Organising metabolic networks: cycles in flux distributions

Metabolic networks are among the most widely studied biological systems. The topology and interconnections of metabolic reactions have been well described for many species, but are not sufficient to understand how their activity is regulated in living organisms. The principles directing the dynamic organisation of reaction fluxes remain poorly understood. Cyclic structures are thought to play a central role in the homeostasis of biological systems and in their resilience to a changing environment. In this work, we investigate the role of fluxes of matter cycling in metabolic networks. First, we introduce a methodology for the computation of cyclic and acyclic fluxes in metabolic networks, adapted from an algorithm initially developed to study cyclic fluxes in trophic networks. Subsequently, we apply this methodology to the analysis of three metabolic systems, including the central metabolism of wild type and a deletion mutant of Escherichia coli, erythrocyte metabolism and the central metabolism of the bacterium Methylobacterium extorquens. The role of cycles in driving and maintaining the performance of metabolic functions upon perturbations is unveiled through these examples. This methodology may be used to further investigate the role of cycles in living organisms, their pro-activity and organisational invariance, leading to a better understanding of biological entailment and information processing

Reconstruction of an in silico metabolic model of _Arabidopsis thaliana_ through database integration

The number of genome-scale metabolic models has been rising quickly in recent years, and the scope of their utilization encompasses a broad range of applications from metabolic engineering to biological discovery. However the reconstruction of such models remains an arduous process requiring a high level of human intervention. Their utilization is further hampered by the absence of standardized data and annotation formats and the lack of recognized quality and validation standards.

Plants provide a particularly rich range of perspectives for applications of metabolic modeling. We here report the first effort to the reconstruction of a genome-scale model of the metabolic network of the plant _Arabidopsis thaliana_, including over 2300 reactions and compounds. Our reconstruction was performed using a semi-automatic methodology based on the integration of two public genome-wide databases, significantly accelerating the process. Database entries were compared and integrated with each other, allowing us to resolve discrepancies and enhance the quality of the reconstruction. This process lead to the construction of three models based on different quality and validation standards, providing users with the possibility to choose the standard that is most appropriate for a given application. First, a _core metabolic model_ containing only consistent data provides a high quality model that was shown to be stoichiometrically consistent. Second, an _intermediate metabolic model_ attempts to fill gaps and provides better continuity. Third, a _complete metabolic model_ contains the full set of known metabolic reactions and compounds in _Arabidopsis thaliana_.

We provide an annotated SBML file of our core model to enable the maximum level of compatibility with existing tools and databases. We eventually discuss a series of principles to raise awareness of the need to develop coordinated efforts and common standards for the reconstruction of genome-scale metabolic models, with the aim of enabling their widespread diffusion, frequent update, maximum compatibility and convenience of use by the wider research community and industry

Calcul rapide de forces et de déformations mécaniques non-linéaires et visco-élastiques pour la simulation de chirurgie

Ce travail présente une méthode de calcul rapide de déformations et de forces mécaniques destinée à la simulation d'applications chirurgicales. La simulation de chirurgie vise à offrir aux praticiens des outils leur permettant de pratiquer des entraînements intensifs et de pouvoir planifier avec précision certaines interventions. La conception de tels simulateurs nécessite de disposer de modèles géométriques et mécaniques précis des organes du corps humain, et d'algorithmes de calcul suffisamment rapides pour être capable d'utiliser ces modèles dans des conditions de temps réel. La plupart des simulateurs existants utilisent des modèles mécaniques extrêmement simples, basés sur les lois de l'élasticité linéaire. Or de nombreux résultats de biomécanique indiquent que les tissus biologiques se comportent selon des lois beaucoup plus complexes, incluant des effets non-linéaires et visco-élastiques importants. Pour cette raison, nous avons développé une méthode permettant le calcul rapide de déformations et de forces incluant des effets mécaniques non-linéaires et visco-élastiques. Cette méthode utilise la théorie des éléments finis et a été conçue comme une extension de l'algorithme dit des masses-tenseurs pour l'élasticité linéaire. Son principe consiste à pré-calculer un certain nombre de tenseurs dépendant des caractéristiques géométriques et mécaniques de chaque élément fini, qui sont ensuite combinés dans la phase de simulation proprement dite. Notre modèle non-linéaire ne présage d'aucune forme particulière de loi mécanique, de sorte que la méthode proposée est suffisamment générique pour s'appliquer à une grande variété de comportements et d'objets. Après la description de l'algorithme, de ses performances en terme de temps de calcul et de ses conditions de stabilité numérique, nous démontrons que cette méthode est capable de reproduire avec précision le comportement mécanique d'un tissu biologique mou. Ce travail s'inscrivant plus spécifiquement dans le cadre du développement d'un système de simulation de la cryochirurgie du foie, nous avons étudié expérimentalement les propriétés du foie lors de sa perforation par une aiguille à biopsie. Le modèle de masses-tenseurs non-linéaire et visco-élastique construit à l'aide des paramètres expérimentaux a pu reproduire avec une bonne précision les propriétés observées.This work presents a method for the fast computation of mechanical deformations and forces for the simulation of surgical applications. Surgery simulation aims at providing physicians with tools allowing extensive training and precise planning of given interventions. The design of such simulation systems requires accurate geometrical and mechanical models of the organs of the human body, as well as fast computation algorithms suitable for real-time conditions. Most existing simulation systems use very simple mechanical models, based on the laws of linear elasticity. Numerous biomechanical results yet indicate that biological tissues exhibit much more complex behaviour, including important non-linear and visco-elastic effects. For this reason, we developed a method allowing the fast computation of mechanical deformations and forces including non-linear and visco-elastic effects. This method uses finite element theory and has been constructed as an extension of the so-called tensor-mass algorithm for linear elasticity. It consists in pre-computing a set of tensors depending on the geometrical and mechanical properties of each finite element, which are later combined in the simulation part itself. Our non-linear model does not assume any particular form of mechanical law, so that the proposed method is generic enough to be applied to a wide variety of behaviours and objects. Following the description of the algorithm, of its performances in terms of computation time, and of its numerical stability conditions, we show that this method allows to reproduce the mechanical behaviour of a biological soft tissue with good precision. As this project is part of a broader effort aiming more specifically at developing a simulation system for liver cryosurgery, we experimentally characterized the properties of liver in perforation by a biopsy needle. The non-linear and visco-elastic tensor-mass model constructed from experimental parameters succeeded in accurately reproducing the observed properties

Sensory-motor interactions in speech perception, production and imitation: behavioral evidence from close shadowing, perceptuo-motor phonemic organization and imitative changes.

International audienceSpeech communication can be viewed as an interactive process involving a functional coupling between sensory and motor systems. In the present study, we combined three classical experimental paradigms to further test perceptuomotor interactions in both speech perception and production. In a first close shadowing experiment, auditory and audiovisual syllable identification led to faster oral than manual responses. In a second experiment, participants were asked to produce and to listen to French vowels, varying from height feature, in order to test perceptuo-motor phonemic organization and idiosyncrasies. In a third experiment, online imitative changes on the fundamental frequency in relation to acoustic vowel targets were observed in a non-interactive situation of communication during both unintentional and voluntary imitative production tasks. Altogether our results appear exquisitely in line with a functional coupling between action and perception speech systems and provide further evidence for a sensory-motor nature of speech representations

Sensory-motor interactions in speech perception, production and imitation: behavioral evidence from close shadowing, perceptuo-motor phonemic organization and imitative changes.

International audienceSpeech communication can be viewed as an interactive process involving a functional coupling between sensory and motor systems. In the present study, we combined three classical experimental paradigms to further test perceptuomotor interactions in both speech perception and production. In a first close shadowing experiment, auditory and audiovisual syllable identification led to faster oral than manual responses. In a second experiment, participants were asked to produce and to listen to French vowels, varying from height feature, in order to test perceptuo-motor phonemic organization and idiosyncrasies. In a third experiment, online imitative changes on the fundamental frequency in relation to acoustic vowel targets were observed in a non-interactive situation of communication during both unintentional and voluntary imitative production tasks. Altogether our results appear exquisitely in line with a functional coupling between action and perception speech systems and provide further evidence for a sensory-motor nature of speech representations

The shadow of a doubt? Evidence for perceptuo-motor linkage during auditory and audiovisual close-shadowing

One classical argument in favor of a functional role of the motor system in speech perception comes from the close shadowing task in which a subject has to identify and to repeat as quickly as possible an auditory speech stimulus. The fact that close shadowing can occur very rapidly and much faster than manual identification of the speech target is taken to suggest that perceptually-induced speech representations are already shaped in a motor-compatible format. Another argument is provided by audiovisual interactions often interpreted as referring to a multisensory-motor framework. In this study, we attempted to combine these two paradigms by testing whether the visual modality could speed motor response in a close-shadowing task. To this aim, both oral and manual responses were evaluated during the perception of auditory and audio-visual speech stimuli, clear or embedded in white noise. Overall, oral responses were faster than manual ones, but it also appeared that they were less accurate in noise, which suggests that motor representations evoked by the speech input could be rough at a first processing stage. In the presence of acoustic noise, the audiovisual modality led to both faster and more accurate responses than the auditory modality. No interaction was however observed between modality and response. Altogether, these results are interpreted within a two-stage sensory-motor framework, in which the auditory and visual streams are integrated together and with internally generated motor representations before a final decision may be available

Flux balance analysis reveals acetate metabolism modulates cyclic electron flow and alternative glycolytic pathways in Chlamydomonas reinhardtii

Cells of the green alga Chlamydomonas reinhardtii cultured in the presence of acetate perform mixotrophic growth, involving both photosynthesis and organic carbon assimilation. Under such conditions, cells exhibit a reduced capacity for photosynthesis but a higher growth rate, compared to phototrophic cultures. Better understanding of the downregulation of photosynthesis would enable more efficient conversion of carbon into valuable products like biofuels. In this study, Flux Balance Analysis (FBA) and Flux Variability Analysis (FVA) have been used with a genome scale model of C. reinhardtii to examine changes in intracellular flux distribution in order to explain their changing physiology. Additionally, a reaction essentiality analysis was performed to identify which reaction subsets are essential for a given growth condition. Our results suggest that exogenous acetate feeds into a modified tricarboxylic acid cycle, which bypasses the CO2 evolution steps, explaining increases in biomass, consistent with experimental data. In addition, reactions of the oxidative pentose phosphate and glycolysis pathways, inactive under phototrophic conditions, show substantial flux under mixotrophic conditions. Importantly, acetate addition leads to an increased flux through cyclic electron flow (CEF), but results in a repression of CO2 fixation via Rubisco, explaining the down regulation of photosynthesis. However, although CEF enhances growth on acetate, it is not essential – impairment of CEF results in alternative metabolic pathways being increased. We have demonstrated how the reactions of photosynthesis interconnect with carbon metabolism on a global scale, and how systems approaches play a viable tool in understanding complex relationships at the scale of the organism

Interaction between articulatory gestures and inner speech in a counting task

International audienceInteraction between covert and overt orofacial gestures has been poorly studied apart from old and rather qualitative experiments. The question deserves special interest in the context of the debate between auditory and motor theories of speech perception, where dual tasks may be of great interest. It is shown here that dynamic mandible and lips movement produced by a participant result in strong and stable perturbations to an inner speech counting task that has to be realized at the same time, while static orofacial configurations and static or dynamic manual actions produce no perturbation. This enables the authors to discuss how such kinds of orofacial perturbations could be introduced in dual task paradigms to assess the role of motor processes in speech perception

Deterministic mathematical models of the cAMP pathway in Saccharomyces cerevisiae

<p>Abstract</p> <p>Background</p> <p>Cyclic adenosine monophosphate (cAMP) has a key signaling role in all eukaryotic organisms. In <it>Saccharomyces cerevisiae</it>, it is the second messenger in the Ras/PKA pathway which regulates nutrient sensing, stress responses, growth, cell cycle progression, morphogenesis, and cell wall biosynthesis. A stochastic model of the pathway has been reported.</p> <p>Results</p> <p>We have created deterministic mathematical models of the PKA module of the pathway, as well as the complete cAMP pathway. First, a simplified conceptual model was created which reproduced the dynamics of changes in cAMP levels in response to glucose addition in wild-type as well as cAMP phosphodiesterase deletion mutants. This model was used to investigate the role of the regulatory Krh proteins that had not been included previously. The Krh-containing conceptual model reproduced very well the experimental evidence supporting the role of Krh as a direct inhibitor of PKA. These results were used to develop the Complete cAMP Model. Upon simulation it illustrated several important features of the yeast cAMP pathway: Pde1p is more important than is Pde2p for controlling the cAMP levels following glucose pulses; the proportion of active PKA is not directly proportional to the cAMP level, allowing PKA to exert negative feedback; negative feedback mechanisms include activating Pde1p and deactivating Ras2 via phosphorylation of Cdc25. The Complete cAMP model is easier to simulate, and although significantly simpler than the existing stochastic one, it recreates cAMP levels and patterns of changes in cAMP levels observed experimentally <it>in vivo </it>in response to glucose addition in wild-type as well as representative mutant strains such as <it>pde1Δ, pde2Δ</it>, <it>cyr1Δ</it>, and others. The complete model is made available in SBML format.</p> <p>Conclusion</p> <p>We suggest that the lower number of reactions and parameters makes these models suitable for integrating them with models of metabolism or of the cell cycle in <it>S. cerevisiae</it>. Similar models could be also useful for studies in the human pathogen <it>Candida albicans </it>as well as other less well-characterized fungal species.</p

L'ombre d'un doute ? Interactions perceptivo-motrices lors de tâches de close-shadowing auditive et audio-visuelles

International audienceOne classical argument in favor of a functional role of the motor system in speech perception comes from the close shadowing task in which a subject has to identify and to repeat as quickly as possible an auditory speech stimulus. The fact that close shadowing can occur very rapidly and much faster than manual identification of the speech target is taken to suggest that perceptually-induced speech representations are already shaped in a motor-compatible format. Another argument is provided by audiovisual interactions often interpreted as referring to a multisensory-motor framework. In this study, we attempted to combine these two paradigms by testing whether the visual modality could speed motor response in a close-shadowing task. To this aim, both oral and manual responses were evaluated during the perception of auditory and audio-visual speech stimuli, clear or embedded in white noise. Overall, oral responses were much faster than manual ones, but it also appeared that they were less accurate in noise, which suggests that motor representations evoked by the speech input could be rough at a first processing stage. In the presence of acoustic noise, the audiovisual modality led to both faster and more accurate responses than the auditory modality. No interaction was however observed between modality and response. Altogether, these results are interpreted within a two-stage sensory-motor framework, in which the auditory and visual streams are integrated together and with internally generated motor representations before a final decision may be available.Un argument classique en faveur des théories motrices de la perception de la parole provient du paradigme de " close-shadowing " (répétition rapide). Le fait que cette tâche de close-shadowing entraîne des réponses orales bien plus rapides qu'en réponses manuelles suggère en effet un codage des représentations perceptives dans un format moteur, compatible avec une réponse orale. Un autre argument est apporté par les interactions audio-visuelles lors de la perception de parole, souvent interprétées en référence à un couplage fonctionnel entre audition, vision et motricité. Dans cette étude, nous avons combiné ces deux paradigmes de manière à tester si la modalité visuelle pouvait induire des réponses motrices plus rapides lors d'une tâche de close-shadowing. Pour ce faire, différentes tâches de catégorisation orale et manuelle de stimuli de parole présentés auditivement ou audio-visuellement, en présence ou non d'un bruit blanc, ont été réalisées. De manière générale, les réponses orales ont été plus rapides que les réponses manuelles, mais aussi moins précises, notamment dans le bruit, ce qui suggère que la représentation motrice induite par la stimulation pourrait être peu précise dans un premier niveau de traitement. En présence d'un bruit acoustique, la modalité audiovisuelle s'est avérée à la fois plus rapide et plus précise que la modalité auditive. Aucune interaction entre le mode de réponse et la modalité de présentation des stimuli n'a cependant été observée. Nous interprétons l'ensemble de ces résultats dans un cadre théorique proposant l'existence de boucles perceptivo-motrices, dans lesquelles les entrées auditives et visuelles seraient intégrées et reliées à la génération interne de représentations motrices préalablement au processus final de décision