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1

Reilly, Thomas P. "Circadian rhythms and exercise." Thesis, Liverpool John Moores University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297911.

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Otway, Daniella Theresia. "Circadian rhythms in adipose tissue." Thesis, University of Surrey, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.511108.

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Jasper, Isabelle. "Circadian rhythms in sensorimotor control." Tönning Lübeck Marburg Der Andere Verl, 2009. http://d-nb.info/997031034/04.

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Pearson, Kristen A. "Circadian rhythms, fatigue, and manpower scheduling." Thesis, Monterey, Calif. : Springfield, Va. : Naval Postgraduate School ; Available from National Technical Information Service, 2004. http://library.nps.navy.mil/uhtbin/hyperion/04Dec%5FPearson.pdf.

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MORBIATO, ELISA. "Modulation of circadian rhythms by glucocorticoids." Doctoral thesis, Università degli studi di Ferrara, 2020. http://hdl.handle.net/11392/2478787.

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Il comportamento è concepito come una relazione dipendente stimolo-risposta tra un input sensoriale e una risposta motoria. Nel passaggio da input a output, l’omeostasi interna è continuamente modellata per mantenere un equilibrio ottimale della spesa energetica. Lo scopo ultimo di mantenere l’omeostasi in relazione al mondo circostante viene raggiunto attraverso la produzione di comportamenti adattativi che permettono di incrementare la fitness alla luce della selezione naturale. L’ambiente circostante può essere sia prevedibile sia imprevedibile. La prima condizione ha portato all’evoluzion
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Trujillo, Jennifer L. "Relationships between circadian rhythms and ethanol intake in mice." Diss., [La Jolla] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p3359855.

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Thesis (Ph. D.)--University of California, San Diego, 2009.<br>Title from first page of PDF file (viewed July 23, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 127-136).
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Power, Andrea. "Neuronal Regulation of Circadian Rhythms in Mice." Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.501978.

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Middleton, Benita. "Investigations of factors influencing human circadian rhythms." Thesis, University of Surrey, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265103.

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O'Neill, John Stuart. "The molecular biology of mammalian circadian rhythms." Thesis, University of Cambridge, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612807.

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Ragsdale, Raven, Colin Shone, Madeleine Miller, Andrew Shields, Thomas C. Jones, and Darrell Moore. "Circadian Resonance and Entrainment in Three Spider Species (Frontinella communis, Metazygia wittfeldae, and Cyclosa turbinata)." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/140.

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Circadian clocks are vital to the proper functioning of organisms’ internal processes and behavioral outputs and typically have endogenous periods that approximate (within 1-2 hours) the 24-hour solar day. Clocks that deviate significantly from about 24 hours are often associated with metabolic syndromes or other disease states. For instance, organisms with near-24-hour clocks have higher survivorship under 24-h light:dark (LD) cycles than with 22- or 26-hour cycles. Likewise, mutant organisms with 22-hour clocks survive better under 22-h cycles but fare poorly under 24- and 26-h cycles. In ot
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Simões, Ana Leda Bertoncini. "Estudo comparativo e variabilidade circadiana das temperaturas timpanica, oral e axilar em adultos hospitalizados." [s.n.], 2005. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311342.

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Orientador: Milva Maria Figueiredo De Martino<br>Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas<br>Made available in DSpace on 2018-08-04T03:29:08Z (GMT). No. of bitstreams: 1 Simoes_AnaLedaBertoncini_M.pdf: 1152293 bytes, checksum: 939294f259cff182dfd66288e6a3ac44 (MD5) Previous issue date: 2005<br>Resumo: Esta pesquisa teve como objetivo verificar a variabilidade circadiana das temperaturas timpânica, oral e axilar; correlacionar as medidas da temperatura timpânica considerando o ângulo de posicionamento e comparar as medidas entre si, em paciente
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12

Han, Linqu. "Molecular and genetic analysis of a novel F-box protein, ZEITLUPE, in the Arabidopsis circadian clock." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1155569207.

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Long, Mitchell, Thomas C. Jones, and Darrell Moore. "Temporal Factors Affecting Foraging Patterns of a Diurnal Orb-weaving Spider, Micrathena gracilis (Araneae: Araneidae)." Digital Commons @ East Tennessee State University, 2020. https://dc.etsu.edu/asrf/2020/presentations/54.

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Many studies have investigated the ecological factors that affect behavior in Micrathena gracilis, a diurnal orb-weaving spider that forages exclusively on flying insects during the day. However, none yet have considered how the temporal distributions of prey and predator occurrences shape their daily behavioral rhythms, especially web construction which involves a heavy energetic investment well in advance of potential nutritional benefit. Recently, other spider species have been found to express significant circadian plasticity, suggesting that circadian clock-controlled rhythms may play a l
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Timothy, Joseph. "Circadian rhythms in the neuorbiology of bipolar disorder." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/circadian-rhythms-in-the-neuorbiology-of-bipolar-of-bipolar-disorder(8d7f6f92-b7cd-4835-8e53-d15334c2dfe3).html.

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Daily rhythms of physiology and behaviour in mammals are orchestrated by a hierarchical network of cellular oscillators. The master pacemaker that defines local and systemic timing across the brain and body are the suprachiasmatic nuclei of the hypothalamus (SCN). Disruption to the timing of sleep and daily behavioural activity can manifest in a range of pathologies including neuropsychiatric disorders. Bipolar disorder (BPD) is once such neurological condition that exhibits profound associations with altered circadian rhythm generation and whose toolkit of pharmacological interventions impact
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Harper, David G. "Circadian rhythm disturbances in advanced dementia /." Thesis, Connect to Dissertations & Theses @ Tufts University, 2000.

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Thesis (Ph.D.)--Tufts University, 2000.<br>Adviser: David Harder. Submitted to the Dept. of Psychology. Includes bibliographical references (leaves 90-116). Access restricted to members of the Tufts University community. Also available via the World Wide Web;
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Valekunja, Utham Kashyap. "The mammalian circadian transcriptome and epigenome." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709142.

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Janich, Peggy 1981. "The role of circadian rhythms in epidermal homeostasis." Doctoral thesis, Universitat Pompeu Fabra, 2012. http://hdl.handle.net/10803/84112.

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The natural daily cycles of light and dark have played a fundamental role in shaping the development of an adaptive intrinsic clock mechanism which allows organisms to coordinate the function of multiple organs by setting the correct circadian timing of cellular processes ensuring proper homeostasis. In mammalian skin, homeostasis is maintained by epidermal stem cells (epSCs). EpSCs localize to specialized niches where they undergo cycles of quiescence and proliferation. Several pathways are known to play essential rol
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Dadi, Kamalaker Reddy. "Circadian Rhythms in the Brain - A first step." Thesis, Linköpings universitet, Institutionen för medicinsk teknik, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-89698.

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Circadian Rhythms (CR) are driven by a biological clock called as suprachiasmaticnucleus (SCN), located in a brain region called the hypothalamus. These rhythms are very much necessary in maintaining the sleep and wake cycle at appropriate times in a day. As a starting step towards non-invasive investigation of CR, aim is to study changes in the physiological processes of two Regions of Interest (ROI), the hypothalamus and the visual cortex. This was studied using a functional Magnetic Resonance Imaging (fMRI) technique to investigate for any changes or differences in the Blood Oxygen Level De
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Montagnese, Sara. "Sleep and circadian rhythms in patients with cirrhosis." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/17258/.

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Circadian regulation synchronises the sleep-wake cycle to the light-dark cycle. Light cues reach the hypothalamus, the site of the circadian clock, via the retino-hypothalamic tract. In turn, the hypothalamus projects to the pineal, regulating melatonin synthesis, which is high at night. The rhythms of plasma melatonin, its urinary metabolite 6-sulphatoxymelatonin (aMT6s) and plasma cortisol are reliable markers of ihe phase of the clock. Sleep-wake abnormalities are common in patients with cirrhosis and have traditionally been attributed to hepatic encephalopathy. Melatonin rhythm abnormaliti
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Joseph, Desaline Veronica. "The development of circadian rhythms in human infants." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/9636.

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Introduction: The first four postnatal months, for a newborn infant, is a period of rapid adaptation and change. Infants undergo a series of integrated physiological changes that culminate in mature physiological diurnal rhythms by which they establish equilibrium with the new environment, all of which are under the genetic control of the biological clock. This is a longitudinal study of 35 infants in which the age related changes in physiology, are assessed during night time sleep and related to circadian genes, melatonin and cortisol. Aim: The aim of the study is to monitor the physiological
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Gardner, M. J. "Circadian rhythms in transcript abundance in Arabidopsis thaliana." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599310.

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To characterise the circadian transcriptome, the expression profiles of transcripts in whole leaves of mature, soil grown <i>A. thaliana </i>plants were analysed. Circadian-regulated transcripts constituted approximately 9.5% of the transcripts detected, and were found to encode proteins involved both a well-described circadian processes and in pathways that have not been previously identified as having circadian regulation. Transcripts encoding proteins involved in core metabolic processes and stress response pathways were particularly highly representative in the dataset, which suggested a p
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Malloy, Jaclyn. "CENTRAL AND PERIPHERAL REGULATION OF CIRCADIAN GASTROINTESTINAL RHYTHMS." UKnowledge, 2012. http://uknowledge.uky.edu/biology_etds/5.

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Circadian clocks are responsible for daily rhythms in gastrointestinal function which are vital for normal digestive rhythms and health. The present study examines the roles of the circadian pacemaker, the suprachiasmatic nuclei (SCN), and the sympathetic nervous system in regulation of circadian gastrointestinal rhythms in Mus musculus. Surgical ablation of the SCN abolishes circadian locomotor, feeding, and stool output rhythms when animals are presented with food ad libitum, while restricted feeding reestablishes these rhythms temporarily. In intact mice, chemical sympathectomy with 6- hydr
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Jenkins, H. A. "Circadian and ultradian rhythms in Chlamydomonas and Euglena." Thesis, Bucks New University, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233011.

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Kearney, Louise. "Circadian rhythms in glucocorticoid signalling and pulmonary inflammation." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/circadian-rhythms-in-glucocorticoid-signalling-and-pulmonary-inflammation(e064e4fc-d011-49ce-ad0c-4c80ea40acec).html.

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The circadian clock drives ~24hr rhythms in a variety of processes, from gene expression through to behaviour, facilitating anticipation of daily changes in the external environment and temporal separation of internal processes. This pacemaker is a critical regulator of immune function and many inflammatory diseases show time-of-day variation in symptom severity. Disruption of the pacemaker by manipulation of the daily cycle of light and dark exposure (experimental 'jet lag') is known to exacerbate inflammatory responses to innate immune challenge, and recent evidence has highlighted immuno-mo
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Hong, Christian I. "Mathematical Modeling of Circadian Rhythms in Drosophila melanogaster." Thesis, Virginia Tech, 1999. http://hdl.handle.net/10919/42168.

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Circadian rhythms are periodic physiological cycles that recur about every 24 hours, by means of which organisms integrate their physiology and behavior to the daily cycle of light and temperature imposed by the rotation of the earth. Circadian derives from the Latin word circa "about" and dies "day". Circadian rhythms have three noteworthy properties. They are endogenous, that is, they persist in the absence of external cues (in an environment of constant light intensity, temperature, etc.). Secondly, they are temperature compensated, that is, the nearly 24 hour period of the endogenous o
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Kirveskari, Erika. "Circadian rhythms and sleep in neuronal ceroid lipofuscinoses." Helsinki : University of Helsinki, 2000. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/kirveskari/.

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Filardi, Marco <1984&gt. "Circadian Rhythms and Attentional Dysfunction in type1 Narcolepsy." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amsdottorato.unibo.it/7590/1/Circadian_rhythms_and_attentional_dysfunction_in_type_1_Narcolepsy.pdf.

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The aim of this investigation was to explore the nature and the severity of circadian abnormalities and attentional deficit in type 1 narcolepsy. In three studies, narcolepsy patients were compared with patients suffering from other central disorders of hypersomnolence and healthy controls on attentional functions and circadian rhythms. Study 1 evaluated the sensibility of actigraphic monitoring in distinguishing the features of daytime and nighttime sleep between adult patients with type 1 Narcolepsy, Idiopathic Hypersomnia and healthy controls. Actigraphy provides a reliable assessment of sl
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Filardi, Marco <1984&gt. "Circadian Rhythms and Attentional Dysfunction in type1 Narcolepsy." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2016. http://amsdottorato.unibo.it/7590/.

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The aim of this investigation was to explore the nature and the severity of circadian abnormalities and attentional deficit in type 1 narcolepsy. In three studies, narcolepsy patients were compared with patients suffering from other central disorders of hypersomnolence and healthy controls on attentional functions and circadian rhythms. Study 1 evaluated the sensibility of actigraphic monitoring in distinguishing the features of daytime and nighttime sleep between adult patients with type 1 Narcolepsy, Idiopathic Hypersomnia and healthy controls. Actigraphy provides a reliable assessment of sl
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Trogen, Greta. "Circulating Oligomeric State and Circadian Rhythm Regulation of CTRP3." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/120.

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Adipose tissue secretes many important biologically active proteins called adipokines. A subset of adipokines, called C1q tumor necrosis factor (TNF) related proteins (CTRPs), play a key role in metabolism, inflammation, and cell signaling. C1q TNF Related Protein 3 (CTRP3) increases hepatic fatty acid oxidation, decreases inflammation, and aids in cardiovascular recovery following a myocardial infarction. However, the mechanisms behind CTRP3’s protective effects on organ systems are unknown. This exploratory study aims to analyze the circulating oligomeric state of CTRP3 and the circadian reg
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Dolaptchieva, Maria [Verfasser]. "Circadian Rhythms and microRNAs in Energy Metabolism / Maria Dolaptchieva." Berlin : Freie Universität Berlin, 2015. http://d-nb.info/1075190886/34.

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Liao, Kiong Sen. "Circadian rhythms in lung ventilation in wakefulness and sleep." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/MQ58865.pdf.

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Sobczyk, Melanie Victoria. "Exploring the relationship between schizophrenia, sleep and circadian rhythms." Thesis, University of Oxford, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.542974.

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Gibbs, Michelle A. "Consequences of shift work on circadian rhythms and metabolism." Thesis, University of Surrey, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.418079.

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Hack, Lisa M. "Melatonin and free-running circadian rhythms in the blind." Thesis, University of Surrey, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402886.

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Mitchell, Megan Irvette. "Circadian rhythms as novel chemotherapeutic strategies for breast cancer." Thesis, Stellenbosch : Stellenbosch University, 2014. http://hdl.handle.net/10019.1/95890.

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Thesis (MSc)--Stellenbosch University, 2014.<br>ENGLISH ABSTRACT: Introduction: Mammalian circadian rhythms form an integral physiological system allowing for the synchronisation of all metabolic processes to daily light/dark cycles, thereby optimising their efficacy. Circadian disruptions have been implicated in the onset and progression of different types of cancers, including those arising in the breast. Several links between the circadian protein Per2 and DNA damage responses exist. Aberrant Per2 expression results in potent downstream effects to both cell cycle and apoptotic targets, sugg
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Bourne, Richard Stanley. "Melatonin, sleep and circadian rhythms in critical care patients." Thesis, University of Sheffield, 2009. http://etheses.whiterose.ac.uk/15108/.

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Critical care patients commonly experience sleep fragmentation, in which sleep quality is poor and distributed throughout the 24 hour cycle. This irregular sleep wake pattern is a form of circadian rhythm sleep disorder. The causes of sleep disturbances are multifactorial and contribute to patient morbidity. Conventional hypnotic treatment is often ineffective and, indeed, may cause delirium and reduced sleep quality. Administration of exogenous melatonin has been shown to re-enforce circadian rhythm disorders and improve sleep in other patient groups. An open evaluation of 5 mg oral melatonin
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Prior, Kimberley Faith. "The evolutionary ecology of circadian rhythms in malaria parasites." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/29562.

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Biological rhythms are thought to have evolved to enable organisms to organise their activities according to the Earth’s predictable cycles, but quantifying the fitness advantages of rhythms is challenging and data revealing their costs and benefits are scarce. More difficult still is explaining why parasites that exclusively live within the bodies of other organisms have biological rhythms. Rhythms exist in the development and traits of parasites, in host immune responses, and in disease susceptibility. This raises the possibility that timing matters for how hosts and parasites interact and,
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Herrman, Erin Rae. "Estrous Cyclicity Modulates Circadian Rhythms In Female Syrian Hamsters." Kent State University / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=kent1228154599.

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Carter, James Edward. "Alternative Scheduling in the Middle School: Considering Circadian Rhythms." Digital Commons @ East Tennessee State University, 2011. https://dc.etsu.edu/etd/1259.

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The passage of No Child Left Behind has increased the level of accountability for all educators. There are many factors that affect student achievement. One factor that may be overlooked is the schedule configuration of schools. Addressing student needs through scheduling options may assist school systems and students in performing at the level they are being held accountable. The population for this study was students from a rural East Tennessee middle school with a population of approximately 700 students. The low socioeconomic students represent 68% of the school total enrollment while 18%
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Edwards, Mathew David. "Molecular neurobiology of the mammalian circadian clock." Thesis, University of Cambridge, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709384.

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Palacios, Jordán Héctor. "Metabolomics strategy to comprehend the interactions between circadian rhythms and flavanol activity on the hepatic metabolism." Doctoral thesis, Universitat Rovira i Virgili, 2019. http://hdl.handle.net/10803/668962.

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Un extracte de proantocianidinas extretes de la llavor del raïm (GSPE) ha estat relacionat amb un ampli rang de efectes beneficiosos per la prevenció i tractament de les alteracions metabòliques hepàtiques induïdes per l’obesitat, p.e., la resistència a la insulina o l’esteatosi. A més, el GPSE és capaç de modular els ritmes circadians del fetge, els quals es troben desajustats a l’obesitat, suggerint que el GSPE pot regular parcialment el metabolisme de lípids i glucosa modulant els ritmes circadians hepàtics. La metabolòmica per RMN pot ser una tècnica adequada per l’estudi de la interacci
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Rutterford, Zoë Susan. "The barley circadian clock in relation to photoperiod response." Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609468.

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Bailey, Sandra Lynn. "Morningness-eveningness and circadian rhythms of HPA- and SNS-mediated variables /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/7301.

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Crain, Shae, Thomas Jones, and Darrell 2346742 Moore. "Average Free-Running Period in Spider (Frontinella communis) Peaks and Desynchronizes Throughout its Active Season." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/5.

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An organism’s circadian clock exists as a self-regulating oscillator that can synchronize with its surroundings. This manifests as physiological and behavioral output which can anticipate changes in environment. These rhythms may even persist internally and are known to oscillate at a period (tau) of around 24 hours even in the absence of external cues. In the laboratory, such rhythmic output is known as a free-running period (FRP). Given that circadian rhythms are distributed in a number of taxa as well as their tendency to oscillate along with the solar day, it has been suggested that they r
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Bambaeichi, Effat. "The influence of circadian and circamensal rhythms on muscle performance." Thesis, Liverpool John Moores University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439059.

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Morjaria, Rupal. "Impact of ocular disease on circadian rhythms and brain connectivity." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10059298/.

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Investigation into the impact of ocular disease on sleep and mood has shown that in humans eyes have an important role, and that absence of eyes or interference with light reaching the retina can have deleterious effects. Light is the main zeitgeber 'time-giver' used by most species for the regulation of circadian rhythms and is detected by rods, cones and photosensitive retinal ganglion cells (pRGCs) in mammals. The aims of this research project were to investigate this from three different perspectives. Three prospective studies were undertaken. The first, studied the impact of ocular diseas
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Purple, Ross. "Sleep physiology, circadian rhythms, and the risk for developing psychosis." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:788031c2-62ef-44f1-9dd7-8b3a7be53057.

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Sleep and circadian rhythm disruption (SCRD) is frequently found to co-occur in psychotic disorders. This can include a range of phenotypes such as insomnia, circadian delays, deficits in sleep spindles, and sleep-dependent cognitive impairments. However, increasing evidence suggests that psychosis occurs across a continuum of severity within the general population, yet few studies have investigated sleep and circadian rhythms prior to clinical diagnosis. Furthermore, SCRD and psychosis are posited to share underlying neuropathologies and although increasing evidence implicates shared genetic
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Mikulets, L. V. "Circadian rhythms of proteolysis indices in patients with rheumatoid arthritis." Thesis, БДМУ, 2020. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18053.

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Chowdhury, Debajyoti. "Quantitative understanding of transcriptional regulatory logics in modulating circadian rhythms." HKBU Institutional Repository, 2020. https://repository.hkbu.edu.hk/etd_oa/743.

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The day-to-day physiologies are largely influenced by circadian rhythms. Disruptions of such rhythms are associated with many diseases. Adjusting them to a healthy one can be promising to treat different circadian rhythms disruption associated diseases such as sleep disorders, cardiovascular disorders, metabolic disorders. The regulations underlying the circadian rhythms are much complicated and systematic which may involve thousands of genes. In mammals, these robust circadian rhythms are primarily intended by the concerted molecular interplays, knowingly, transcriptional-translational feedba
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Starkey, Lewis Philip. "The relevance of microRNAs and circadian rhythms in drug safety." Thesis, University of Liverpool, 2012. http://livrepository.liverpool.ac.uk/11753/.

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Drug-induced liver injury (DILI) is a serious adverse drug reaction (ADR) that is frequently encountered during drug development, representing a major cause of drug attrition. Furthermore, DILI is also a serious concern in the clinic, accounting for approximately half of all acute liver failure cases. Paracetamol overdose (acetaminophen; APAP) accounts for the majority of DILI-associated cases of ALF encountered in patients. The identification and development of novel biomarkers of DILI that are sensitive, specific, and rise early during hepatotoxicity are urgently required in the clinic and i
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