Tesi: "Circadian"

1

Zhang, Yuan. "Circadian clocks and cancer : The implication of BMAL1 (brain and muscle Arnt-like protein-1) in colorectal and breast carcinoma development and treatment". Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS422.

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BMAL1, une protéine centrale de l'horloge circadienne.L’inactivation de BMAL1 (BMAL1-KO) entraîne une perte complète de la rythmicité dans les horloges central et périphérique. Le travail de ma thèse se concentre sur le rôle du gène BMAL1 dans la développement et le traitement des cancers du sein et du côlon.1. Pharmacodynamique in vitro de l’Everolimus en fonction du temps d’administration malgré une horloge circadienne défectueuse ((Zhang et al., 2018) (Zhang, Levi and Chang, 2018)L’everolimus (EV) est un inhibiteur de la mTOR chez les mammifères et il est utilisé pour traiter le cancer du sein positif aux oestrogènes (ER+). Nous avons focalisé nos recherches sur la chronopharmacologie de l’Everolimus administré sur des cellules MCF-7 (ER+). Les MCF-7 présentent une oscillation circadienne de l’activité de mTOR sans mise en évidence d’une oscillation des gènes d’horloge. L’oscillation d’activité de mTOR induirait une oscillation de synthèse et/ou de phosphorylation de protéines importantes dans la progression de la phase G1, notamment la Cycline D1 et RB phosphorylée. Ces variations rythmiques des MCF-7 synchronisées expliquent la chrono-efficacité de l’Everolimus selon des temps différents d’administration.Ce travail a révélé que même dans un système de cellules cancéreuses dont l’horloge était perturbée, l'intégration d'autres rythmes cellulaires dans la chronothérapie pouvait augmenter l'efficacité du médicament. Ce principe peut être appliqué à des traitements du cancer pour optimiser la chronothérapie du cancer.2. Le Knockdown BMAL1 a déclenché différents destins de cellules du carcinome du côlon (CRC) en modifiant l'équilibre délicat entre les voies AKT / mTOR et P21 / P53 (Article soumis)Premièrement, nos résultats ont révélé que le knockdown BMAL1 par le shRNA (BMAL1-KD) avait déclenché une activation plus évidente de l’AKT / mTOR dans deux lignées cellulaires primaires (HCT116 et SW480) que une lignée métastatique de CRC, SW620. De plus, bien que les deux lignées cellulaires primaires de CRC aient présenté une augmentation significative de l'activité de l'AKT/mTOR, elles avaient des statuts différents de P53 (WT ou mutant). Dans ce contexte, les cellules SW480 BMAL1-KD avec P53 mutant présentaient une sénescence accrue, mais les cellules HCT116 BMAL1-KD avec P53 WT présentaient d’abord une apoptose transitoire, puis un taux de prolifération plus élevé.Ainsi, nos travaux ont révélé le rôle crucial de BMAL1 pour équilibrer un régulateur central du métabolisme AKT / mTOR et une voie de réponse au stress P53 / P21 dans des lignées cellulaires de CRC, ce qui met en évidence l’importance de BMAL1 dans le développement de CRC et la progression du vieillissement.3. BMAL1 renforce les propriétés épithéliales et diminue la chimiorésistance des cellules du CRC (article en préparation)La transition épithélo-mésenchymateuse (EMT) est un événement critique dans l'invasion et la métastase des carcinomes, y compris le CRC.Dans ce travail, nous avons étudié comment BMAL1 knockdown (Bmal1-KD) altère l’équilibre délicat entre les propriétés épithéliales et mésenchymateuse de trois lignées cellulaires de CRC (HCT116, SW480 et SW620).Après BMAL1-KD, la diminution de l’expression Twist, un facteur de transcription favorisé l’EMT et des marqueurs mésenchymateux (N-Cadhérine, Vimentine) étaient associées à une expression accrue des marqueurs épithéliaux (E-cadhérine, CK20 et EpCAM). De manière constante, l'augmentation de l'expression de l’E-cadhérine après BMAL1-KD était accompagnée d'une co-localisation membranaire accrue de la β-caténine avec l'E-cadhérine, ainsi que d'une diminution de la localisation nucléaire de la β-caténine, suggérant une diminution de l'activation de la voie Wnt. De plus, les cellules BMAL1-KD ont montré une diminution des capacités de migration et de la résistance aux médicaments.Au total, ces données soulignent l’importance de BMAL1 dans l’EMT des cellules de CRC
BMAL1 is a core circadian clock protein, forming a heterodimer with CLOCK to initiate the transcription of circadian and output genes. Among canonical clock genes, only BMAL1 knockout results in complete loss of rhythmicity in both the SCN and peripheral tissues. My thesis work focuses on exploring the important role of BMAL1 in human breast and colon cancer progression and treatment. My work is divided into three main parts:1. Dosing time dependent in vitro pharmacodynamics of Everolimus despite a defective circadian clock (Zhang et al., 2018)(Zhang, Levi and Chang, 2018) Everolimus (EV) is an inhibitor of mammalian target of Rapamycin (mTOR) and is used to treat estrogen positive (ER+) breast cancer. Here, we investigated whether EV efficacy varied according to administration timing by using the ER+ breast cancer cell line MCF-7 as a model system. Serum shock synchronization induced a circadian oscillation in mTOR activity in MCF-7 cells, which rhythmically regulated the synthesis or phosphorylation of key G1 progression proteins, such as Cyclin D1 and phosphorylated RB, ultimately resulting in different G0/G1 blockage efficiency according to different EV administration timing. Thus, the different delivery schedule of EV presented different efficacy in G0/G1 phase blockage in serum shocked MCF-7 cells.This investigation revealed that, even in a breast cancer cell system with disrupted circadian organization, modulating drug administration according to other protein rhythms could still increase drug efficacy. This principle may be applied to many other cancer systems and treatment types to optimize cancer chronotherapy.2. Knockdown BMAL1 triggered different colon carcinoma cells fates by altering the delicate equilibrium between AKT/mTOR and P21/P53 pathways (Article in preparation)We tried to evaluate in vitro how knockdown BMAL1 (BMAL1-KD) by shRNA influences human colorectal cancer cell (CRC) behavior.The results revealed that BMAL1-KD triggered different CRC cell fates based on distinct p53 status in different cell lines. First, after BMAL1 knockdown, two primary CRC cell lines (HCT116 and SW480) presented a more evident AKT/mTOR activation than the metastatic colon carcinoma cell line, SW620. Furthermore, although both primary CRC cell lines presented a significant increase of AKT/mTOR activity, they had different P53 status (WT or mutant) and activation pattern. Under these context, SW480 BMAL1-KD cells exhibited increased senescence but HCT116 BMAL1-KD cells showed firstly a transient apoptosis and then higher proliferation rate.Thus, our work uncovered the crucial role of BMAL1 to balance a central metabolism regulator AKT/mTOR and a stress response pathway P53/P21 in CRC cell lines, which highlighted the importance of BMAL1 in CRC development and aging progression.3. BMAL1 knockdown leans epithelial–mesenchymal balance toward epithelial properties and decreased the chemoresistance of colon carcinoma cell (Article in preparation)Epithelial-mesenchymal transition (EMT) is a critical early event in the invasion and metastasis of carcinoma, including colorectal cancer (CRC). In this work, we studied how BMAL1-KD alters the delicate equilibrium between epithelial and mesenchymal properties of three colon carcinoma cell lines (HCT116, SW480 and SW620).The results showed the molecular alterations after BMAL1-KD promote mesenchymal-to-epithelial transition-like changes mostly appeared in two primary CRC cell lines (HCT116 and SW480) compared to the metastatic cell line SW620. Subsequently, BMAL1-KD HCT116 and SW480 cells harbored a decreased migration, invasiveness and drug resistance capacities relative to their scramble counterpart cells. All these data suggested the importance of BMAL1 on EMT inducing in colon carcinoma cells

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2

Cervela, Cardona Luis Manuel. "Functional studies on the circadian regulation of mitochondrial activity in Arabidopsis thaliana". Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/669786.

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El reloj circadiano es un mecanismo celular endógeno capaz de medir el paso del tiempo y traducir las señales medioambientales, principalmente luz y temperatura, en respuestas temporales que resultan en ritmos metabólicos y fisiológicos de aproximadamente 24 horas. Esta coordinación temporal les permite a los seres vivos predecir y anticipar cambios periódicos en el medioambiente. A pesar de su importancia para la adaptación y supervivencia de las plantas, la posible función regulatoria del reloj circadiano sobre la actividad y homeostasis mitocondrial ha sido difícil de elucidar. En esta Tesis Doctoral, hemos seguido un enfoque integral para demostrar el mecanismo molecular mediante el cual uno de los componentes clave del reloj circadiano, TOC1 (TIMING OF CAB EXPRESSION 1), controla la actividad mitocondrial. Con este fin, hemos estudiado la fluctuación in vivo de los niveles del ATP citosólico mediante la utilización de un biosensor de ATP basado en la tecnología FRET. También hemos realizado análisis transcriptómicos correlacionándolos con datos de los cambios en la acumulación de metabolitos observados en plantas sobre-expresantes y mutantes de TOC1. Hemos identificado el mecanismo molecular por el cual TOC1 regula la actividad mitocondrial a través de la unión directa al promotor del gen relacionado con el ciclo del ácido tricarboxílico, FUMARASE 2. Nuestros estudios de interacción genética también han validado este mecanismo. Las plantas que sobre-expresan TOC1 acumulan menos biomasa y tienden a presentar un fenotipo similar al de plantas sometidas a inanición. La sobre-expresión del gen FUMARASE 2 en estas plantas ayuda a la recuperación de la biomasa y alivia el fenotipo de inanición. En general, con este estudio se ha demostrado el papel que ejerce el reloj circadiano en la regulación de la demanda energética celular en sincronización con el medioambiente.
Circadian clocks are molecular timekeeping mechanisms that translate environmental cues, mostly light and temperature, into temporal information to generate ~24h rhythms in metabolism and physiology. The temporal coordination by the clock enables organisms to predict and anticipate periodic changes in the environment. Despite its importance for plant fitness and survival, the possible role of the circadian clock directly regulating plant mitochondrial activity and energy homeostasis has remained elusive. In this Doctoral Thesis, we have followed a comprehensive approach to demonstrate the molecular mechanism by which the key clock component TOC1 (TIMING OF CAB EXPRESSION 1) sets the time of mitochondrial activity. To that end, we have followed the in vivo dynamics of cytosolic ATP production using a FRET-based ATP biosensor. We have also performed transcriptomic analyses and examined their correlation with actual changes in metabolite content using plants miss-expressing TOC1. We have identified the molecular mechanism by which TOC1 regulates the mitochondrial activity through direct binding to the promoter of the tricarboxylic acid cycle related gene FUMARASE 2. Our genetic interaction studies have validated this mechanism, as over-expression of FUMARASE 2 in TOC1 over-expressing plants alleviates the reduced biomass and the starvation-like phenotypes observed in TOC1 overexpressing plants. Overall, ours studies uncover the role of the circadian clock controlling the cell energetic demands in synchronization with the environment.

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Chen, Weiwei. "Characterization of the movement of a circadian protein in the temperature-dependent root synchronization of Arabidopsis thaliana". Doctoral thesis, Universitat Autònoma de Barcelona, 2020. http://hdl.handle.net/10803/670449.

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El rellotge circadià està sincronitzat per senyals mediambientals externes, principalment la llum i la temperatura. Entendre com respon el rellotge circadià de la planta a les oscil·lacions de temperatura és crucial per comprendre la capacitat de resposta de la planta a l'entorn. En aquesta tesi doctoral, trobem una funció prevalent depenent de la temperatura de l'component de el rellotge d'Arabidopsis EARLY Flowering 4 (ELF4) en el rellotge circadià de l'arrel. En plantes en les quals l'àpex aeri s'ha eliminat, el rellotge pot funcionar en les arrels, tot i que exhibeix un període més curt i una fase avançada en comparació amb les arrels de plantes completes. Els assajos de microempelt mostren que ELF4 es mou des de l'àpex aeri per regular els ritmes en les arrels. El moviment de la proteïna ELF4 no transmet informació fotoperiòdica, sinó que és essencial per controlar el període de el rellotge circadià en l'arrel d'una manera depenent de la temperatura. Les baixes temperatures afavoreixen la mobilitat de ELF4, el que resulta en un rellotge de de ritme lent, mentre que les altes temperatures disminueixen el moviment, el que porta a un rellotge més ràpid. Per tant, el moviment de la proteïna ELF4 mòbil proporciona informació sobre la temperatura i ajuda a establir un diàleg entre l'àpex aeri i l'arrel de la planta per controlar el ritme circadià en l'arrel.
El reloj circadiano está sincronizado por señales medioambientales externas, principalmente la luz y la temperatura. Entender cómo responde el reloj circadiano de la planta a las oscilaciones de temperatura es crucial para comprender la capacidad de respuesta de la planta al medio ambiente. En esta Tesis Doctoral, encontramos una función prevalente dependiente de la temperatura del componente del reloj de Arabidopsis EARLY FLOWERING 4 (ELF4) en el reloj circadiano de la raíz. En plantas en las que el ápice aéreo se ha eliminado, el reloj puede funcionar correctamente en las raíces, aunque exhibe un período más corto y una fase avanzada en comparación con las raíces de plantas completas. Los ensayos de microinjerto muestran que ELF4 se mueve desde el ápice aéreo para regular los ritmos en las raíces. El movimiento de la proteína ELF4 no transmite información fotoperiódica, sino que es esencial para controlar el período del reloj circadiano en la raíz de una manera dependiente de la temperatura. Las bajas temperaturas favorecen la movilidad de ELF4, lo que resulta en un reloj de de ritmo lento, mientras que las altas temperaturas disminuyen el movimiento, lo que lleva a un reloj más rápido. Por lo tanto, el movimiento de la proteína ELF4 móvil proporciona información sobre la temperatura y ayuda a establecer un diálogo entre el ápice aéreo y la raíz de la planta para controlar el ritmo circadiano en la raíz.
The circadian clock is synchronized by external environment cues, mostly through light and temperature. Explaining how the plant circadian clock responds to temperature oscillations is crucial to understanding plant responsiveness to the environment. In this thesis, we found a prevalent temperature-dependent function of the Arabidopsis clock component EARLY FLOWERING 4 (ELF4) in the root clock. The clocks in roots are able to run properly in the absence of shoots although shoot excision leads to a shorter period and advanced phase in excised roots compared to entire roots. Micrografting assays show that ELF4 moves from shoots to regulate rhythms in roots. ELF4 movement does not convey photoperiodic information, but trafficking is essential for controlling the period of the root clock in a temperature-dependent manner. Low temperatures favour ELF4 mobility, resulting in a slow paced root clock, whereas high temperatures decrease movement, leading to a faster clock. Hence, the mobile ELF4 delivers temperature information and establishes a shoot-to-root dialogue that sets the pace of the clock in roots.
Universitat Autònoma de Barcelona. Programa de Doctorat en Biologia i Biotecnologia Vegetal

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Murphy, Barbara Anne. "INVESTIGATIONS OF CIRCADIAN REGULATION AND IMMUNE-CIRCADIAN INTERACTION IN THE HORSE". UKnowledge, 2007. http://uknowledge.uky.edu/gradschool_diss/546.

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The circadian system provides animals with a means to adapt internal physiology to the constantly changing environmental stimuli that exists on a rotating planet. Light information is translated into molecular timing mechanisms within individual pacemaker cells of the mammalian hypothalamic suprachiasmatic nucleus (SCN) via transcriptionaltranslational feedback loops. Humoral and neural outputs from this master clock result in circadian rhythms of physiology and behavior. The hierarchy of the circadian system involves SCN synchronization of cellular clocks within peripheral tissues so that differential transcriptional profiles in individual organs reflect their specific function. The first step to investigating equine circadian regulation was to identify and isolate the core components of the molecular clock in the horse. Successful isolation and sequencing of equine Bmal1, Per2, Cry1 and Clock cDNAs revealed high sequence homology with their human counterparts. Real Time RT-PCR assays were subsequently designed to quantitatively assess clock gene expression in equine peripheral tissues. Synchronization of equine fibroblasts revealed temporal profiles of clock gene expression identical to those of the SCN and peripheral tissues of other species. However, while clock gene expression varies over time in equine adipose tissue, there was no observable oscillation of clock gene transcripts in equine blood. Spurred by recent reports of immune-circadian interactions, this novel finding prompted an investigation of clock gene expression in equine blood during a systemic inflammatory response. The results demonstrated that acute inflammation upregulates Per2 and Bmal1 in equine blood. Subsequent experiments identified neutrophils as the source of this upregulation and highlighted exciting new immunecircadian interplay during an innate immune response. Finally, the effect of a 6-h phase advance of the light/dark cycle, mimicking an easterly transmeridian journey, on circadian melatonin and core body temperature rhythms was investigated. In contrast to the gradual adaptation observed in other species, these markers of equine circadian phase adapt immediately to a time zone transition. Combined, the results of these experiments highlight important interspecies differences in circadian regulation with practical implications regarding the potential impact of jet lag on equine athletes. Furthermore, the results underline the relevance of chronobiological investigation in a large mammalian species such as the horse.

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Jaeger, Cassie Danielle. "Chronic Circadian Misalignment Disrupts the Circadian Clock and Promotes Metabolic Syndrome". OpenSIUC, 2015. https://opensiuc.lib.siu.edu/dissertations/1081.

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Obesity, metabolic syndrome, and diabetes represent a major source of morbidity and mortality in the United States and worldwide. Chronic misalignment of an organism’s internal circadian clock with diurnal, cyclic changes in the external environment, prevalent in professions that require shift work, contributes significantly to Type 2 Diabetes development. Experimentally, only short-term models of circadian disruption have been explored. Therefore, the goal of this study was to establish an animal model of chronic circadian disruption, which would more closely mimic the harmful misalignment associated with metabolic syndrome in clinical studies. Moreover, since high fat diet consumption alters circadian behavior and rhythmic gene expression, contributing to the diet-induced phenotype, I hypothesized that chronic circadian disruption interacts with a high fat diet to worsen metabolic syndrome. To investigate circadian misalignment and diet-induced metabolic syndrome, I examined the contribution of the Aryl Hydrocarbon Receptor (AhR). AhR has similar PAS domain containing motifs as circadian clock proteins allowing for protein/protein interactions and crosstalk between AhR signaling and circadian rhythms. Furthermore, AhR activation is implicated in Type 2 Diabetes risk. To examine chronic circadian disruption, male wild-type (WT; C57Bl/6J) and AhR +/- mice were entrained to 12/12-hour light/dark cycles where lights were on from 10pm-10am and off from 10am-10pm. Misalignment was initiated by delaying the time of lights on by 8 hours on Monday. Mice were exposed to the misalignment schedule Monday-Friday then returned to the entrainment schedule Saturday and Sunday to mimic readjustment to society during the weekend. Circadian misaligned mice were exposed to the altered light schedule for 15 weeks and control animals remained on the12/12-hour light/dark cycle. Mice were fed a normal chow diet (10% fat) or a high fat diet (60% fat). Animals were sacrificed and samples were collected at 4-hour intervals on day 2 of the weekend. Exposure to chronic circadian misalignment by light disruption or high fat diet altered circadian rhythms of behavior, metabolic outputs, and expression of circadian clock, clock-controlled nuclear receptor, and lipid metabolism genes. A combination of light misalignment and high fat diet exacerbated the effects of either treatment alone further disrupting behavior, enhancing % body fat and fasting glucose, and dampening circadian clock gene expression. AhR +/- mice also were protected from the metabolic consequences of chronic misalignment and a high fat diet by resistance to altered behavioral and molecular circadian rhythms and disruption of metabolic outputs. With metabolic syndrome and Type 2 Diabetes occurrence on the rise, it is important to understand all contributing factors, including circadian disruption. Differences between chronic circadian misalignment and high fat diet-induced obesity in WT and AhR +/- mice furthers our understanding of the complex mechanisms that underlie Type 2 Diabetes development and advocates the discovery of potential therapeutic targets for the development of novel treatment options.

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Gegnaw, Shumet T. "The connection between circadian clock impairment and retinal disease". Electronic Thesis or Diss., Strasbourg, 2023. http://www.theses.fr/2023STRAJ120.

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Cette thèse a étudié comment une dérégulation de l'horloge circadienne, qui n'avait pas été clairement associée à une maladie rétinienne jusqu'à présent, pourrait contribuer à la dégénérescence et influencer le développement et la fonction de la rétine. L'inactivation spécifique du gène horloge Bmal1 (rod-Bmal1KO) dans la lignée de souris portant la mutation P23H de la rhodopsine aggrave les symptômes de dégénérescence rétinienne, tels que la réduction de la réponse ERG et la perte de bâtonnets, induits par la seule mutation P23H. Ces observations ont été corroborées par l'analyse RNA-Seq qui a révélé des changements majeurs dans l'expression des gènes, liés à la phototransduction et aux processus métaboliques, entre le double mutant (rod-Bmal1KO/P23H) et les rétines P23H. Nous avons montré qu'au cours du développement, l’invalidation des gènes horloge Per1 et Per2 chez la souris affecte de manière significative l'expression des gènes de la phototransduction et du cycle cellulaire. Nous avons observé que les souris adultes déficientes en Per1 et Per2 ne modulent pas quotidiennement leur sensibilité à la lumière, dans des conditions scotopiques et mésopiques. Nous avons également constaté une altération de la régulation journalière de la sensibilité à la lumière chez les souris déficientes en gène d'horloge Bmal1 dans les bâtonnets. De plus, nous avons investigué comment la dégénérescence des bâtonnets pourrait influencer la capacité rythmique globale de la rétine en mesurant les rythmes de bioluminescence PER2::LUC chez des souris P23H. Nos résultats montrent que l'horloge rétinienne chez les souris hétérozygotes P23H/+ présente des rythmes circadiens avec une robustesse et une amplitude significativement accrues. Ces effets impliquent probablement l’activation des cellules gliales
This thesis investigated how circadian clock misregulation, which has not been clearly associated with retinal genetic disease so far, could contribute to degeneration and influence development and function in the retina. The rod-specific knockout of Bmal1 clock gene (rod-Bmal1KO) from the mouse line carrying the P23H mutation of rhodopsin exacerbated the retinal degeneration phenotypes, such as reduction in ERG response and rods loss, induced by the P23H mutation alone. These observations were corroborated by RNA-Seq analysis, where we found major changes in expression of genes related to phototransduction and metabolic processes, between the (rod-Bmal1KO/P23H) double mutant and P23H retinas. We showed that during development, Per1 and Per2 clock genes deficiency in mice significantly affects gene expression of phototransduction and cell cycle components. We found that adult mice deficient for Per1 and Per2 genes lack a daily modulation of light sensitivity, under scotopic and mesopic conditions. We also found an impaired daily modulation of light sensitivity in mice deficient for Bmal1 clock gene in rods. Additionally, we investigated how rod degeneration could impact on the global rhythmic capacity of the retina by measuring PER2::LUC bioluminescence rhythms in P23H mice. We showed that the retinal clock in P23H/+ heterozygous mice displays circadian rhythms with significantly increased robustness and amplitude. These effects likely involve activation of glial cells

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Cretenet, Gaspard. "Coordination par l'horloge circadienne de l'activation rythmique du stress du RE et de la traduction dans le foie de souris". Thesis, Montpellier 2, 2010. http://www.theses.fr/2010MON20115/document.

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En premier lieu, l'horloge circadienne des mammifères joue un rôle fondamental dans le foie en régulant le métabolisme des acides gras, du glucose et des xénobiotiques. L'altération de ce rythme a été montrée comme menant à diverses pathologies incluant le syndrome métabolique. Il est supposé que l'horloge circadienne régule principalement le métabolisme en régulant l'expression des enzymes hépatiques au niveau transcriptionnel. Nous montrons que l'horloge circadienne contrôle au ssi le métabolisme hépatique en synchronisant un rythme secondaire d'une période de 12 heures caractérisé par l'activation rythmique de la voie IRE1a dans le RE. L'absence d'horloge circadienne perturbe cette horloge secondaire et provoque une dérégulation des enzymes localisées dans le RE. Cela mène à une altération du métabolisme lipidique, résultant en une activation aberrante du facteur de transcription SREBP. Cette altération dans le métabolisme lipidique circadien chez les souris sans horloge pourrait être impliquée dans l'apparition du syndrome métabolique. D'autre part, la croissance cellulaire animale est principalement régulée par la détection des nutriments et est principalement médiée par la voie TOR. Chez la souris, un gène est identifié pour la kinase TOR et son association en complexe avec d'autres protéines permet de discriminer TORC1 et TORC2. TORC1 est la forme majeure sensible à la rapamycine et est le premier médiateur de la détection d'énergie et d'acides aminés pour le contrôle de la croissance. Ce contrôle consiste en la régulation de la traduction par la phosphorylation de S6 Kinase et 4E-BP et le contrôle de la biogenèse des ribosomes. Nous sommes intéressés de montrer si l'horloge circadienne régule la traduction régulée par TOR dans le foie de souris
In one hand, The mammalian circadian clock plays a fundamental role in the liver by regulating fatty acid, glucose, and xenobiotic metabolism. Impairment of this rhythm has been shown to lead to diverse pathologies, including metabolic syndrome. Currently, it is supposed that the circadian clock regulates metabolism mostly by regulating expression of liver enzymes at the transcriptional level. We show that the circadian clock also controls hepatic metabolism by synchronizing a secondary 12 hr period rhythm characterized by rhythmic activation of the IRE1a pathway in the endoplasmic reticulum. The absence of circadian clock perturbs this secondary clock and provokes deregulation of endoplasmic reticulum localized enzymes. This leads to impaired lipid metabolism, resulting in aberrant activation of the sterol-regulated SREBP transcription factors. The resulting aberrant circadian lipid metabolism in mice devoid of the circadian clock could be inv olved in the appearance of the associated metabolic syndrome.In a second hand, the tissue growth in animals is principally regulated by nutrient sensing and principally by the protein kinase TOR. In mice one gene is identified as TOR kinase and the association of Tor protein associated with 2 different complex of protein (TORC1 and TORC2). TORC1 is the major rapamycin sensitive form and is the primary mediator of energy and amino acid sensing for growth control. This control consists in the regulation of translation through the phosphorylation of S6 Kinase (ribosomal S6 kinase) and 4E-BP (Eif4E binding protein) and the control of ribosome biogenesis. We are interested to show if the circadian clock regulate TOR translation regulation in mice liver

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Gon?alves, Bruno da Silva Brand?o. "Estudo da organiza??o funcional do sistema circadiano por meio de ferramentas computacionais e matem?ticas". Universidade Federal do Rio Grande do Norte, 2013. http://repositorio.ufrn.br:8080/jspui/handle/123456789/17232.

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Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
Circadian rhythms are variations in physiological processes that help living beings to adapt to environmental cycles. These rhythms are generated and are synchronized to the dark light cycle through the suprachiasmatic nucleus. The integrity of circadian rhythmicity has great implication on human health. Currently it is known that disturbances in circadian rhythms are related to some problems of today such as obesity, propensity for certain types of cancer and mental disorders for example. The circadian rhythmicity can be studied through experiments with animal models and in humans directly. In this work we use computational models to gather experimental results from the literature and explain the results of our laboratory. Another focus of this study was to analyze data rhythms of activity and rest obtained experimentally. Here we made a review on the use of variables used to analyze these data and finally propose an update on how to calculate these variables. Our models were able to reproduce the main experimental results in the literature and provided explanations for the results of experiments performed in our laboratory. The new variables used to analyze the rhythm of activity and rest in humans were more efficient to describe the fragmentation and synchronization of this rhythm. Therefore, the work contributed improving existing tools for the study of circadian rhythms in mammals
Os ritmos circadianos s?o varia??es em processos fisiol?gicos que auxiliam os seres vivos na adapta??o aos ciclos ambientais. Esses ritmos s?o gerados e se sincronizam ao ciclo claro escuro por meio do n?cleo supraquiasm?tico. A integridade da ritmicidade circadiana tem grande implica??o na sa?de dos seres humanos. Atualmente sabe-se que dist?rbios nos ritmos circadianos est?o relacionados com alguns problemas da atualidade como a obesidade, propens?o a determinados tipos de c?ncer e transtornos mentais por exemplo. A ritmicidade circadiana pode ser estudada por meio de experimentos com modelos animais e diretamente nos seres humanos. Nesse trabalho utilizamos modelos computacionais para reunir resultados experimentais da literatura e explicar resultados de nosso laborat?rio. Outro foco desse trabalho foi na an?lise de dados de ritmos de atividade e repouso obtidos experimentalmente. Aqui fizemos uma revis?o sobre o uso de vari?veis utilizadas para analisar esses dados e por ?ltimo propomos uma atualiza??o na forma de calcular essas vari?veis. Os nossos modelos foram capazes de reproduzir os principais resultados experimentais da literatura e nos forneceram explica??es para resultados de experimentos realizados em nosso laborat?rio. As novas vari?veis utilizadas para analisar o ritmo de atividade e repouso em humanos se mostraram mais eficiente para descrever a fragmenta??o e sincroniza??o desse ritmo. Assim esse trabalho contribuiu aperfei?oando as ferramentas existentes para o estudo da ritmicidade circadiana nos mam?feros

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9

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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10

Brettschneider, Christian. "The cyanobacterial circadian clock". Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2011. http://dx.doi.org/10.18452/16385.

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Abstract (sommario):

Cyanobakterien zŠhlen zu den Šltesten Lebewesen auf der Erde. Diese Bakterien, auch Blaualgen genannt, trugen wesentlich zur Sauerstoffanreicherung der Erde bei, da sie eine ausgeprŠgte FŠhigkeit zur Photosynthese besitzen. Der produzerte Sauerstoff der Photosynthese hemmt jedoch eine weitere AktivitŠt von Cyanobakterien, die Stickstofffixierung. Um die Hemmung zu vermeiden, werden diese AktivitŠten zeitlich getrennt und optimal dem tŠglichen Hell-Dunkel-Rhythmus angepasst. Ein evolutionŠrer Vorteil wird erzielt, wenn der Organismus diesen Rhythmus antizipiert und sich darauf vorbereitet. Aus diesem Grund haben Cyanobakterien eine innere Uhr entwickelt, deren Rhythmus zirkadian ist, ãzirka diemÒ bedeutet ãungefŠhr ein TagÒ. Cyanobakterien der Spezies Synechococcus elongatus PCC 7942 haben sich als Modellorganismus etabliert, weil in ihnen die ersten bakteriellen zirkadianen Oszillationen auf molekularer Ebene entdeckt worden sind. Ihre zirkadiane Uhr entspringt dreier, auf der DNS beieinanderliegenden, Gene (kaiA, kaiB, kaiC) und ihrer dazugehšrigen Proteine. Phosphorylierte KaiC-Proteine Ÿben eine RŸckkopplung auf die Transkription von kaiB und kaiC aus, wodurch die AktivitŠt des kaiBC-Promotors zirkadian oszilliert. Eines der wichtigsten Experimente der letzten Jahre hat gezeigt, dass dieser Transkriptions-Translations-Oszillator mit einem weiteren Oszillator gekoppelt ist, der nicht von Transkription und Translation abhŠngt. Das Experiment des Kondo Labors rekonstruiert zirkadiane Oszillationen mit nur drei Proteinen KaiA, KaiB, KaiC und ATP. Die Proteine bilden Komplexe verschiedener Stoichiometrie, die durchschnittliche Phosphorylierung des Proteins KaiC zeigt stabile Oszillationen mit einer zirkadianen Periode. Da ein Entfernen von einem der Proteine zum Verlust der Oszillationen fŸhrt, wird dieser Post-Translations-Oszillator auch als Kernoszillator bezeichnet. Der Phosphorylierungszyklus von KaiC wird bestimmt durch fortlaufende Phosphorylierung und Dephosphorylierung an zwei Positionen des Proteins, den AminosŠuren Serin 431 und Threonin 432. Die Phase des Kernoszillators kann an der Verteilung der vier PhosphorylierungszustŠnde (nicht-, serin-, threonin- und doppeltphosphoryliert) abgelesen werden. KaiC wechselwirkt mit KaiA und KaiB, damit verschieden phosphorylierte KaiC synchronisieren und die Uhr Ÿber mehrere Tage konstante Oszillationen zeigt. Die Details dieser Wechselwirkung sind jedoch unbekannt. In dieser Dissertation erstelle ich ein mathematisches Modell des Kernoszillators und simuliere die vorliegenden Experimente des O''Shea Labors. Die Simulation reproduziert den KaiC Phosphorylierungszyklus der Uhr quantitativ. Um die wichtigsten experimentellen Nebenbedingungen zu erfŸllen, muss das theoretische Modell zwei molekulare Eigenschaften von KaiC berŸcksichtigen, wodurch ich wichtige Vorhersagen treffe. Die erste Nebenbedingung ist durch die Robustheit des Systems gegeben. Die KaiC-Phosphorylierung Šndert sich nicht, wenn die Gesamtkonzentrationen der drei Proteine in gleicher Weise variiert werden. Um diese Bedingung zu erfŸllen, muss das Modell zwei verschiedenartige Komplexe von KaiA und KaiC berŸcksichtigen. ZusŠtzlich zu einem KaiAC Komplex, der die Autophosphorylierung von KaiC unterstŸtzt, muss KaiC den grš§ten Teil von KaiA unabhŠngig vom Phosphorylierungszustand sequestrieren. Diese zweite Bindestelle ist meine erste theoretische Vorhersage. Die zweite Nebenbedingung ist durch das Ÿbergangsverhalten nach Hinzugabe von KaiB gegeben. KaiB induziert eine Dephosphorylierung von KaiC, die abhŠngig vom Phosphorylierungsniveau ist. Ein Umschalten zwischen phosphoylierendem und dephosphorylierendem KaiC ist deshalb nur in bestimmten Zeitfenstern mšglich. Um die gemessenen Zeitfenster in der Simulation zu reproduzieren, postuliere ich im Modell, dass sechsfach Serin phosphorylierte KaiBC Komplexe KaiA inaktivieren. Diese hochgradig nichtlineare RŸckkopplung ist meine zweite theoretische Vorhersage. Die beiden Vorhersagen werden anschlie§end experimentell ŸberprŸft. HierfŸr werden aufgereinigte Kai-Proteine mit ATP gemischt. Proben an ausgewŠhlten Zeitpunkten werden mit der nativen Massenspektrometrie untersucht. Diese ist eine neuartige Methode, die es erlaubt, intakte Proteinkomplexe zu untersuchen. Die Spektren bestŠtigen sowohl die zweite KaiAC-Bindestelle als auch die nichtlineare RŸckkopplung. Das mathematische Modell erlaubt es au§erdem, die drei definierenden Prinzipien von zirkadianen Uhren fŸr den Kernoszillator zu erklŠren. Erstens sichern konstante Phosphorylierungs- und Dephosphorylierungsraten von KaiC und ein pŸnktliches Umschalten zwischen beiden Phasen den Freilauf des Oszillators. Dieser Freilauf bewirkt, dass die zirkadiane Uhr auch unter konstanten Bedingungen, vor allem gleichbleibenden LichtverhŠltnissen, weiterlaufen kann. Zweitens muss die Periodendauer des Oszillators zu unterschiedlichen Šu§eren Bedingungen erhalten bleiben (Temperaturkompensation). Diese Bedingung wird realisiert, indem temperaturabhŠngige Dissoziationskonstanten von KaiAC und KaiBC Komplexen Phasenverschiebungen erzeugen, die sich gegenseitig kompensieren. Drittens muss die Phase des Oszillators sich dem Tagesrhythmus anpassen kšnnen. Diese Anpassung folgt aus einem Šu§eren Warm-Kalt-Rhythmus, der die drei temperaturabhŠngigen Phasenverschiebungen nur zum Teil einschaltet und damit die Kompensation verhindert. Eine in silico Evolutionsanalyse zeigt, dass eine zweite phosphorylierbare AminosŠure einen evolutionŠren Vorteil bringt und die Verteilung der PhosphorylierungszustŠnde optimiert ist, um eindeutig die Zeit zu bestimmen. Das Ergebnis weist darauf hin, dass diese Verteilung die physiologisch wichtige Ausgangsgrš§e der Uhr ist und die vier PhosphroylierungszustŠnde die Funktionen der zirkadianen Uhr von Cyanobakterien sichern.
Biological activities in cyanobacteria are coordinated by an internal clock. The rhythm of the cyanobacterium Synechococcus elongatus PCC 7942 originates from the kai gene cluster and its corresponding proteins. In a test tube, the proteins KaiA, KaiB and KaiC form complexes of various stoichiometry and the average phosphorylation level of KaiC exhibits robust circadian oscillations in the presence of ATP. The characteristic cycle of individual KaiC proteins is determined by phosphorylation of serine 431 and threonine 432. Differently phosphorylated KaiC synchronize due to an interaction with KaiA and KaiB. However, the details of this interaction are unknown. Here, I quantitatively investigate the experimentally observed characteristic phosphorylation cycle of the KaiABC clockwork using mathematical modeling. I thereby predict the binding properties of KaiA to both KaiC and KaiBC complexes by analyzing the two most important experimental constraints for the model. In order to reproduce the KaiB-induced dephosphorylation of KaiC a highly non-linear feedback loop has been identified. This feedback originates from KaiBC complexes, which are exclusively phosphorylated at the serine residue. The observed robustness of the KaiC phosphorylation level to concerted changes of the total protein concentrations demands an inclusion of two KaiC binding sites to KaiA in the mathematical model. Besides the formation of KaiAC complexes enhancing the autophosphorylation activity of KaiC, the model accounts for a KaiC binding site, which constantly sequestrates a large fraction of free KaiA. These theoretical predictions have been confirmed by the novel method of native mass spectrometry, which was applied in collaboration with the Heck laboratory. The mathematical model elucidates the mechanism by which the circadian clock satisfies three defining principles. First, the highly non-linear feedback loop assures a rapid and punctual switch to dephosphorylation which is essential for a precise period of approximately 24 h (free-running rhythm). Second, the dissociation of the protein complexes increases with increasing temperatures. These perturbations induce opposing phase shifts, which exactly compensate during one period (temperature compensation). Third, a shifted external rhythm of low and high temperature affects only a part of the three compensating phase perturbations, which leads to phase shifts (phase entrainment). An in silico evolution analysis shows that the existing second phosphorylatable residue of KaiC is not necessary for the existence of sustained oscillations but provides an evolutionary benefit. The analysis demonstrates that the distribution of four phosphorylated states of KaiC is optimized in order for the organism to uniquely distinguish between dusk and dawn. Consequently, this thesis emphasizes the importance of the four phosphorylated states of KaiC, which assure the outstanding performance of the core oscillator.

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11

Galvanin, Silvia. "Circadian Clock Study Through Frequency-Encoded Entrainment Stimulations". Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3422301.

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Abstract (sommario):

Circadian clocks are intrinsic, time-tracking systems that enable organisms to maintain their physiological state and their synchrony with the 24-hour rotation of the Earth, by partitioning behavioural and metabolic processes according to time of day within each tissue. They are entrained to the external environment by light/dark cycles and by food timing, which act as clock synchronizers. Emerging evidence suggests that circadian regulation is intimately linked to metabolic homeostasis and that dysregulation of circadian rhythms can contribute to disease. Conversely, metabolic signals also feed back into the circadian system, modulating circadian gene expression and behaviour. Conventional experimental approach of circadian clock in vitro studies is based on single-pulse stimulation of only one metabolite or hormone, while in vivo peripheral tissues are exposed to periodic oscillating stimuli of a large number of metabolites and hormones, whose variations are in most cases interconnected, as for example glucose and insulin. Moreover, only one or few clock genes are generally considered, while it is known that a large number of genes, thus biological processes, are under circadian regulation. Therefore, this Ph.D. research work is aimed at the development of technologies and data analysis tools to investigate the entrainment of peripheral mammalian circadian clock to frequency-encoded metabolic stimuli, which well mimic physiological oscillations at which peripheral tissues are exposed in vivo. Technologies, and, more specifically, microtechnologies have been developed to investigate the effects of periodic metabolic entrainment, showing that in murine fibroblasts oscillatory periodic metabolic stimulations entrain the expression of Per2, one of the core genes of the circadian molecular mechanism. Moreover, it has been proven that only by metabolic oscillations it is possible to completely reset the phase of cell-autonomous clocks. In order to develop a physiological and pathological in vitro model, achieving a high spatio-temporal control of cell culture microenvironment, frequency-encoded perturbations have been automated in a newly designed microfluidic platform for circadian applications. Finally, to broaden the description of genes expressed with a circadian temporal pattern, a new data analysis method has been proposed and characterized, that allows to identify circadian genes in whole transcriptome data, to group genes based on the phase of their expression, to visualize transcriptome data at a glance and clearly identifying modifications at the transcriptome level from one biological condition to another one.
I ritmi circadiani sono meccanismi biologici di organizzazione temporale intrinseci e autosostenuti, che consentono agli organismi di anticipare i cambiamenti ambientali e permettono loro di adattare il loro comportamento e la loro fisiologia nell’arco della giornata. L’orologio circadiano è sincronizzato dai cicli luce/buio e dall’ora dei pasti. La funzione biologica essenziale del ritmo circadiano è mantenere lo stato fisiologico dell’organismo e la sua sincronia comportamentale e metabolica con l’ambiente esterno. Recentemente è stato dimostrato che l’orologio circadiano garantisce il mantenimento dell’omeostasi metabolica, e che una distruzione del ritmo circadiano è causa di numerose malattie. L’approccio sperimentale convenzionale per lo studio dell’orologio circadiano in vitro è basato su una singola stimolazione di un solo metabolita o ormone, mentre in vivo i tessuti sono esposti in continuo a stimoli oscillatori periodici di una grande vastità di metaboliti e ormoni, le cui variazioni sono spesso interconnesse, come nel caso di glucosio e insulina. Inoltre, nell’analisi sperimentale convenzionale, sono studiati solo uno o pochi geni noti per essere implicati nell’orologio circadiano, mentre è noto che un elevato numero di geni sono espressi in modo circadiano. Lo scopo di questo progetto di ricerca è quindi sviluppare tecnologie e metodi di analisi per studiare l’effetto di stimoli metabolici in frequenza sull’orologio circadiano di tessuti periferici. Questi stimoli riproducono infatti in vitro le oscillazioni metaboliche a cui i tessuti sono esposti in vivo. Tecnologie, e più nello specifico, microtecnologie sono state sviluppate per studiare gli effetti di stimoli metabolici oscillatori, ed è stato dimostrato che in fibroblasti murini l’espressione di Per2 (uno dei geni principali del meccanismo molecolare dell’orologio circadiano) è sincronizzata da stimoli metabolici oscillatori. Inoltre, è stato dimostrato che le oscillazioni metaboliche sono di per sé sufficienti per allineare l’orologio circadiano nei tessuti periferici. Per sviluppare un modello che riproducesse in vitro condizioni sia fisiologiche che patologiche, raggiungendo un controllo spazio-temporale preciso del microambiente cellulare, le stimolazioni in frequenza sono state automatizzate in un dispositivo microfluidico progettato in modo dedicato per studi del ritmo circadiano. Infine, per estendere lo studio ai geni espressi con un pattern temporale circadiano, un nuovo metodo di analisi è stato proposto e caratterizzato. Il metodo permette di identificare geni circadiani da dati di trascrittomica, di suddividere i geni basandosi sulla fase della loro espressione, di visualizzare dati di trascrittomica nel loro complesso e di individuare rapidamente e in modo semplice modifiche a livello trascrizionale da una condizione biologica ad un’altra.

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12

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 interacció entre l’efecte de les proantocianidines i els ritmes circadians del metabolisme hepàtic. En aquest sentit, aquesta tesi te com a objectius avaluar si el GSPE té diferents efectes sobre el metabolisme hepàtic depenent del temps d’administració en animals que pateixen la síndrome metabòlica. Addicionalment, es va estudiar la disrupció dels ritmes circadians del metabolisme hepàtic, causats per l’obesitat, a ambdós gèneres per a eludir si aquesta disrupció és depenent del sexe. Les femelles van mostrar una major resistència i flexibilitat quan eren alimentades amb una dieta obesogénica. L’administració crònica de GSPE va presentar efectes diferents en rates mascles obeses depenent del temps d’administració. Moltes dels efectes beneficiosos es van trobar en els animals que van ser tractats al principi de la fase lluminosa. A més, també es va observar un possible efecte antioxidant i una millora en la sensibilitat hepàtica a la insulina en aquest animals. Els resultats d’aquesta tesi ens mostren la importància del temps d’administració del GPSE. A més, aquesta tesi ens ensenya que les rates femelles obeses tenen una millor flexibilitat dels ritmes circadians hepàtics.
El extracto de proantocianidinas procedente de la semilla de uva (GSPE) se ha asociado a un amplio rango de efectos beneficiosos para la prevención o tratamiento de las alteraciones metabólicas hepáticas causadas por la obesidad, p.ej. resistencia a la insulina o esteatosis. Además, el GPSE es capaz de modular los ritmos circadianos hepáticos, los cuales son alterados por la obesidad. Por lo tanto, esto sugiere que el GPSE puede regular parcialmente el metabolismo lipídico y glucídico a través de la modulación de los ritmos circadianos. La metabolòmica basada en RMN es una técnica adecuada para el estudio de las interacciones entre los efectos de las proantocianidinas i los ritmos circadianos del metabolismo hepático. El objetivo de esta tesis es evaluar si los efectos del GSPE son diferentes dependiendo del momento del día de administración en animales que padecen síndrome metabólico. También se han estudiado las alteraciones en los ritmos circadianos del metabolismo hepático provocadas por una dieta obesogénica para determinar si, dicha alteración, es diferente en función el género. Las ratas hembra obesas mostraron una mayor resistencia y flexibilidad en los ritmos circadianos del metabolismo hepático. La administración crónica de GSPE presentó diferentes efectos en ratas macho obesas en función del momento de su administración. La mayoría de los efectos beneficiosos fueron hallados cuando el GSPE fue dado al inicio de la fase lumínica. Solo en dichos animales se observó un posible efecto antioxidante y una mejora en la sensibilidad a la insulina en el hígado. Los resultados de esta tesis eluciden la importancia del momento de administración del GSPE. Además, esta tesis demuestra una mayor flexibilidad en los ritmos circadianos en ratas hembra obesas.
A grape seed proanthocyanidin extract (GSPE) has been associated with a widely range of beneficial effects for the prevention and treatment of hepatic metabolic disturbances induced by obesity, such as insulin resistance or steatosis. Moreover, GSPE is capable to modulate the clock system in the liver, which is also disrupted in an obesity status, thus suggesting that GSPE can partially regulate lipid and glucose metabolism by modulating the hepatic circadian rhythms. NMR-based metabolomics strategy is an adequate approach to study the interaction between the proanthocyanidin effects and the circadian rhythmicity of the hepatic metabolism. In this regard, this thesis aims to evaluate whether a grape seed proanthocyanidin extract (GSPE) has different effects on the hepatic metabolism depending on the administration time, in a metabolic syndrome situation. The circadian rhythm disruption of the hepatic metabolism, caused by obesity, was studied in both genders in order to elucidate whether this disruption is gender-dependent. Female animals showed to be more resistance and flexible against an obesogenic diet. The chronic administration of GSPE presented different effects in obese male rats depending on its administration time. A large amount of its beneficial effects were found when GSPE was given at the beginning of the light phase. Possible antioxidant effects and an improvement in hepatic insulin sensitivity were only observed in those animals. The results of this thesis elucidate the importance of the administration time of GSPE. Additionally, this thesis shows the better circadian rhythm flexibility of obese female rats.

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13

Silva, Patrícia Tachinardi Andrade. "To be diurnal or nocturnal: the interplay of energy balance and time of activity in subterranean rodents (Ctenomys aff. knighti) and laboratory mice (Mus musculus)". Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/41/41135/tde-25072017-110626/.

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Abstract (sommario):

Studies that show discrepancy between nocturnal and diurnal activity under laboratory and field conditions, respectively, have become increasingly common in rodents and suggest that the definition of temporal niche is far more plastic than originally suspected. Recently, it has been proposed that factors that challenge the animal\'s energy balance play an important role in temporal niche switches. Food availability and environmental temperatures could then be one of the fundamental differences between field and laboratory that could alter the temporal daily pattern of activity. In laboratory, animals are fed ad libitum, while in nature they need to expend energy for foraging. The \"circadian thermo-energetics hypothesis\" suggests that daytime activity could be a response to the high energetic costs of foraging, allowing the animal to save energy during the cooler night hours by resting and taking shelter in burrows where temperatures are higher than on the surface. In this thesis, we explored the interplay of plasticity in nocturnal/diurnal activity definition and energetic metabolism in two rodent species, tuco-tucos (Ctenomys aff. knighti) and laboratory mice (Mus musculus). Tuco-tucos are subterranean rodents which face peculiar energetic challenges in their habitat and were shown to be diurnal in the field and nocturnal in the laboratory. We characterized how their energy expenditure varies across day and night and described the peculiar finding of some factor inside the metabolic chamber being itself a trigger for the nocturnal to diurnal switch. Moreover, we estimated the amount of energy tuco-tucos would save by being diurnal in the field, by combining metabolic rate measurements at various ambient temperatures with records of environmental temperature in the tuco-tuco\'s natural habitat. We also described further investigations of circadian plasticity in both locomotor activity and body temperature of laboratory mice subjected to food restriction in semi-natural conditions. The findings of these three studies provided valuable evidence for the discussion of the role of environmental factors, particularly energetic challenges, in the plasticity of daily rhythms
Estudos que apontam discrepâncias entre atividade noturna e diurna, respectivamente, sob condições de laboratório e de campo, estão cada vez mais comuns em roedores e sugerem que a definição de nicho temporal é muito mais plástica do que se suspeitava inicialmente. Recentemente, foi proposto que fatores que desafiam o balanço energético do animal desempenham um papel importante em mudanças de nicho temporal. A disponibilidade de alimento e as temperaturas ambientais poderiam ser algumas das diferenças fundamentais entre campo e laboratório, os quais poderiam alterar o padrão temporal de atividade diária. No laboratório, os animais são alimentados ad libitum, enquanto na natureza eles precisam gastar energia para forrageamento. A \"hipótese circadiana termoenergética\" sugere que a atividade diurna pode ser uma resposta aos altos custos energéticos do forrageamento, permitindo que o animal economize energia durante as horas mais frias da noite, descansando e se abrigando em tocas onde as temperaturas são mais altas do que na superfície. Nesta tese, exploramos a interação entre a plasticidade da definição noturnalidade/diurnalidade e o metabolismo energético em duas espécies de roedores, o tuco-tucos (Ctenomys aff. knighti) e o camundongo de laboratório (Mus musculus). Tuco-tucos são roedores subterrâneos que enfrentam desafios energéticos peculiares em seu habitat e verificamos que são diurnos em campo e noturnos em laboratório. Nós caracterizamos a variação de seu gasto energético ao longo do dia e da noite e descrevemos o achado peculiar de que algum fator presente no interior da câmara metabólica pode ser um gatilho para a mudança de noturnalidade para diurnalidade. Além disso, estimamos a quantidade de energia que os tuco-tucos economizariam ao serem diurnos em campo, combinando medidas de taxa metabólica em várias temperaturas ambientes com registros dessa temperatura no habitat natural do tuco-tuco. Descrevemos também investigações adicionais sobre a plasticidade circadiana na atividade locomotora e na temperatura corporal de camundongos submetidos à restrição alimentar, em condições seminaturais. Os achados desses três estudos forneceram evidências valiosas para a discussão do papel dos fatores ambientais, particularmente os desafios energéticos, na plasticidade dos ritmos diários

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14

Chassard, David. "Implication du système circadien dans la fonction de reproduction chez la souris femelle". Thesis, Strasbourg, 2015. http://www.theses.fr/2015STRAJ060/document.

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Les neurones à Kisspeptine (Kp) de l'AVPV sont essentiels pour la survenue du pic de LH. Celle-ci est conditionnée par les concentrations circulantes d'oestrogènes (E2) et le moment du jour. Nous avons étudié si les neurones à Kp de l'AVPV étaient le lieu d'intégration de deux messages chez des souris sauvages intactes : un message E2, et un message temporel. Nous voulions savoir si ces neurones hébergeaient une horloge secondaire impliquée dans la temporalité du pic de LH. Durant l'après-midi du proestrus, une baisse drastique de l'immunoréactivité (ir) de Kp apparaît 2h avant la survenue du pic de LH au moment où l'expression de l'ARNm Kiss1 est élevée. Au contraire durant le diestrus, Kpir,l'expression de l'ARNm Kiss1 et les concentrations circulantes de LH restent basses. Les neurones à Kp de l'AVPV expriment une protéine horloge PER1 avec un rythme journalier exhibant un retard de phase de 2.8 h en diestrus comparativement au proestrus. Des explants d'AVPV exprimant les Kp provenant de souris PER2::LUCIFERASE dévoilent des oscillations circadiennes soutenues avec une période de 23.2h, significativement plus courte que celle observée dans les NSC. L'incubation des explants d'AVPV en présence d'E2 (10nM) rallonge la période d'une heure. En conclusion, cette étude indique que les neurones à Kp de l'AVPV présentent un rythme journalier dépendant des E2, qui pourrait être piloté par la présence d'une horloge secondaire au sein de ces neurones
The kisspeptin (Kp) neurons in the anteroventral periventricular nucleus (AVPV) are essential for the preovulatory LH surge, which is gated by circulating estradiol (E2) and the time of day. We investigated whether AVPV Kp neurons in intact female mice may be the site in which both E2 and daily signals are integrated and whether these neurons may host a circadian oscillator involved in the timed LH surge. In the afternoon of proestrous day, Kp immunoreactivity displayed a marked and transient decrease 2 hours before the LH surge. In contrast, Kp content was stable throughout the day of diestrus, when LH levels are constantly low. AVPV Kp neurons expressed the clock protein period1 (PER1) with a daily rhythm that is phase delayed compared with the PER1 rhythm measured in the main clock of the suprachiasmatic nuclei (SCN). PER1 rhythm in the AVPV, but not in the SCN,exhibited a significant phase delay of 2.8 hours in diestrus as compared with proestrus. Isolated Kp expressing AVPV explants from PER2::LUCIFERASE mice displayed sustained circadian oscillations of bioluminescence with a circadian period (23.2 h) significantly shorter than that of SCN explants(24.5 h). Furthermore, in AVPV explants incubated with E2 (10 nM to 1 μM), the circadian period was lengthened by 1 hour, whereas the SCN clock remained unaltered. In conclusion, these findings indicate that AVPV Kp neurons display an E2-dependent daily rhythm, which may possibly be driven by an intrinsic circadian clock acting in combination with the SCN timing signal

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15

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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16

Vijayan, Vikram. "Circadian Gene Expression in Cyanobacteria". Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10665.

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Abstract (sommario):

Cyanobacteria are photosynthetic prokaryotes that live in aquatic environments. The cyanobacterium Synechococcus elongatus PCC 7942, (hereafter S. elongatus) coordinates its day and night behaviors via a circadian clock. The clock is entrained by light/dark cycles but continues to run in constant light conditions. The core circadian clock in S. elongatus is encoded by post-translational modifications of three Kai proteins, but the extent and mechanism of circadian gene expression are unknown. We provide the first unbiased characterization of circadian gene expression in S. elongatus, demonstrating that \(\sim 65\%\) of genes display oscillation in continuous light conditions, with some genes peaking in expression at subjective dawn and others at subjective dusk. We next sought to identify the mechanism by which such a large fraction of the genome could be rhythmically controlled. Through bioinformatic, correlative, and perturbation experiments, we find that circadian changes in chromosome topology/supercoiling are sufficient to drive rhythmic expression (Chapter 2). To further investigate how chromosome topology can control gene expression we performed a high resolution characterization of transcripts and RNA polymerase across the S. elongatus genome (Chapter 3). Bioinformatic analysis of transcription start sites suggests that the AT/GC content a particular region of the promoter is informative in defining the phase at which a transcript is maximally expressed. We find that these sequences are sufficient to drive circadian gene expression at a particular phase and that mutation of single nucleotides in this region can reverse the expression phase of a transcript (Chapter 4). To understand the role of chromosome dynamics in circadian gene expression and cyanobacterial physiology, we tagged and followed chromosomes over multiple cell divisions. We find that S. elongatus cells harbor multiple ordered copies of a single chromosome, and the organization of chromosomes in the cytoplasm facilitates equal segregation of chromosomes to daughter cells (Chapter 5).

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17

Coyle, Kieran. "Circadian variation in cognitive functioning". Thesis, Cardiff University, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.293015.

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18

Smith, Karen Lynn. "Entrainment of the circadian clock". Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624358.

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19

Topacio, Tracey Karen B. "Circadian Disruption, Diet, and Exercise". Kent State University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=kent1382122230.

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20

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

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21

Crosby, Priya. "Metabolic regulation of circadian timekeeping". Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/269019.

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Circadian rhythms are self-sustained endogenous biological oscillations with a period of approximately 24 hours. These rhythms are observed widely across kingdoms and at all levels of biological scale. Recent work has shown there to be circadian variation in metabolism, both at the organismal and cellular level. It has also been posited that rhythmic production of metabolites might be essential for maintenance of circadian rhythmicity within cells, even in the absence of nascent transcription. The first portion of this thesis investigates the contribution of primary carbohydrate metabolism to cellular timekeeping, with particular emphasis on the pentose phosphate pathway. I also describe and validate a new 13C labelling technique for accurate determination of the relative flux through early primary metabolic pathways. This is accompanied by the development and optimisation of a microfluidic system for long-term perfused tissue culture, which allows for longitudinal study of metabolic flux within the same population of cells with simultaneous recording of clock gene activity. This perfused system provides several advantages over static tissue culture. The second portion considers the effects of the metabolic hormone insulin on circadian rhythmicity, both at the level of the cell and of the whole organism. It shows that administration of insulin is sufficient to shift the phase of circadian gene expression and elicits induction of clock protein PER2. Strikingly, manipulation of insulin signalling is sufficient to determine all the essential parameters of the cellular clock (phase, period and amplitude) in a dose-dependent but glucose independent fashion. Using pharmacological and genetic approaches, a molecular explanation for this effect is determined. This data suggests that insulin is a primary determinant of rhythms in peripheral tissues and is most likely a major signal for circadian entrainment to feeding in mammals, for which I now propose a mechanistic basis.

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22

Busza, Ania. "Molecular and Behavioral Analysis of Drosophila Circadian Photoreception and Circadian Thermoreception: A Dissertation". eScholarship@UMMS, 2007. https://escholarship.umassmed.edu/gsbs_diss/343.

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Circadian clocks are biological timekeepers that help maintain an organism’s behavior and physiological state optimally timed to the Earth’s day/night cycle. To do this, these internal pacemakers must accurately keep track of time. Equally importantly, they must be able to adjust their oscillations in response to external time cues to remain properly synchronized with the environment, and correctly anticipate environmental changes. When the internal clock is offset from its surrounding day/night cycle, clinically relevant disruptions develop, ranging from inconveniences such as jet-lag to more severe problems such as sleep disorders or mood disorders. In this work, I have used the fruit fly, Drosophila melanogaster, as a model organism to investigate how light and temperature can synchronize circadian systems. My initial studies centered on an intracellular photoreceptor, CRYPTOCHROME (CRY). CRY is a blue light photoreceptor previously identified as a major component of the primary light-input pathway into the Drosophila circadian clock. We used molecular techniques to show that after light-activation, CRY binds to the key circadian molecule TIMELESS (TIM). This interaction irreversibly targets TIM, but not CRY, for degradation. Further studies characterizing a newly isolated cry mutant, crym, showed that the carboxyl-terminus of CRY is not necessary for CRY’s ability to impart photic information to the molecular clock. Instead, the C-terminus appears to be necessary for normal CRY stability and protein-protein interactions. Thus, we conclude that in contrast to previous reports on CRYs of other species, where the C-terminal domain was required for transduction of photic information, the C-terminus of DrosophilaCRY has a purely modulatory function. During the second part of my dissertation work, I focused my studies on circadian thermoreception. While the effects of light in synchronization of the Drosophilaclock to environmental cycles have been extensively characterized, significantly less is known about temperature input pathways into the circadian pacemaker. I have used two approaches to look at how temperature affects the circadian system. First, I conducted a series of behavioral analyses looking at how locomotor rhythms can be phase-shifted in response to temperature cycles. By examining the behavior of genetically ablated flies, we determined that the well-characterized neurons controlling morning and evening surges of activity during light/dark cycles are also implicated in morning and evening behaviors under temperature cycles. However, we also find evidence of cells that contribute to modulating afternoon and evening behavior specifically under temperature cycles. These data contribute to a growing number of studies in the field suggesting that pacemaker cells may play different roles under various environmental conditions. Additionally, we provide data showing that intercellular communication plays an important role in regulating circadian response to temperature cycles. When the morning oscillator is absent or attenuated, the evening cells respond abnormally quickly to temperature cycles. My work thus provides information on the roles of different cell groups during temperature cycles, and suggests that beyond simply synchronizing individual oscillating cells, intercellular network activity may also have a role in modulating proper response to environmental time cues. Finally, I present some preliminary work looking at effects of temperature on known circadian molecules. Using a combination of in vivo and cell culture techniques, I have found that TIM protein levels decrease at higher temperatures. My cell culture data suggest that this is a proteasome-independent degradation event. As TIM is also a key molecule in the light-input pathway, the stability of TIM proteins may be a key point of integration for light and temperature input pathways. While additional research needs to be conducted to confirm these effects in vivoin wild-type flies, these preliminary results identify a possible avenue for further study. Taken together, my work has contributed new data on both molecular and neuronal substrates involved in processing light and temperature inputs into the Drosophila circadian clock.

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23

Fung, Uceda Jorge Alberto. "Characterization of the circadian clock function in the control of cell cycle progression to modulate growth in Arabidopsis thaliana". Doctoral thesis, Universitat Autònoma de Barcelona, 2018. http://hdl.handle.net/10803/664286.

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La función circadiana es esencial para el crecimiento y adaptación de las plantas a su entorno. La maquinaria molecular responsable de la generación de ritmos circadianos está basada en la expresión rítmica de genes cuyo pico de expresión oscila en diferentes fases durante el día y la noche. Los ritmos de expresión génica se traducen en oscilaciones de procesos fisiológicos y de desarrollo. El crecimiento de las plantas está regulado por una plétora de procesos que en última instancia operan a través del control de la proliferación y diferenciación celular. La proliferación celular depende de la progresión del ciclo mitótico, el cual está dividido en 4 fases: S (Síntesis del ADN), M (Mitosis) y de las interfases G1 y G2 (en inglés Gap 1 y 2) que ocurren antes de las fases S y M respectivamente. El proceso de diferenciación celular coincide con el cambio al endociclo, una variante del ciclo mitótico en la que el ADN genómico se duplica pero sin posterior división, es decir en ausencia de fase M. Aunque la regulación circadiana y el ciclo celular han sido individualmente estudiados en plantas, no se ha demostrado hasta la fecha la posible conexión de ambos ciclos en plantas. El trabajo realizado durante esta Tesis Doctoral se ha centrado en el estudio del papel del reloj circadiano en el control del ciclo celular durante la regulación del crecimiento de la planta. Los resultados obtenidos muestran que plantas con un reloj circadiano de ritmo lento desaceleran la progresión del ciclo celular, mientras que un reloj de ritmo rápido lo acelera. El componente esencial del reloj denominado en inglés TIMING OF CAB EXPRESSION 1 (TOC1) controla la transición de la fase G1 a la fase S, regulando así el ritmo del ciclo mitótico durante los estadios tempranos del desarrollo foliar. Asimismo, TOC1 también controla la ploidía somática característica del endociclo durante estadios tardíos del desarrollo foliar y en las células del hipocotilo. Utilizando técnicas de citometría de flujo y parámetros de cinéticas de crecimiento foliar se pudo determinar que en plantas que sobre-expresan TOC1 la fase S es más corta, lo que se correlaciona con la represión diurna del gen CELL DIVISION CONTROL 6 (CDC6). Este gen codifica un factor esencial en la formación de los complejos de pre-replicación que determinan los orígenes de replicación del ADN. Mediante técnicas de inmunoprecipitación de cromatina encontramos que la represión de CDC6 ocurre a través de la unión directa de TOC1 al promotor de CDC6. Los análisis de interacción genética demostraron que los fenotipos de crecimiento reducido y de ploidía somática alterada observados en plantas que sobre-expresan TOC1, quedaban revertidos al sobre-expresarse también CDC6. Estos resultados confirman que la función de TOC1 en el ciclo celular ocurre en gran medida a través de la represión de CDC6. La desaceleración de la progresión del ciclo celular en plantas que sobre-expresan TOC1 afecta no solo el desarrollo de los órganos de la planta, sino también el desarrollo tumoral en los tallos de las inflorescencias. Por lo tanto, nuestros estudios demuestran que la función de TOC1 es importante en la regulación rítmica de la maquinaria pre-replicativa del ADN para controlar el crecimiento de las plantas en resonancia con el medio ambiente.
The circadian function is essential for plant growth and its adaptation to the environment. The molecular machinery responsible for the establishment of the circadian rhythmicity relies on the rhythmic oscillation of differentially expressed genes with different peaks of expression along the day and night. The rhythms in gene expression are translated into oscillations of physiological and developmental processes. Plant growth is controlled by a plethora of different processes that ultimately work through the control of cell proliferation and differentiation. Cell proliferation relies on the proper progression of the mitotic cycle, which is divided in 4 phases: S (DNA synthesis), M (Mitosis) and two gap phases G1 and G2, that take place before S and M phases, respectively. Cell differentiation coincides with the entry into the endocycle, a variant of the mitotic cycle in which genomic DNA duplicates without further division or mitosis. Even though the circadian clock and cell cycle as separate pathways have been well documented in plants, the possible direct interplay between these two cyclic processes has not been previously addressed. The work performed during this Thesis has focused on the characterization of the role of the circadian clock in the control of the cell cycle during plant growth. We found that plants with slower than Wild-Type circadian clocks slow down the progression of the cell cycle, while plants with faster clocks speed it up. The core clock component TIMING OF CAB EXPRESSION 1 (TOC1) controls the G1 to S-phase transition, thereby regulating the rhythm of the mitotic cycle during the early stages of leaf development. Likewise, TOC1 controls somatic ploidy during later stages of leaf development and of hypocotyl cell elongation. The use of flow cytometry analyses and of leaf growth kinetics showed that in plants over-expressing TOC1, the S-phase is shorter, which correlates with the diurnal repression of the CELL DIVISION CONTROL 6 (CDC6) gene. This gene encodes an essential component of the pre-replication complex, which is responsible for the specification of DNA origins of replication. Chromatin immunoprecipitation assays showed that the diurnal repression of CDC6 most likely relies on the direct binding of TOC1 to the CDC6 promoter. Genetic interaction analyses showeed that the reduced growth and altered somatic ploidy phenotypes observed in plants over-expressing TOC1 were reverted when CDC6 was over-expressed. Thus, our results confirm that TOC1 regulation of the cell cycle occurs through CDC6 repression. The slow cell cycle progression in plants over-expressing TOC1 has an impact not only in organ development but also on tumor growth in stems and inflorescences. Thus, TOC1 sets the time of the DNA pre-replicative machinery to control plant growth in resonance with the environment.

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24

Val, Casals Maria 1993. "Circadian regulation of macrophages in homeostasis and disease". Doctoral thesis, Universitat Pompeu Fabra, 2020. http://hdl.handle.net/10803/669532.

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Els ritmes circadians són oscil·lacions diàries en paràmetres fisiològics necessaris per a què els organismes adaptin la seva activitat als cicles de llum i foscor. A nivell molecular, la maquinària circadiana consisteix en bucles oscil·latoris de traducció-transcripció dirigides per l’activitat de les proteïnes BMAL1 i CLOCK de manera autònoma a cada cèl·lula. La maquinària circadiana regula l’activitat de diversos tipus de cèl·lules immunitàries, inclosos els macròfags. Concretament, BMAL1 pot controlar la magnitud diària de les respostes inflamatòries dels macròfags. En el present treball, es caracteritza la regulació circadiana dels macròfags en contextos encara no explorats. Hem analitzat l’expressió i els patrons oscil·ladors dels components del rellotge en poblacions de macròfags i també hem valorat el paper potencial dels rellotges en les funcions dels macròfags. Presentem resultats identificant aspectes de la funció del rellotge en macròfags que poden ajudar a comprendre la influència dels ritmes circadians en la modulació de respostes immunitàries innates.
Circadian rhythms are daily oscillations in physiological parameters required for organisms to adapt their activity to cycles of light and darkness. At the molecular level, the circadian machinery consists of cell-autonomous transcription-translation oscillation loops led by the activity of BMAL1 and CLOCK proteins. The circadian machinery regulates the activity of diverse immune cell types, including macrophages. Specifically, BMAL1 can control the daily magnitude of macrophage inflammatory responses. In the present work we characterize the circadian regulation of macrophages in yet unexplored contexts. We have analyzed the expression and oscillatory patterns of clock components in macrophage populations, and also assessed the potential role of clocks in macrophage functions. We present results identifying aspects of clock function in macrophages that can help understand the influence of circadian rhythms in the modulation of innate immune responses.

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25

Ragsdale, Raven, Colin Shone, Madeleine Miller, Andrew Shields, Thomas C. Jones e 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 other words, organisms suffer if their circadian clocks do not “resonate” with environmental cycles. Organisms fail to synchronize (entrain) their activity with non-resonant LD cycles and this failure typically leads to a number of physiological disruptions. Interestingly, several spider species have endogenous circadian periods that deviate by several hours from the period of the Earth’s solar day. The object of the present study is to investigate whether the phenomenon of circadian resonance also pertains to these atypical spider circadian rhythms. We investigated three spider species, two of which have internal periods (τ) significantly different from 24 hours. Approximately 50 individuals of each species of spider (Frontinella communis: τ=29.05±0.62 hours; Metazygia wittfeldae: τ=22.74±0.24h; and Cyclosa turbinata: τ=18.54±0.28h) were placed into chambers with periods of 19 (9.5:9.5h L:D), 24 (12:12h L:D), or 29 hours (14.5:14.5h L:D). If resonance is pertinent for spiders, we would expect survivorship to decrease in non-resonant LD cycles. Instead, no spider species exhibited decreased longevity in non-resonant L:D cycles. These findings contradict all previous research into circadian resonance and suggest that spiders do not suffer the costs of extreme desynchronization. In a second experiment, 10-11 spiders from each species were placed into infrared activity monitors to determine if their locomotor activity could entrain to (synchronize with) the three different LD cycles. Individuals from all three spider species entrained to all LD period lengths, again in contrast with prior research in other species. These results indicate that spider circadian clocks have highly unusual limits of entrainment and suggest a remarkable level of plasticity in their release from the selective pressure to maintain an internal period of approximately 24 hours.

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26

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
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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
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 pacientes adultos hospitalizados. Participaram, 15 pacientes do sexo masculino sem sinais de processos infecciosos, com idade entre 22 a 75 anos com diversos diagnósticos clínico e cirúrgico, internados nas enfermarias de Cardiologia, Gastroclínica e Enfermaria Geral de Adultos (EGA). Foram medidas as temperaturas ao longo do período de vigília, iniciando às 6 horas da manhã e a última às 22 horas, com um total de nove medidas. Verificou-se também a temperatura ambiente nas enfermarias durante o período das 5h30, às 14 horas e às 20 horas. Os resultados mostraram que houve diferença significativa entre as médias dos termômetros; as médias dos horários medidos; às médias entre as temperaturas dos termômetros no período noturno e entre as médias nos períodos matutino e vespertino (p-value=0,0001). Não houve diferença significativa entre os horários medidos no período noturno (p-value=0,8) e entre as médias das temperaturas nos períodos matutino e vespertino (p-value=0,4), quando utilizada a técnica paramétrica de análise de variância e o teste de Tukey para comparações múltiplas. O nível de significância adotado foi ? = 0,05. O termômetro timpânico registrou a variabilidade circadiana dos pacientes e seus valores de temperatura foram maiores em relação aos outros locais de medida
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 pacientes adultos hospitalizados. Participaram, 15 pacientes do sexo masculino sem sinais de processos infecciosos, com idade entre 22 a 75 anos com diversos diagnósticos clínico e cirúrgico, internados nas enfermarias de Cardiologia, Gastroclínica e Enfermaria Geral de Adultos (EGA). Foram medidas as temperaturas ao longo do período de vigília, iniciando às 6 horas da manhã e a última às 22 horas, com um total de nove medidas. Verificou-se também a temperatura ambiente nas enfermarias durante o período das 5h30, às 14 horas e às 20 horas. Os resultados mostraram que houve diferença significativa entre as médias dos termômetros; as médias dos horários medidos; às médias entre as temperaturas dos termômetros no período noturno e entre as médias nos períodos matutino e vespertino (p-value=0,0001). Não houve diferença significativa entre os horários medidos no período noturno (p-value=0,8) e entre as médias das temperaturas nos períodos matutino e vespertino (p-value=0,4), quando utilizada a técnica paramétrica de análise de variância e o teste de Tukey para comparações múltiplas. O nível de significância adotado foi ? = 0,05. O termômetro timpânico registrou a variabilidade circadiana dos pacientes e seus valores de temperatura foram maiores em relação aos outros locais de medida
Abstract: The aim of this research was to verify the daily variation of the tympanic, oral and axillary temperatures, and correlate measurements of the Tympanic temperature considering the positioning angle and to compare the set of measurements in adult volunteer patients during treatment in the Clinics Hospital of Universidade Estadual de Campinas, São Paulo. The results refer to fifteen male in patients, 22 to 75 years old with no signal of infectious processes, having different clinical and cirurgic diagnostics in the Cardiology, Gastroclinics, and Adult General Nursery. The temperatures were measured nine times between 6 am and 10 pm. The ambient nurserys temperature was also monitored, at 5:30 am, 2 pm, and 8 pm. The results show that there was a significant difference between: the mean measured temperatures in different positions; the mean values of the different scheduled times; the mean values of the morning and afternoon periods (p-value=0,0001). When using the parametric technique of analysis of variance and the Tukey¿s test of multiple comparation, there was no significant difference between the measured values (p-value=0,8). The significance level adopted was ? = 0,05. The tympanic thermometer has registered the daily variation of the patients¿ temperature and its values were bigger than the measured by the other places of measurement
Abstract: The aim of this research was to verify the daily variation of the tympanic, oral and axillary temperatures, and correlate measurements of the Tympanic temperature considering the positioning angle and to compare the set of measurements in adult volunteer patients during treatment in the Clinics Hospital of Universidade Estadual de Campinas, São Paulo. The results refer to fifteen male in patients, 22 to 75 years old with no signal of infectious processes, having different clinical and cirurgic diagnostics in the Cardiology, Gastroclinics, and Adult General Nursery. The temperatures were measured nine times between 6 am and 10 pm. The ambient nurserys temperature was also monitored, at 5:30 am, 2 pm, and 8 pm. The results show that there was a significant difference between: the mean measured temperatures in different positions; the mean values of the different scheduled times; the mean values of the morning and afternoon periods (p-value=0,0001). When using the parametric technique of analysis of variance and the Tukey¿s test of multiple comparation, there was no significant difference between the measured values (p-value=0,8). The significance level adopted was ? = 0,05. The tympanic thermometer has registered the daily variation of the patients¿ temperature and its values were bigger than the measured by the other places of measurement
Mestrado
Enfermagem e Trabalho
Mestre em Enfermagem

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27

Peschel, Nicolai. "New insights into circadian photoreception and the molecular regulation of the resetting of Drosophilas circadian clock". kostenfrei, 2008. http://www.opus-bayern.de/uni-regensburg/volltexte/2009/1063/.

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28

Martínez, Nicolás Antonio. "Interrelación entre los sincronizadores y el sistema circadiano humano= Crosstalk between synchronizers and the human circadian system". Doctoral thesis, Universidad de Murcia, 2014. http://hdl.handle.net/10803/277216.

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Establecer el patrón de temperatura de la piel de la muñeca como ritmo marcador para evaluar el sistema circadiano humano. Para ello, se plantearon los siguientes objetivos específicos: 1. Obtener el ritmo endógeno de temperatura periférica distal por medio de procedimientos matemáticos para eliminar y cuantificar los efecto enmascarantes. 2. Describir la ontogenia y el envejecimiento del patrón de temperatura periférica distal. 3. Caracterizar el régimen de exposición a la luz y su influencia sobre el sistema circadiano evaluado mediante el ritmo de temperatura en la muñeca. 4. Analizar el efecto de la temperatura ambiental sobre las variables termofisiológicas y cardiofisiológicas. 5. Evaluar el estilo de vida, la exposición a sincronizadores y la cronodisrupción en ancianos sanos comparados con jóvenes, y proponer un método para evaluar la edad del sistema circadiano sin tener en cuenta la edad biológica. 6. Estudiar la influencia del contraste día/noche en la exposición a sincronizadores y en los hábitos de vida sobre el sistema circadiano humano. 7. Idear una luminaria saludable para el sistema circadiano. MATERIAL Y MÉTODOS La presente tesis cumple los principios bioéticos para investigación humana. Se monitorizaron 456 voluntarios (99 bebés, 250 universitarios, 27 adultos y 80 ancianos) apropiadamente informados sobre el estudio. La temperatura de la piel se monitorizó mediante un data logger (Thermochron iButton, Maxim Integrated Products, Sunnyvale, California, USA). Actividad y posición se registraron mediante un actímetro (HOBO Pendant G Acceleration Data Logger UA-004-64, Onset Computer, Bourne, Massachusetts, USA). La exposición a la luz y la temperatura ambiental se monitorizaron mediante un luxómetro (HOBO Pendant Temperature/Light Data Logger UA-002-64, Onset Computer, Bourne, Massachusetts, USA). Las variables cardiovasculares se registraron mediante un holter de presión arterial (Mobil-O-Graph NG, IEM GmbH, Stolberg, Germany). Además, temperatura, actividad y posición se integraron en una nueva variable compuesta (TAP). Los patrones obtenidos se caracterizaron mediante análisis de series temporales utilizando programas específicos como Cosinor o El Temps (Antoni Díez-Noguera, Universitat de Barcelona, 1999) o diferentes versiones de Excel. Los análisis estadísticos se realizaron con SPSS (Inc. Chicago, Illinois, USA) o R, y los árboles de decisión se realizaron en WEKA 3.0.0 (University of Waikato, New Zealand). CONCLUSIONES Las principales conclusiones de la presente tesis fueron: 1. El ritmo de temperatura periférica distal presenta un fuerte componente endógeno a pesar de la influencia fase-dependiente de otras variables. 2. La maduración del patrón circadiano de temperatura periférica de la muñeca se asocia con un aumento de la circadianidad y el envejecimiento se relaciona con un adelanto de fase. 3. El contraste día/noche en la exposición a la luz y la calidad de la luz se relacionan con mejores patrones de temperatura de la muñeca y de sueño, mientras que la exposición a luz nocturna se asocia a los peores patrones. 4. Las variaciones en la temperatura ambiental afectan la presión arterial a través de cambios en la temperatura periférica distal. 5. El sistema circadiano del anciano se caracteriza por un menor contraste en las variables sincronizadoras, un avance de fase generalizado y un deterioro del orden interno; estas características permiten diferenciar entre jóvenes y ancianos. 6. Las alteraciones en el ritmo de temperatura se asocian con un bajo contraste día/noche. El modelado matemático apunta a que el aumento del contraste en el estilo de vida podría mejorar el ritmo de temperatura. 7. Se patentó un dispositivo de iluminación circadiana saludable. CONCLUSIÓN GENERAL La temperatura periférica de la piel de la muñeca ha demostrado ser un ritmo marcador fiable y cómodo con un fuerte componente endógeno que permite evaluar la robustez del sistema circadiano y el envejecimiento.
OBJECTIVES To establish distal skin temperature pattern as marker rhythm for human circadian system assessing. For this, the following specific objectives were approached: 1. To obtain the endogenous circadian pattern of wrist temperature rhythm by mathematical removing and quantifying masking. 2. To describe and differentiate distal skin temperature during maturation and aging. 3. To characterize human light exposure and its influence on the circadian system assessed by wrist temperature. 4. To analyze the effect of temperature exposure on thermophysiological and cardiophysiological variables. 5. To assess lifestyle, chronodisruption and synchronizers exposure in healthy elders comparing with young people and to propose a method for assessing circadian system aging without taking into account the biological age. 6. To study the influence of day/night contrast in lifestyle and synchronizers, on human circadian system. 7. To create a healthy circadian lighting design. MATERIALS AND METHODS The present thesis accomplishes the bioethical principles for human research. 456 volunteers were recruited (99 babies, 250 undergraduate students, 27 middle-aged adults and 80 elderly people) and properly informed about the study. Skin temperature was recorded using a temperature data logger (Thermochron iButton DS1921H, Maxim Integrated Products, Sunnyvale, California, USA). Activity and position were recorder by an actimeter (HOBO Pendant G Acceleration Data Logger UA-004-64, Onset Computer, Bourne, Massachusetts, USA). Light exposure and environmental temperature were recorded by a luxometer (HOBO Pendant Temperature/Light Data Logger UA-002-64, Onset Computer, Bourne, Massachusetts, USA). Cardiovascular variables were recorded by an automated oscillometric ambulatory system (Mobil-O-Graph NG, IEM GmbH, Stolberg, Germany). In addition, temperature, activity and position were integrated in a new variable (TAP). Rhythm characteristics were extracted by time series analysis using Cosinor or El Temps (Antoni Díez-Noguera, Universitat de Barcelona, 1999) or different versions of Excel. Statistical analysis was performed using SPSS (Inc. Chicago, Illinois, USA) or R, while decision trees were performed in WEKA 3.0.0 (University of Waikato, New Zealand). CONCLUSIONS The main conclusions of the present thesis are: 1. Wrist temperature rhythm has a strong endogenous component, in spite of the influence of other variables, which affect in a phase-dependent manner. 2. Distal skin temperature maturation is associated with an increase in circadianity, whereas aging is related to a phase advance. 3. Day-night contrast and light quality are related with more robust distal skin temperature and sleep patterns, whereas night-time light is associated with worse circadian patterns. 4. Variations in environmental temperature affect arterial blood pressure by changes produced in distal skin temperature. 5. Aged circadian system is characterized by less contrast in synchronizing variables, a generalized phase advance and internal order impairment; these differences allow discerning between a young and elderly people. 6. Temperature rhythm impairment is associated with low contrast between day and night. Mathematical modelling demonstrates that increasing contrast in lifestyle should improve temperature rhythm. 7. A healthy circadian lighting device was patented. GENERAL CONCLUSION Wrist temperature has demonstrated to be a comfortable and reliable marker rhythm with a strong endogenous component that allows evaluating circadian system robustness and ageing.

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29

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.
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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30

Dowling, Glenna Annette. "Women with Parkinson's disease : circadian function /". Thesis, Connect to this title online; UW restricted, 1989. http://hdl.handle.net/1773/7326.

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31

Seifert, Erin. "Circadian patterns of breathing and thermoregulation". Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37657.

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Circadian rhythms, ∼24-h oscillations in physiological variables, are pervasive throughout nature. Synchronization of these oscillations to the 24-h day enables organisms to take advantage of environmental cycles. In mammals, a circadian pacemaker located in the hypothalamus coordinates the overt rhythms.
The present study investigates aspects of the 24-h organization of breathing, and its chemical control, and of thermoregulation in mammals. Pulmonary ventilation (V˙E), oxygen consumption ( V&d2;O2 ), body temperature (Tb), and locomotor activity were monitored by non-invasive means, in freely-moving male adult rats. Rats are nocturnal, and it is well known that their Tb, activity and metabolic rate are highest during the dark hours of the day.
Hypoxia inhibits thermogenesis, and the Tb and V&d2;O2 circadian patterns are contributed to by changes in thermogenesis, implying that hypoxia blunts the daily oscillations of these variables. Indeed, the amplitude of both oscillations was smaller, due to a decrease in the dark phase values. Evidence supports an action of hypoxia on the hypothalamic thermoregulatory mechanisms, rather than on the clock itself.
Metabolism is well known to be a major determinant of V˙E, and of the V˙E response to changes in inspired gases. Using a custom-designed system to monitor breathing continuously, during air breathing, V˙ E was found to oscillate, with higher values during the dark compared to the light hours of the day; these changes were almost in proportion to those of V&d2;O2 , and did not depend on those of activity.
The depressant effect of hypoxia on the high values of the V&d2;O2 oscillation predict that the hypoxic V˙E response would be blunted at this time. Indeed, the response was lower during the dark compared to the light hours; however, the daily changes in the V˙E response were in proportion to those of V&d2;O2 , such that the hyperventilatory response (% increase in V˙ E/ V&d2;O2 ) was similar throughout the day. The V˙E/ V&d2;O2 response was also similar throughout the day in hypercapnia, even though the metabolic response to hypercapnia differed from that in hypoxia.
Globally taken, these results indicate that (1) breathing and its control mechanisms accompany the daily oscillations of many physiological variables, and (2) the advantages of a biological clock do not compromise the adequacy of the hyperventilatory responses to chemical challenges.

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32

Shaw, Linda Marie. "Characterisation of ENU-induced circadian mutants". Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497452.

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33

Gesto, João Silveira Moledo. "Circadian clock genes and seasonal behaviour". Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/10266.

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Circadian and photoperiodic phenomena serve to organize the temporal pattern of various biological processes. While the former generates endogenous daily rhythms, the latter is related to seasonality. In Drosophila melanogaster, the gene timeless (tim) encodes a cardinal component of the circadian clock and also contributes to photoperiodism, which is observed as an adult reproductive diapause. In this work, natural tim variants were examined for diapause across different temperatures and photoperiods. The newly derived allele, ls-tim, exhibited consistently higher diapause levels than the ancestral one, s-tim, implicating a putative adaptive advantage in the seasonal European environment and providing a perfect substrate for the recently proposed scenario of directional selection. To investigate further genetic links between circadian and photoperiodic mechanisms, classical clock mutations and transgenes were placed on a natural congenic background and assayed for locomotor activity behaviour and diapause response. Surprisingly, the results not only highlighted the importance of tim, and its natural alleles, but also revealed the participation of other clock components in diapause, suggesting that both daily and seasonal timers might have molecularly coevolved. The phenotypic effects promoted by ls-tim arise from the protein isoform LTIM, which expresses an additional N-terminal fragment. To study the adaptive significance of the N-terminal residues, including putative phosphorylation sites, a number of mutagenized TIM constructs were generated and functionally analysed. At the molecular level, it was demonstrated that both the N-terminus length and the order of its residues are important variables modulating the interaction dynamics between TIM and CRYPTOCHROME (CRY). At the behaviour level, the overall amino acid composition, rather than a particular order, appeared to be more critical for the phaseshift responses. Interestingly, despite the functional importance of the N-terminus, a deletion mapping analysis revealed that CRY directly binds to a protein sequence located at TIM C-terminus.

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34

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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35

Curran, Jack. "Ageing and the Drosophila circadian clock". Thesis, University of Bristol, 2019. http://hdl.handle.net/1983/7b02ec7c-f6a2-4640-b50f-ce97a66a5a11.

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It is well established that elderly individuals have increased difficulty sleeping at night combined with falling asleep and waking up earlier. Although these age-related declines in circadian output are clearly observable in activity recordings of laboratory animals, the underlying changes in molecular and neuronal activity remain unknown. The fruit fly, Drosophila melanogaster, has long been used as a model for studying the circadian system and for ageing research. In this thesis Drosophila was used as a model to study the effect of ageing on circadian and sleep behaviour. Circadian behaviour was measured using the Drosophila Activity Monitoring system, recording activity of flies at various stages of the ageing process, demonstrating a linear decline in rhythm strength with age combined with an increase in period length. Weakened circadian output is combined with significant alterations of diurnal behaviour of Drosophila, namely a reduction in morning and evening anticipatory behaviour. Ageing also has a significant impact on sleep behaviour, significantly increasing sleep duration whilst reducing latency, with larger effects observed on day- time sleep. Age-related changes in neuronal activity were investigated using whole-cell patch clamp electrophysiology to record from large lateral ventral (l-LNV) clock neurons, finding that ageing was associated with a significant decrease in input resistance, but no significant changes in spontaneous electrical activity or membrane potential. Manipulating the electrical properties of the circadian system by knocking down expression of candidate ion channels in all clock neurons had significant effects on behaviour, linking electrical activity with clock outputs. The results presented in this thesis demonstrate the suitability of Drosophila as a model to interrogate how ageing effects the circadian clock, identifying Alterations in the electrical properties of the l-LNV neurons may underlie observed changes in diurnal activity and sleep, while decreased remodelling of the s-LNV neurons can explain weakened circadian behaviour.

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36

Beynon, Amy Louise. "Neuroimmune modulation of the circadian clock". Thesis, Swansea University, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.678517.

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37

Kushniryk, O. V. "Impact of seasons on circadian rhythm". Thesis, БДМУ, 2020. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18035.

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38

Santos, Carlo Steven. "Circadian Control of Cell Cycle Progression". Thesis, Virginia Tech, 2009. http://hdl.handle.net/10919/76987.

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Tumorigenesis is the result of uncontrolled cell growth due to the deregulation of cell cycle checkpoints 1. Period 2 (Per2) is a tumor suppressor that oscillate in expression in a 24-hour cycle 2, 3. Here, we show that Per2 interacts with the tumor suppressor protein p53. Both G1 and G2 checkpoint pathways involve a p53 dependent pathway which can trigger the cell to go through cell arrest or programmed cell death4. Understanding all the mitigating factors involved in regulating cell cycle progression under DNA damage can offer a better idea in how cells become immortal. Initially discovered through screening of a human liver cDNA library, the novel interaction between p53-Per2 was further documented using co-precipitation. Interestingly, under genotoxic stress conditions, p53 and Per2 were not found to bind which leads us to suspect that Per2 does not affect active p53 which may possibly be due to post translational modifications of its active state. Furthermore we investigated p53's ability to act as a transcription factor in the presence of Per2, showing that the Per2-p53 complex prevents p53 from binding to DNA. This implies that the tetramerization of p53 may also be another factor in Per2's ability to bind to p53. A truncated p53 lacking the last 30 amino acids that theoretically increase p53's ability to form a tetramer showed a drastic reduction in binding to Per2 5, 6. On the other hand, p53 lacking the tetramerization domain showed binding similar to wildtype. Consequently we speculate that the ability of Per2 to modulate p53 and act as a tumor suppressor protein may be dependent on either the post translational modifications of p53 or its oligomeric state.
Master of Science

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39

Wang, Louisa Mei-Chen. "Circadian Regulation of learning and memory". Diss., Restricted to subscribing institutions, 2008. http://proquest.umi.com/pqdweb?did=1695050971&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.

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40

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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41

Sra, Sana. "Circadian Variations and Risky Decision Making". Scholarship @ Claremont, 2019. https://scholarship.claremont.edu/scripps_theses/1291.

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Over the past decades, decision making under risk has garnered a great amount of attention both in the field of economics and psychology. Although state-dependent variabilities of risk taking are well-documented, little is known about the effects of a person’s preferred time of day, or chronotype, in risky decision making. Under circumstances of circadian mismatch (e.g., when an “early bird” makes decisions in the evening), research suggests that decision making may reflect a greater reliance on heuristics, such as using stereotypes in social judgments. However, the effects of circadian mismatch on heuristics in risky decision making are relatively unexplored. This paper looks into the effects of circadian mismatch on the reflection effect: a behavioral bias in financial decision making, wherein individuals are risk averse when facing potential gains, and risk seeking when facing potential losses. Participants will be randomly assigned to their circadian matched or circadian mismatched conditions and will play a series of financial gambling tasks with real monetary incentives. This study predicts that the reflection effect will be exacerbated in circadian mismatched individuals as compared to matched participants. Exploring such an effect could have real-world implications on decision making under risk by providing critical knowledge about the effects of time of day on our susceptibility to behavioral biases. It could therefore point to the existence of a more optimal time of day to engage in such critical decision making.

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42

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’evoluzione del ritmo circadiano che promuove la fase di attività durante il momento più favorevole della giornata, mentre la seconda si serve dell’asse dei glucocorticoidi per affrontare le sfide imprevedibili. Quindi, un dialogo tra il sistema circadiano e il sistema dei glucocorticoidi è mantenuto allo scopo di ottenere una regolazione ottimale dell’attività animale. Il mio obiettivo è quello di capire il dialogo tra i due sistemi monitorando il comportamento giornaliero e circadiano, e la sua controparte molecolare, in fase a differenti cicli di luce e cibo. La mia specie modello è lo zebrafish (Danio rerio), in particolare, ho utilizzato un mutante costruito con la tecnica CRISPR/Cas9 che manca della capacità di coordinare la via di trascrizione dei glucocorticoidi a causa della mancata funzionalità del loro recettore cognato tale che l’interazione ligando recettore non è mantenuta. Di conseguenza, i livelli circolanti di glucocorticoidi restano elevati, conferendo al mutante un fenotipo ansioso. Zebrafish gr-/- è stato costruito e gentilmente fornito dal laboratorio della Prof.ssa Luisa Dalla Valle, Università degli studi di Padova. L’analisi sistematica del comportamento in larve e adulti di gr-/- ha mostrato che l’attività locomotoria sincronizzata alla luce mantiene le sue proprietà oscillatorie endogene. Tuttavia, l’attività locomotoria giornaliera insorge con un ritardo di un giorno nei mutanti rispetto ai wild type. Questa insorgenza ritardata è associata a un rallentamento nello sviluppo del tessuto muscolare striato, la normale densità delle fibre muscolari viene ripristinata nei gr-/- al sesto giorno dopo la fertilizzazione. Inoltre, le larve gr-/- hanno mostrato differenze nei livelli di espressione e nelle relative acrofasi di elementi positivi (arntl1a and clock1a) e negativi (per1, per2a and cry1a) dell’orologio molecolare. Al di là degli elementi del cuore dell’orologio circadiano, un’analisi nel fegato di adullti gr-/- rivela un’abolizione dell’espressione di pck2, un gene implicato nella gluconeogenesi. In aggiunta, srebp1 ha un’acrofase anticipata nei mutanti. La sincronizzazione circadiana al cibo fallisce nei gr-/-, sia larve sia adulti producono profili anomali dell’attività locomotoria. L’analisi molecolare non associa la disfunzionalità comportamentale a quella genetica, infatti i geni orologio non mostrano alterate oscillazioni a eccezione di cry1a. Questi dati suggeriscono l’esistenza di un confine sfuocato tra il sistema circadiano e quello dei glucocorticoidi e una complessa organizzazione dei due ha prodotto un alterato output comportamentale negli zebrafish gr-/-. La causa prossima del disallineamento tra lo stimolo alimentare e la locomozione non è stata chiarita sebbene un passo avanti verso una maggiore comprensione del dialogo tra glucocorticoidi e orologio circadiano getta le basi per un’indagine più profonda.
Behavior is conceived as a stimulus-response dependent relationship between a sensory input and a motor output. While moving from an input to an output, internal homeostasis is continuously shaped to maintain an optimal energies expenditure balance. The ultimate purpose of enabling animals to adjust their homeostasis with the surrounding world is by producing adaptive behaviors in order to increase their fitness in light of natural selection. The environment can be either predictable or unpredictable. The former condition led to the evolution of the circadian rhythm to promote an active behavior at the time you mostly benefit from, while the latter take advantage of glucocorticoids axis to face sudden challenges. Thus, a crosstalk between the circadian and the glucocorticoid systems allows a fine tuning of animal’s activity. My goal is to understand the circadian-glucocorticoids dialogue by monitoring the locomotor daily/circadian behavior and its molecular oscillation counterpart under differentially phased light and feeding cycle. My model species is the zebrafish, particularly, I utilized a CRISPR/Cas9 mutant lacking the capability to coordinate glucocorticoids transcription because it lacks functional receptors which permit a correct ligand-receptor interaction. As a result, level of circulating glucocorticoids stays raised conferring an anxiety-related phenotype to the mutant. Zebrafish gr-/- has been built and kindly provided by Dr. Luisa Dalla Valle, University of Padua. Systematic behavioral analysis in gr-/- larvae and adults showed that the light entrainable locomotor activity is synchronized to the zeitgeber and maintain its oscillatory properties in absence of any cue. The onset of daily locomotor activity occurred one day later in mutants with respects to the wild type. This delay is linked to the slower striated muscle development in the gr-/- which recover regular fiber density at 6 days post fertilization. Furthermore, gr-/- larvae showed differences in the expression levels or in the peak phase of positive (arntl1a and clock1a) and negative (per1, per2a and cry1a) elements of the molecular clock. Outside the core clock network, an analysis on gr-/- adult livers reported an abolished daily expression of pck2, a gene involved in gluconeogenesis. In addition, srebp1 expression level has an anticipated acrophase in gr-/-. Feeding entrainment fails to occur in the mutants. Larvae and adults produced abnormal proﬁles of circadian locomotor activity. Further molecular investigation revealed this behavioral disruption wasn’t associated with a breakdown of molecular rhythms in the core clock genes. Nevertheless, the molecular phenotypes observed during feeding entrainment underlined a cry1a lack of rhythmicity. These data suggest the existence of a blurred boundary between the circadian-glucocorticoids crosstalk. A complex organization of the two produces an altered behavioral output in a food entrained schedule in gr-/- zebrafish. The proximate cause of input and output misalignment underlying food entrained locomotion has not been provided, but a step towards a more exhaustive comprehension about the circadian-glucocorticoids interaction paves the way for an in-depth investigation.

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43

Southern, Megan Morgan. "Mutants in the Arabidopsis circadian clock : genetic approaches to explore circadian mechanisms in the model higher plant". Thesis, University of Warwick, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425525.

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44

Gil, Rodríguez Sergio. "Functional characterization of the connection between the circadian clock and the DNA damage and repair response in Arabidopsis thaliana". Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/669601.

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En la mayoría de los organismos estudiados, el reloj circadiano mantiene ritmos en fisiología, metabolismo y desarrollo en sintonía con los cambios medioambientales que suceden durante los ciclos diurnos y nocturnos. En plantas, el reloj circadiano regula la correcta periodicidad de muchos procesos cruciales como las respuestas a un gran número de estreses abióticos y bióticos. En esta Tesis Doctoral, hemos estudiado la conexión entre el reloj circadiano y la vía de respuesta al daño y reparación del DNA (DNA Damage and Repair (DDR)) en respuesta al daño de doble cadena del DNA (double strand breaks (DSBs)). Los resultados obtenidos indican que el reloj circadiano rítmicamente regula las respuestas biológicas y moleculares frente a los DSBs. También identificamos al foto-receptor de luz azul CRYPTOCHROME 2 (CRY2) como regulador clave en la repuesta DDR. En respuesta a los DSBs inducidos por la droga bleomicina, nuestros comet assays realizados a diferentes momentos del ciclo diurno mostraron que los DSBs disminuyen por la noche en comparación con los DSBs durante el día. Además, la actividad de los promotores y expresión del mRNA de genes cruciales en la respuesta DDR mostraron oscilaciones rítmicas y robustas con un pico máximo en la noche. Los resultados sugieren que los mecanismos de reparación del DNA podrían estar favorecidos en la noche. La función circadiana no sólo controla transcripción si no también modificaciones post-traduccionales como la parilación de las proteínas. Nuestros estudios mostraron que la sobre-expresión y mutación de un número de genes del reloj circadiano modifica los ritmos de la respuesta DDR. Sin embargo, con algunas excepciones, la expresión de la mayoría de los genes clave del reloj no presenta importantes cambios en respuesta a los tratamientos con bleomicina. Nuestros estudios también mostraron que la desregulación del foto-receptor CRY2 altera el grado de formación de los DSBs y la expresión transcripcional de genes clave en la respuesta DDR como POLY-(ADP-RIBOSE) POLYMERASE 2 (PARP2) y RAD ASSOCIATED WITH DIABETES 51 (RAD51). La regulación podría suceder mediante la interacción directa de CRY2, ya que ensayos de immunoprecipitación de la cromatina revelaron enriquecimiento de la proteína CRY2 en varios loci de genes importantes de la DDR, que incluyen PARP2 y POLY-(ADP-RIBOSE) GLYCOHYDROLASE 1 (PARG1 or TEJ). La correcta expresión y función de CRY2 es también importante en la formación de una clase particular de estructuras secundarias del DNA o híbridos de DNA-RNA conocidos como R-loops. Los resultados que conectan CRY2 con los híbridos de DNA-RNA en los genes de la respuesta DDR son relevantes, ya que los R-loops han sido previamente conectados con la localización y reparación de los DSBs. Mediante el uso de plantas con la función de CRY2 alterada también hallamos que la muerte celular programada y la aparición de hojas verdaderas en respuesta a los DSBs, requieren una correcta expresión y función de CRY2. Por lo tanto, nuestros estudios demuestran una regulación circadiana de la DDR en Arabidopsis thaliana. Esta regulación podría ser relevante para proteger el DNA en momentos en los que es más vulnerable como durante la replicación, que en varios organismos incluidas las plantas, sucede cuando anochece o durante la noche. Nuestros estudios también sugieren que la función de CRY2 en la respuesta DDR podría llevarse a cabo mediante cambios en la compactación de la cromatina y la formación de R-loops.
In most organisms examined to date, the circadian clock sustains rhythms in physiology, metabolism and development in tune with the environmental changes that occur during the day and night cycle. In plants, the circadian clock controls the proper timing of many essential processes including among others plant responses to a number of abiotic and biotic stresses. In this Doctoral Thesis, we aimed to study the connection between the circadian clock and the DNA Damage and Repair (DDR) response triggered by DNA double strand breaks (DSBs). We found that the circadian clock rhythmically regulates molecular and biological responses to DSBs. We also identified the blue-light photoreceptor CRYPTOCHROME 2 (CRY2) as an important regulator of the DDR response. Upon DSB formation by the drug bleomycin, our comet assays performed at different times during the diurnal cycle showed that DSBs are decreased at night compared to DSBs during the day. In addition, the promoter activity and mRNA expression of key DDR genes followed robust rhythmic oscillations with a peak during the night. The results suggest that DNA repair mechanisms might be enhanced at night. The circadian function not only controls transcription but also post-translational modifications such as protein parylation. Our studies showed that over-expression and mutation of a number of circadian clock genes alter the rhythms of the DDR response. However, with some exceptions, the expression of most key clock genes is not importantly affected by bleomycin treatment. Our studies also showed that miss-expression of the photoreceptor CRY2 affects the degree of DSB formation and the transcriptional expression of key DDR response genes including the POLY-(ADP-RIBOSE) POLYMERASE 2 (PARP2) and RAD ASSOCIATED WITH DIABETES 51 (RAD51). The regulation might occur through direct binding as chromatin immunoprecipitation assays revealed the enrichment of CRY2 protein at several key DDR loci including PARP2 and POLY-(ADP-RIBOSE) GLYCOHYDROLASE 1 (PARG1 or TEJ). Proper expression and function of CRY2 is also important for the formation of a particular class of DNA secondary structure or DNA-RNA hybrids known as R-loops. The results connecting CRY2 with DNA-RNA hybrids at the DDR response genes are relevant as R-loops have been previously connected with DSB localization and repairing. By using plants miss-expressing CRY2 we also found that programmed cell death and true leaf emergence in response to DSBs also require proper expression and activity of CRY2. Altogether, our results demonstrate an important role for the circadian clock regulating the timing of the DDR response in Arabidopsis thaliana. This regulation might be relevant for protecting the DNA at a very sensitive time such as during replication, which in several organisms including plants is timed to occur at dusk or during the night. Our studies also suggest that CRY2 function in the DDR response might occur through changes in chromatin compaction and R-loop formation.

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45

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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Abstract (sommario):

Thesis (Ph. D.)--University of California, San Diego, 2009.
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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46

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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47

Bailey, Michael J. "Functional genomics of the avian circadian system". Texas A&M University, 2004. http://hdl.handle.net/1969.1/3318.

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Abstract (sommario):

The genetic identification of molecular mechanisms responsible for circadian rhythm generation has advanced tremendously over the past 25 years. However the molecular identities of the avian clock remain largely unexplored. The present studies seek to determine candidate clock components in the avian species Gallus domesticus. Construction and examination of the transcriptional profiles of the pineal gland and retina using DNA microarray analysis provided a clear view into the avian clock mechanism. Investigation of the pineal and retina transcriptomes determined the mRNA profiles of several thousand genes over the course of one day in LD (daily) and one day in DD (circadian) conditions. Several avian orthologs of mammalian clock genes were identified and many exhibited oscillating patterns of mRNA abundance including several of the putative avian clock genes. Comparison of the pineal transcriptional profile to that of the retina revealed several intriguing candidate genes that may function as core clock components. Including the putative avian clock genes and several others implicated in phototransduction, metabolism, and immune response. A more detailed examination of several candidate photoisomerase/photopigment genes identified from our transcriptional profiling was conducted. These include peropsin (rrh), RGR-opsin (rgr), melanopsin (opn4) and cryptochrome 2 (cry2) genes. This analysis revealed several interesting patterns of mRNA distribution and regulation for these genes in the chick. First, the mRNA of all 4 genes is located within the Inner Nuclear Layer (INL) and Retinal Ganglion cell Layers (RGL) of the ocular retina, where circadian photoreception is present. Second, opn4 and cry2 mRNA is expressed in the photoreceptor layer of the chick retina where melatonin biosynthesis occurs. Lastly, the mRNA for all 4 candidate photopigment genes is regulated on a circadian basis in the pineal gland. As a whole these data yield significant insight into the mechanisms of the avian circadian system and present several candidate genes that may function to integrate photic information, and/or regulate circadian rhythm generation in birds.

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48

Lamba, Pallavi. "Neuronal circuitry controlling circadian photoreception in Drosophila". eScholarship@UMMS, 2017. http://escholarship.umassmed.edu/gsbs_diss/925.

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Abstract (sommario):

Circadian clocks are endogenous timekeeping mechanisms, which give the sense of time-of-day to most organisms. To help the organisms to adapt to daily fluctuations in the environment, circadian clocks are reset by various environmental cues. Light is one of the cardinal environmental cues that synchronize circadian clocks. In a standard 12:12 light-dark condition, Drosophila exhibits bimodal activity pattern in the anticipation of lights-on and -off. The morning peak of activity is generated by Pigment Dispersing Factor (PDF) positive small ventro-lateral neurons (sLNvs) called the M-oscillators, while the evening peak of activity is generated by the dorsolateral neurons (LNds) and the 5th sLNv together referred to as the E-oscillators. Since the Drosophila circadian clock is extremely sensitive to light, a brief light exposure can robustly shift the phase of circadian behavior. The model for this resetting posits that circadian photoreception is cell-autonomous: the photoreceptor CRYPTOCHROME (CRY) senses light, binds to TIMELESS (TIM) and promotes its degradation via JETLAG (JET). However, it was more recently proposed that interactions between circadian neurons are also required for phase resetting. The goal of my thesis was to map the neuronal circuitry controlling circadian photoreception in Drosophila. In the first half of my dissertation (Chapter II), using a novel severe jetset mutant and JET RNAi, we identified M- and E-oscillators as critical light sensing neurons. We also found that JET functions cell-autonomously to promote TIM degradation in M- and E-oscillators, and non-autonomously in E-oscillators when expressed in M-oscillators. However, JET expression was required in both groups of neurons to phase-shift locomotor rhythms in response to light input. Thus M- and E-oscillators cooperate to shift circadian behavior in response to photic cues. In chapter III, unexpectedly, we found that light can delay or advance circadian behavior even when the M- or E-oscillators are genetically ablated or incapacitated suggesting that behavioral phase shifts in response to light are largely a consequence of cell autonomous light detection by CRY and governed by the molecular properties of the pacemaker. Nevertheless, neural interactions are integral in modulating light responses. The M-oscillator neurotransmitter, PDF was important in coordinating M- and E-oscillators for circadian behavioral response to light input. Moreover, we uncover a potential role for a subset of Dorsal neurons in control of phase advances specifically. Hence, neural modulation of cell autonomous light detection contributes to plasticity of circadian behavior and facilitates its adaptation to environmental inputs.

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Abdou, Jeanne Anne. "Circadian rhythm disruption and post-surgical recovery". FIU Digital Commons, 1998. http://digitalcommons.fiu.edu/etd/1252.

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Abstract (sommario):

Circadian rhythms, patterns of each twenty-four hour period, are found in most bodily functions. The biological cycles of between 20 and 28 hours have a profound effect on an individual's mood, level of performance, and physical well being. Loss of synchrony of these biological rhythms occurs with hospitalization, surgery and anesthesia. The purpose of this comparative, correlational study was to determine the effects of circadian rhythm disruption in post-surgical recovery. Data were collected during the pre-operative and post-operative periods in the following indices: body temperature, blood pressure, heart rate, urine cortisol level and locomotor activity. The data were analyzed by cosinor analysis for evidence of circadian rhythmicity and disruptions throughout the six day study period which encompassed two days pre-operatively, two days post-operatively, and two days after hospital discharge. The sample consisted of five men and five women who served as their own pre-surgical control. The surgical procedures were varied. Findings showed evidence of circadian disruptions in all subjects post-operatively, lending support for the hypotheses.

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50

Walmsley, Lauren. "Sensory processing in the mouse circadian system". Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/sensory-processing-in-the-mouse-circadian-system(bd32ea60-48a8-46d4-b5db-dd83d0326d87).html.

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In order to anticipate the predictable changes in the environment associated with the earth’s rotation, most organisms possess intrinsic biological clocks. To be useful, such clocks require a reliable signal of ‘time’ from the external world. In mammals, light provides the principle source of such information; conveyed to the suprachiasmatic nucleus circadian pacemaker (SCN) either directly from the retina or indirectly via other visual structures such as the thalamic intergeniculate leaflet (IGL). Nonetheless, while the basic pathways supplying sensory information to the clock are well understood, the sensory signals they convey or how these are processed within the circadian system are not. One established view is that circadian entrainment relies on measuring the total amount of environmental illumination. In line with that view, the dense bilateral retinal input to the SCN allows for the possibility that individual neurons could average signals from across the whole visual scene. Here I test this possibility by examining responses to monocular and binocular visual stimuli in the SCN of anaesthetised mice. In fact, these experiments reveal that SCN cells provide information about (at most) irradiance within just one visual hemisphere. As a result, overall light-evoked activity across the SCN is substantially greater when light is distributed evenly across the visual scene when the same amount of light is non-uniformly distributed. Surprisingly then, acute electrophysiological responses of the SCN population do not reflect the total amount of environmental illumination. Another untested suggestion has been that the circadian system might use changes in the spectral composition of light to estimate time of day. Hence, during ‘twilight’, there is a relative enrichment of shortwavelength light, which is detectable as a change in colour to the dichromatic visual system of most mammals. Here I used a ‘silent substitution’ approach to selectively manipulate mouse cone photoreception, revealing a subset of SCN neurons that exhibit spectrally-opponent (blue-yellow) visual responses and are capable of reliably tracking sun position across the day-night transition. I then confirm the importance of this colour discrimination mechanism for circadian entrainment by demonstrating a reliable change in mouse body temperature rhythms when exposed to simulated natural photoperiods with and without simultaneous changes in colour. This identification of chromatic influences on circadian entrainment then raises important new questions such as which SCN cell types process colour signals and do these properties originate in the retina or arise via input from other visual regions? Advances in mouse genetics now offer powerful ways to address these questions. Our original method for studying colour discrimination required transgenic mice with red-shifted cone sensitivity – presenting a barrier to applying this approach alongside other genetic tools. To circumvent this issue I validated a modified approach for manipulating wildtype cone photoreception. Using this approach alongside optogenetic cell-identification I then demonstrate that the thalamic inputs to the SCN are unlikely to provide a major source of chromatic information. To further probe IGL-contributions to SCN visual responses, I next used electrical microstimulation to show that the thalamus provides inhibitory input to both colour and brightness sensitive SCN cells. Using local pharmacological inhibition I then show that thalamic inputs supress specific features of the SCN light response originating with the contralateral retina, including colour discrimination. These data thus provide new insight into the ways that arousal signals reaching the visual thalamus could modulate sensory processing in the SCN. Together then, the work described in this thesis provides important new insight into sensory control of the circadian system and the underlying neural mechanisms.

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Tesi sul tema "Circadian"

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