1,720,968 research outputs found
Intrinsic Feedbacks in MAPK Signaling Cascades Lead to Bistability and Oscillations
Get PDFPrevious studies have demonstrated that double phosphorylation of a protein can lead to bistability if some conditions are fulfilled. It was also shown that the signaling behavior of a covalent modification cycle can be quantitatively and, more importantly, qualitatively modified when this cycle is coupled to a signaling pathway as opposed to being isolated. This property was named retroactivity. These two results are studied together in this paper showing the existence of interesting phenomena—oscillations and bistability—in signaling cascades possessing at least one stage with a double-phosphorylation cycle as in MAPK cascades.Fil: Sepulchre, Jacques Alexandre. Universite Nice; FranciaFil: Ventura, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin
Pseudo-nullclines enable the analysis and prediction of signaling model dynamics
Get PDFA powerful method to qualitatively analyze a 2D system is the use of nullclines, curves which separate regions of the plane where the sign of the time derivatives is constant, with their intersections corresponding to steady states. As a quick way to sketch the phase portrait of the system, they can be sufficient to understand the qualitative dynamics at play without integrating the differential equations. While it cannot be extended straightforwardly for dimensions higher than 2, sometimes the phase portrait can still be projected onto a 2-dimensional subspace, with some curves becoming pseudo-nullclines. In this work, we study cell signaling models of dimension higher than 2 with behaviors such as oscillations and bistability. Pseudo-nullclines are defined and used to qualitatively analyze the dynamics involved. Our method applies when a system can be decomposed into 2 modules, mutually coupled through 2 scalar variables. At the same time, it helps track bifurcations in a quick and efficient manner, key for understanding the different behaviors. Our results are both consistent with the expected dynamics, and also lead to new responses like excitability. Further work could test the method for other regions of parameter space and determine how to extend it to three-module systems.Fil: Marrone, Juan Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Sepulchre, Jacques Alexandre. Centre National de la Recherche Scientifique; FranciaFil: Ventura, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentin
Signaling cascades transmit information downstream and upstream but unlikely simultaneously
Get PDFBackground: Signal transduction is the process through which cells communicate with the external environment, interpret stimuli and respond to them. This mechanism is controlled by signaling cascades, which play the role of intracellular transmitter, being able to transmit biochemical information between cell membrane and nucleus. In theory as well as in practice, it has been shown that a perturbation can propagate upstream (and not only downstream) a cascade, by a mechanism known as retroactivity. This study aims to compare the conditions on biochemical parameters which favor one or the other direction of signaling in such a cascade. Results: From a mathematical point of view, we show that the steady states of a cascade of arbitrary length n are described by an iterative map of second order, meaning that the cascade tiers are actually coupled three-by-three. We study the influence of the biochemical parameters in the control of the direction of transmission - upstream and/or downstream - along a signaling cascade. A numerical and statistical approach, based on the random scan of parameters describing a 3-tier signaling cascade, provides complementary findings to the analytical study. In particular, computing the likelihood of parameters with respect to various signaling regimes, we identify conditions on biochemical parameters which enhance a specific direction of propagation corresponding to forward or retro-signaling regimes. A compact graphical representation is designed to relay the gist of these conditions. Conclusions: The values of biochemical parameters such as kinetic rates, Michaelis-Menten constants, total concentrations of kinases and of phosphatases, determine the propensity of a cascade to favor or impede downstream or upstream signal transmission. We found that generally there is an opposition between parameter sets favoring forward and retro-signaling regimes. Therefore, on one hand our study supports the idea that in most cases, retroactive effects can be neglected when a cascade which is efficient in forward signaling, is perturbed by an external ligand inhibiting the activation at some tier of the cascade. This result is relevant for therapeutic methodologies based on kinase inhibition. On the other hand, our study highlights a less-known part of the parameter space where, although the forward signaling is inefficient, the cascade can interestingly act as a retro-signaling device.Fil: Catozzi, Simona. Université Côte d’Azur; FranciaFil: Di Bella, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Ventura, Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Sepulchre, Jacques Alexandre. Université Côte d’Azur; Franci
Retroactivity in signal transduction : a comparative study of forward and backward responses in signaling cascades
No full textLes cellules communiquent avec leur environnement par l’intermédiaire d’un réseau de transduction du signal, leur permettant d’interpréter des signaux physico-chimiques et de produire des réponses appropriées. Ce mécanisme est orchestré par des cascades de signalisation, qui jouent le rôle d’émetteurs intracellulaires en transférant des stimuli biochimiques entre la membrane et le noyau. Il a été montré qu’une perturbation peut se propager en amont (et pas seulement en aval) d’une cascade par un phénomène appelé rétroactivité. Notre étude vise à comparer les conditions biochimiques qui favorisent un et/ou l’autre sens de signalisation dans des cascades linéaires. Au moyen d’approches analytiques et numériques, nous avons caractérisé les différents régimes de signalisation résultants, que nous avons résumés avec une représentation graphique compacte. Nous avons également développé le concept de profil d’activation d’une voie de signalisation qui est, pour un stimulus donné, la séquence des protéines activées à chaque niveau de la cascade à l’état stationnaire. Ces séquences correspondent à des morceaux d’orbites d’un système dynamique discret bidimensionnel. A partir de l’étude des portraits de phase, en fonction des paramètres biochimiques, nous avons étudié les propriétés de contraction/expansion autour des points fixes et de leurs bifurcations. Nous avons classifié les niveaux de cascade en trois types et examiné leur impact biologique au sein d’un réseau de signalisation. Cette méthode a également fourni une vision globale de l’interaction entre la signalisation en avant et rétroactive, et de l’amplification du signal le long du profil d’activation de la cascadeLiving cells communicate with their external environment, by means of a signal transduction network, which allows them to interpret physico-chemical signals and produce appropriate responses. This complex machinery is orchestrated by signaling cascades, which play the role of intracellular transmitters, by transferring biochemical stimuli between cellular membrane and nucleus. It has been shown that a perturbation can propagate upstream (and not only downstream) a cascade, through a phenomenon called retroactivity. Our investigation aims to compare the biochemical conditions promoting one and/or the other direction of signaling in linear cascades. By means of analytical and numerical approaches, we have answered to this question, by characterizing the arising different signaling regimes, and we have designed a compact graphical representation to relay the gist of such conditions. We have also developed the concept of pathway activation profile which is, for a given stimulus, the sequence of activated proteins at each tier of the cascade, at steady state. Such sequences correspond to pieces of orbits of a two-dimensional discrete dynamical system. From the study of the possible phase portraits, as a function of the biochemical parameters, we focused on the contraction/expansion properties around the fixed points of this discrete map, and their bifurcations. We have deduced a classification of the cascade tiers into three main types, whose biological impact within a signaling network has been examined. This method also provided global insights about the interplay between forward and retroactive signaling, and how signal is amplified along the cascade activation profil
Phénomènes spatio-temporels dans des réseaux d'oscillateurs
No full textDoctorat en Sciencesinfo:eu-repo/semantics/nonPublishe
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Linear response, susceptibility and resonances in chaotic toy models
No full text16International audienceWe consider simple examples illustrating some new features of the linear response theory developed by Ruelle for dissipative and chaotic systems [D. Ruelle, Smooth dynamics and new theoretical ideas in nonequilibrium statistical mechanics, J. Stat. Phys. 95 (1999) 393–468]. In this theory the concepts of linear response, susceptibility and resonance, which are familiar to physicists, have been revisited due to the dynamical contraction of the whole phase space onto attractors. In particular the standard framework of the “fluctuation–dissipation” theorem breaks down and new resonances can show up outside the power spectrum. In previous papers we proposed and used new numerical methods to demonstrate the presence of the new resonances predicted by Ruelle in a model of chaotic neural networks. In this article we deal with simpler models which can be worked out analytically in order to gain more insights into the genesis of the “stable” resonances and their consequences on the linear response of the system. We consider a class of two-dimensional time-discrete maps describing simple rotator models with a contracting radial dynamics onto the unit circle and a chaotic angular dynamics ?t+1=2?t(mod2?). A generalisation of this system to a network of interconnected rotators is also analysed and related with our previous studies [B. Cessac, J.-A. Sepulchre, Stable resonances and signal propagation in a chaotic network of coupled units, Phys. Rev. E 70 (2004) 056111; B. Cessac, J.-A. Sepulchre, Transmitting a signal by amplitude modulation in a chaotic network, Chaos 16 (2006) 013104-1–13104-12]. These models permit us to classify the different types of resonances in the susceptibility and to discuss in particular the relation between the relaxation time of the system to equilibrium with the mixing time given by the decay of the correlation functions. Also it enables one to propose some general mechanisms responsible for the creation of stable resonances with arbitrary frequencies, widths, and dependence on the pair of perturbed/observed variables
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