Antifragility Predicts the Robustness and Evolvability of Biological Networks through Multi-class Classification with a Convolutional Neural Network

Robustness and evolvability are essential properties to the evolution of biological networks. To determine if a biological network is robust and/or evolvable, it is required to compare its functions before and after mutations. However, this sometimes takes a high computational cost as the network size grows. Here we develop a predictive method to estimate the robustness and evolvability of biological networks without an explicit comparison of functions. We measure antifragility in Boolean network models of biological systems and use this as the predictor. Antifragility occurs when a system benefits from external perturbations. By means of the differences of antifragility between the original and mutated biological networks, we train a convolutional neural network (CNN) and test it to classify the properties of robustness and evolvability. We found that our CNN model successfully classified the properties. Thus, we conclude that our antifragility measure can be used as a predictor of the robustness and evolvability of biological networks.Comment: 22 pages, 10 figure

BTR: training asynchronous Boolean models using single-cell expression data

Abstract Background Rapid technological innovation for the generation of single-cell genomics data presents new challenges and opportunities for bioinformatics analysis. One such area lies in the development of new ways to train gene regulatory networks. The use of single-cell expression profiling technique allows the profiling of the expression states of hundreds of cells, but these expression states are typically noisier due to the presence of technical artefacts such as drop-outs. While many algorithms exist to infer a gene regulatory network, very few of them are able to harness the extra expression states present in single-cell expression data without getting adversely affected by the substantial technical noise present. Results Here we introduce BTR, an algorithm for training asynchronous Boolean models with single-cell expression data using a novel Boolean state space scoring function. BTR is capable of refining existing Boolean models and reconstructing new Boolean models by improving the match between model prediction and expression data. We demonstrate that the Boolean scoring function performed favourably against the BIC scoring function for Bayesian networks. In addition, we show that BTR outperforms many other network inference algorithms in both bulk and single-cell synthetic expression data. Lastly, we introduce two case studies, in which we use BTR to improve published Boolean models in order to generate potentially new biological insights. Conclusions BTR provides a novel way to refine or reconstruct Boolean models using single-cell expression data. Boolean model is particularly useful for network reconstruction using single-cell data because it is more robust to the effect of drop-outs. In addition, BTR does not assume any relationship in the expression states among cells, it is useful for reconstructing a gene regulatory network with as few assumptions as possible. Given the simplicity of Boolean models and the rapid adoption of single-cell genomics by biologists, BTR has the potential to make an impact across many fields of biomedical research

Molecular logic of neocortical projection neuron specification, development and diversity

The sophisticated circuitry of the neocortex is assembled from a diverse repertoire of neuronal subtypes generated during development under precise molecular regulation. In recent years, several key controls over the specification and differentiation of neocortical projection neurons have been identified. This work provides substantial insight into the 'molecular logic' underlying cortical development and increasingly supports a model in which individual progenitor-stage and postmitotic regulators are embedded within highly interconnected networks that gate sequential developmental decisions. Here, we provide an integrative account of the molecular controls that direct the progressive development and delineation of subtype and area identity of neocortical projection neurons.Stem Cell and Regenerative Biolog

Reducing Boolean Networks with Backward Boolean Equivalence

Boolean Networks (BNs) are established models to qualitatively describe biological systems. The analysis of BNs might be infeasible for medium to large BNs due to the state-space explosion problem. We propose a novel reduction technique called \emph{Backward Boolean Equivalence} (BBE), which preserves some properties of interest of BNs. In particular, reduced BNs provide a compact representation by grouping variables that, if initialized equally, are always updated equally. The resulting reduced state space is a subset of the original one, restricted to identical initialization of grouped variables. The corresponding trajectories of the original BN can be exactly restored. We show the effectiveness of BBE by performing a large-scale validation on the whole GINsim BN repository. In selected cases, we show how our method enables analyses that would be otherwise intractable. Our method complements, and can be combined with, other reduction methods found in the literature

Precis of neuroconstructivism: how the brain constructs cognition

Neuroconstructivism: How the Brain Constructs Cognition proposes a unifying framework for the study of cognitive development that brings together (1) constructivism (which views development as the progressive elaboration of increasingly complex structures), (2) cognitive neuroscience (which aims to understand the neural mechanisms underlying behavior), and (3) computational modeling (which proposes formal and explicit specifications of information processing). The guiding principle of our approach is context dependence, within and (in contrast to Marr [1982]) between levels of organization. We propose that three mechanisms guide the emergence of representations: competition, cooperation, and chronotopy; which themselves allow for two central processes: proactivity and progressive specialization. We suggest that the main outcome of development is partial representations, distributed across distinct functional circuits. This framework is derived by examining development at the level of single neurons, brain systems, and whole organisms. We use the terms encellment, embrainment, and embodiment to describe the higher-level contextual influences that act at each of these levels of organization. To illustrate these mechanisms in operation we provide case studies in early visual perception, infant habituation, phonological development, and object representations in infancy. Three further case studies are concerned with interactions between levels of explanation: social development, atypical development and within that, developmental dyslexia. We conclude that cognitive development arises from a dynamic, contextual change in embodied neural structures leading to partial representations across multiple brain regions and timescales, in response to proactively specified physical and social environment

SBML qualitative models: a model representation format and infrastructure to foster interactions between qualitative modelling formalisms and tools

Background: Qualitative frameworks, especially those based on the logical discrete formalism, are increasingly used to model regulatory and signalling networks. A major advantage of these frameworks is that they do not require precise quantitative data, and that they are well-suited for studies of large networks. While numerous groups have developed specific computational tools that provide original methods to analyse qualitative models, a standard format to exchange qualitative models has been missing. Results: We present the Systems Biology Markup Language (SBML) Qualitative Models Package (“qual”), an extension of the SBML Level 3 standard designed for computer representation of qualitative models of biological networks. We demonstrate the interoperability of models via SBML qual through the analysis of a specific signalling network by three independent software tools. Furthermore, the collective effort to define the SBML qual format paved the way for the development of LogicalModel, an open-source model library, which will facilitate the adoption of the format as well as the collaborative development of algorithms to analyse qualitative models. Conclusions: SBML qual allows the exchange of qualitative models among a number of complementary software tools. SBML qual has the potential to promote collaborative work on the development of novel computational approaches, as well as on the specification and the analysis of comprehensive qualitative models of regulatory and signalling networks

Engineering biocomputers in mammalian cells

Endowing cells with enhanced decision-making capacities is essential for creating smarter therapeutics and for dissecting phenotypes. Implementation of synthetic gene circuits affords a means for enhanced cellular control and genetic processing; however, genetic circuits for mammalian cells often require extensive fine-tuning to perform as intended. Here, a robust, general, and scalable system, called 'Boolean logic and arithmetic through DNA excision' (BLADE) is presented that is used to engineer genetic circuits with multiple inputs and outputs in mammalian cells with minimal optimization. The reliability of BLADE arises from its reliance on site-specific recombinases that regulate genes under the control of a single promoter that integrates circuit signals on a single transcriptional layer. Using BLADE, >100 circuits were tested in human embryonic kidney and Jurkat T cells and a quantitative metric was used to evaluate their performance. The circuits include a 3-input, two-output full adder; a 6-input, one-output Boolean logic look-up table; and circuits that incorporate CRISPR–Cas9 to regulate endogenous genes. Moreover, a large library of over 15 small-molecule, light and temperature-inducible recombinases has been established for fine-tuned control. BLADE enables execution of sophisticated cellular computation in mammalian cells, with applications in cell and tissue engineering

Artificial Neural Network Inference (ANNI): A Study on Gene-Gene Interaction for Biomarkers in Childhood Sarcomas

Objective: To model the potential interaction between previously identified biomarkers in children sarcomas using artificial neural network inference (ANNI). Method: To concisely demonstrate the biological interactions between correlated genes in an interaction network map, only 2 types of sarcomas in the children small round blue cell tumors (SRBCTs) dataset are discussed in this paper. A backpropagation neural network was used to model the potential interaction between genes. The prediction weights and signal directions were used to model the strengths of the interaction signals and the direction of the interaction link between genes. The ANN model was validated using Monte Carlo cross-validation to minimize the risk of over-fitting and to optimize generalization ability of the model. Results: Strong connection links on certain genes (TNNT1 and FNDC5 in rhabdomyosarcoma (RMS); FCGRT and OLFM1 in Ewing’s sarcoma (EWS)) suggested their potency as central hubs in the interconnection of genes with different functionalities. The results showed that the RMS patients in this dataset are likely to be congenital and at low risk of cardiomyopathy development. The EWS patients are likely to be complicated by EWS-FLI fusion and deficiency in various signaling pathways, including Wnt, Fas/Rho and intracellular oxygen. Conclusions: The ANN network inference approach and the examination of identified genes in the published literature within the context of the disease highlights the substantial influence of certain genes in sarcomas