Effects of TV airtime regulation on advertising quality and welfare
In: Information economics and policy, Band 55, S. 100897
ISSN: 0167-6245
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In: Information economics and policy, Band 55, S. 100897
ISSN: 0167-6245
In: ECB Working Paper No. 1388
SSRN
Wineries face unprecedented challenges due to new market demands and climate change effects on wine quality. New yeast starters including non-conventional Saccharomyces species, such as S. kudriavzevii, may contribute to deal with some of these challenges. The design of new fermentations using non-conventional yeasts requires an improved understanding of the physiology and metabolism of these cells. Dynamic modeling brings the potential of exploring the most relevant mechanisms and designing optimal processes more systematically. In this work we explore mechanisms by means of a model selection, reduction and cross-validation pipeline which enables to dissect the most relevant fermentation features for the species under consideration, Saccharomyces cerevisiae T73 and Saccharomyces kudriavzevii CR85. The pipeline involved the comparison of a collection of models which incorporate several alternative mechanisms with emphasis on the inhibitory effects due to temperature and ethanol. We focused on defining a minimal model with the minimum number of parameters, to maximize the identifiability and the quality of cross-validation. The selected model was then used to highlight differences in behavior between species. The analysis of model parameters would indicate that the specific growth rate and the transport of hexoses at initial times are higher for S. cervisiae T73 while S. kudriavzevii CR85 diverts more flux for glycerol production and cellular maintenance. As a result, the fermentations with S. kudriavzevii CR85 are typically slower; produce less ethanol but higher glycerol. Finally, we also explored optimal initial inoculation and process temperature to find the best compromise between final product characteristics and fermentation duration. Results reveal that the production of glycerol is distinctive in S. kudriavzevii CR85, it was not possible to achieve the same production of glycerol with S. cervisiae T73 in any of the conditions tested. This result brings the idea that the optimal design of mixed cultures may have an enormous potential for the improvement of final wine quality. ; This project has received funding from the Spanish government (MINECO) and the European Regional Development Fund (ERDF) through the projects IMPROWINE (grant numbers AGL2015-67504-C3-1-R; AGL2015-67504-C3-2-R) to AQ and EB-C and the PROMETEO grant (ref. PROMETEOII/2014/042) from Generalitat Valenciana, Spain, to AQ. JA-d-R was supported by a FPI grant from the Ministerio de Economa y Competitividad, Spain (ref. BES-2013-066434). ; Peer Reviewed
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25 páginas, 7 figuras, 2 tablas.-- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited ; Despite significant efforts and remarkable progress, the inference of signaling networks from experimental data remains very challenging. The problem is particularly difficult when the objective is to obtain a dynamic model capable of predicting the effect of novel perturbations not considered during model training. The problem is ill-posed due to the nonlinear nature of these systems, the fact that only a fraction of the involved proteins and their posttranslational modifications can be measured, and limitations on the technologies used for growing cells in vitro, perturbing them, and measuring their variations. As a consequence, there is a pervasive lack of identifiability. To overcome these issues, we present a methodology called SELDOM (enSEmbLe of Dynamic lOgic-based Models), which builds an ensemble of logic-based dynamic models, trains them to experimental data, and combines their individual simulations into an ensemble prediction. It also includes a model reduction step to prune spurious interactions and mitigate overfitting. SELDOM is a data-driven method, in the sense that it does not require any prior knowledge of the system: the interaction networks that act as scaffolds for the dynamic models are inferred from data using mutual information. We have tested SELDOM on a number of experimental and in silico signal transduction case-studies, including the recent HPN-DREAM breast cancer challenge. We found that its performance is highly competitive compared to state-of-the-art methods for the purpose of recovering network topology. More importantly, the utility of SELDOM goes beyond basic network inference (i.e. uncovering static interaction networks): it builds dynamic (based on ordinary differential equation) models, which can be used for mechanistic interpretations and reliable dynamic predictions in new experimental conditions (i.e. not used in the training). For this task, SELDOM's ensemble prediction is not only consistently better than predictions from individual models, but also often outperforms the state of the art represented by the methods used in the HPN-DREAM challenge ; JRB and DH acknowledge funding from the EU FP7 project NICHE (ITN Grant number 289384). JRB acknowledges funding from the Spanish MINECO project SYNBIOFACTORY (grant number DPI2014-55276-C5-2-R). AFV acknowledges funding from the Galician government (Xunta de Galiza) through the I2C postdoctoral fellowship ED481B2014/133-0. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Peer reviewed
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Signaling pathways play a key role in complex diseases such as cancer, for which the development of novel therapies is a difficult, expensive and laborious task. Computational models that can predict the effect of a new combination of drugs without having to test it experimentally can help in accelerating this process. In particular, network-based dynamic models of these pathways hold promise to both understand and predict the effect of therapeutics. However, their use is currently hampered by limitations in our knowledge of the underlying biochemistry, as well as in the experimental and computational technologies used for calibrating the models. Thus, the results from such models need to be carefully interpreted and used in order to avoid biased predictions. Here we present a procedure that deals with this uncertainty by using experimental data to build an ensemble of dynamic models. The method incorporates steps to reduce overfitting and maximize predictive capability. We find that by combining the outputs of individual models in an ensemble it is possible to obtain a more robust prediction. We report results obtained with this method, which we call SELDOM (enSEmbLe of Dynamic lOgic-based Models), showing that it improves the predictions previously reported for several challenging problems. ; JRB and DH acknowledge funding from the EU FP7 project NICHE (ITN Grant number 289384). JRB acknowledges funding from the Spanish MINECO project SYNBIOFACTORY (grant number DPI2014-55276-C5-2-R). AFV acknowledges funding from the Galician government (Xunta de Galiza) through the I2C postdoctoral fellowship ED481B2014/133-0. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ...
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32 páginas, 12 figuras, 6 tablas.-- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited ; [Background] We consider a general class of global optimization problems dealing with nonlinear dynamic models. Although this class is relevant to many areas of science and engineering, here we are interested in applying this framework to the reverse engineering problem in computational systems biology, which yields very large mixed-integer dynamic optimization (MIDO) problems. In particular, we consider the framework of logic-based ordinary differential equations (ODEs) ; [Methods] We present saCeSS2, a parallel method for the solution of this class of problems. This method is based on an parallel cooperative scatter search metaheuristic, with new mechanisms of self-adaptation and specific extensions to handle large mixed-integer problems. We have paid special attention to the avoidance of convergence stagnation using adaptive cooperation strategies tailored to this class of problems. ; [Results] We illustrate its performance with a set of three very challenging case studies from the domain of dynamic modelling of cell signaling. The simpler case study considers a synthetic signaling pathway and has 84 continuous and 34 binary decision variables. A second case study considers the dynamic modeling of signaling in liver cancer using high-throughput data, and has 135 continuous and 109 binaries decision variables. The third case study is an extremely difficult problem related with breast cancer, involving 690 continuous and 138 binary decision variables. We report computational results obtained in different infrastructures, including a local cluster, a large supercomputer and a public cloud platform. Interestingly, the results show how the cooperation of individual parallel searches modifies the systemic properties of the sequential algorithm, achieving superlinear speedups compared to an individual search (e.g. speedups of 15 with 10 cores), and significantly improving (above a 60%) the performance with respect to a non-cooperative parallel scheme. The scalability of the method is also good (tests were performed using up to 300 cores) ; [Conclusions] These results demonstrate that saCeSS2 can be used to successfully reverse engineer large dynamic models of complex biological pathways. Further, these results open up new possibilities for other MIDO-based large-scale applications in the life sciences such as metabolic engineering, synthetic biology, drug scheduling ; This research received financial support from the Spanish Ministerio de Economía y Competitividad (and the FEDER) through projects "SYNBIOFACTORY" (DPI2014-55276-C5-2-R) and TIN2016-75845-P (AEI/FEDER, UE), and from the Galician Government under the Consolidation Program of Competitive Research Units (Network ref. R2016/045 and competitive reference groups GRC2013/055). DRP acknowledges financial support from the MICINN-FPI programme ; Peer reviewed
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