Inferring Drosophila gap gene regulatory network: a parameter sensitivity and perturbation analysis

<p>Abstract</p> <p>Background</p> <p>Inverse modelling of gene regulatory networks (GRNs) capable of simulating continuous spatio-temporal biological processes requires accurate data and a good description of the system. If quantitative relations between genes cannot be extracted from direct measurements, an efficient method to estimate the unknown parameters is mandatory. A model that has been proposed to simulate spatio-temporal gene expression patterns is the connectionist model. This method describes the quantitative dynamics of a regulatory network in space. The model parameters are estimated by means of model-fitting algorithms. The gene interactions are identified without making any prior assumptions concerning the network connectivity. As a result, the inverse modelling might lead to multiple circuits showing the same quantitative behaviour and it is not possible to identify one optimal circuit. Consequently, it is important to address the quality of the circuits in terms of model robustness.</p> <p>Results</p> <p>Here we investigate the sensitivity and robustness of circuits obtained from reverse engineering a model capable of simulating measured gene expression patterns. As a case study we use the early gap gene segmentation mechanism in <it>Drosophila melanogaster</it>. We consider the limitations of the connectionist model used to describe GRN Inferred from spatio-temporal gene expression. We address the problem of circuit discrimination, where the selection criterion within the optimization technique is based of the least square minimization on the error between data and simulated results.</p> <p>Conclusion</p> <p>Parameter sensitivity analysis allows one to discriminate between circuits having significant parameter and qualitative differences but exhibiting the same quantitative pattern. Furthermore, we show that using a stochastic model derived from a deterministic solution, one can introduce fluctuations within the model to analyze the circuits' robustness. Ultimately, we show that there is a close relation between circuit sensitivity and robustness to fluctuation, and that circuit robustness is rather modular than global. The current study shows that reverse engineering of GRNs should not only focus on estimating parameters by minimizing the difference between observation and simulation but also on other model properties. Our study suggests that multi-objective optimization based on robustness and sensitivity analysis has to be considered.</p

Inferring Drosophila gap gene regulatory network: pattern analysis of simulated gene expression profiles and stability analysis

<p>Abstract</p> <p>Background</p> <p>Inference of gene regulatory networks (GRNs) requires accurate data, a method to simulate the expression patterns and an efficient optimization algorithm to estimate the unknown parameters. Using this approach it is possible to obtain alternative circuits without making any <it>a priori </it>assumptions about the interactions, which all simulate the observed patterns. It is important to analyze the properties of the circuits.</p> <p>Findings</p> <p>We have analyzed the simulated gene expression patterns of previously obtained circuits that describe gap gene dynamics during early <it>Drosophila melanogaster </it>embryogenesis. Using hierarchical clustering we show that amplitude variation and defects observed in the simulated gene expression patterns are linked to similar circuits, which can be grouped. Furthermore, analysis of the long-term dynamics revealed four main dynamical attractors comprising stable patterns and oscillatory patterns. In addition, we also performed a correlation analysis on the parameters showing an intricate correlation pattern.</p> <p>Conclusions</p> <p>The analysis demonstrates that the obtained gap gene circuits are not unique showing variable long-term dynamics and highly correlating scattered parameters. Furthermore, although the model can simulate the pattern up to gastrulation and confirms several of the known regulatory interactions, it does not reproduce the transient expression of all gap genes as observed experimentally. We suggest that the shortcomings of the model may be caused by overfitting, incomplete model description and/or missing data.</p

Effects of Seven Fungicides on Non-Target Aquatic Fungi

Aquatic risk assessments for fungicides are carried out without information on their toxicity to non-target aquatic fungi. This might cause an underestimation of the toxic effects to the aquatic fungal community. This study focuses on the question whether recently derived concentrations limits for fungicides considered to protect populations of primary producers and (in)vertebrates also do protect the aquatic fungi. A panel of fungal species and Oomycetes was isolated and identified from unpolluted surface waters in the Netherlands. Toxicity tests were used to determine effects of seven fungicides with different modes of actions. For the triazoles epoxiconazole and tebuconazole, the chronic lowest observable effect concentration was lower than the regulatory acceptable concentration based on acute HC5 values

The effect of financial and educational incentives on rational prescribing:A state-space approach

In 2005, a Dutch health insurer introduced a financial incentive directed to general practitioners to promote rational prescribing of statins and proton pump inhibitors (PPIs). Concomitantly, a regional institution that develops pharmacotherapeutic guidelines implemented two educational interventions also aiming at promoting rational statin and PPI prescribing. Utilizing a prescription database, we estimated the effect of the interventions on drug utilization and cost of statins and PPIs over time. We measured the effect of the interventions within an implementation and a control region. The implementation region included prescriptions from the province of Groningen where the educational intervention was implemented and where the health insurer is most active. The control region comprised all other provinces covered by the database. We modelled the effect of the intervention using a state-space approach. Significant differences in prescribing and cost patterns between regions were observed for statins and PPIs. These differences however were mostly related to the concurrent interventions of Proeftuin Farmacie Groningen. We found no evidence indicating a significant effect of the rational prescribing intervention on the prescription patterns of statins and PPIs. Our estimates on the economic impact of the Proeftuin Farmacie Groningen interventions indicate that educational activities as such can achieve significant cost savings. Copyright © 2014 John Wiley & Sons, Ltd

A cell-based model of Nematostella vectensis gastrulation including bottle cell formation, invagination and zippering

AbstractThe gastrulation of Nematostella vectensis, the starlet sea anemone, is morphologically simple yet involves many conserved cell behaviors such as apical constriction, invagination, bottle cell formation, cell migration and zippering found during gastrulation in a wide range of more morphologically complex animals.In this article we study Nematostella gastrulation using a combination of morphometrics and computational modeling. Through this analysis we frame gastrulation as a non-trivial problem, in which two distinct cell domains must change shape to match each other geometrically, while maintaining the integrity of the embryo. Using a detailed cell-based model capable of representing arbitrary cell-shapes such as bottle cells, as well as filopodia, localized adhesion and constriction, we are able to simulate gastrulation and associate emergent macroscopic changes in embryo shape to individual cell behaviors.We have developed a number of testable hypotheses based on the model. First, we hypothesize that the blastomeres need to be stiffer at their apical ends, relative to the rest of the cell perimeter, in order to be able to hold their wedge shape and the dimensions of the blastula, regardless of whether the blastula is sealed or leaky. We also postulate that bottle cells are a consequence of cell strain and low cell–cell adhesion, and can be produced within an epithelium even without apical constriction. Finally, we postulate that apical constriction, filopodia and de-epithelialization are necessary and sufficient for gastrulation based on parameter variation studies

В. Липинський про бюрократію ("Листи до братів-хліборобів"): до проблеми визначення теоретичного підґрунтя поглядів

Розглянуто формування поглядів В. Липинського на бюрократію під впливом ідей Ж. Сореля, Р. Міхельса, К. Маркса, А. де Токвіля. Стверджено, що основу його поглядів становлять ідеї про бюрократію, запозичені у Ж. Сореля та Р. Міхельса. Підкреслено, що під час розгляду проблеми бюрократії вітчизняний мислитель не звертався до ідей М. Вебера.Deals with the formation of attitudes of Viacheslav Lypynsky on bureaucracy under the influence of Georges Sorel, Robert Michels, Karl Marx, Alexis de Tocqueville. It is alleged that his views were based on ideas of the bureaucracy borrowed from Georges Sorel and Robert Michels. Emphasizing that, in considering the problem of bureaucracy Ukrainian thinker did not approach the ideas of Max Weber

Exposure to TARC alters beta2-adrenergic receptor signaling in human peripheral blood T lymphocytes

The beta(2)-adrenergic receptor (beta(2)-AR) negatively regulates T cell activity through the activation of the G(s)/adenylyl cyclase/cAMP pathway. beta(2)-AR desensitization, which can be induced by its phosphorylation, may have important consequences for the regulation of T cell function in asthma. In the present study we demonstrate that the C-C chemokine thymus and activation-regulated chemokine (TARC) impairs the ability of beta(2)-agonist fenoterol to activate the cAMP downstream effector cAMP-responsive element binding protein (CREB) in freshly isolated human T cells. The TARC-induced activation of Src kinases resulted in membrane translocation of both G protein-coupled receptor kinase (GRK) 2 and beta-arrestin. Moreover, TARC was able to induce Src-dependent serine phosphorylation of the beta(2)-AR as well as its association with GRK2 and beta-arrestin. Finally, in contrast to CREB, phosphorylation of Src and extracellular signal-regulated kinase was enhanced by fenoterol upon TARC pretreatment. In summary, we show for the first time that TARC exposure impairs beta(2)-AR function in T cells. Our data suggest that this is mediated by Src-dependent activation of GRK2, resulting in receptor phosphorylation, binding to beta-arrestin, and a switch from cAMP-dependent signaling to activation of the MAPK pathway. We propose that aberrant T cell control in the presence of endogenous beta-agonists promotes T cell-mediated inflammation in asthma