WebMaBoSS: A Web Interface for Simulating Boolean Models Stochastically

WebMaBoSS is an easy-to-use web interface for conversion, storage, simulation and analysis of Boolean models that allows to get insight from these models without any specific knowledge of modeling or coding. It relies on an existing software, MaBoSS, which simulates Boolean models using a stochastic approach: it applies continuous time Markov processes over the Boolean network. It was initially built to fill the gap between Boolean and continuous formalisms, i.e., providing semi-quantitative results using a simple representation with a minimum number of parameters to fit. The goal of WebMaBoSS is to simplify the use and the analysis of Boolean models coping with two main issues: 1) the simulation of Boolean models of intracellular processes with MaBoSS, or any modeling tool, may appear as non-intuitive for non-experts; 2) the simulation of already-published models available in current model databases (e.g., Cell Collective, BioModels) may require some extra steps to ensure compatibility with modeling tools such as MaBoSS. With WebMaBoSS, new models can be created or imported directly from existing databases. They can then be simulated, modified and stored in personal folders. Model simulations are performed easily, results visualized interactively, and figures can be exported in a preferred format. Extensive model analyses such as mutant screening or parameter sensitivity can also be performed. For all these tasks, results are stored and can be subsequently filtered to look for specific outputs. This web interface can be accessed at the address: https://maboss.curie.fr/webmaboss/ and deployed locally using docker. This application is open-source under LGPL license, and available at https://github.com/sysbio-curie/WebMaBoSS.

Minimum complexity drives regulatory logic in Boolean models of living systems

The properties of random Boolean networks as models of gene regulation have been investigated extensively by the statistical physics community. In the past two decades, there has been a dramatic increase in the reconstruction and analysis of Boolean models of biological networks. In such models, neither network topology nor Boolean functions (or logical update rules) should be expected to be random. In this contribution, we focus on biologically meaningful types of Boolean functions, and perform a systematic study of their preponderance in gene regulatory networks. By applying the k[P] classification based on number of inputs k and bias P of functions, we find that most Boolean functions astonishingly have odd bias in a reference biological dataset of 2687 functions compiled from published models. Subsequently, we are able to explain this observation along with the enrichment of read-once functions (RoFs) and its subset, nested canalyzing functions (NCFs), in the reference dataset in terms of two complexity measures: Boolean complexity based on string lengths in formal logic which is yet unexplored in the biological context, and the average sensitivity. Minimizing the Boolean complexity naturally sifts out a subset of odd-biased Boolean functions which happen to be the RoFs. Finally, we provide an analytical proof that NCFs minimize not only the Boolean complexity, but also the average sensitivity in their k[P] set.

Classical and Probabilistic Information Retrieval Techniques: An Audit

Information retrieval is acquiring particular information from large resources and presenting it according to the user’s need. The incredible increase in information resources on the Internet formulates the information retrieval procedure, a monotonous and complicated task for users. Due to over access of information, better methodology is required to retrieve the most appropriate information from different sources. The most important information retrieval methods include the probabilistic, fuzzy set, vector space, and boolean models. Each of these models usually are used for evaluating the connection between the question and the retrievable documents. These methods are based on the keyword and use lists of keywords to evaluate the information material. In this paper, we present a survey of these models so that their working methodology and limitations are discussed. This is an important understanding because it makes possible to select an information retrieval technique based on the basic requirements. The survey results showed that the existing model for knowledge recovery is somewhere short of what was planned. We have also discussed different areas of IR application where these models could be used.

Patient-specific Boolean models of signaling networks guide personalized treatments

Prostate cancer is the second most occurring cancer in men worldwide. To better understand the mechanisms of tumorigenesis and possible treatment responses, we developed a mathematical model of prostate cancer which considers the major signalling pathways known to be deregulated. We personalised this Boolean model to molecular data to reflect the heterogeneity and specific response to perturbations of cancer patients. 488 prostate samples were used to build patient-specific models and compared to available clinical data. Additionally, eight prostate cell-line-specific models were built to validate our approach with dose-response data of several drugs. The effects of single and combined drugs were tested in these models under different growth conditions. We identified 15 actionable points of interventions in one cell-line-specific model whose inactivation hinders tumorigenesis. To validate these results, we tested nine small molecule inhibitors of five of those putative targets and found a dose-dependent effect on four of them, notably those targeting HSP90 and PI3K. These results highlight the predictive power of our personalized Boolean models and illustrate how they can be used for precision oncology.

Local Measures Distribution for the Estimation of the Elongation Ratio of the Typical Grain in Homogeneous Boolean Models

We introduce a particular localization of the Minkowski functionals to characterize and discriminate different random spatial structures. The aim of this paper is to present a method estimating the typical grain elongation ratio in a homogeneous Boolean model. The use of this method is demonstrated on a range of Boolean models of rectangles featuring fixed and random elongation ratio. An optimization algorithm is performed to determine the elongation ratio which maximize the likelihood function of the probability density associated with the local perimeter measure. Therefore, the elongation ratio of the typical grain can be deduced.

Computing Minimal Boolean Models of Gene Regulatory Networks

Models of Gene Regulatory Networks (GRNs) capture the dynamics of the regulatory processes that occur within the cell as a means to understand the variability observed in gene expression between different conditions. Possibly the simplest mathematical construct used for modeling is the Boolean network, which dictates a set of logical rules for transition between states described as Boolean vectors. Due to the complexity of gene regulation and the limitations of experimental technologies, in most cases knowledge about regulatory interactions and Boolean states is partial. In addition, the logical rules themselves are not known a-priori. Our goal in this work is to present a methodology for inferring this information from the data, and to provide a measure for comparing network states under different biological conditions. Methods: We present a novel methodology for integrating experimental data and performing a search for the optimal consistent structure via optimization of a linear objective function under a set of linear constraints. We also present a statistical approach for testing the similarity of network states under different conditions. Results: Our methodology finds the optimal model using an experimental gene expression dataset from human CD4 T-cells and shows that network states are different between healthy controls and rheumatoid arthritis patients. Conclusion: The problem can be solved optimally using real-world data. Properties of the inferred network show the importance of a general approach. Significance: Our methodology will enable researchers to obtain a better understanding of the function of gene regulatory networks and their biological role.

Lac Operon Boolean Models: Dynamical Robustness and Alternative Improvements

In Veliz-Cuba and Stigler 2011, Boolean models were proposed for the lac operon in Escherichia coli capable of reproducing the operon being OFF, ON and bistable for three (low, medium and high) and two (low and high) parameters, representing the concentration ranges of lactose and glucose, respectively. Of these 6 possible combinations of parameters, 5 produce results that match with the biological experiments of Ozbudak et al., 2004. In the remaining one, the models predict the operon being OFF while biological experiments show a bistable behavior. In this paper, we first explore the robustness of two such models in the sense of how much its attractors change against any deterministic update schedule. We prove mathematically that, in cases where there is no bistability, all the dynamics in both models lack limit cycles while, when bistability appears, one model presents 30% of its dynamics with limit cycles while the other only 23%. Secondly, we propose two alternative improvements consisting of biologically supported modifications; one in which both models match with Ozbudak et al., 2004 in all 6 combinations of parameters and, the other one, where we increase the number of parameters to 9, matching in all these cases with the biological experiments of Ozbudak et al., 2004.

Integrating Patient-Specific Information into Logic Models of Complex Diseases: Application to Acute Myeloid Leukemia

High throughput technologies such as deep sequencing and proteomics are increasingly becoming mainstream in clinical practice and support diagnosis and patient stratification. Developing computational models that recapitulate cell physiology and its perturbations in disease is a required step to help with the interpretation of results of high content experiments and to devise personalized treatments. As complete cell-models are difficult to achieve, given limited experimental information and insurmountable computational problems, approximate approaches should be considered. We present here a general approach to modeling complex diseases by embedding patient-specific genomics data into actionable logic models that take into account prior knowledge. We apply the strategy to acute myeloid leukemia (AML) and assemble a network of logical relationships linking most of the genes that are found frequently mutated in AML patients. We derive Boolean models from this network and we show that by priming the model with genomic data we can infer relevant patient-specific clinical features. Here we propose that the integration of literature-derived causal networks with patient-specific data should be explored to help bedside decisions.