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Register a new userThe Practice of Ensuring Repeatable and Reproducible Computational Models
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Herbert M. Sauro
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Recent studies have shown that the majority of published computational models in systems biology and physiology are not repeatable or reproducible. There are a variety of reasons for this. One of the most likely reasons is that given how busy modern researchers are and the fact that no credit is given to authors for publishing repeatable work, it is inevitable that this will be the case. The situation can only be rectified when government agencies, universities and other research institutions change policies and that journals begin to insist that published work is in fact at least repeatable if not reproducible. In this chapter guidelines are described that can be used by researchers to help make sure their work is repeatable. A scoring system is suggested that authors can use to determine how well they are doing.
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Astrocytes affect neural transmission by a tight control via glutamate transporters on glutamate concentrations in direct vicinity to the synaptic cleft and by extracellular glutamate. Their relevance for information representation has been supported by in-vivo studies in ferret and mouse primary visual cortex. In ferret blocking glutamate transport pharmacologically broadened tuning curves and enhanced the response at preferred orientation. In knock-out mice with reduced expression of glutamate transporters sharpened tuning was observed. It is however unclear how focal and ambient changes in glutamate concentration affect stimulus representation. Here we develop a computational framework, which allows the investigation of synaptic and extrasynaptic effects of glutamate uptake on orientation tuning in recurrently connected network models with pinwheel-domain (ferret) or salt-and-pepper (mouse) organization. This model proposed that glutamate uptake shapes information representation when it affects the contribution of excitatory and inhibitory neurons to the network activity. Namely, strengthening the contribution of excitatory neurons generally broadens tuning and elevates the response. In contrast, strengthening the contribution of inhibitory neurons can have a sharpening effect on tuning. In addition local representational topology also plays a role: In the pinwheel-domain model effects were strongest within domains - regions where neighboring neurons share preferred orientations. Around pinwheels but also within salt-and-pepper networks the effects were less strong. Our model proposes that the pharmacological intervention in ferret increases the contribution of excitatory cells, while the reduced expression in mouse increases the contribution of inhibitory cells to network activity.
Untargeted metabolomic studies are revealing large numbers of naturally occurring metabolites that cannot be characterized because their chemical structures and MS/MS spectra are not available in databases. Here we present iMet, a computational tool based on experimental tandem mass spectrometry that could potentially allow the annotation of metabolites not discovered previously. iMet uses MS/MS spectra to identify metabolites structurally similar to an unknown metabolite, and gives a net atomic addition or removal that converts the known metabolite into the unknown one. We validate the algorithm with 148 metabolites, and show that for 89% of them at least one of the top four matches identified by iMet enables the proper annotation of the unknown metabolite. iMet is freely available at http://imet.seeslab.net.
The amount of mutual information contained in time series of two elements gives a measure of how well their activities are coordinated. In a large, complex network of interacting elements, such as a genetic regulatory network within a cell, the average of the mutual information over all pairs <I> is a global measure of how well the system can coordinate its internal dynamics. We study this average pairwise mutual information in random Boolean networks (RBNs) as a function of the distribution of Boolean rules implemented at each element, assuming that the links in the network are randomly placed. Efficient numerical methods for calculating <I> show that as the number of network nodes N approaches infinity, the quantity N<I> exhibits a discontinuity at parameter values corresponding to critical RBNs. For finite systems it peaks near the critical value, but slightly in the disordered regime for typical parameter variations. The source of high values of N<I> is the indirect correlations between pairs of elements from different long chains with a common starting point. The contribution from pairs that are directly linked approaches zero for critical networks and peaks deep in the disordered regime.
Normal mode analysis offers an efficient way of modeling the conformational flexibility of protein structures. Simple models defined by contact topology, known as elastic network models, have been used to model a variety of systems, but the validation is typically limited to individual modes for a single protein. We use anisotropic displacement parameters from crystallography to test the quality of prediction of both the magnitude and directionality of conformational variance. Normal modes from four simple elastic network model potentials and from the CHARMM forcefield are calculated for a data set of 83 diverse, ultrahigh resolution crystal structures. While all five potentials provide good predictions of the magnitude of flexibility, the methods that consider all atoms have a clear edge at prediction of directionality, and the CHARMM potential produces the best agreement. The low-frequency modes from different potentials are similar, but those computed from the CHARMM potential show the greatest difference from the elastic network models. This was illustrated by computing the dynamic correlation matrices from different potentials for a PDZ domain structure. Comparison of normal mode results with anisotropic temperature factors opens the possibility of using ultrahigh resolution crystallographic data as a quantitative measure of molecular flexibility. The comprehensive evaluation demonstrates the costs and benefits of using normal mode potentials of varying complexity. Comparison of the dynamic correlation matrices suggests that a combination of topological and chemical potentials may help identify residues in which chemical forces make large contributions to intramolecular coupling.
We study kinetic model of Nuclear Receptor Binding to Promoter Regions. This model is written as a system of ordinary differential equations. Model reduction techniques have been used to simplify chemical kinetics.In this case study, the technique of Pseudo-first order approximation is applied to simplify the reaction rates. CellDesigner has been used to draw the structures of chemical reactions of Nuclear Receptor Binding to Promoter Regions. After model reduction, the general analytical solution for reduced model is given and the number of species and reactions are reduced from 9 species and 6 reactions to 6 species and 5 reactions.
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