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Background: Dynamic modelling is one of the cornerstones of systems biology. Many research efforts are currently being invested in the development and exploitation of large-scale kinetic models. The associated problems of parameter estimation (model calibration) and optimal experimental design are particularly challenging. The community has already developed many methods and software packages which aim to facilitate these tasks. However, there is a lack of suitable benchmark problems which allow a fair and systematic evaluation and comparison of these contributions. Results: Here we present BioPreDyn-bench, a set of challenging parameter estimation problems which aspire to serve as reference test cases in this area. This set comprises six problems including medium and large-scale kinetic models of the bacterium E. coli, baker's yeast S. cerevisiae, the vinegar fly D. melanogaster, Chinese Hamster Ovary cells, and a generic signal transduction network. The level of description includes metabolism, transcription, signal transduction, and development. For each problem we provide (i) a basic description and formulation, (ii) implementations ready-to-run in several formats, (iii) computational results obtained with specific solvers, (iv) a basic analysis and interpretation. Conclusions: This suite of benchmark problems can be readily used to evaluate and compare parameter estimation methods. Further, it can also be used to build test problems for sensitivity and identifiability analysis, model reduction and optimal experimental design methods. The suite, including codes and documentation, can be freely downloaded from the BioPreDyn-bench website, https://sites.google.com/site/biopredynbenchmarks/. [ABSTRACT FROM AUTHOR]

Models of the development and early progression of colorectal cancer are based upon understanding the cycle of stem cell turnover, proliferation, differentiation and death. Existing crypt compartmental models feature a linear pathway of cell types, with little regulatory mechanism. Previous work has shown that there are perturbations in the enteroendocrine cell population of macroscopically normal crypts, a compartment not included in existing models. We show that existing models do not adequately recapitulate the dynamics of cell fate pathways in the crypt. We report the progressive development, iterative testing and fitting of a developed compartmental model with additional cell types, and which includes feedback mechanisms and cross-regulatory mechanisms between cell types. The fitting of the model to existing data sets suggests a need to invoke cross-talk between cell types as a feature of colon crypt cycle models. [ABSTRACT FROM AUTHOR]

Abstract: Acid-mediated tumour invasion is receiving increasing experimental and clinical attention. Previous models proposed to describe this phenomenon failed to capture key properties of the system, such as the existence of the benign steady state, or predicted incorrectly the size of the inter-tissue gap. Here we show that taking proper account of quiescence ameliorates these drawbacks as well as revealing novel behaviour. The simplicity of the model allows us to fully identify the key parameters controlling different aspects of behaviour. [Copyright &y& Elsevier]

Abstract: As genome-scale metabolic reconstructions emerge, tools to manage their size and complexity will be increasingly important. Flux balance analysis (FBA) is a constraint-based approach widely used to study the metabolic capabilities of cellular or subcellular systems. FBA problems are highly underdetermined and many different phenotypes can satisfy any set of constraints through which the metabolic system is represented. Two of the main concerns in FBA are exploring the space of solutions for a given metabolic network and finding a specific phenotype which is representative for a given task such as maximal growth rate. Here, we introduce a recursive algorithm suitable for overcoming both of these concerns. The method proposed is able to find the alternate optimal patterns of active reactions of an FBA problem and identify the minimal subnetwork able to perform a specific task as optimally as the whole. Our method represents an alternative to and an extension of other approaches conceived for exploring the space of solutions of an FBA problem. It may also be particularly helpful in defining a scaffold of reactions upon which to build up a dynamic model, when the important pathways of the system have not yet been well-defined. [Copyright &y& Elsevier]