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Damineli, Daniel Santa Cruz. "Synchronization properties of multi-oscillator circadian systems." Doctoral thesis, Universidade Nova de Lisboa. Instituto de Tecnologia Química e Biológica, 2014. http://hdl.handle.net/10362/13561.
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Dissertation presented to obtain the Ph.D degree in Computational BiologyCircadian oscillators are usually regarded as time-keeping mechanisms that can synchronize to environmental cycles (zeitgebers) and coordinate the timing of virtually all aspects of organismal function. Circadian pacemakers would be the main time-keepers that synchronize to light/dark cycles and convey temporal information to peripheral oscillators. However, the idea of circadian systems as being simple clocks is challenged by the coexistence, within the same organism, of multiple circadian oscillators with diverse synchronization strategies.(...)
Fundação para a Ciência e a Tecnologia (FCT)
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Locke, James C. W. "A systems biology approach to the Arabidopsis circadian clock." Thesis, University of Warwick, 2006. http://wrap.warwick.ac.uk/58550/.
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Circadian clocks involve feedback loops that generate rhythmic expression of key genes. Molecular genetic studies in the higher plant Arabidopsis theliene have revealed a complex clock network. We begin by modelling the first part of the Arabidopsis clock network to be identified, a transcriptional feedback loop comprising TIMING OF CAB EXPRESSION 1 (TOCl), LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED 1 (CCA1). As for many biological systems, there are no experimental values for the parameters in our model, and the data available for parameter fitting is noisy and varied. To tackle this we construct a cost function, which quantifies the agreement between our model and various key experimental features. We then undertake a global search of parameter space, to test whether the proposed circuit can fit the experimental data. Our optimized solution for the Arabidopsis clock model is unable to account for significant experimental data. Thanks to our search of parameter space, we are able to interpret this as a failure of the network architecture. We develop an extended clock model that is based upon a wider range of data and accurately predicts additional experimental results. The model comprises two interlocking feedback loops comparable to those identified experimentally in other circadian systems. We propose that each loop receives input signals from light, and that each loop includes a hypothetical component that had not been explicitly identified. Analysis of the model predicts the properties of these components, including an acute light induction at dawn that is rapidly repressed by LHY and CCAL We find this unexpected regulation in RNA levels of the evening-expressed gene GIGANTEA (GI), supporting our proposed network and making GI a strong candidate for this component. We go on to develop reduced models of the Arabidopsis clock to aid conceptual understanding, and add a further proposed feedback loop to develop a 3-loop model of the circadian clock. This 3-loop model is able to reproduce further key experimental data.
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Brager, Allison Joy. "Roles of the circadian and reward systems in alcoholism." Kent State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=kent1306869438.
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Ton, That Long. "Nonlinear control studies for circadian models in system biology." Thesis, University of Manchester, 2011. https://www.research.manchester.ac.uk/portal/en/theses/nonlinear-control-studies-for-circadian-models-in-system-biology(f616f360-99e4-4314-ba51-be7a49e9ff0e).html.
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Circadian rhythms exist in almost all of living species, and they occupy an important role in daily biological activities of these species. This thesis deals with reduction of measurements in circadian models, and recovery of circadian phases. Two mathematical models of circadian rhythms are considered, with a 3rd order model for Neurospora, and a 7th order model for Mammals. The reduction of measurements of circadian models is shown by the proposals of observer designs to the two mathematical models of circadian rhythms. Both mathematical models contain strong nonlinearities, which make the observer design challenging. Two observer designs, reduced-order and one-sided Lipschitz, are applied to the circadian models to tackle the nonlinearities. Reduced-order observer design is based on a state transformation to make certain nonlinearities have no impact on the observer errors, and the design of one-sided Lipschitz observer is based on systems with one-sided Lipschitz nonlinearities. Both observer designs are based on the existing methods in literature. The existing method of reduced-order observer has been applied to a class of multi-output nonlinear systems. A new reduced-order observer design which extends the existing one in literature is presented in this thesis. In this new reduced-order observer method, the observer error dynamics can be designed by choosing the observer gain, unlike the existing one, of which the observer error dynamics depend on the invariant zeros under certain input-output map. The recovery of circadian phases is carried out to provide a solution to phase shifts occurred in circadian disorders. The restoration of circadian phases is performed by the synchronizations of trajectories of a controlled model with trajectories of a reference model. The reference model and the controlled model have phase differences, and both these models are based on a given 3rd order model of Neurospora circadian rhythms. The phase differences are reflected by different initial conditions, and by parameter uncertainty. The synchronizations of the two models are performed by using back-stepping method for the case of different initial conditions, and by using adaptive back-stepping method for the remaining case. Several simulation studies of the proposed observer designs and the proposed schemes of synchronizations are carried out with the results shown in this thesis.
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Pearson, Kristen A. "Circadian rhythms, fatigue, and manpower scheduling." Thesis, Monterey, Calif. : Springfield, Va. : Naval Postgraduate School ; Available from National Technical Information Service, 2004. http://library.nps.navy.mil/uhtbin/hyperion/04Dec%5FPearson.pdf.
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Trané, Camilla. "Robustness Analysis of Intracellular Oscillators with Application to the Circadian Clock." Licentiate thesis, KTH, Automatic Control, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-4815.
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Periodic oscillations underlie many intracellular functions, such as circadian time keeping, cell cycle control and locomotor pattern generation in nerve cells. These intracellular oscillations are generated in intricate biochemical reaction networks involving genes, proteins and other biochemical components. In most cases, robust oscillations are of pivotal importance for the organism, i.e., the oscillations must be maintained in the presence of internal and external perturbations.
Model based analysis of robustness in intracellular oscillators has attracted considerable attention in recent years. The analysis has almost exclusively been based on either complete removal of network components, e.g., single genes, or perturbation of model parameters. In this thesis, a control theoretic approach to analyze structural robustness of intracellular oscillators is proposed. The method is based on adding dynamic perturbations to the network interactions. Determination of the smallest perturbation translating the underlying steady-state into a Hopf bifurcation point is used to quantify the robustness. The method can be used to determine critical substructures within the overall network and to identify specific network fragilities. Also, an approach to nonlinear model reduction based on the robustness analysis is proposed.
The proposed robustness analysis method is applied to elucidate mechanisms underlying robust oscillations in circadian clocks. Circadian clocks, molecular oscillators generating 24 hour rhythms in many organisms, are known to display a striking robustness towards internal and external perturbations. The underlying networks involve a large number of genes that are transcribed into mRNA which produce proteins subsequently regulating the activity of other genes, together forming an intricate network with a large number of embedded feedback loops. An often recurring hypothesis is that the interlocked feedback loop structure of circadian clocks serves the purpose of robustness. From analysis of several recently published models of circadian clocks, it is found in this thesis that the robustness of circadian clocks primarily results from a high gain in a single gene regulatory feedback loop generating the oscillations. This gain can be elevated by additional feedback loops, involving either gene regulation or post-translational feedback, but a similar robustness can be achieved by simply increasing the amplification within the master feedback loop.
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Bellman, Jacob. "Phase Response Optimization of the Circadian Clock in Neurospora crassa." University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1459438726.
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Jin, Junyang. "Novel methods for biological network inference : an application to circadian Ca2+ signaling network." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/285323.
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Biological processes involve complex biochemical interactions among a large number of species like cells, RNA, proteins and metabolites. Learning these interactions is essential to interfering artificially with biological processes in order to, for example, improve crop yield, develop new therapies, and predict new cell or organism behaviors to genetic or environmental perturbations. For a biological process, two pieces of information are of most interest. For a particular species, the first step is to learn which other species are regulating it. This reveals topology and causality. The second step involves learning the precise mechanisms of how this regulation occurs. This step reveals the dynamics of the system. Applying this process to all species leads to the complete dynamical network. Systems biology is making considerable efforts to learn biological networks at low experimental costs. The main goal of this thesis is to develop advanced methods to build models for biological networks, taking the circadian system of Arabidopsis thaliana as a case study. A variety of network inference approaches have been proposed in the literature to study dynamic biological networks. However, many successful methods either require prior knowledge of the system or focus more on topology. This thesis presents novel methods that identify both network topology and dynamics, and do not depend on prior knowledge. Hence, the proposed methods are applicable to general biological networks. These methods are initially developed for linear systems, and, at the cost of higher computational complexity, can also be applied to nonlinear systems. Overall, we propose four methods with increasing computational complexity: one-to-one, combined group and element sparse Bayesian learning (GESBL), the kernel method and reversible jump Markov chain Monte Carlo method (RJMCMC). All methods are tested with challenging dynamical network simulations (including feedback, random networks, different levels of noise and number of samples), and realistic models of circadian system of Arabidopsis thaliana. These simulations show that, while the one-to-one method scales to the whole genome, the kernel method and RJMCMC method are superior for smaller networks. They are robust to tuning variables and able to provide stable performance. The simulations also imply the advantage of GESBL and RJMCMC over the state-of-the-art method. We envision that the estimated models can benefit a wide range of research. For example, they can locate biological compounds responsible for human disease through mathematical analysis and help predict the effectiveness of new treatments.
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Carignano, Alberto. "Genome wide analysis of differentially expressed systems : an application to circadian networks." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708703.
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Urquiza, García José María Uriel. "Mathematical model in absolute units for the Arabidopsis circadian oscillator." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31132.
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The Earth’s oblique rotation results in changes in light and temperature across the day and time of year. Living organisms evolved rhythmic behaviours to anticipate these changes and execute appropriate responses at particular times. The current paradigm for the biological clocks in several branches of life is an underlying biochemical oscillator mainly composed by a network of repressive transcription factors. The slow decay in their activity is fundamental for generating anticipatory dynamics. Interestingly, these dynamics can be well appreciated when the biological system is left under constant environmental conditions, where oscillation of several physiological readouts persists with a period close to 24 hours, hence the term “circadian clocks”, circa=around dian=day. In plants the model species Arabidopsis thaliana has served as an invaluable tool for analysing the genetics, biochemical, developmental, and physiological effects of the oscillator. Many of these experimental results have been integrated in mechanistic and mathematical theories for the circadian oscillator. These models predict the timing of gene expression and protein presence in several genetic backgrounds and photoperiodic conditions. The aim of this work is the introduction of a correct mass scale for both the RNA transcript and protein variables of the clock models. The new mass scale is first introduced using published RNA data in absolute units, from qRT-PCR. This required reinterpreting several assumptions of an established clock model (P2011), resulting in an updated version named U2017. I evaluate the performance of the U2017 model in using data in absolute mass units, for the first time for this clock system. Introducing absolute units for the protein variables takes place by generating hypothetical protein data from the existing qRT-PCR data and comparing a data-driven model with western blot data from the literature. I explore the consequences of these predicted protein numbers for the model’s dynamics. The process required a meta-analysis of plant parameter values and genomic information, to interpret the biological relevance of the updated protein parameters. The predicted protein amounts justify, for example, the revised treatment of the Evening Complex in the U2017 model, compared to P2011. The difficulties of introducing absolute units for the protein components are discussed and components for experimental quantification are proposed. Validating the protein predictions required a new methodology for absolute quantification. The methodology is based on translational fusions with a luciferase reporter than has been little used in plants, NanoLUC. Firstly, the characterisation of NanoLUC as a new circadian reporter was explored using the clock gene BOA. The results show that this new system is a robust, sensitive and automatable approach for addressing quantitative biology questions. I selected five clock proteins CCA1, LHY, PRR7, TOC1 and LUX for absolute quantification using the new NanoLUC methodology. Functionality of translation fusions with NanoLUC was assessed by complementation experiments. The closest complementing line for each gene was selected to generate protein time series data. Absolute protein quantities were determined by generation of calibration curves using a recombinant NanoLUC standard. The developed methodology allows absolute quantification comparable to the calibrated qRT-PCR data. These experimental results test the predicted protein amounts and represent a technical resource to understand protein dynamics of Arabidopsis’ circadian oscillator quantitatively. The new experimental, meta-analysis and modelling results in absolute units allows future researchers to incorporate further, quantitative biochemical data.
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Keily, Jack. "The systems biology of the circadian control of freezing tolerance in Arabidopsis thaliana." Thesis, University of Exeter, 2012. http://hdl.handle.net/10871/14265.
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The Arabidopsis thaliana circadian clock is involved in regulating several plant systems including light signalling, germination and the cold signalling pathway. The role of the circadian clock in regulating far-red and red light induced dormancy and germination, however, is not well understood. In this thesis it is shown that the circadian clock does not seem to be involved in regulating far-red light induction of dormancy, but that the TIMING OF CAB EXPRESSION 1 (TOC1) gene is vital for red light induced germination to occur. In Arabidopsis thaliana, the transcription factors, C-REPEAT BINDING FACTORs (CBFs) are key components of the cold acclimation pathway. The expression of the CBFs has recently been shown to be regulated by the circadian clock; however, our understanding of how the CBFs are regulated by the clock is far from complete. In the main focus of this thesis a systems biology approach was utilised to try and better understand the circadian regulation of plant cold responses, specifically the manner by which the circadian clock regulates the cold acclimation pathway C-REPEAT BINDING FACTOR 3 (CBF3) gene. Freezing tolerance assays were carried out to increase our knowledge of the clock regulation of the cold signalling pathway. Circadian clock mutant lines without previously reported freezing tolerance phenotypes were identified in the TOC1 mutant, toc1-101, and the EARLY FLOWERING 3 (ELF3) and LUX ARRHYTHMO (LUX) mutants elf3-1 and lux. The freezing assay data was used to influence model designs for the circadian regulation of CBF3 expression. Several potential models of CBF3 regulation were created. The models were then optimised against publically available microarray gene expression data. Model selection using a Corrected Akaike Information Criterion (AICc) was utilised to establish models that best fit biological data. Predictions made by the models were then tested, thus leading to the establishment of new circadian clock mechanisms of CBF3 being discovered. 4 The modelling procedure predicted the involvement of the Evening Complex (EC) and TOC1 in regulating CBF3 expression as well as the already reported regulation by LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED1 (CCA1); the PSEUDO-RESPONSE REGULATORS (PRRs) which had been predicted as direct regulators of the CBFs were not needed to produce correct CBF3 expression in any of the potential models. The direct TOC1 and Evening Complex regulation of CBF3 promotion was then confirmed by chromatin immunoprecipitation.
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Wilkins, Anna Katharina. "Sensitivity analysis of oscillating dynamical systems with applications to the mammalian circadian clock." Thesis, Massachusetts Institute of Technology, 2008. http://hdl.handle.net/1721.1/42944.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2008.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.
Includes bibliographical references (p. 227-234).
The work presented in this thesis consists of two major parts. In Chapter 2, the theory for sensitivity analysis of oscillatory systems is developed and discussed. Several contributions are made, in particular in the precise definition of phase sensitivities and in the generalization of the theory to all types of autonomous oscillators. All methods rely on the solution of a boundary value problem, which identifies the periodic orbit. The choice of initial condition on the limit cycle has important consequences for phase sensitivity analysis, and its influence is quantified and discussed in detail. The results are exact and efficient to compute compared to existing partial methods. The theory is then applied to different models of the mammalian circadian clock system in the following chapters. First, different types of sensitivities in a pair of smaller models are analyzed. The models have slightly different architectures, with one having an additional negative feedback loop compared to the other. The differences in their behavior with respect to phases, the period and amplitude are discussed in the context of their network architecture. It is found that, contrary to previous assumptions in the literature, the additional negative feedback loop makes the model less "flexible" in at least one sense that was studied here. The theory was also applied to larger, more detailed models of the mammalian circadian clock, based on the original model of Forger and Peskin. Between the original model's publication in 2003 and the present time, several key advances were made in understanding the mechanistic detail of the mammalian circadian clock, and at least one additional clock gene was identified. These advances are incorporated in an extended model, which is then studied using sensitivity analysis. Period sensitivity analysis is performed first and it was found that only one negative feedback loop dominates the setting of the period.
(cont.) This was an interesting one-to-one correlation between one topological feature of the network and a single metric of network performance. This led to the question of whether the network architecture is modular, in the sense that each of the several feedback loops might be responsible for a separate network function. A function of particular interest is the ability to separately track "dawn" and "dusk", which is reported to be present in the circadian clock. The ability of the mammalian circadian clock to modify different relative phases --defined by different molecular events -- independently of the period was analyzed. If the model can maintain a perceived day -- defined by the time difference between two phases -- of different lengths, it can be argued that the model can track dawn and dusk separately. This capability is found in all mammalian clock models that were studied in this work, and furthermore, that a network-wide effort is needed to do so. Unlike in the case of the period sensitivities, relative phase sensitivities are distributed throughout several feedback loops. Interestingly, a small number of "key parameters" could be identified in the detailed models that consistently play important roles in the setting of period, amplitude and phases. It appears that most circadian clock features are under shared control by local parameters and by the more global "key parameters". Lastly, it is shown that sensitivity analysis, in particular period sensitivity analysis, can be very useful in parameter estimation for oscillatory systems biology models. In an approach termed "feature-based parameter fitting", the model's parameter values are selected based on their impact on the "features" of an oscillation (period, phases, amplitudes) rather than concentration data points. It is discussed how this approach changes the cost function during the parameter estimation optimization, and when it can be beneficial.
(cont.) A minimal model system from circadian biology, the Goodwin oscillator, is taken as an example. Overall, in this thesis it is shown that the contributions made to the theoretical understanding of sensitivities in oscillatory systems are relevant and useful in trying to answer questions that are currently open in circadian biology. In some cases, the theory could indicate exactly which experiments or detailed mechanistic studies are needed in order to perform meaningful mathematical analysis of the system as a whole. It is shown that, provided the biologically relevant quantities are analyzed, a network-wide understanding of the interplay between network function and topology can be gained and differences in performance between models of different size or topology can be quantified.
by Anna Katharina Wilkins.
Ph.D.
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Pett, Jan Patrick. "Systems level generation of mammalian circadian rhythms and its connection to liver metabolism." Doctoral thesis, Humboldt-Universität zu Berlin, 2019. http://dx.doi.org/10.18452/19960.
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Circadiane Uhren sind endogene Oszillatoren, die 24-Stunden Rhythmen erzeugen. Sie erlauben Organismen deren Physiologie und Verhalten an tägliche Änderungen der Umwelt anzupassen. In Säugetieren basieren solche Uhren auf transkriptional-translationalen Rückkopplungsschleifen, aber es ist noch nicht ganz verstanden, welche Schleifen zur Erzeugung von Rhythmen beitragen. Eine der physiologischen Schlüsselfunktionen von cirkadianen Uhren scheint die zeitliche Anordnung von metabolischen Prozessen zu sein. Im ersten Projekt haben wir eine Methode eingeführt, um systematisch Regulationen in einem datengetriebenen mathematischen Modell der Kernuhr zu testen. Überraschenderweise haben wir ein Rückkopplungsmotif entdeckt, das vorher noch nicht im Zusammenhang mit der circadianen Uhr in Säugetieren in Betracht gezogen wurde. Dieser Repressilator ist mit Gen-knockout Studien und weiteren Perturbationsexperimenten konsistent. Im zweiten Projekt haben wir das Modell wiederholt auf gewebespezifische Datensätze gefitted und essentielle Rückkopplungen in allen Modellversionen identifiziert. Interessanterweise fanden wir dabei für alle gewebespezifischen Datensätze Synergien von Rückkopplungen, die zusammen Rhythmen erzeugen. Desweiteren haben wir festgestellt, dass die Synergien sich abhängig vom Gewebe unterscheiden. Im dritten Projekt haben wir die circadianen Aspekte des Metabolismus untersucht. Wir haben circadiane Komponenten in verschiedenen omics Studien identifiziert, integriert und auf ein metabolisches Netzwerk gemapped. Unsere Analyse hat bestätigt, dass viele Stoffwechselwege vermutlich circadianen Rhythmen folgen. Interessanterweise haben wir festgestellt, dass die durchschnittlichen Phasen von rhythmischen Komponenten sich zwischen verschiedenen Stoffwechselwegen unterscheiden. Solche Unterschiede könnten eine zeitliche Anpassung metabolischer Funktionen an Zeiten darstellen zu denen sie gebraucht werden.Circadian clocks are endogenous oscillators that generate 24-hour rhythms. They allow many organisms to synchronize their physiology and behaviour with daily changes of the environment. In mammals such clocks are based on transcriptional-translational feedback loops, however, it is not fully understood which feedback loops contribute to rhythm generation. Within an organism different clocks are distinguished by their localization in different organs. One of the key physiological functions of circadian clocks in various organs seems to be the temporal alignment of metabolic processes. In the first project we introduced and applied a method to systematically test regulations in a data-driven mathematical model of the core clock. Surprisingly, we discovered a feedback loop that has previously not been considered in the context of the mammalian circadian clock. This repressilator is consistent with knockout studies and further perturbation experiments. It could constitute an explanation for different phases observed between Cryptochromes, which are part of the core clock. In the second project we repeatedly fitted the same mathematical model to tissue-specific data sets and identified essential feedback loops in all model versions. Interestingly, for all tissue-specific data sets we found synergies of loops generating rhythms together. Further, we found that the synergies differ depending on the tissue. In the third project we examined the circadian aspects of metabolism. We identified rhythmic data in different omics studies, integrated and mapped them to a metabolic network. Our analysis confirmed that many metabolic pathways may follow circadian rhythms. Interestingly, we also found that the average peak times of rhythmic components between various pathways differ. Such differences might reflect a temporal alignment of metabolic functions to the time when they are required.
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Campbell, Colleen Elizabeth. "Intersection of the Hypocretin and Serotonin Neural Systems." Kent State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=kent1185720576.
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Tseng, Yu-Yao. "Systems biology of the Neurospora circadian clock and its response to light and temperature." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/systems-biology-of-the-neurospora-circadian-clock-and-its-response-to-light-and-temperature(4680ee43-3f65-4398-bc79-bac70d463e58).html.
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Circadian clocks are internal timekeepers that aid survival by allowing organisms, from photosynthetic cyanobacteria to humans, to anticipate predictable daily changes in the environment and make appropriate adjustments to their cellular biochemistry and behaviour. Whilst many of the molecular cogs and gears of circadian clocks are known, the complex interactions of clock components in time and space that generate a reliable internal measure of external time are still under investigation. Computational modelling has aided our understanding of the molecular mechanisms of circadian clocks, nevertheless it remains a major challenge to integrate the large number of clock components and their interactions into a single, comprehensive model that is able to account for the full breadth of clock properties. An important property of circadian clocks is their ability to maintain a constant period over a range of temperatures. Temperature compensation of circadian period is the least understood characteristic of circadian clocks. To investigate possible mechanisms underlying temperature compensation, I first constructed a comprehensive dynamic model of the Neurospora crassa circadian clock that incorporates its key components and their transcriptional and post-transcriptional regulation. The model is based on a compilation of published and new experimental data and incorporates facets of previously described Neurospora clock models. Light components were also incorporated into the model to test it and to reproduce our knowledge of light response of the clock. Also, experiments were carried out to investigate the unknown mechanisms of light response, such as the molecular mechanisms supporting the correct timing of conidiation after light to dark transfer. The model accounts for a wide range of clock characteristics including: a periodicity of 21.6 hours, persistent oscillation in constant conditions, resetting by brief light pulses, and entrainment to full photoperiods. Next, I carried out robustness tests and response coefficient analysis to identify components that strongly influence the period and amplitude of the molecular oscillations. These data measure the influence of the parameters in the model and were beneficial for making and testing predictions in the model. Thermodynamic properties were then introduced into reactions that experimental observations suggested might be temperature sensitive. This analysis indicated that temperature compensation can be achieved if nuclear localisation of a key clock component, FRQ, decreases with increasing temperature. Experiments have been carried out to validate this hypothesis and simulations were made to explore other possible mechanisms. However, from my experimental data and modelling results, the restriction of FRQ nuclear localisation might not be the only mechanism required to achieve temperature compensation. In conclusion, temperature compensation is most likely a complex property and may involve a combination of multiple mechanisms regulating clock component activity over a range of temperatures.
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Bohn, Andreas. "Analysis and Simulation of Circadian Multi-Oscillator Systems in a Crassulacean Acid Metabolism Plant." Phd thesis, [S.l. : s.n.], 2003. http://tuprints.ulb.tu-darmstadt.de/367/1/abohn_dr_1.pdf.
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Crassulacean acid metabolism (CAM) is an adaptation of photosynthetic organisms to drought stress: improved water-use efficiency is achieved by an optimized temporal arrangement of photosynthetic subprocesses, which are driven by an endogenous pacemaker, i.e. a circadian clock. The present work deals with the hypothesis that the circadian rhythm of gas-exchange of entire leaves of the CAM plant Kalanchoë daigremontiana has to be understood as the collective signal of the population of cells in the leaf. In this multi-oscillator picture, certain features of the whole-leaf rhythm can be understood as a desynchronization of the population due to noise and synchronization due to common environmental stimuli, respectively. This hypothesis is checked by comparison of numerical simulations of uncoupled populations of two different phenomenological models of circadian rhythms to experimental data obtained from monitoring the spatio-temporal metabolic dynamics in the leaf by means of chlorophyll-fluorescence imaging. The comparison shows that the features of the whole-leaf rhythm are also exhibited by each individual cell, hence the predicted emergence of new effects at the population level cannot be confirmed. Further spatio-temporal analyses and simulations suggest that pattern formation and the appearance of synchronized clusters in the leaf are induced by spatially heterogeneous fluctuations of environmental parameters. A further focus of interest is on the analysis of multi-variate time-series of whole-leaf gas exchange. Comparison of numerical simulations based on a physiological model of CAM to experimental data suggests that circadian rhythm generation cannot be understood by considering a single pacemaker situated at the metabolic level. Rather, evidence is presented that the observable rhythms are the output of a functional network of multiple original oscillators, situated at multiple levels from gene expression to stomatal guard cells. Future work, both experimental and numerical, is proposed to address questions of pattern formation by spatial heterogeneity, as well as unraveling the network structure of circadian rhythm generation in CAM.
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Wang, Haifang [Verfasser]. "Studying the regulation and development of circadian clock by systems biology approaches / Haifang Wang." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2020. http://d-nb.info/1218299282/34.
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SILVERI, GIULIA. "Analysis of the circadian rhythm of cardiovascular signals and their prognostic use in decision support systems." Doctoral thesis, Università degli Studi di Trieste, 2021. http://hdl.handle.net/11368/2982152.
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The focus of my research activity has been on the processing of cardiovascular signals in order to be able to use them as a support tool for doctors in their clinical decision making. Although the analysis of these cardiovascular signals has mainly been based on the punctual estimation of blood pressure and heart rate parameters, it is well known that the outpatient information, obtained from the 24h ambulatory monitoring, can provide prognostic support. Therefore I have tried to examine in detail how the values of the parameters related to blood pressure and heart rate over 24h change and how the relationship between them varies. Since the cardiovascular risk factors alter the trend of these biological signals, I have performed an analysis of the effects of each single risk factors on the circadian trend of the two signals and their relationship. Since, in recent years, mathematical approaches have been developed for the construction of clinical decision support systems applied, in the cardiovascular field, only to the classification of single heart beats of different etiologies; I have developed decision support systems to identify subjects with or without cardiovascular diseases. The pathologies examined were ischemic heart (IHD) and dilated cardiomyopathy (DCM). The described problems have been addressed using linear and nonlinear methods of signal processing and applying artificial intelligence algorithms. The average circadian trends of pressure and heart rate and their relationship on different categories of subjects were obtained. The linear and non-linear parameters were calculated from the heart rate variability signal and machine learning techniques were developed, the Artificial Neural Network (ANN) and Classification and Regression Tree (CART), applied to the previous parameters in addition to age, gender and to a specific clinical parameter. The results showed that the cardiovascular signals over 24h show a characteristic linear circadian rhythm divisible into four time intervals for the pressure signal (three intervals for the heart rate) in both normotensive and hypertensive subjects highlighting the importance of taking into account the time of day in which the signal is measured. The relationship between these two signals evaluated over 24h could be useful for understanding the control mechanism of the autonomic nervous system. The examination of the effects of risk factors such as smoking, obesity and dyslipidemia on cardiovascular signals showed that each factor modifies the physiological signals. The investigation of the influence of age and gender on cardiovascular signals highlighted an inversion of the trend in linear and non-linear parameters of heart rate variability in subjects>60 years of age and a gender differentiation only during the night. Finally, the results obtained by developing decision support systems based on machine learning techniques applied to various combinations of parameters, selected through principal component analysis, stepwise regression or correlated for less than 90%, showed that the ANN technique identify normal subjects and IHD with an accuracy of 80% and that the CART algorithm classify DCM patients with an accuracy of 97%. The latter technique was also able to distinguish these two etiologies from each other and from normal subjects with an accuracy of 81%. The results of my PhD activity highlight the importance of circadian analysis of cardiovascular signals, suggesting that particular attention should be paid to the time in which the measurements are performed providing useful information for the evaluation of the mechanisms that regulate the physiological control of the examined signals. Furthermore, the use of decision support systems based on machine learning techniques applied to parameters obtained in a non-invasive way from the processing of the heart rate variability is useful for diagnosing various cardiovascular diseases.
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Smith, Robert William. "Mathematical modelling of photoperiodic external coincidence mechanisms in the model plant, Arabidopsis thaliana." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/11734.
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As plants are sessile organisms, processes controlling plant growth and development must react to fluctuations in the external environment to aid plant survival. However, as the climate of the Earth changes and becomes more extreme, plants become less able to develop to their optimal capacity and this can have an adverse effect on crop yield and biofuel feedstock production. Thus, it is becoming increasingly important to understand the molecular mechanisms used by plants to respond to external stimuli. One important system that plants utilise in their response to environmental fluctuations is the circadian clock. The circadian clock is a time-measuring device that buffers the timing of plant growth and development against fluctuations in the local environment, such as temperature, light quality and light intensity. Importantly, the circadian clock is also able to measure day-length (photoperiod). Thus, plant development and growth is co-ordinated with photoperiod that is closely linked to seasonal changes. A key example of this is the time taken for a plant to flower. Flowering of Arabidopsis thaliana occurs specifically in long-days (LDs) of spring/summer months. Thus, the circadian clock is a key regulator promoting flowering in LD conditions. In conjunction with experimental studies, mathematical modelling has proven to be a successful method of elucidating the mechanisms that underlie complex biological systems. One example of this 'systems biology' approach is in uncovering the components that make up the Arabidopsis circadian clock mechanism. Previous research in our group has also led to the development of a model describing photoperiodic flowering that is tentatively linked to the circadian clock mechanism. In this thesis I shall develop on these models to highlight five key results: 1. using rhythmic PHYTOCHROME INTERACTING FACTOR 4 (PIF4) and PIF5 mRNA as an example, I shall show that multiple circadian regulators are required to describe rhythmic transcription of target genes across multiple photoperiods; 2. the stabilisation of CONSTANS (CO) protein by the blue light-signalling component FLAVIN-BINDING, KELCH REPEAT, F-BOX 1 (FKF1) is required to for flowering in LDs and has a relatively larger impact on photoperiodic flowering than FKF1-dependent degradation of CYCLING DOF FACTOR 1 (CDF1), an inhibitor of flowering; 3. multiple components of the circadian clock play specific post-translational roles in photoperiodic flowering to promote the acceleration of flowering specifically in LDs; 4. temperature regulation of photoperiodic flowering can be explained through an interaction between CO and PIF proteins, limiting the effects of temperature to a specific time-window in a 24-hour day; 5. red light- and temperature-control of the circadian clock can be explained by altering the post-translational regulation of circadian clock components.
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Bain, Evelyn Louisa. "The physics of biological systems : Part (i), The circadian systems of neurospora crassa; Part (ii), The diffusion of proteins in biological membranes." Thesis, University of Warwick, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404831.
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Sarout, Bruna Nunes Marsiglio. "Behavioural circadian rhythms : a novel approach to monitor sheep in extensive systems and study the differences between beef steers for methane emission, feed efficiency and growth." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2017. http://hdl.handle.net/10183/164375.
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As tecnologias baseadas em sensores estão cada vez mais disponíveis e podem ser usadas para coletar informações detalhadas sobre o comportamento animal. Com esta informação é possível avaliar o ritmo circadiano de variáveis comportamentais e monitorar sua resposta. A identificação de variações na resposta deste ritmo tem o potencial de detectar problemas de saúde e questões de bem-estar animal. O objetivo deste trabalho foi estudar os ritmos circadianos comportamentais como uma nova abordagem para monitorar ovelhas em sistemas extensivos e estudar a emissão de metano, eficiência alimentar e crescimento de novilhos de corte. Este trabalho foi composto por dois experimentos (ovinos e bovinos). Foram utilizados cochos automatizados e sensores de atividade baseados em acelerômetro para coletar informações detalhadas do comportamento ingestivo (bovinos) e do comportamento de atividade (ovinos e bovinos), juntamente com as características de desempenho animal. Estes dados foram utilizados para calcular a percentagem de comportamento cíclico harmônico/sincronizado a cada período de 24 h. Essa porcentagem é chamada de grau de acoplamento funcional (DFC) e é calculada com uso de um período móvel de sete dias. No experimento com ovinos, um total de 29 ovelhas Scottish Blackface foram monitoradas por quatro semanas em cada estação do ano, em sistema extensivo nas terras altas da Escócia. Dados meteorológicos foram coletados diariamente. Modelos estatísticos de regressão com efeito aleatório foram utilizados para avaliar a variação da resposta entre indivíduos. Houve uma forte dinâmica criada pelas estações do ano e pelo ciclo produtivo/fisiológico das ovelhas. Durante a primavera e o verão, o desvio padrão do DFC foi um melhor estimador do ganho de peso quando comparado ao índice de moção. A combinação da análise do DFC e o agrupamento de indivíduos com base em sua resposta às variáveis ambientais oferece potencial para obter informações relevantes para o manejo do rebanho. O experimento de bovinos foi conduzido com duas dietas contrastantes (volumoso: concentrado 8:92 e 50:50) e duas raças (40 mestiços Charolês e 40 Luing). Os padrões diurnos de ingestão e atividade foram altamente sincronizados. O ritmo circadiano da atividade foi importante para explicar as diferentes emissões de metano entre indivíduos, independente da raça ou dieta, e também teve ligação com a eficiência alimentar e o crescimento dos novilhos. Este trabalho mostra a importância dos ritmos circadianos comportamentais e como essas abordagens podem melhorar a qualidade e o significado dos dados provenientes de sensores automatizados.Sensor-based technologies are becoming increasingly available and can be used to gather detailed information about animal behaviour. With this information it is possible to assess animal behavioural circadian rhythm and monitor its response. Identifying breakdowns of this rhythm has the potential to detect health problems and animal welfare issues. The aim of this work was to study the behavioural circadian rhythms as a novel approach to monitor sheep in extensive systems and to study the differences between beef steers production traits, in methane emission, feed efficiency and growth. This work consisted of two experiments, one dealing with sheep in an extensive system and the other with housed beef steers. Automated feed intake equipment and accelerometer-based activity sensors were used to collect detailed information on feed intake (for cattle) and activity behaviour (for sheep and cattle), alongside animal performance characteristics. These data were used to calculate the percentage of cyclic behaviour that is harmonic/synchronized to each 24 h period as Degree of Functional Coupling (DFC) shown within rolling seven day periods. In the sheep experiment, in total twenty-nine Scottish Blackface ewes were monitored for four consecutive weeks in each season across a full year, in an extensive system on Scottish upland pastures. Weather data were collected daily. Random regression statistical models were used to assess between-individual variation in response to the weather. There was a strong dynamic created by the seasons and by the production and physiological cycle in sheep in these high latitude systems. Over the spring and summer period, the variation in the response of DFC was a better estimator of BWG (Body Weight Gain) than the use of a simple motion index. The combination of circadian rhythm analysis and the clustering of individuals into groups based around their regression response to environmental variables provides considerable potential to glean information relevant for group and individual animal management. The cattle experiment was conducted with two contrasting diets (concentrate-based and mixed diet) and two breeds (40 crossbred Charolais and 40 purebred Luing). The diurnal patterns of feeding and activity behaviours were strong and highly synchronised. Activity rhythmicity was well suited to show up differences between individual methane emissions independent of breed or diet, and it was also well related to important production traits as feed efficiency and growth of beef steers. This work shows the importance of the behavioural circadian rhythms and that these approaches may enhance the quality and meaningfulness of data coming from automated sensors.
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El, Cheikh Raouf. "Multiscale modeling for the regulation of cell cycle by the circadian clock : applications to chronotherapy." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10082/document.
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Cette thèse est dédiée au développement d’un modèle mathématique multi-échelle pour la régulation du cycle cellulaire par l’horloge circadienne. Ceci est motivé par le fait que plusieurs études ont montré un lien direct entre certains cancers et un dysfonctionnement du mécanisme de l’horloge circadienne. Le but est de comprendre l’effet des rythmes circadiens et leur perturbation sur la prolifération d’une population de cellulesThis thesis is dedicated to the development of a multiscale mathematical model that describes the regulation of the cell cycle by the circadian clock. What motivated this work is the fact that several tumorigenic diseases are linked to circadian rhythms disruption. We would like to understand the effect of circadian rhythms on the proliferation of a cell population and hence give plausible explanation for diseases that arise form circadian clock disruption. The mammalian cell cycle and the circadian clock are two molecular processes that operate in a rhythmic manner and exquisite precision. On one hand, the cell cycle is driven by the rhythmic activity of cyclin dependent kinases which dictate the time a cell must engage mitosis and the time it must divide giving birth to two daughter cells. On the other hand, the circadian clock is a system of transcriptional and translational feedback-loops that generates sustained oscillations of different mRNAs and proteins with a period of approximately 24 h. It turns out that several components of the circadian clock regulates various cyclin-dependent kinases at different stages of the cell cycle. This makes the circadian clock a key player of the temporal organization of the cell cycle and makes these two biological processes act as two tightly coupled oscillators. Our modeling approach consists of using a molecular-structured partial differential equation that describes the proliferation of a cell population. Proliferation depends on the coupled cell cycle-circadian clock molecular state of cells. Due to the large number of molecular components involved in the cell cycle-circadian clock system, the problem becomes of high-dimensionality and specific numerical techniques are needed to solve the equation
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DI, MAURO Giuseppe. "Evolution of UV-photoreception and DNA repair systems in blind cavefish." Doctoral thesis, Università degli studi di Ferrara, 2019. http://hdl.handle.net/11392/2488148.
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La luce ha dominato la biologia animale sin dall'origine della vita. Serve come fonte primaria di energia, ha un impatto sul metabolismo e coordina il comportamento degli animali. L'eccessiva esposizione alla luce solare rappresenta anche una delle principali fonti di danno per biomolecole complesse e quindi è alla base di patologie. È noto che la luce ha un effetto cruciale su molti aspetti della fisiologia di pesci, che vanno dallo sviluppo alla crescita, dalla determinazione del sesso al comportamento e alla riproduzione. Recenti scoperte hanno rivelato la presenza di diversi tipi di fotorecettori nei pesci. Gli estremi fenotipi dei pesci di grotta che si sono evoluti in completa assenza di luce sono una testimonianza di quanto la luce modella l’evoluzione dei pesci. Utilizzando zebrafish e due specie di pesci di grotta, Phreatichthys andruzzii e Astyanax mexicanus, evoluti in diverse nicchie ecologiche, abbiamo studiato l'evoluzione della percezione UV e il meccanismo di riparazione del danno al DNA causato da UV. Gli elementi principali di questi processi sono altamente conservati: i fotorecettori UV sono espressi negli occhi, nel cervello e nei tessuti periferici di quasi tutti i pesci, mentre le fotoliasi, enzimi di riparazione del DNA attivati dalla luce blu, sono essenzialmente conservati in tutto il regno animale. Confrontando meccanismi relazionati alla luce di specie che vivono nell’habitat di superficie con specie che risiedono nell'habitat di grotta, possiamo apprendere molti dettagli su come la luce e meccanismi biologici connessi evolvono in risposta alle loro condizioni ambientali. Nella seguente tesi, tentiamo di illustrare come l'uso di strumenti comportamentali, molecolari e computazionali conducano la risposta a questa domanda.Light has dominated animal biology since the origin of life. It serves as the primary source of energy, has an impact on metabolism and coordinates the behavior of animals. Excess exposure to sunlight also represents a major source of damage for complex biomolecules and thereby underlies pathology. Light is known to have a crucial effect on many aspects of fish physiology ranging from development and growth to sex determination, behavior and reproduction. Recent discoveries have revealed the presence of different types of photoreceptors in fish. The extreme phenotypes of cavefish which have evolved in the complete absence of light are a testimony to how much light shapes fish evolution. Using the zebrafish and two species of cavefish, Phreatichthys andruzzii and Astyanax mexicanus, evolved in different ecological niches, we investigated the evolution of UV perception and DNA UV-damage repair mechanism. The main elements of these processes are highly conserved: UV photoreceptors are expressed in eye, brain and peripheral tissues of almost all fish, while the photolyases, blue-light activated DNA repair enzymes, are essentially preserved throughout the animal kingdom. Comparing the light-related mechanisms of species inhabiting surface habitat with species linving in subterranean habitat, we can learn much details about how light and related biological mechanisms evolve in response to their environmental conditions. In the following thesis, we attempt to illustrate how the use of behavioral, molecular and computational tools lead the answer on this question.
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Relógio, Angela Moreira Borralho [Verfasser]. "A systems biology view on the role of alternative splicing and the circadian clock in tumour progression / Angela Moreira Borralho Relógio." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2016. http://d-nb.info/111213350X/34.
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Tang, Ni. "Circadian and non-visual regulation of light on sleep-wake states in humans and nocturnal rodents." Electronic Thesis or Diss., Lyon 1, 2024. http://www.theses.fr/2024LYO10356.
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La lumière influence de nombreuses fonctions comportementales et physiologiques, comme les cycles veille-sommeil, la sécrétion de mélatonine, le réflexe pupillaire et le métabolisme du glucose. En tant que facteur environnemental clé, elle synchronise le système circadien sur un cycle de 24 heures. Les signaux lumineux sont perçus par les cellules ganglionnaires rétiniennes intrinsèquement photosensibles (ipRGCs), distinctes des bâtonnets et cônes responsables de la vision. Ces ipRGCs envoient les informations lumineuses au noyau suprachiasmatique (NSC) de l'hypothalamus, l'horloge circadienne principale du cerveau. Le NSC projette vers diverses structures cérébrales pour coordonner les processus rythmiques. Cependant, les ipRGCs influencent aussi directement des fonctions non visuelles, comme le sommeil et le métabolisme, en contournant la régulation circadienne. Cette double voie, circadienne et non circadienne, régule les effets non visuels de la lumière. Toutefois, les mécanismes précis par lesquels la lumière affecte les états veille-sommeil restent encore méconnus, de même que les structures cérébrales et les neurotransmetteurs impliqués. La lumière artificielle, omniprésente dans la vie moderne, notamment la nuit, perturbe les cycles naturels jour/nuit, ce qui suscite des inquiétudes.Notre projet vise à comprendre les effets de la lumière sur la veille et le sommeil en utilisant des modèles animaux et des études humaines. Dans nos expériences sur des souris génétiquement modifiées, nous avons étudié si l'orexine et l'histamine jouent un rôle dans les effets inducteurs du sommeil de la lumière. Les souris ont été exposées à différents cycles lumineux (LD12:12, DD et LD1:1). Nous avons observé que la lumière augmentait le sommeil à ondes lentes (SWS) durant la phase sombre chez les souris sauvages (WT), mais cet effet était atténué chez les souris knock-out OX, HDC et OX/HDC. La lumière augmentait également l'activité delta de l'EEG pendant le SWS chez les souris WT, OX knock-out et OX/HDC knock-out, mais pas chez les souris HDC knock-out. De plus, la lumière induisait un sommeil rapide et durable chez les souris WT, alors que cet effet était plus lent et de plus courte durée chez les modèles knock-out, suggérant que la transmission de l'orexine et de l'histamine est nécessaire pour les effets inducteurs de la lumière. Dans l'étude humaine, 20 hommes en bonne santé ont été exposés à quatre intensités lumineuses (0, 3, 8 et 20 lux) pendant 5 jours dans un environnement contrôlé. Nous avons constaté que le réveil après l'endormissement (WASO) était plus long sous 20 lux comparé aux intensités lumineuses plus faibles, et que l'efficacité du sommeil était réduite sous 20 lux. Les niveaux de mélatonine et de cortisol au réveil n'ont pas varié entre les conditions lumineuses. En revanche, la fréquence cardiaque (HR) a diminué et la variabilité de la fréquence cardiaque (HRV) a augmenté sous 20 et 3 lux par rapport à 0 lux. Le taux de glucose durant le sommeil était plus élevé sous faible lumière (3 et 20 lux) que sous 0 lux. De plus, l'exposition nocturne à la lumière a altéré la sensibilité à la lumière et la performance cognitive le lendemain. Nous concluons que même une faible intensité de lumière artificielle nocturne (ALAN) peut perturber le sommeil et affecter les fonctions physiologiquesLight influences a wide range of behavioral and physiological functions, including sleep-wake cycles, melatonin secretion, pupil light reflex, glucose metabolism, and more. As a key environmental factor, light synchronizes the circadian system with a roughly 24-hour cycle. Light signals are detected by a specific type of retinal cell, intrinsically photosensitive retinal ganglion cells (ipRGCs), which are distinct from the classical photoreceptors—rods and cones—that are primarily involved in vision. These ipRGCs transmit light information to the brain's master circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN then projects to various brain structures, coordinating rhythmic behavioral and physiological processes. Notably, ipRGCs also send projections to brain regions beyond the SCN, bypassing circadian regulation to directly influence non-visual functions like sleep, wakefulness, and metabolism. This dual pathway—circadian and non-circadian—mediates light's non-visual effects on the body. However, the exact mechanisms by which light affects sleep-wake states, and which brain structures and neurotransmitters are involved, remain largely unknown. As artificial light becomes increasingly common in modern life, including during nighttime, its disruption of natural light-dark cycles raises concerns. The aim of our project is to explore the wake-promoting and sleep-inhibiting effects of light using both animal models and human studies. In the animal studies, we employed genetically modified mouse models with disrupted histamine and/or orexin transmission to investigate whether these neurotransmitters mediate the sleep-inducing effects of light. Mice were exposed to three conditions: LD12:12, DD, and LD1:1 cycles. Our findings revealed that light significantly increased slow-wave sleep (SWS) during the dark phase in wild-type (WT) mice, but this effect was diminished in OX knockout, HDC knockout, and dual OX/HDC knockout mice. Additionally, light induced a significant increase in EEG delta activity during SWS in WT, OX knockout, and OX/HDC knockout mice, but not in HDC knockout mice. Furthermore, while light induced sleep rapidly and for a sustained duration in WT mice, this effect was slower and shorter-lasting in the knockout models. These results suggest that the sleep-inducing effects of light require both orexin and histamine transmission. In the human study, 20 healthy male participants were exposed to four different light conditions (0, 3, 8, and 20 lux) during a 5-day protocol in a controlled laboratory setting. We found that wake after sleep onset (WASO) was significantly higher under 20 lux compared to lower light intensities, and sleep efficiency was lower under 20 lux than under 3 and 8 lux. Interestingly, there were no significant differences in salivary melatonin and cortisol levels at wake time between the four light conditions. Similarly, body temperature during sleep remained unchanged across light conditions, but heart rate (HR) and heart rate variability (HRV) were affected, with a decrease in HR and an increase in HRV under 20 lux and 3 lux compared to 0 lux. Glucose levels during sleep were significantly higher under low-light conditions (3 and 20 lux) than under 0 lux. Moreover, nocturnal light exposure impaired sensitivity to light and cognitive performance the following morning. Our study concludes that even very low-intensity artificial light at night (ALAN) can disturb sleep and affect physiological functions
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Pett, Jan Patrick [Verfasser], Hanspeter [Gutachter] Herzel, Nils [Gutachter] Blüthgen, and Didier [Gutachter] Gonze. "Systems level generation of mammalian circadian rhythms and its connection to liver metabolism / Jan Patrick Pett ; Gutachter: Hanspeter Herzel, Nils Blüthgen, Didier Gonze." Berlin : Humboldt-Universität zu Berlin, 2019. http://d-nb.info/1189145871/34.
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Ackermann, Simone. "Environmental effects on the circadian systems of a diurnal ( rhabdomys dilectus) and noctural (micaelamys namaquensis) rodent species with specific reference to light pollution." Diss., University of Pretoria, 2019. http://hdl.handle.net/2263/77808.
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The presence of artificial light at night (ALAN) is one of many contributing factors to global change today. The spectral range of ALAN can also alter the potential effects of light pollution in certain contexts which creates an exceptionally complex cascade of impacts. The purpose of this thesis was to examine the interactions of various environmental factors including ALAN on biological variables, locomotor activity and corticosterone concentration, of two species of rodent. This was accomplished by manipulating the environmental factors; environmental enrichment, temperature and lighting in captivity. A pilot field study was also conducted in order to test the future feasibility of incorporating information garnered from the laboratory study into larger scale real world experiments. The two species were collected from the field and was subsequently subjected to various light cycles, during which locomotor activity was monitored and urinary corticosterone stress hormone was assessed. Results showed that Micaelamys namaquensis, a nocturnal species, reacted favourably to the addition of enrichment by increasing activity levels whereas Rhabdomys dilectus, a diurnal species decreased activity levels while improving the strength of entrainment. Both M. namaquensis and R. dilectus decreased activity during a light cycle which simulated natural dawn and dusk patterns of light. The two species reacted differently when a 24hr
ambient temperature cycle was introduced, with M. namaquensis increasing its locomotor activity and R. dilectus decreasing overall activity. M. namaquensis decreased its average activity in response to ALAN and did not show any difference in reaction towards different types of light at night. R. dilectus on the other hand increased its activity under ALAN but also showed no preference between different spectra of light at night. While corticosterone concentrations were monitored during all the environmental factor experiments, fluctuations in hormone concentrations were noted, however found to be statistically non-significant. Thus, only speculations could be made regarding the impacts of the various environmental factors on the stress physiology of M. namaquensis and R. dilectus. These results highlight the importance of considering species specific outcomes even under virtually identical circumstances. Understanding the impacts of environmental factors is crucial in order to extrapolate laboratory-based findings into real world experiments. This work can be used to further understand the impacts of different environmental factors on the circadian systems of nocturnal and diurnal rodent species as well as the potential implication of ALAN under various environmental conditions. In future, this can be combined into a large-scale field experiment in order to monitor the impacts of light pollution using the methodology elucidated during the pilot study. The results of this study show that the impacts of ALAN can be incredibly diverse and specific to the species in which they are examined.Dissertation (MSc)--University of Pretoria, 2019.
Zoology and Entomology
MSc
Unrestricted
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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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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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Maddi, Shravya Reddy. "Cloning of a CHLAMYDOMONAS REINHARDTII Marker into a RNA Interference Construct to Test Whether the Photoreceptor Chlamyrhodopsin Is Involved in Circadian Clock Resetting." TopSCHOLAR®, 2010. http://digitalcommons.wku.edu/theses/215.
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Chlamydomonas reinhardtii, a unicellular eukaryotic green alga, serves as a model organism to study the circadian clock in plants and animals. Rhodopsins are blue/green-light photoreceptors also found in C. reinhardtii. Chlamyrhodopsin (COP), the most abundant eyespot protein, was reported to have no role in the phototactic and photophobic responses in C. reinhardtii. Its function is yet unknown. In the present study, we hypothesized that the function of COP is to mediate entrainment of the circadian clock by light. In order to test this hypothesis, a C. reinhardtii selection marker conferring resistance to the antibiotic paromomycin was cloned into a COP RNAi construct obtained from another lab. Firstly, the COP RNAi construct was restriction digested to linearize it. The linearized plasmid was then blunt ended with T4 DNA polymerase and dephosphorylated with phosphatase. The linearized fragment was ligated with the paromomycin resistance marker obtained by restriction digestion of the plasmid containing it and transformed into E.coli. The recombinant clones obtained were confirmed by restriction digests. Fusion regions and the orientation of the insert in the recombinant plasmid were confirmed by sequencing. An attempt was made to transform C. reinhardtii with the construct, but this was not successful. Future studies will be required to optimize the C. reinhardtii transformation method. Transformants with reduced COP amounts can then be tested for defects in resetting the clock after light pulses. This will determine whether chlamyrhodopsin is involved in the circadian input pathway or not. The results of the complete project are expected to contribute to our understanding of the circadian clock of many other organisms including humans.
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Sawyer, Tiffoney L. "The effects of reversing sleep-Wake cycles on mood states, sleep, and fatigue on the crew of the USS John C. Stennis /." Thesis, Monterey, Calif. : Springfield, Va. : Naval Postgraduate School ; Available from National Technical Information Service, 2004. http://library.nps.navy.mil/uhtbin/hyperion/04Jun%5FSawyer.pdf.
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Thesis (M.S. in Applied Science (Operations Research))--Naval Postgraduate School, June 2004.Thesis advisor(s): Nita Lewis Miller. Includes bibliographical references (p. 103-107). Also available online.
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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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Xie, Zhi. "Modelling genetic regulatory networks: a new model for circadian rhythms in Drosophila and investigation of genetic noise in a viral infection process." Phd thesis, Lincoln University. Agriculture and Life Sciences Division, 2007. http://theses.lincoln.ac.nz/public/adt-NZLIU20070712.144258/.
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In spite of remarkable progress in molecular biology, our understanding of the dynamics and functions of intra- and inter-cellular biological networks has been hampered by their complexity. Kinetics modelling, an important type of mathematical modelling, provides a rigorous and reliable way to reveal the complexity of biological networks. In this thesis, two genetic regulatory networks have been investigated via kinetic models.
In the first part of the study, a model is developed to represent the transcriptional regulatory network essential for the circadian rhythms in Drosophila. The model incorporates the transcriptional feedback loops revealed so far in the network of the circadian clock (PER/TIM and VRI/PDP1 loops). Conventional Hill functions are not used to describe the regulation of genes, instead the explicit reactions of binding and unbinding processes of transcription factors to promoters are modelled. The model is described by a set of ordinary differential equations and the parameters are estimated from the in vitro experimental data of the clocks components. The simulation results show that the model reproduces sustained circadian oscillations in mRNA and protein concentrations that are in agreement with experimental observations. It also simulates the entrainment by light-dark cycles, the disappearance of the rhythmicity in constant light and the shape of phase response curves resembling that of experimental results. The model is robust over a wide range of parameter variations. In addition, the simulated E-box mutation, perS and perL mutants are similar to that observed in the experiments. The deficiency between the simulated mRNA levels and experimental observations in per01, tim01 and clkJrk mutants suggests some differences in the model from reality. Finally, a possible function of VRI/PDP1 loops is proposed to increase the robustness of the clock.
In the second part of the study, the sources of intrinsic noise and the influence of extrinsic noise are investigated on an intracellular viral infection system. The contribution of the intrinsic noise from each reaction is measured by means of a special form of stochastic differential equation, the chemical Langevin equation. The intrinsic noise of the system is the linear sum of the noise in each of the reactions. The intrinsic noise arises mainly from the degradation of mRNA and the transcription processes. Then, the effects of extrinsic noise are studied by means of a general form of stochastic differential equation. It is found that the noise of the viral components grows logarithmically with increasing noise intensities. The system is most susceptible to noise in the virus assembly process. A high level of noise in this process can even inhibit the replication of the viruses.
In summary, the success of this thesis demonstrates the usefulness of models for interpreting experimental data, developing hypotheses, as well as for understanding the design principles of genetic regulatory networks.
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Maier, Benjamin F. "Spreading Processes in Human Systems." Doctoral thesis, Humboldt-Universität zu Berlin, 2020. http://dx.doi.org/10.18452/20950.
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Menschliche Systeme werden seit einiger Zeit modelliert und analysiert auf der Basis der Theorie komplexer Netzwerke. Dies erlaubt es quantitativ zu untersuchen, welche strukturellen und zeitlichen Merkmale eines Systems Ausbreitungsprozesse beeinflussen, z.B. von Informationen oder von Infektionskrankheiten.
Im ersten Teil der Arbeit wird untersucht, wie eine modular-hierarchische Struktur von statischen Netzwerken eine schnelle Verbreitung von Signalen ermöglicht. Es werden neue Heuristiken entwickelt um die Random-Walk-Observablen “First Passage Time” und “Cover Time” auf lokal geclusterten Netzwerken zu ermitteln. Vergleiche mit der Approximation eines gemittelten Mediums zeigen, dass das Auftreten der beobachteten Minima der Observablen ein reiner Netzwerkeffekt ist. Es wird weiterhin dargelegt, dass nicht alle modular-hierarchischen Netzwerkmodelle dieses Phänomen aufweisen.
Im zweiten Teil werden zeitlich veränderliche face-to-face Kontaktnetzwerke auf ihre Anfälligkeit für Infektionskrankheiten untersucht. Mehrere Studien belegen, dass Menschen vornehmlich Zeit in Isolation oder kleinen, stark verbundenen Gruppen verbringen, und dass ihre Kontaktaktivität einem zirkadianen Rhythmus folgt. Inwieweit diese beiden Merkmale die Ausbreitung von Krankheiten beeinflussen, ist noch unklar. Basierend auf einem neuen Modell wird erstmals gezeigt, dass zirkadian variierende Netzwerke Trajektorien folgen in einem Zustandsraum mit einer strukturellen und einer zeitlichen Dimension. Weiterhin wird dargelegt, dass mit zunehmender Annäherung der zeitlichen Dimension von System und Krankheit die systemische Infektionsanfälligkeit sinkt. Dies steht in direktem Widerspruch zu Ergebnissen anderer Studien, die eine zunehmende Anfälligkeit vorhersagen, eine Diskrepanz, die auf die Ungültigkeit einer weit verbreiteten Approximation zurückzuführen ist. Die hier vorgestellten Ergebnisse implizieren, dass auf dem Gebiet die Entwicklung neuer theoretischer Methoden notwendig ist.Human systems have been modeled and analyzed on the basis of complex networks theory in recent time. This abstraction allows for thorough quantitative analyses to investigate which structural and temporal features of a system influence the evolution of spreading processes, such as the passage of information or of infectious diseases. The first part of this work investigates how the ubiquitous modular hierarchical structure of static real-world networks allows for fast delivery of messages. New heuristics are developed to evaluate random walk mean first passage times and cover times on locally clustered networks. A comparison to average medium approximations shows that the emergence of these minima are pure network phenomena. It is further found that not all modular hierarchical network models provide optimal message delivery structure. In the second part, temporally varying face-to-face contact networks are investigated for their susceptibility to infection. Several studies have shown that people tend to spend time in small, densely-connected groups or in isolation, and that their connection behavior follows a circadian rhythm. To what extent both of these features influence the spread of diseases is as yet unclear. Therefore, a new temporal network model is devised here. Based on this model, circadially varying networks can for the first time be interpreted as following trajectories through a newly defined systemic state space. It is further revealed that in many temporally varying networks the system becomes less susceptible to infection when the time-scale of the disease approaches the time-scale of the network variation. This is in direct conflict with findings of other studies that predict increasing susceptibility of temporal networks, a discrepancy which is attributed to the invalidity of a widely applied approximation. The results presented here imply that new theoretical advances are necessary to study the spread of diseases in temporally varying networks.
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Hofer, Sabine. "The circadian system of the cockroach Leucophaea maderae role of the neuropeptide orcokinin and light entrainment = (Das circadiane System der Schabe Leucophaea maderae) /." [S.l. : s.n.], 2004. http://archiv.ub.uni-marburg.de/diss/z2004/0634/.
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Ortiz, Tudela Elisabet. "Evaluación ambulatoria del estatus funcional del sistema circadiano humano= Ambulatory assessment of the functional status of the human circadian system." Doctoral thesis, Universidad de Murcia, 2014. http://hdl.handle.net/10803/132913.
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OBJETIVOS Esta tesis pretende desarrollar una herramienta de fácil aplicación, fiable, consistente y no invasiva que sea capaz de evaluar el estatus del sistema circadiano. Para conseguir este objetivo, se plantearon los siguientes objetivos específicos: 1. Crear un algoritmo para la evaluación ambulatoria y no invasiva del sistema circadiano mediante la integración de los ritmos de temperatura periférica, actividad motora y posición corporal en la variable compuesta TAP. 2. Validar la variable integrada TAP para la detección de sueño y vigilia en comparación con el gold standard para este propósito, la polisomnografía. Además, se pretende comprobar si TAP mejora la detección de sueño con respecto a las estimaciones obtenidas mediante la actigrafía convencional. 3. Transferir la utilidad de TAP, implementada en un dispositivo de registro ambulatorio en una patente internacional. 4. Evaluar la validez de la variable TAP para la detección de alteraciones circadianas en condiciones patológicas: 4.1. Revisar los conocimientos previos sobre cáncer y ritmos circadianos, prestando especial atención a los tratamientos que tienen en cuenta el sistema circadiano. 4.2. Estudiar las diferencias interindividuales del ritmo de actividad-reposo que podrían potencialmente afectar el resultado del tratamiento en pacientes de cáncer. 4.3. Evaluar cómo los tratamientos cronomodulados afectan la sincronización interna de diferentes ritmos circadianos en pacientes de cáncer. 4.4. Evaluar las perturbaciones circadianas de sujetos con deterioro cognitivo leve con el fin de establecer la utilidad de la variable TAP para evaluar objetivamente la progresión de la enfermedad. METODOLOGÍA En esta tesis, se evaluaron tres ritmos y procesaron con el fin de obtener la variable TAP que después se aplicó en varias condiciones de salud y enfermedad. Ritmo de temperatura Este ritmo se evaluó mediante un sensor de temperatura (Thermochron iButton DS1921H, Dallas, Maxim) cosido a una muñequera de modo que la superficie del sensor quedara en contacto con la arteria radial de la muñeca de la mano no dominante. Ritmo de actividad motora y posición corporal Estos ritmos se evaluaron gracias a un actímetro (Hobo Pendant G Acceleration Data Logger, Massachusetts, USA) colocado en el brazo no dominante mediante un brazalete deportivo. De la información proporcionada por el actímetro, se definieron 2 variables: actividad motora, expresada como grados de cambio de posición y posición corporal, definida como el ángulo entre el eje X y el plano horizontal. Procesamiento de los datos Cada variable se normalizó entre 0 y 1 después de haber eliminado los artefactos mediante inspección visual de los datos. Además, los datos de temperatura se invirtieron de modo que los valores máximos de todas las variables coincidieran en el mismo momento. Después, calculamos la media de las variables normalizadas para cada sujeto obteniendo la variable TAP cuyos valores varían entre 0 (para periodos de reposo) y 1 (para periodos activos). CONCLUSIÓN GENERAL La monitorización circadiana ambulatoria, no invasiva y fiable del estado funcional del sistema circadiano humano es un procedimiento muy útil para la prognosis de ciertas enfermedades como cáncer, deterioro cognitivo leve y perturbaciones del sueño. La monitorización conjunta y la integración de varias salidas del reloj biológico mejora la consistencia de los resultados y facilita la evaluación de la desincronización interna entre diferentes variables rítmicas. De este modo, la variable TAP, basada en la integración de los ritmos de Temperatura periférica, Actividad motora y Posición corporal, ha superado las premisas de alta fiabilidad, aceptación y versatilidad para el estudio ambulatorio y prolongado del estado del sistema circadiano humano en muy distintas situaciones de salud y enfermedad. Además, ha sido posible implementar este algoritmo en un dispositivo bajo patente internacional.OBJECTIVES This thesis aims to develop a reliable, consistent, non-invasive and easily applied tool based on multivariable recordings, able to depict circadian system status and circadian rhythmic synchrony in humans. In order to pursue this final goal, the following specific objectives were determined: 1. To create a multivariable tool able to reliably and non-invasively ambulatory assess the circadian system status by integrating wrist temperature, motor activity and body position rhythms into the composite TAP variable. 2. To validate this integrated variable for sleep and wake detection against the gold standard for this purpose, the polysomnography and test if TAP improves the detection from that obtained with actigraphy alone. 3. To test the validity of TAP variable in specific pathological conditions with known circadian impairments: 3.1. To review, the previous knowledge on cancer and circadian rhythms, as well as circadian-based treatments for this disease. 3.2. To study the inter-individual differences in rest-activity rhythm, that could potentially affect treatment outcome, in colorectal cancer patients. 3.3. To assess how chronomodulated treatment affects internal synchronization on cancer patients by multivariable recordings. 3.4. To evaluate circadian disturbances in mild cognitively impaired subjects, a previous condition to Alzheimer’s Disease, in order to establish its potential usefulness to objectively assess the disease progression. 4. To transfer the usefulness of TAP implemented in an ambulatory monitoring device for its clinical application and its potential commercialization by an international patent. METHODOLOGY In these PhD, three rhythms were recorded and processed as to obtain an integrated variable TAP in several conditions of health and disease. Temperature rhythm The wrist temperature rhythm was assessed using a temperature sensor (Thermochron iButton DS1921H, Dallas, Maxim) attached to a double-sided cotton sport wrist band, and the sensor surface was placed over the inside of the wrist on the radial artery of the non-dominant hand. Body position and rest-activity rhythm The body position and rest-activity rhythm was assessed using an actimeter (Hobo Pendant G Acceleration Data Logger, Massachusetts, USA) placed on the non-dominant arm by means of a sports band, with its X-axis parallel to the humerus bone. From the information provided by the actimeter, we defined 2 variables: motor activity (A) and body position (P). Motor activity was expressed as degrees of change in position. Body position was calculated as the angle between the X-axis of the actimeter and a horizontal plane. Thus, P oscillated between 0º for maximum horizontality and 90º for maximum verticality. Data processing Each variable was normalized between 0 and 1, after removing artifacts identified by visual inspection of the data. In addition, wrist temperature data were inverted in such a way that maximum values for all variables occurred at the same time. We then calculated the mean of the normalized variables for each subject, obtaining TAP values which range between 0 (for rest periods) and 1 (for active periods). GENERAL CONCLUSION The reliable ambulatory monitoring of circadian system in humans has proven very relevant for disease prognosis in such conditions as cancer, mild cognitive impairments and sleep disturbances. The joint recording and following integration of several clock outputs increase results’ consistency as isolated variable artifacts are minimized by the integration of several variables and enables the calculation of internal desynchronization among different rhythmic variables. TAP, integration of wrist Temperature, motor Activity and body Position rhythms, has supported the premises of high reliability, acceptance and versatility for the long-period ambulatory study of human circadian system status under several conditions of health and disease. Thus, these positive results have facilitated the implementation of TAP’s algorithm in a new device for ambulatory monitoring and registered in an international patent, already in exploitation.
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Cardasis, Helene L. "Mass spectrometric analysis of two phosphorylation-based signal transduction systems site-specific effects of the circadian clock on Limulus Myosin III phosphorylation, and binding selectivity of the Arabidopsis family of 14-3-3 isoforms /." [Gainesville, Fla.] : University of Florida, 2006. http://purl.fcla.edu/fcla/etd/UFE0015520.
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Necchi, Lúcia Helena de Góes. "Modulação do sistema nervoso autônomo mensurado pela análise da variabilidade da freqüência cardíaca em pacientes com fibromialgia." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/5/5145/tde-18042007-102231/.
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INTRODUÇÃO: Pacientes com fibromialgia (FM) apresentam distúrbios no sistema de resposta ao estresse, o qual é composto pelo eixo hipotalâmico-pituitário-adrenal (HPA) e pelo sistema nervoso autônomo. Recentemente, tem havido muito interesse na possível função do sistema nervoso autônomo na patogênese da FM. O objetivo deste estudo foi avaliar a interação entre os sistemas simpático e parassimpático, em mulheres com FM e mulheres saudáveis, utilizando a análise da variabilidade da freqüência cardíaca (VFC). MÉTODOS: Foram estudadas 20 mulheres com FM com idades entre 35 e 55 anos, e 20 controles saudáveis pareados pela idade, gênero e índice de massa corporal. A VFC foi analisada sobre gravações eletrocardiográficas, obtidas através da monitorização eletrocardiográfica ambulatorial (Holter) de 24 horas, e avaliada pelos índices da VFC no domínio do tempo (SDNN, SDANN, SDNNi, RMSSD e pNN50) e no domínio da freqüência (LF, HF, WF e LF/HF). A VFC foi analisada durante o período de 24 horas e também durante o período noturno, entre 01:00 e 04:00 h AM, consideradas como horas de sono. O equilíbrio simpato-vagal foi analisado através da razão LF/HF, sendo as faixas de freqüências da LF (0,04-0,15 Hz) considerada como predominantemente simpática, e da HF (0,15-0,50 Hz) considerada como predominantemente parassimpática. RESULTADOS: Não houve diferença de idade entre pacientes com FM e o grupo controle (44,40 ± 5,01 e 44,65 ± 5,32 anos, respectivamente; p=0,879). Os índices que refletem o sistema nervoso parassimpático, mostraram um comportamento similar entre pacientes com FM, mas revelaram atividade significativamente diminuída quando comparado ao grupo controle, ambos durante o período noturno e durante o período de 24 horas (p<0,05). Não houveram diferenças entre os índices que refletem o sistema simpático entre os grupo FM e controle (p>0,05), assim como não mostraram hiperatividade simpática. Contudo, a razão LF/HF foi significativamente maior em pacientes com FM, quando comparado ao grupo controle, ambos durante o período de sono (p=0,015) como durante o período de 24 horas (p=0,025), sugerindo predominância simpática em indivíduos com FM. CONCLUSÃO: Nossos resultados sugerem que pacientes com FM apresentam predominância da atividade simpática, associado ao tônus parassimpático diminuído. Sob condições basais não foi detectada hiperatividade simpática, uma vez que a atividade simpática não mostrou alterações significantes.INTRODUCTION: Patients with fibromyalgia (FM) exhibit disturbances of the stress-response system, which is composed by hypothalamic-pituitary-adrenal axis (HPA) and autonomic nervous system. Recently, much interest has been expressed in the possible role of the autonomic nervous system in the pathogenesis of FM. The aim of this study was to assess the interation between sympathetic and parasympathetic systems, in FM and health women, using heart hate variability (HRV) analysis. METHODS: It was studied 20 women with FM aged between 35 and 55 years-old, and 20 healthy controls matched for age, sex and body mass index. HRV was assessed over electrocardiographic recordings, obtained by 24-hours ambulatory electrocardiography monitoring (Holter), and evaluated by time domain indexes (SDNN, SDANN, SDNNi, RMSSD e pNN50) and frequency domain indexes (LF, HF, WF e LF/HF). HRV was analyzed over the 24-hours period and also over the night period, between 01:00 and 04:00 AM, considered as sleep hours. Sympathovagal balance was analysed by LF/HF ratio, with LF band (0.04-0.15 Hz) considered as sympathetic predominance, and HF band (0.15-0.50 Hz) considered as parasympathetic predominance. RESULTS: There was no age difference between FM patients and control group (44.40 ± 5.01 and 44.65 ± 5.32 years, respectively; p=0.879). The indexes that reflect parasympathetic nervous system, showed a similar behavior among FM patients, but revealed a significantly decreased activity when compared to control group, both during the nocturnal period as well during the 24h period (p<0.05). There was no difference between the indexes that reflect sympathetic system in FM patients and controls (p>0.05), as did not show sympathetic hyperactivity. However, the ratio LH/HF was significantly higher in FM patients, when compared to control group, both during the sleep period (p=0.015) as well as over the 24h period (p=0.025), suggesting a sympathetic predominance in FM subjects. CONCLUSION: Our data suggest that FM patients present a predominance of sympathetic activity, associated with a reduced parasympathetic tonus. Under basal conditions sympathetic hyperactivity was not detected, since sympathetic activity did not show significant alterations.
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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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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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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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Vujovic, Nina. "Functional organization of the circadian timing system." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11271.
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The circadian timing system establishes daily rhythms in behavior and physiology throughout the body, ensuring that functions like activity, sleep and hormone release are appropriately timed. Research suggests that his temporal synchrony within the body is quite important for health and survival. In mammals, the central circadian pacemaker in the suprachiasmatic nucleus (SCN) drives rhythms in behavior and physiology in large part by stimulating or inhibiting other brain regions responsible for these functions at the appropriate times of day. This timed signal is often indirect, i.e. relayed or possibly processed through a series of neurons in different brain regions before reaching the effector site. The subparaventricular zone (SPZ), a region adjacent to the SCN which is the main recipient of direct neuronal inputs from the SCN, is thought to be a critical relay for SCN signals, since loss of the SPZ results in loss of circadian rhythms in body temperature, activity and sleep/wakefulness. Another important relay site, the dorsomedial hypothalamic nucleus (DMH) gets direct input from both the SCN and SPZ and is critical for normal expression of various circadian rhythms.
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Ballesta, Annabelle. "Approche combinée expérimentale et mathématique pour la personnalisation sur base moléculaire des thérapies anticancéreuses standards et chronomodulées." Phd thesis, Université Paris Sud - Paris XI, 2011. http://tel.archives-ouvertes.fr/tel-00628629.
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Personnaliser les traitements anticancéreux sur base moléculaire consiste à optimiser la thérapie en fonction des profils d'expression de gènes des cellules saines et tumorales du patient. Les différences au niveau moléculaire entre tissus normaux et cancéreux sont exploitées afin de maximiser l'efficacité du traitement et minimiser sa toxicité. Cette thèse propose une approche pluridisciplinaire expérimentale et mathématique ayant pur but la détermination de stratégies anticancéreuses optimales sur base moléculaire. Cette approche est, tout d'abord, mise en œuvre pour la personnalisation de la chronothérapeutique des cancers, puis pour l'optimisation de la thérapie anticancéreuse dans le cas d'une mutation de l'oncogène SRC. La plupart des fonctions physiologiques chez les mammifères présentent une rythmicité circadienne, c'est-à-dire de période environ égale à 24 h. C'est par exemple le cas de l'alternance activité-repos, de la température corporelle, et de la concentration intracellulaire d'enzymes du métabolisme. Ces rythmes ont pour conséquence une variation de la toxicité et de l'efficacité d'un grand nombre de médicaments anticancéreux selon leur heure circadienne d'administration. De récentes études soulignent la nécessité d'adapter les schémas d'injection chronomodulés au profil moléculaire du patient. La première partie de cette thèse propose une approche combinée expérimentale et modélisatrice pour personnaliser sur base moléculaire la chronothérapie. La première étape a consisté en une preuve de concept impliquant des expérimentations in vitro sur cultures de cellules humaines et des travaux de modélisation in silico. Nous nous sommes focalisés sur l'étude de l'irinotecan (CPT11), un médicament anticancéreux actuellement utilisé en clinique dans le traitement des cancers colorectaux, et présentant des rythmes de chronotoxicité et de chronoefficacité chez la souris et chez l'homme. Sa pharmacocinétique (PK) et pharmacodynamie (PD) moléculaires ont été étudiées dans la lignée de cellules d'adénocarcinome colorectal humain Caco-2. Un modèle mathématique de la PK-PD moléculaire du CPT11, à base d'équations différentielles ordinaires, a été conçu. Il a guidé l'expérimentation qui a été réalisée dans le but de d'évaluer les paramètres du modèle. L'utilisation de procédures d'optimisation, appliquées au modèle calibré aux données biologiques, a permis la conception de schéma d'exposition au CPT11 théoriquement optimaux dans le cas particulier des cellules Caco-2. Le CPT11 s'est accumulé dans les cellules Caco-2 où il a été biotransformé en son métabolite actif le SN38, sous l'action des carboxylestérases (CES). La pré-incubation des cellules avec du verapamil, un inhibiteur non spécifique des transporteurs ABC (ATP-Binding Cassette) a permis la mise en évidence du rôle de ces pompes d'efflux ABC dans le transport du CPT11. Après synchronisation des cellules par choc sérique, qui définit le temps circadien (CT) 0, des rythmes circadiens d'une période de 26 h 50 (SD 63 min) ont été mis en évidence pour l'expression de trois gènes de l'horloge circadienne: REV-ERBα, PER2, et BMAL1; et six gènes de la pharmacologie du CPT11: la cible du médicament la topoisomerase 1 (TOP1), l'enzyme d'activation CES2, l'enzyme de désactivation UGT1A1, et les quatre transporteurs ABCB1, ABCC1, ABCC2, ABCG2. Au contraire, l'expression protéique et l'activité de la TOP1 sont restées constantes. Enfin, la quantité de TOP1 liée à l'ADN en présence de CPT11, un marqueur de la PD du médicament, a été plus importante pour une exposition à CT14 (47±5.2% de la quantité totale de TOP1), que pour une exposition à CT28 (35.5±1.8%). Les paramètres du modèle mathématique de la PK-PD du CPT11 ont ensuite été estimés par une approche de bootstrap, en utilisant des résultats expérimentaux obtenus sur les cellules Caco-2, combinés aux données de la littérature. Ensuite, des algorithmes d'optimisation ont été utilisés pour concevoir les schémas d'exposition théoriquement optimaux des cellules Caco-2 à l'irinotecan. Les cellules synchronisées par un choc sérique ont été considérées comme les cellules saines et les cellules non-synchronisées ont joué le rôle de cellules cancéreuses puisque l'organisation circadienne est souvent perturbée dans les tissus tumoraux. La stratégie thérapeutique optimale a été définie comme celle qui maximise l'efficacité sur les cellules cancéreuses, sous une contrainte de toxicité maximale sur les cellules saines. Les schémas d'administration considérés ont pris la forme d'une exposition à une concentration donnée de CPT11, débutant à un CT particulier, sur une durée comprise entre 0 et 27 h. Les simulations numériques prédisent que toute dose de CPT11 devrait être optimalement administrée sur une durée de 3h40 à 7h10, débutant entre CT2h10 et CT2h30, un intervalle de temps correspondant à 1h30 à 1h50 avant le minimum des rythmes de bioactivation du CPT11 par les CES. Une interprétation clinique peut être établie en ramenant à 24 h ces résultats pour les cellules Caco-2 qui présentent une période de 27 h. Ainsi, une administration optimale du CPT11 chez le patient cancéreux résulterait en une présence du médicament dans le sang pendant 3h30 à 6h30, débutant de 1h30 à 1h40 avant le minimum des rythmes d'activité des CES chez le patient. La deuxième étape de nos travaux a consisté à adapter l'approche mise en œuvre pour optimiser l'exposition des cellules Caco-2 au CPT11, pour l'optimisation de l'administration du médicament chez la souris. Des études récentes mettent en évidence trois classes de chronotoxicité à l'irinotecan chez la souris. La classe 1, les souris de la lignée B6D2F1 femelles, présentent la pire tolérabilité au CPT11 après une administration à ZT3, et la meilleure pour une administration à ZT15, où ZT est le temps de Zeitgeber, ZT0 définissant le début de la phase de lumière. La classe 2, les souris B6D2F1 mâles, montrent une pire heure d'administration à ZT23 et une meilleure à ZT11. Enfin, la classe 3, les B6CBAF1 femelles présentent la pire tolérabilité pour une injection à ZT7, et la meilleure pour ZT15. Nous avons entrepris une approche pluridisciplinaire in vivo et in silico dont le but est la caractérisation moléculaire des trois classes de chronotoxicité, ainsi que la conception de schémas optimaux d'administration pour chacune d'elles. Le modèle mathématique mis au point pour une population de cellules en culture a été adapté pour la construction d'un modèle "corps entier" à base physiologique de la PK-PD de l'irinotecan. Un ensemble de paramètres a été estimé pour la classe 2, en utilisant deux sortes de résultats expérimentaux: d'une part, les concentrations sanguines et tissulaires (foie, colon, moelle osseuse, tumeur) du CPT11 administré aux pire et meilleure heures circadiennes de tolérabilité, et d'autre part, les variations circadiennes des protéines de la pharmacologie du médicament dans le foie et l'intestin. Le modèle ainsi calibré reproduit de façon satisfaisante les données biologiques. Cette étude est en cours pour les classes 1 et 3. Une fois les ensembles de paramètres validés pour chacune des trois classes, ils seront comparés entre eux pour mettre en évidence de possibles différences moléculaires. L'étape suivante consiste en l'application d'algorithmes d'optimisation sur le modèle corps entier pour définir des schémas d'administration chronomodulés optimaux pour chaque classe. La deuxième partie de cette thèse s'intéresse à l'étude de la tyrosine kinase SRC, dont l'expression est dérégulée dans de nombreux cancers. Des études récentes montrent un contrôle de SRC sur la voie mitochondriale de l'apoptose dans des fibroblastes de souris NIH-3T3 transfectés avec l'oncogène v-src, cette régulation étant inexistante dans les cellules parentales. L'oncogène SRC active la voie RAS / RAK / MEK1/2 / ERK1/2 qui augmente la vitesse de phosphorylation de la protéine pro-apoptotique BIK, menant ainsi à sa dégradation par le protéasome. La faible expression de BIK résultant de ce mécanisme rendrait ainsi les cellules v-src résistantes à la plupart des stress apoptotiques. Notre étude a consisté à déterminer, par une approche combinée mathématique et expérimentale, les stratégies thérapeutiques optimales lorsque les cellules NIH-3T3 parentales jouent le rôle de cellules saines, et les fibroblastes transformés celui de cellules cancéreuses. Pour cela, nous avons, tout d'abord, construit un modèle mathématique de la cinétique de BIK en conditions non-apoptotiques. L'estimation des paramètres de ce modèle, en utilisant des données expérimentales existantes, confirme que la phosphorylation de BIK sous le contrôle de SRC est inactive dans les cellules normales. L'étude exprimentale de l'évolution de BIK après le signal apoptotique que constitue une exposition à la staurosporine, démontre une relocalisation de BIK aux mitochondries, la concentration totale de la protéine restant constante durant le stress. Nous avons ensuite conçu un modèle mathématique de la voie mitochondriale de l'apoptose mettant en jeu les protéines anti-apoptotiques de type Bcl2, les protéines effectrices de type BAX, les protéines BH3-only activatrices et les BH3-only sensibilisatrices. Un ensemble de paramètres a été déterminé pour les cellules NIH-3T3 parentales, et celles transformées v-src, en comparant le modèle aux données expérimentales. Le modèle reproduit le fait expérimentalement démontré que la préincubation des cellules v-src avec un inhibiteur de la tyrosine kinase SRC, avant l'exposition à la staurosporine, annihile la résistance des fibroblastes transformés au stress apoptotique. Le modèle prédit que l'administration de l'ABT-737, un inhibiteur de protéines anti-apoptotiques, avant l'exposition à la staurosporine, ne devrait pas être entreprise dans notre systéme biologique, ce qui a été expérimentalement validé. Enfin, le modèle a été utilisé dans des procédures d'optimisation pour déterminer la stratégie thérapeutique théoriquement optimale, lorsque les cellules normales et transformées sont exposées aux mêmes médicaments. Les combinaisons médicamenteuses considérées consiste en une exposition à la staurosporine, précédée d'une exposition à des répresseurs ou activateurs d'expression des protéines de la famille Bcl2. La stratégie optimale est définie comme celle qui maximise le pourcentage de cellules apoptotiques dans les fibroblastes v-src, sous la contrainte que celui dans les cellules normales reste au-dessous d'un seuil de tolérabilité. Les simulations numériques nous permettent de conclure à une combinaison médicamenteuse optimale constituée d'une exposition à la staurosporine, précédée d'une exposition à un répresseur de l'expression de BAX (de manière à diminuer sa concentration en-dessous du seuil apoptotique dans les cellules normales, mais pas dans les cellules cancéreuses), combinée à un répresseur de BCL2 ou un inhibiteur de tyrosines kinases SRC. Cette stratégie optimale aboutit à moins d'1% de cellules apoptotiques dans les cellules saines et plus de 98% dans les cellules cancéreuses.
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Gisela, Helfer. "Molecular characterisation of the circadian system in birds." Thesis, University of Birmingham, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.487496.
Full textAbstract:
The circadian clock is a self-sustaining oscillator system controlling many physiological and behavioural processes. The underlying rhythms are generated by a set of clock genes, which are expressed in an oscillating manner on transcriptional and translational levels. To investigate the avian circadian system, homologues of mammalian clock genes have been cloned in the house sparrow, a model organism in circadian research. Expression levels were investigated in the brain and in peripheral tissues, including the gastro-intestinal tract. Pronounced rhythmic mRNA expression was found in all tissues investigated. .Tissue-specific differences in temporal distribution, peak expression and amplitude suggest that the molecular composition of the avian circadian clock is distinct from that in mammals. A novel cryptochrome gene in birds is described and subsequent molecular analysis reveals that functionally diverse cryptochromes are present in the house sparrow. A comparison of clock gene expression normalised to different house-keeping genes. demonstrates results on phasing and amplitude are strongly influenced by the selection of house-keeping genes for normalisation. This study has therefore improved our understanding of the circadian system in birds and provides new insights into the molecular basis of a complex circadian organisation in birds.
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Ruby, Christina L. "Ethanol Disruption of the Mammalian Circadian Timing System." Kent State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=kent1270053064.
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Wiser, Justin Allen. "Harmonic Resonance Dynamics of the Periodically Forced Hopf Oscillator." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373380266.
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Schendzielorz, Julia [Verfasser]. "Analysis of the circadian system of the cockroach Rhyparobia (Leucophaea) maderae : role of myoinhibitory peptides in the circadian system / Julia Schendzielorz." Kassel : Universitätsbibliothek Kassel, 2013. http://d-nb.info/1045767824/34.
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Martins, Leandro de Mattos Boer 1978. "Variabilidade da função autonômica em pacientes com hipertensão arterial resistente." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/309565.
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Orientador: Heitor Moreno JuniorTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-19T05:00:13Z (GMT). No. of bitstreams: 1 Martins_LeandrodeMattosBoer_D.pdf: 9156362 bytes, checksum: bf77ceb230427d245fc7f1ce0e5d047c (MD5) Previous issue date: 2011
Resumo: Considerando a forte associação entre a atividade do sistema nervoso autônomo, a obesidade e a resistência insulínica na hipertensão arterial resistente (HAR), esta pesquisa teve a finalidade de identificar a associação entre a função do sistema nervoso autonômico e importantes hormônios relacionados à síndrome cardiometabólica como adiponectina, leptina e aldosterona. Vinte e cinco pacientes portadores de hipertensão arterial resistente foram divididos em dois grupos: com (DM2) e sem diabetes mellitus tipo 2 (NDM2). Ambos os grupos foram avaliados em relação à variabilidade da frequência cardíaca (VFC) pelo sistema Holter de 24 horas, nos domínios do tempo e da frequência, e aos hormônios plasmáticos adiponectina, leptina e aldosterona. A análise dos resultados demonstrou maior disfunção autonômica e hipoadiponectinemia no subgrupo DM2 em relação ao subgrupo NDM2, correlação positiva entre VFC no domínio do tempo e a adiponectina no total de pacientes, ruptura do ritmo circadiano de ambos os grupos (tônus simpático aumentado no período noturno e diminuído no período diurno; tônus parassimpático aumentado no período diurno e diminuído no período noturno) e correlação positiva entre a banda de baixa de frequência em unidades normalizadas (LFnu) e aldosterona, e correlação negativa entre a banda de alta frequência em unidades normalizadas (HFnu) e aldosterona no total de pacientes e em ambos os grupos. O grupo DM2 obteve maiores valores de leptina e índice de massa corporal. Entretanto, não houve correlação entre a VFC e leptina em ambos os grupos. Desta forma, identificou-se ruptura do ritmo circadiano e a associação entre o balanço autonômico e os níveis de adiponectina e aldosterona plasmática na HAR com e sem diabetes tipo 2
Abstract: Considering the strong association between the autonomic nervous system activity, obesity and insulin resistance in resistant hypertension (RH), this research aimed to identify the association of the autonomic nervous system function and important hormones related to the cardiometabolic syndrome such as adiponectin, leptin and aldosterone. Twenty five RH patients were divided into two groups: with (T2D) and without type-2 diabetes (NT2D). Both groups were evaluated regarding the heart rate variability (HRV) by the Holter system in 24 hours, in time and frequency domains, and the plasma hormones adiponectin, leptin and aldosterone. The analysis of the results demonstrated greater autonomic dysfunction and hypoadiponectinemia in T2D subgroup compared to the NT2D subgroup, positive correlation between HRV in time domain and adiponectin in all patients, circadian disruption in both groups (increased sympathetic drive during nighttime and decreased during daytime; increased parasympathetic drive during daytime and decreased during nighttime) and positive correlation between the low frequency band in normalized units (LFnu) and aldosterone, and negative correlation between the high frequency band in normalized units (HFnu) and aldosterone in all patients and both subgroups. The T2D subgroup had higher levels of leptin and body mass index. However, there was no correlation between HRV and leptin in both groups. Thereby, it was found circadian disruption and the relationship between autonomic balance and plasma adiponectin and aldosterone in RH with or without type 2 diabetes
Doutorado
Doutor em Farmacologia
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Alejevski, Faredin. "Photoentrainment of the Drosophila circadian clock through visual system." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS200.
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La rotation de la Terre oblige les organismes vivants à s’adapter aux modifications cycliques de l’environnement, et tout particulièrement aux changements de lumière et de température. Des unicellulaires à l’Homme, la plupart des espèces ont développé des horloges circadiennes, qui leur permettent d’anticiper les transitions jour-nuit. La lumière constitue le signal majeur pour la synchronisation de l’horloge. En cycles jour-nuit, les drosophiles présentent un profil d’activité locomotrice bimodal, avec un premier pic autour de l’aube et le deuxième au crépuscule. Chez cet insecte, la perception de la lumière est assurée à la fois par un système complexe, constitué des yeux composés, des ocelles et de l’eyelet d’Hofbauer-Buchner. Ces organes contiennent des photorécepteurs (PRs) exprimant six protéines photosensibles différentes, les rhodopsines (Rh1 à Rh6). Une septième rhodopsine (Rh7) a été décrite dans quelques neurones de l’horloge cérébrale. La lumière est également perçue directement dans la plupart des neurones d’horloge grâce à une protéine photosensible, le cryptochrome (Cry). Les différentes études du rôle de la lumière sur l’entraînement de l’horloge ont essentiellement porté sur la voie cry-dépendante, en utilisant de courts flashs lumineux pour recaler l’horloge cérébrale. Notre étude s’est intéressée à l’entraînement de l’horloge via les rhodopsines. Quels types de photorécepteur sont impliqués ? Après l’activation de la cascade de phototransduction et la libération de l’histamine par les photorécepteurs, quels neurones, exprimant les récepteurs à l’histamine Ort et Hiscl1, participent à l’entraînement de l’horloge circadienne ? Une première partie présente l’étude de l’implication des 6 rhodopsines dans l’entraînement circadien. Tout d’abord, nous avons mis en évidence la fonction de photorécepteurs spécifiques (exprimant Rh1 ou Rh6) dans la voie NorpA-dépendante (Saint-Charles et al. J Comp Neurol 2016). Nous avons ensuite généré des lignées de drosophiles n’exprimant aucune ou qu’une seule rhodopsine. Sans rhodopsine ni Cry les mouches sont incapables de se synchroniser sur les cycles jour-nuit, quelle que soit l’intensité lumineuse. En lumière faible, l’input pour l’entraînement vient principalement des photorécepteurs exprimant Rh1 et Rh6. En forte lumière, chacune des 6 rhodopsines des différents photorécepteurs est capable d’entrainer l’horloge, Rh1, Rh5 et Rh6 étant les plus efficaces ( Alejevski et al., in prep). Une deuxième partie présente la caractérisation des voies neuronales connectant directement ou indirectement les PRs à l’horloge cérébrale. L’horloge circadienne de mouches mutantes, à la fois pour le cryptochrome et les 2 récepteurs à l’histamine, est « aveugle » alors que les mutantes pour Cry mais possédant l’un ou l’autre récepteur à l’histamine sont capables de se synchroniser sur les cycles de lumière. La ré-expression chez les mutants de Ort ou Hiscl1 dans les neurones d’horloge ne restaure pas l’entraînement, suggérant ainsi l’absence de connexions directes entre les PRs histaminergiques et les neurones d’horloge. Nos expériences de sauvetage comportemental mettent en évidence des connexions fonctionnelles entre certains interneurones Ort des lobes optiques et les neurones d’horloge. En revanche et de façon inattendue, nous n’observons d’entraînement circadien que lorsque nous ré-exprimons Hiscl1 dans les seuls PRs Rh6. Nos résultats révèlent que les photorécepteurs interviennent dans l’entraînement à la fois comme photorécepteurs et comme interneurones, cibles d’input histaminergique, rappelant ainsi le double rôle des cellules ganglionnaires de la rétine exprimant la mélanopsine chez les mammifères (Alejevski et al. Nat Commun, in revision)The rotation of the earth forces living organisms to adapt to its cyclic environment, in particular light and temperature changes. From unicellular organisms to humans, almost all species have evolved circadian clocks, which allow them to anticipate day-night transitions and use light as the most powerful synchronizing cue. In light-dark cycles, D. melanogaster flies display a bimodal locomotor activity with peaks around dawn and dusk. To perceive light, Drosophila has evolved a complex visual system, composed of compound eyes, ocelli and Hofbauer-Buchner eyelet. These organs contain photoreceptors (PRs) expressing six different light receptors named rhodopsins (Rh1 to Rh6). In addition, one rhodopsin (Rh7) is found in some of the clock neurons in the brain. Most of the clock cells also express another type of light receptor, Cryptochrome (Cry). Most studies about clock entrainment by light have focused on the Cry-dependent light input, which allows short light pulses to reset the brain clock. The present thesis focuses on the entrainment of the brain clock through rhodopsins. In photoreceptors, rhodopsins capture photons and activate a transduction cascade, where a key player is the phospholipase C (PLC) encoded by norpA. Mutants deficient for Cry and NorpA do not synchronize at low light intensity but still entrain with high light, indicating that an unknown NorpA-independent pathway is also used by the clock. Light induces a depolarization of the PRs, which release histamine as a neurotransmitter, but their role in circadian entrainment is unknown. Which type of rhodopsine-expressing photoreceptors are implicated? After the phototransduction cascade activation and the release of histamine from the photoreceptors, which downstream neurons expressing the histamine-gated chloride channels Ort and Hiscl1 (whose function has been studied in the visual behavior) are involved in the circadian entrainment? The first part of the thesis was to study the function of the 6 PR rhodopsins in circadian entrainment. I first contributed to studying the function of the specific photoreceptors in the NorpA-dependent pathway (Saint-Charles et al. J Comp Neurol 2016). Then, we generated genotypes having either none or only one of the six PR rhodopsins. Mutants with no Cry and none of the 6 PR rhodopsins could not synchronize with light-dark (LD) cycles (low light or high light). In low light, Rh1 and Rh6 were the main light input for entrainment. In high-light, each one of the 6 PR rhodopsins can provide entrainment, with Rh1, Rh5 and Rh6 being the most efficient (Alejevski et al., in prep).The second part of the work was to identify the neuronal pathways that connect the PRs to the brain circadian clock. Flies deficient for Cry and the two histamine receptors are circadianly blind, whereas Cry mutants having either Ort or Hiscl1 are able to entrain. Thus, each one of the two receptors supports circadian entrainment. Rescuing Ort or Hiscl1 in the clock cells could not restore entrainment, indicating that there is no direct histaminergic connection between PRs and clock neurons. Our rescue experiments revealed several pathways in otic lobes that rely on Ort-expressing interneurons to entrain the clock. In contrast and unexpectedly, we observed that the expression of Hiscl1 in PRs but not in interneurons was involved in circadian entrainment. In fact, only Hiscl1 expression in Rh6 PRs mediates entrainment. Our work thus reveals Rh6-expressing PRs as both photoreceptors and histamine-receiving interneurons in the rhodopsin-dependent entrainment pathway, which recalls the role of melanopsin-expressing retinal ganglion cells in the mammalian retina (Alejevski et al. Nat Commun, in revision)
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Malloy, Jaclyn. "CENTRAL AND PERIPHERAL REGULATION OF CIRCADIAN GASTROINTESTINAL RHYTHMS." UKnowledge, 2012. http://uknowledge.uky.edu/biology_etds/5.
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Circadian clocks are responsible for daily rhythms in gastrointestinal function which are vital for normal digestive rhythms and health. The present study examines the roles of the circadian pacemaker, the suprachiasmatic nuclei (SCN), and the sympathetic nervous system in regulation of circadian gastrointestinal rhythms in Mus musculus. Surgical ablation of the SCN abolishes circadian locomotor, feeding, and stool output rhythms when animals are presented with food ad libitum, while restricted feeding reestablishes these rhythms temporarily. In intact mice, chemical sympathectomy with 6- hydroxydopamine has no effect on feeding and locomotor rhythmicity, but attenuates stool output rhythms. Again, restricted feeding reestablishes these rhythms. Ex vivo, intestinal tissue from mPer2LUC knockin mice expresses circadian rhythms of luciferase bioluminescence. 6-hydroxydopamine has little effect upon these rhythms, but timed administration of β−adrenergic agonist isoproterenol causes a phase-dependent phase shift in PERIOD2 expression rhythms. Collectively, the data suggest the SCN are required to maintain feeding, locomotor and stool output rhythms during ad libitum conditions, acting at least in part through daily activation of sympathetic activity. Even so, this input is not necessary for entrainment to timed feeding, which may be the province of oscillators within the intestines themselves or other components of the gastrointestinal system.
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Zhang, Xiaofan. "Function of CikA in the cyanobacterial circadian system: the pseudo-receiver domain of CikA regulates the circadian input pathway." Texas A&M University, 2006. http://hdl.handle.net/1969.1/4261.
Full textAbstract:
The circadian input kinase gene (cikA) was first identified from a Tn5 mutant
of Synechococcus elongatus PCC 7942. A cikA null strain shows a striking
phenotype related to circadian gene regulation: all sampled loci show a
shortened circadian period and reduced amplitude of oscillation and a failure to
exhibit a wild-type resetting of the phase of the rhythm after an environmental
signal. This global defect in response to the environment suggests a key role for
CikA in the circadian input pathways. Bioinformatics results classify CikA as a
divergent member of the bacteriophytochrome family, suggesting a role in light
signal transduction. In vitro analysis previously showed that CikA is a bona fide
histidine protein kinase (HPK), and its kinase activity is regulated by the
presence of other domains. Its own pseudo-receiver (PsR) domain is not the
cognate receiver domain of its kinase HPK domain, and its GAF domain does
not likely bind a bilin chromophore as do photoreceptive phytochromes. Recent
results suggested that CikA may function as a redox-sensor. In this study, we examined the function of each domain of CikA using
different mutant cikA alleles, and determined their phenotypes with respect to
complementation of a null mutant and overexpression in both wild type and cikA
null strains. All domains except the featureless N-terminus were required for
CikA function. Overexpression of all mutant alleles that encoded the PsR
domain, whether or not the HPK was functional, caused a dominant arrhythmia
phenotype. In the absence of PsR, overexpressed variants did not cause
arrhythmia, but affected the amplitude and period of oscillation. The results
suggest a model in which the PsR domain regulates kinase activity and
mediates interaction with other input pathway components to allow CikA to reach
the correct cellular position to fulfill its function. Cellular localization assays
showed CikA can interact with a complex and showed a polar localization
pattern, whereas its variant without PsR showed uniform distribution in the cell.
In summary, CikA is an autoregulated kinase in which the PsR domain
regulates activity of the HPK domain and also serves as an interaction module to
lead the CikA to a specific cellular position.
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Diop, Ousmane. "Analyse mathématique de la dynamique de réseaux de régulation biologique." Electronic Thesis or Diss., université Paris-Saclay, 2020. http://www.theses.fr/2020UPASG013.
Full textAbstract:
Dans cette thèse, nous nous intéressons à l'analyse qualitative de la dynamique de deux cycles biologiques centraux dans les cellules eucaryotes, le cycle de division cellulaire et l'horloge circadienne. Nous utilisons pour cela des réseaux Booléens asynchrones, bien adaptés à une analyse qualitative. Dans ces réseaux, les cycles sont capturés par des attracteurs complexes, pouvant contenir des centaines d'états. Nous proposons une nouvelle méthode d'analyse de ces attracteurs complexes, basée sur la construction d'un graphe résumé. Cette méthode permet de comparer les trajectoires contenues l'attracteur avec les propriétés qualitatives du cycle biologique. Nous illustrons notre méthode sur un modèle du cycle cellulaire de la littérature et sur un modèle de l'horloge circadienne, que nous avons construit à partir d'un modèle continu existant. Dans ces deux modèles, notre méthode s'est montrée efficace pour visualiser la structure de l'attracteur complexe et le comparer avec un cycle biologique. En combinant le graphe résumé avec une chaîne de Markov, nous estimons les proportions de temps passé dans les phases décrites par les oscillations. En le combinant avec une méthode d'inférence Booléenne, nous montrons également comment ajuster localement la dynamique asymptotique du modèle, afin de forcer certaines propriétés dynamiques. Ces deux applications montrent l'intérêt de notre méthode pour la modélisation et l'analyse de réseaux de régulation cellulaireIn this thesis, we are interested in the qualitative analysis of the dynamics of two biological cycles that are central in eukaryotic cells, the cell division cycle and the circadian clock. For that purpose, we use asynchronous Boolean networks that provide an adapted qualitative framework. In these networks, cycles are captured by complex attractors containing hundreds of states. A new method for the analysis of such complex attractors is proposed. It is based on the construction of a summary graph of the attractor, enabling the comparison between the attractor's trajectories and qualitative properties of the biological cycle. The method is illustrated on a cell cycle model from the literature and of a circadian clock model we built from an existing continuous model. In both models our method proves to be efficient to visualize the attractor's structure and to compare it with the biological cycle. By combining the summary graph with a Markov chain, proportions of time spent in each phase are estimated. By combining it with a Boolean inference technique, we show how to locally adjust the asymptotic dynamics of the model in order to force specific dynamical properties. These two applications show the interest of our method in the modeling and analysis of cellular regulatory networks