "Computational modelling unravels the precise clockwork of cyanobacteria." Interface Focus 8, no. 6 (October 19, 2018): 20180038. http://dx.doi.org/10.1098/rsfs.2018.0038.
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Precisely timing the regulation of gene expression by anticipating recurring environmental changes is a fundamental part of global gene regulation. Circadian clocks are one form of this regulation, which is found in both eukaryotes and prokaryotes, providing a fitness advantage for these organisms. Whereas many different eukaryotic groups harbour circadian clocks, cyanobacteria are the only known oxygenic phototrophic prokaryotes to regulate large parts of their genes in a circadian fashion. A decade of intensive research on the mechanisms and functionality using computational and mathematical approaches in addition to the detailed biochemical and biophysical understanding make this the best understood circadian clock. Here, we summarize the findings and insights into various parts of the cyanobacterial circadian clock made by mathematical modelling. These findings have implications for eukaryotic circadian research as well as synthetic biology harnessing the power and efficiency of global gene regulation.
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Herzog, Erik D., Tracey Hermanstyne, Nicola J. Smyllie, and Michael H. Hastings. "Regulating the Suprachiasmatic Nucleus (SCN) Circadian Clockwork: Interplay between Cell-Autonomous and Circuit-Level Mechanisms." Cold Spring Harbor Perspectives in Biology 9, no. 1 (January 2017): a027706. http://dx.doi.org/10.1101/cshperspect.a027706.
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HAMAGUCHI, Hidenori, Katsumi FUJIMOTO, Takeshi KAWAMOTO, Mitsuhide NOSHIRO, Koji MAEMURA, Norihiko TAKEDA, Ryozo NAGAI, et al. "Expression of the gene for Dec2, a basic helix–loop–helix transcription factor, is regulated by a molecular clock system." Biochemical Journal 382, no. 1 (August 10, 2004): 43–50. http://dx.doi.org/10.1042/bj20031760.
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Dec2, a member of the basic helix–loop–helix superfamily, is a recently confirmed regulatory protein for the clockwork system. Transcripts of Dec2, as well as those of its related gene Dec1, exhibit a striking circadian oscillation in the suprachiasmatic nucleus, and Dec2 inhibits transcription from the Per1 promoter induced by Clock/Bmal1 [Honma, Kawamoto, Takagi, Fujimoto, Sato, Noshiro, Kato and Honma (2002) Nature (London) 419, 841–844]. It is known that mammalian circadian rhythms are controlled by molecular clockwork systems based on negative-feedback loop(s), but the molecular mechanisms for the circadian regulation of Dec2 gene expression have not been clarified. We show here that transcription of the Dec2 gene is regulated by several clock molecules and a negative-feedback loop. Luciferase and gel retardation assays showed that expression of Dec2 was negatively regulated by binding of Dec2 or Dec1 to two CACGTG E-boxes in the Dec2 promoter. Forced expression of Clock/Bmal1 and Clock/Bmal2 markedly increased Dec2 mRNA levels, and up-regulated the transcription of the Dec2 gene through the CACGTG E-boxes. Like Dec, Cry and Per also suppressed Clock/Bmal-induced transcription from the Dec2 promoter. Moreover, the circadian expression of Dec2 transcripts was abolished in the kidney of Clock/Clock mutant mice. These findings suggest that the Clock/Bmal heterodimer enhances Dec2 transcription via the CACGTG E-boxes, whereas the induced transcription is suppressed by Dec2, which therefore must contribute to its own rhythmic expression. In addition, Cry and Per may also modulate Dec2 transcription.
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Wu, Lisa, and Akhilesh B. Reddy. "Rethinking the clockwork: redox cycles and non-transcriptional control of circadian rhythms." Biochemical Society Transactions 42, no. 1 (January 23, 2014): 1–10. http://dx.doi.org/10.1042/bst20130169.
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Circadian rhythms are a hallmark of living organisms, observable in all walks of life from primitive bacteria to highly complex humans. They are believed to have evolved to co-ordinate the timing of biological and behavioural processes to the changing environmental needs brought on by the progression of day and night through the 24-h cycle. Most of the modern study of circadian rhythms has centred on so-called TTFLs (transcription–translation feedback loops), wherein a core group of ‘clock’ genes, capable of negatively regulating themselves, produce oscillations with a period of approximately 24 h. Recently, however, the prevalence of the TTFL paradigm has been challenged by a series of findings wherein circadian rhythms, in the form of redox reactions, persist in the absence of transcriptional cycles. We have found that circadian cycles of oxidation and reduction are conserved across all domains of life, strongly suggesting that non-TTFL mechanisms work in parallel with the canonical genetic processes of timekeeping to generate the cyclical cellular and behavioural phenotypes that we commonly recognize as circadian rhythms.
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Challet, Etienne. "Minireview: Entrainment of the Suprachiasmatic Clockwork in Diurnal and Nocturnal Mammals." Endocrinology 148, no. 12 (December 1, 2007): 5648–55. http://dx.doi.org/10.1210/en.2007-0804.
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Daily rhythmicity, including timing of wakefulness and hormone secretion, is mainly controlled by a master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN clockwork involves various clock genes, with specific temporal patterns of expression that are similar in nocturnal and diurnal species (e.g. the clock gene Per1 in the SCN peaks at midday in both categories). Timing of sensitivity to light is roughly similar, during nighttime, in diurnal and nocturnal species. Molecular mechanisms of photic resetting are also comparable in both species categories. By contrast, in animals housed in constant light, exposure to darkness can reset the SCN clock, mostly during the resting period, i.e. at opposite circadian times between diurnal and nocturnal species. Nonphotic stimuli, such as scheduled voluntary exercise, food shortage, exogenous melatonin, or serotonergic receptor activation, are also capable of shifting the master clock and/or modulating photic synchronization. Comparison between day- and night-active species allows classifications of nonphotic cues in two, arousal-independent and arousal-dependent, families of factors. Arousal-independent factors, such as melatonin (always secreted during nighttime, independently of daily activity pattern) or γ-aminobutyric acid (GABA), have shifting effects at the same circadian times in both nocturnal and diurnal rodents. By contrast, arousal-dependent factors, such as serotonin (its cerebral levels follow activity pattern), induce phase shifts only during resting and have opposite modulating effects on photic resetting between diurnal and nocturnal species. Contrary to light and arousal-independent nonphotic cues, arousal-dependent nonphotic stimuli provide synchronizing feedback signals to the SCN clock in circadian antiphase between nocturnal and diurnal animals.
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Field, Manuel D., Elizabeth S. Maywood, John A. O'Brien, David R. Weaver, Steven M. Reppert, and Michael H. Hastings. "Analysis of Clock Proteins in Mouse SCN Demonstrates Phylogenetic Divergence of the Circadian Clockwork and Resetting Mechanisms." Neuron 25, no. 2 (February 2000): 437–47. http://dx.doi.org/10.1016/s0896-6273(00)80906-x.
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Zaitsev, N. Yu, Yu M. Zaitsev, E. V. Mikhailova, D. S. Sazanov, and G. P. Svintsov. "Trigger low-voltage devices electromechanical apparatus." E3S Web of Conferences 124 (2019): 05072. http://dx.doi.org/10.1051/e3sconf/201912405072.
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Based on the analysis of the existing classification of low-voltage electromechanical devices, it was proposed, on the basis of the functions performed, to unite into the group of electromagnetic mechanisms the indicating relays, vacuum contactors, time relays with clockwork, and executive bodies of circuit breaker releases. The definition of launching devices is given, the main feature of which is a mechanical characteristic, the change of which, with appropriate coordination with the traction characteristic of an electromagnet, can lead to an improvement of the most important characteristics of these devices, such as power consumption and resistance to mechanical influencing factors. On the example of the calculation of the index relay, it is shown and experimentally confirmed that a change in the initial force of the mechanical characteristic and its rigidity leads to a decrease in power consumption while maintaining shock stability.
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Rumanova, Valentina S., Monika Okuliarova, and Michal Zeman. "Differential Effects of Constant Light and Dim Light at Night on the Circadian Control of Metabolism and Behavior." International Journal of Molecular Sciences 21, no. 15 (July 31, 2020): 5478. http://dx.doi.org/10.3390/ijms21155478.
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The disruption of circadian rhythms by environmental conditions can induce alterations in body homeostasis, from behavior to metabolism. The light:dark cycle is the most reliable environmental agent, which entrains circadian rhythms, although its credibility has decreased because of the extensive use of artificial light at night. Light pollution can compromise performance and health, but underlying mechanisms are not fully understood. The present review assesses the consequences induced by constant light (LL) in comparison with dim light at night (dLAN) on the circadian control of metabolism and behavior in rodents, since such an approach can identify the key mechanisms of chronodisruption. Data suggest that the effects of LL are more pronounced compared to dLAN and are directly related to the light level and duration of exposure. Dim LAN reduces nocturnal melatonin levels, similarly to LL, but the consequences on the rhythms of corticosterone and behavioral traits are not uniform and an improved quantification of the disrupted rhythms is needed. Metabolism is under strong circadian control and its disruption can lead to various pathologies. Moreover, metabolism is not only an output, but some metabolites and peripheral signal molecules can feedback on the circadian clockwork and either stabilize or amplify its desynchronization.
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DeBruyne, Jason P., Julie E. Baggs, Trey K. Sato, and John B. Hogenesch. "Ubiquitin ligase Siah2 regulates RevErbα degradation and the mammalian circadian clock." Proceedings of the National Academy of Sciences 112, no. 40 (September 21, 2015): 12420–25. http://dx.doi.org/10.1073/pnas.1501204112.
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Regulated degradation of proteins by the proteasome is often critical to their function in dynamic cellular pathways. The molecular clock underlying mammalian circadian rhythms relies on the rhythmic expression and degradation of its core components. However, because the tools available for identifying the mechanisms underlying the degradation of a specific protein are limited, the mechanisms regulating clock protein degradation are only beginning to be elucidated. Here we describe a cell-based functional screening approach designed to quickly identify the ubiquitin E3 ligases that induce the degradation of potentially any protein of interest. We screened the nuclear hormone receptor RevErbα (Nr1d1), a key constituent of the mammalian circadian clock, for E3 ligases that regulate its stability and found Seven in absentia2 (Siah2) to be a key regulator of RevErbα stability. Previously implicated in hypoxia signaling, Siah2 overexpression destabilizes RevErbα/β, and siRNA depletion of Siah2 stabilizes endogenous RevErbα. Moreover, Siah2 depletion delays circadian degradation of RevErbα and lengthens period length. These results demonstrate the utility of functional screening approaches for identifying regulators of protein stability and reveal Siah2 as a previously unidentified circadian clockwork regulator that mediates circadian RevErbα turnover.
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Hastings, Michael H., Elizabeth S. Maywood, and Marco Brancaccio. "The Mammalian Circadian Timing System and the Suprachiasmatic Nucleus as Its Pacemaker." Biology 8, no. 1 (March 11, 2019): 13. http://dx.doi.org/10.3390/biology8010013.
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The past twenty years have witnessed the most remarkable breakthroughs in our understanding of the molecular and cellular mechanisms that underpin circadian (approximately one day) time-keeping. Across model organisms in diverse taxa: cyanobacteria (Synechococcus), fungi (Neurospora), higher plants (Arabidopsis), insects (Drosophila) and mammals (mouse and humans), a common mechanistic motif of delayed negative feedback has emerged as the Deus ex machina for the cellular definition of ca. 24 h cycles. This review will consider, briefly, comparative circadian clock biology and will then focus on the mammalian circadian system, considering its molecular genetic basis, the properties of the suprachiasmatic nucleus (SCN) as the principal circadian clock in mammals and its role in synchronising a distributed peripheral circadian clock network. Finally, it will consider new directions in analysing the cell-autonomous and circuit-level SCN clockwork and will highlight the surprising discovery of a central role for SCN astrocytes as well as SCN neurons in controlling circadian behaviour.
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Petzold, Bernd, Michael F. Zaeh, Berthold Faerber, Barbara Deml, Hans Egermeier, Johannes Schilp, and Stella Clarke. "A Study on Visual, Auditory, and Haptic Feedback for Assembly Tasks." Presence: Teleoperators and Virtual Environments 13, no. 1 (February 2004): 16–21. http://dx.doi.org/10.1162/105474604774048207.
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Telepresent tasks involve removal of the human operator from an immediate working area and relocation to a remote environment that offers the operator all necessary control features. In this remote location, the operator must be provided with adequate feedback information such that the task at hand can be effectively executed. This research explores the effectiveness of various feedback methods. More specifically, graphical feedback in the form of video streamed images is compared against rendered 3D models, the overall effectiveness of haptic feedback is analyzed, and the influences of sensory augmentation and sensory substitution are examined. This study involved 48 participants, each of whom executed a simple clockwork assembly task under various feedback mechanisms. The results support the use of 3D models as opposed to live video streams for graphical presentation, utilization of haptic feedback (which was found to significantly enhance operation effectiveness), and the use of sensory augmentation and substitution under specific circumstances.
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Malaguarnera, Roberta, Caterina Ledda, Agnese Filippello, Francesco Frasca, Vincenzo Cristian Francavilla, Tiziana Ramaci, Maria Chiara Parisi, Venerando Rapisarda, and Salvatore Piro. "Thyroid Cancer and Circadian Clock Disruption." Cancers 12, no. 11 (October 24, 2020): 3109. http://dx.doi.org/10.3390/cancers12113109.
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Thyroid cancer (TC) represents the most common malignancy of the endocrine system, with an increased incidence across continents attributable to both improvement of diagnostic procedures and environmental factors. Among the modifiable risk factors, insulin resistance might influence the development of TC. A relationship between circadian clock machinery disfunction and TC has recently been proposed. The circadian clock machinery comprises a set of rhythmically expressed genes responsible for circadian rhythms. Perturbation of this system contributes to the development of pathological states such as cancer. Several clock genes have been found deregulated upon thyroid nodule malignant transformation. The molecular mechanisms linking circadian clock disruption and TC are still unknown but could include insulin resistance. Circadian misalignment occurring during shift work, jet lag, high fat food intake, is associated with increased insulin resistance. This metabolic alteration, in turn, is associated with a well-known risk factor for TC i.e., hyperthyrotropinemia, which could also be induced by sleep disturbances. In this review, we describe the mechanisms controlling the circadian clock function and its involvement in the cell cycle, stemness and cancer. Moreover, we discuss the evidence supporting the link between circadian clockwork disruption and TC development/progression, highlighting its potential implications for TC prevention, diagnosis and therapy.
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Marques, Diogo. "The Endgame or a Wake?: Tropes of Circularity in Literature Then and Now." CounterText 2, no. 2 (August 2016): 191–216. http://dx.doi.org/10.3366/count.2016.0052.
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This paper argues that attending to the tropes of circularity featuring in print-based literature proves to be a useful foil for an analysis of electronic literature. Based on the idea that digital literary mechanisms do not obliviate previous circularity-inducing structuring motifs in analog literature, such as labyrinths, chess, rivers, and clockwork, this argument arrives at a crucial time for literature, which is currently the object of intensified debates on beginnings and ends, especially in the context of digitality and multisensory perception becoming central to some aspects of its processes. Accordingly, circular motion is here analysed in its depiction and actuation across several kinds of literary / literal machines, in reflection also on how sensory perception both mediate and is mediated. If literature is conditional upon a series of unique, though interconnected, mechanisms, it seems reasonable not to discard a certain circularity of the senses that is brought into play there and, indeed, given both thematic and formal substance in analog and digital works. In other words, representations generated at the confluence of both biological and technological bodies cannot but instigate a circularity on which they are dependent: an idea which this article examines and critiques with reference to canonical and electronic literature, particularly Borges, Beckett, and Joyce.
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Mackenzie, Ann Wilbur. "Descartes on Life and Sense." Canadian Journal of Philosophy 19, no. 2 (June 1989): 163–92. http://dx.doi.org/10.1080/00455091.1989.10716476.
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My aim … is to show that the celestial machine is likened not to a kind of divine living being but rather to a clockwork. (Kepler, 1605)I consider the human body to be a machine … (Descartes, 1641)Although it may exaggerate to say that Descartes fathered the mechanization of biology, it is true (without qualification) that his Treatise of Man provided the first systematic development of the idea that a complete understanding of all the phenomena of life, including all abilities and behaviour of (non-human) animals, can be achieved by viewing living things as machines. To make this out, Decartes had to learn to think about living things in a new way. My first aim here is to identify the fundamental conceptual innovations at work in Descartes’ attempt to extend the new mechanics to include biology. My second aim is to locate the point at which Descartes’ mechanical imagination runs out. This requires study of Descartes’ scientific work on sense.
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Moriyama, Miyu, Walter J. Hugentobler, and Akiko Iwasaki. "Seasonality of Respiratory Viral Infections." Annual Review of Virology 7, no. 1 (September 29, 2020): 83–101. http://dx.doi.org/10.1146/annurev-virology-012420-022445.
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The seasonal cycle of respiratory viral diseases has been widely recognized for thousands of years, as annual epidemics of the common cold and influenza disease hit the human population like clockwork in the winter season in temperate regions. Moreover, epidemics caused by viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and the newly emerging SARS-CoV-2 occur during the winter months. The mechanisms underlying the seasonal nature of respiratory viral infections have been examined and debated for many years. The two major contributing factors are the changes in environmental parameters and human behavior. Studies have revealed the effect of temperature and humidity on respiratory virus stability and transmission rates. More recent research highlights the importance of the environmental factors, especially temperature and humidity, in modulating host intrinsic, innate, and adaptive immune responses to viral infections in the respiratory tract. Here we review evidence of how outdoor and indoor climates are linked to the seasonality of viral respiratory infections. We further discuss determinants of host response in the seasonality of respiratory viruses by highlighting recent studies in the field.
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Gray, Kathryn J., and Julie E. Gibbs. "Adaptive immunity, chronic inflammation and the clock." Seminars in Immunopathology 44, no. 2 (March 2022): 209–24. http://dx.doi.org/10.1007/s00281-022-00919-7.
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Abstract The adaptive arm of the immune system facilitates recognition of specific foreign pathogens and, via the action of T and B lymphocytes, induces a fine-tuned response to target the pathogen and develop immunological memory. The functionality of the adaptive immune system exhibits daily 24-h variation both in homeostatic processes (such as lymphocyte trafficking and development of T lymphocyte subsets) and in responses to challenge. Here, we discuss how the circadian clock exerts influence over the function of the adaptive immune system, considering the roles of cell intrinsic clockwork machinery and cell extrinsic rhythmic signals. Inappropriate or misguided actions of the adaptive immune system can lead to development of autoimmune diseases such as rheumatoid arthritis, ulcerative colitis and multiple sclerosis. Growing evidence indicates that disturbance of the circadian clock has negative impact on development and progression of these chronic inflammatory diseases and we examine current understanding of clock-immune interactions in the setting of these inflammatory conditions. A greater appreciation of circadian control of adaptive immunity will facilitate further understanding of mechanisms driving daily variation in disease states and drive improvements in the diagnosis and treatment of chronic inflammatory diseases.
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Wunderer, Florian, Sina Kühne, Antje Jilg, Katrin Ackermann, Tamas Sebesteny, Erik Maronde, and Jörg H. Stehle. "Clock Gene Expression in the Human Pituitary Gland." Endocrinology 154, no. 6 (April 12, 2013): 2046–57. http://dx.doi.org/10.1210/en.2012-2274.
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Abstract Pituitary function relies on strictly timed, yet plastic mechanisms, particularly with respect to the daytime-dependent coordination of hormone synthesis and release. In other systems, clock genes and their protein products are well-described candidates to anticipate the daily demands in neuroendocrine coupling and to manage cellular adaptation on changing internal or external circumstances. To elucidate possible mechanisms of time management, a total of 52 human autoptic pituitary glands were allocated to the 4 time-of-day groups, night, dawn, day, and dusk, according to reported time of death. The observed daytime-dependent dynamics in ACTH content supports a postmortem conservation of the premortem condition, and thus, principally validates the investigation of autoptic pituitary glands. Pituitary extracts were investigated for expression of clock genes Per1, Cry1, Clock, and Bmal1 and corresponding protein products. Only the clock gene Per1 showed daytime-dependent differences in quantitative real-time PCR analyses, with decreased levels observed during dusk. Although the overall amount in clock gene protein products PER1, CRY1, and CLOCK did not fluctuate with time of day in human pituitary, an indication for a temporally parallel intracellular translocation of PER1 and CRY1 was detected by immunofluorescence. Presented data suggest that the observed clock gene expression in human pituitary cells does not provide evidence for a functional intrinsic clockwork. It is suggested that clock genes and their protein products may be directly involved in the daytime-dependent regulation and adaptation of hormone synthesis and release and within homeostatic adaptive plasticity.
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Savino, Maria, Claudio Carmine Guida, Maria Nardella, Emanuele Murgo, Bartolomeo Augello, Giuseppe Merla, Salvatore De Cosmo, et al. "Circadian Genes Expression Patterns in Disorders Due to Enzyme Deficiencies in the Heme Biosynthetic Pathway." Biomedicines 10, no. 12 (December 9, 2022): 3198. http://dx.doi.org/10.3390/biomedicines10123198.
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Heme is a member of the porphyrins family of cyclic tetrapyrroles and influences various cell processes and signalling pathways. Enzyme deficiencies in the heme biosynthetic pathway provoke rare human inherited metabolic diseases called porphyrias. Protein levels and activity of enzymes involved in the heme biosynthetic pathway and especially 5′-Aminolevulinate Synthase 1 are featured by 24-h rhythmic oscillations driven by the biological clock. Heme biosynthesis and circadian pathways intermingle with mutual modulatory roles. Notably, heme is a ligand of important cogs of the molecular clockwork, which upon heme binding recruit co-repressors and inhibit the transcription of numerous genes enriching metabolic pathways and encoding functional proteins bringing on crucial cell processes. Herein, we assessed mRNA levels of circadian genes in patients suffering from porphyrias and found several modifications of core clock genes and clock-controlled genes expression, associated with metabolic and electrolytic changes. Overall, our results show an altered expression of circadian genes accompanying heme biosynthesis disorders and confirm the need to deepen the knowledge of the mechanisms through which the alteration of the circadian clock circuitry could take part in determining signs and symptoms of porphyria patients and then again could represent a target for innovative therapeutic strategies.
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Gessner, Samuel, Michael Korey, and Karsten Gaulke. "The Anomalous Sun." Nuncius 35, no. 2 (September 10, 2020): 191–234. http://dx.doi.org/10.1163/18253911-03502002.
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Abstract Four clockwork-driven planetary automata built to show the true motion of the planets according to Ptolemaic theory, not just their mean motion, survive from the sixteenth century: one each in Paris, Vienna, Kassel, and Dresden. Close, on-site examination of their mechanisms by a team of historians of science and clockmakers has gone beyond existing accounts and revealed that, though they share a common aim, the machines differ fundamentally in their realization of even the “simplest” of the planetary motions, namely that of the Sun. Indeed, three different ways have been detected for producing the solar anomaly, the Sun’s non-uniform motion along the ecliptic in the course of a year. The oldest of the surviving machines (Paris) uses the uniform motion of an eccentric gear, another (Vienna) adapts what would be a geometrically equivalent epicycle, and the two other machines (Kassel and Dresden) make use of a centered gear with non-uniformly spaced teeth. This paper discusses these findings in detail. It argues that such differing approaches not only reflect varying degrees of collaboration among the actors involved in the construction of these four technical masterpieces – princely commissioners, learned astronomers, and artful craftsmen (with these categories sometimes overlapping) – but also that they offer a further, mechanical contribution to the centuries-old reception and refinement of Ptolemaic planetary theory.
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Ikai, Atsushi. "Biological nanosystems: working principle of the molecular mouse trap and future prospects for spring action and/or clockwork machinery." Materials Science and Engineering: C 1, no. 2 (February 1994): 59–61. http://dx.doi.org/10.1016/0928-4931(94)90055-8.
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Rüthnick, Diana, and Elmar Schiebel. "Duplication of the Yeast Spindle Pole Body Once per Cell Cycle." Molecular and Cellular Biology 36, no. 9 (March 7, 2016): 1324–31. http://dx.doi.org/10.1128/mcb.00048-16.
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The yeast spindle pole body (SPB) is the functional equivalent of the mammalian centrosome. Centrosomes and SPBs duplicate exactly once per cell cycle by mechanisms that use the mother structure as a platform for the assembly of the daughter. The conserved Sfi1 and centrin proteins are essential components of the SPB duplication process. Sfi1 is an elongated molecule that has, in its center, 20 to 23 binding sites for the Ca2+-binding protein centrin. In the yeastSaccharomyces cerevisiae, all Sfi1 N termini are in contact with the mother SPB whereas the free C termini are distal to it. During S phase and early mitosis, cyclin-dependent kinase 1 (Cdk1) phosphorylation of mainly serine residues in the Sfi1 C termini blocks the initiation of SPB duplication (“off” state). Upon anaphase onset, the phosphatase Cdc14 dephosphorylates Sfi1 (“on” state) to promote antiparallel and shifted incorporation of cytoplasmic Sfi1 molecules into the half-bridge layer, which thereby elongates into the bridge. The Sfi1 C termini of the two Sfi1 layers localize in the bridge center, whereas the N termini of the newly assembled Sfi1 molecules are distal to the mother SPB. These free Sfi1 N termini then assemble the new SPB in G1phase. Recruitment of Sfi1 molecules into the anaphase SPB and bridge formation were also observed inSchizosaccharomyces pombe, suggesting that the Sfi1 bridge cycle is conserved between the two organisms. Thus, restricting SPB duplication to one event per cell cycle requires only an oscillation between Cdk1 kinase and Cdc14 phosphatase activities. This clockwork regulates the “on”/“off” state of the Sfi1-centrin receiver.
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Asrorov, Farhod, Oleh Perehuda, Valentyn Sobchuk, and Anna Sukretna. "Establishing conditions for the existence of bounded solutions to the weakly nonlinear pulse systems." Eastern-European Journal of Enterprise Technologies 4, no. 4(112) (August 30, 2021): 6–12. http://dx.doi.org/10.15587/1729-4061.2021.238208.
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Processes that involve jump-like changes are observed in mechanics (the movement of a spring under an impact; clockwork), in radio engineering (pulse generation), in biology (heart function, cell division). Therefore, high-quality research of pulse systems is a relevant task in the modern theory of mathematical modeling. This paper considers the issue related to the existence of bounded solutions along the entire real axis (semi-axis) of the weakly nonlinear systems of differential equations with pulse perturbation at fixed time moments. A concept of the regular and weakly regular system of equations for the class of the weakly nonlinear pulse systems of differential equations has been introduced. Sufficient conditions for the existence of a bounded solution to the heterogeneous system of differential equations have been established for the case of poorly regularity of the corresponding homogeneous system of equations. The conditions for the existence of singleness of the bounded solution along the entire axis have been defined for the weakly nonlinear pulse systems. The results were applied to study bounded solutions to the systems with pulse action of a more general form. The established conditions make it possible to use the classical methods of differential equations to obtain statements about solvability and the continuous dependence of solutions on the parameters of a pulse system. It has been shown that classical qualitative methods for studying differential equations are mainly naturally transferred to dynamic systems with discontinuous trajectories. However, the presence of a pulse action gives rise to a series of new specific problems. The theory of systems with pulse influence has a wide range of applications. Such systems arise when studying pulsed automatic control systems, in the mathematical modeling of various mechanical, physical, biological, and other processes.
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EDERY, ISAAC. "Circadian rhythms in a nutshell." Physiological Genomics 3, no. 2 (August 9, 2000): 59–74. http://dx.doi.org/10.1152/physiolgenomics.2000.3.2.59.
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Edery, Isaac. Circadian rhythms in a nutshell. Physiol Genomics 3: 59–74, 2000.—Living organisms on this planet have adapted to the daily rotation of the earth on its axis. By means of endogenous circadian clocks that can be synchronized to the daily and seasonal changes in external time cues, most notably light and temperature, life forms anticipate environmental transitions, perform activities at biologically advantageous times during the day, and undergo characteristic seasonal responses. The effects of transmeridian flight and shift work are stark reminders that although modern technologies can create “cities that never sleep” we cannot escape the recalcitrance of endogenous clocks that regulate much of our physiology and behavior. Moreover, malfunctions in the human circadian timing system are implicated in several disorders, including chronic sleep disorders in the elderly, manic-depression, and seasonal affective disorders (SAD or winter depression). Recent progress in understanding the molecular mechanisms underlying circadian rhythms has been remarkable. In its most basic form, circadian clocks are comprised of a set of proteins that, by virtue of the design principles involved, generate a self-sustaining transcriptional-translational feedback loop with a free-running period of about 24 h. One or more of the clock components is acutely sensitive to light, resulting in an oscillator that can be synchronized to local time. This review provides an overview of the roles circadian clocks play in nature, how they might have arisen, human health concerns related to clock dysfunction, and mainly focuses on the clockworks found in Drosophila and mice, the two best studied animal model systems for understanding the biochemical and cellular bases of circadian rhythms.
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Smieszek, S. P. "0018 Whole Genome Sequencing Study Identifies Novel Variants Associated with Intrinsic Circadian Period in Humans." Sleep 43, Supplement_1 (April 2020): A7—A8. http://dx.doi.org/10.1093/sleep/zsaa056.017.
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Abstract Introduction Non-24 is a circadian rhythm disorder in which the master body clock runs either slightly earlier or, more commonly in the disorder, longer than 24 hours. Methods We conducted the first whole genome sequencing study of a non-24 population of 174 individuals that we identified as being totally blind with Non-24 Disorder. We have directly tested the association between SNPs and circadian period length (tau) (n=69). Linear regression corrected for PCs and covariates identified a strong signal in HCN1, Brain Cyclic Nucleotide-Gated Channel 1, HCN1. Results HCN1 channel is responsible for the feedback on the rods regulating the dynamic range of light reactivity under dim or intermediate light conditions. Minor allele rs72762058 associated with longer tau, a difference of 12 minutes, and mean tau of 24.71. In Drosophila there is only one HCN channel encoding gene, DmIh. Interestingly, DmIh mutant flies display alterations in the rest:activity pattern, and altered circadian rhythms, specifically, arrhythmic behavior or a shorter period in constant darkness. We report a variant that associated with longer tau. In addition, we identify others variants that strongly associate with tau, such as a missense variant (rs16989535), (minor allele associated with longer tau), within DEPDC5, GATOR Complex Protein). Subjects carrying the rare allele have a period > 25.2. DEPDC5 is part of GATOR1 complex, together with NPRL2 and NPRL3acts to inhibit the mTORC1 pathway. The GATOR1 seizure phenotype consists mostly of focal seizures, often sleep-related and drug-resistant and is associated with focal cortical dysplasia (20%). mTOR signaling is part of the photic entrainment pathway in the SCN, it regulates autonomous clock properties in a variety of circadian oscillators. Light-induced mTORC1 activation appears to be important for photic entrainment of the SCN clock, as rapamycin modulates light-induced phase shifts of wheel-running and body temperature rhythms in mice. Conclusion We identify variants in HCN1 and DEPDC5 implicated in significantly longer tau. Knowledge of the circadian clock and period length is not only essential for understanding of the basic clockwork mechanisms but also could provide insights into mechanistic links between circadian dysfunctions and human diseases such as epilepsy. Support Vanda Pharmaceuticals