Nonparametric Bayesian inference for perturbed and orthologous gene regulatory networks

Motivation: The generation of time series transcriptomic datasets collected under multiple experimental conditions has proven to be a powerful approach for disentangling complex biological processes, allowing for the reverse engineering of gene regulatory networks (GRNs). Most methods for reverse engineering GRNs from multiple datasets assume that each of the time series were generated from networks with identical topology. In this study, we outline a hierarchical, non-parametric Bayesian approach for reverse engineering GRNs using multiple time series that can be applied in a number of novel situations including: (i) where different, but overlapping sets of transcription factors are expected to bind in the different experimental conditions; that is, where switching events could potentially arise under the different treatments and (ii) for inference in evolutionary related species in which orthologous GRNs exist. More generally, the method can be used to identify context-specific regulation by leveraging time series gene expression data alongside methods that can identify putative lists of transcription factors or transcription factor targets. Results: The hierarchical inference outperforms related (but non-hierarchical) approaches when the networks used to generate the data were identical, and performs comparably even when the networks used to generate data were independent. The method was subsequently used alongside yeast one hybrid and microarray time series data to infer potential transcriptional switches in Arabidopsis thaliana response to stress. The results confirm previous biological studies and allow for additional insights into gene regulation under various abiotic stresses. Availability: The methods outlined in this article have been implemented in Matlab and are available on request

A Neurogenetic Algorithm Based on Rational Agents

Lately, a lot of research has been conducted on the automatic design of artificial neural networks (ADANNs) using evolutionary algorithms, in the so-called neuro-evolutive algorithms (NEAs). Many of the presented proposals are not biologically inspired and are not able to generate modular, hierarchical and recurrent neural structures, such as those often found in living beings capable of solving intricate survival problems. Bearing in mind the idea that a nervous system's design and organization is a constructive process carried out by genetic information encoded in DNA, this paper proposes a biologically inspired NEA that evolves ANNs using these ideas as computational design techniques. In order to do this, we propose a Lindenmayer System with memory that implements the principles of organization, modularity, repetition (multiple use of the same sub-structure), hierarchy (recursive composition of sub-structures), minimizing the scalability problem of other methods. In our method, the basic neural codification is integrated to a genetic algorithm (GA) that implements the constructive approach found in the evolutionary process, making it closest to biological processes. Thus, the proposed method is a decision-making (DM) process, the fitness function of the NEA rewards economical artificial neural networks (ANNs) that are easily implemented. In other words, the penalty approach implemented through the fitness function automatically rewards the economical ANNs with stronger generalization and extrapolation capacities. Our method was initially tested on a simple, but non-trivial, XOR problem. We also submit our method to two other problems of increasing complexity: time series prediction that represents consumer price index and prediction of the effect of a new drug on breast cancer. In most cases, our NEA outperformed the other methods, delivering the most accurate classification. These superior results are attributed to the improved effectiveness and efficiency of NEA in the decision-making process. The result is an optimized neural network architecture for solving classification problems

Born to learn: The inspiration, progress, and future of evolved plastic artificial neural networks

Biological plastic neural networks are systems of extraordinary computational capabilities shaped by evolution, development, and lifetime learning. The interplay of these elements leads to the emergence of adaptive behavior and intelligence. Inspired by such intricate natural phenomena, Evolved Plastic Artificial Neural Networks (EPANNs) use simulated evolution in-silico to breed plastic neural networks with a large variety of dynamics, architectures, and plasticity rules: these artificial systems are composed of inputs, outputs, and plastic components that change in response to experiences in an environment. These systems may autonomously discover novel adaptive algorithms, and lead to hypotheses on the emergence of biological adaptation. EPANNs have seen considerable progress over the last two decades. Current scientific and technological advances in artificial neural networks are now setting the conditions for radically new approaches and results. In particular, the limitations of hand-designed networks could be overcome by more flexible and innovative solutions. This paper brings together a variety of inspiring ideas that define the field of EPANNs. The main methods and results are reviewed. Finally, new opportunities and developments are presented

The Dynamics of Hybrid Metabolic-Genetic Oscillators

The synthetic construction of intracellular circuits is frequently hindered by a poor knowledge of appropriate kinetics and precise rate parameters. Here, we use generalized modeling (GM) to study the dynamical behavior of topological models of a family of hybrid metabolic-genetic circuits known as "metabolators." Under mild assumptions on the kinetics, we use GM to analytically prove that all explicit kinetic models which are topologically analogous to one such circuit, the "core metabolator," cannot undergo Hopf bifurcations. Then, we examine more detailed models of the metabolator. Inspired by the experimental observation of a Hopf bifurcation in a synthetically constructed circuit related to the core metabolator, we apply GM to identify the critical components of the synthetically constructed metabolator which must be reintroduced in order to recover the Hopf bifurcation. Next, we study the dynamics of a re-wired version of the core metabolator, dubbed the "reverse" metabolator, and show that it exhibits a substantially richer set of dynamical behaviors, including both local and global oscillations. Prompted by the observation of relaxation oscillations in the reverse metabolator, we study the role that a separation of genetic and metabolic time scales may play in its dynamics, and find that widely separated time scales promote stability in the circuit. Our results illustrate a generic pipeline for vetting the potential success of a potential circuit design, simply by studying the dynamics of the corresponding generalized model

Model fusion using fuzzy aggregation: Special applications to metal properties

To improve the modelling performance, one should either propose a new modelling methodology or make the best of existing models. In this paper, the study is concentrated on the latter solution, where a structure-free modelling paradigm is proposed. It does not rely on a fixed structure and can combine various modelling techniques in ‘symbiosis’ using a ‘master fuzzy system’. This approach is shown to be able to include the advantages of different modelling techniques altogether by requiring less training and by minimising the efforts relating optimisation of the final structure. The proposed approach is then successfully applied to the industrial problems of predicting machining induced residual stresses for aerospace alloy components as well as modelling the mechanical properties of heat-treated alloy steels, both representing complex, non-linear and multi-dimensional environments

Characterizing Signal Transduction Networks and Biological Responses Using Computer Simulations and Machine Learning

The use of computer simulations in biology is often limited due to the lack of experimentally measured parameters. In these scenarios, parameter exploration can be used to probe biological systems and refine understanding of biological mechanisms. For systems with few unknown parameters, parameter sweeps that concurrently vary all unknown parameters are tractable. In complex systems with many unknown parameters, supervised machine learning algorithms can be used to discover parameters leading to targeted system responses. In this thesis, we study three biological problems in which we use parameter exploration methods to gain mechanistic insights. We first explore the role of altered metabolism in cancer cells that reside in heterogeneous tumor microenvironments. We use a multiscale, hybrid cellular automaton model to evaluate tumor progression while varying malignant cell traits using a systematic parameter sweep. The results reveal distinct growth regimes associated with varied malignant cell traits. We then study kinetic mechanisms governing fixed-topology signal transduction networks and use evolutionary algorithms to discover kinetic parameters that produce specified network responses. We analyze the growth-response network in Arabidopsis with this supervised machine learning approach. This allows us to identify constraints on kinetic parameters that govern the observed responses. The evolved parameters are used to calculate the responses of individual network components, which are used to generate hypotheses that can be tested in vivo to help determine the network topology. We finally apply a similar approach to redesign signal transduction networks. We demonstrate that the T cell receptor network and an oscillator network show remarkable flexibility in generating altered responses to input, and we further use a nonlinear clustering method to identify design criteria for the underlying kinetic parameters. For each project, observations produced from in silico simulations lead to the formation of hypotheses that are experimentally testable

Time-varying partitioning for predictive control design: density-games approach

The design of distributed optimization-based controllers for large-scale systems (LSSs) implies every time new challenges. The fact that LSSs are generally located throughout large geographical areas makes dicult the recollection of measurements and their transmission. In this regard, the communication network that is required for a centralized control approach might have high associated economic costs. Furthermore, the computation of a large amount of data implies a high computational burden to manage, process and use them in order to make decisions over the system operation. A plausible solution to mitigate the aforementioned issues associated with the control of LSSs consists in dividing this type of systems into smaller sub-systems able to be handled by independent local controllers. This paper studies two fundamental components of the design of distributed optimization-based controllers for LSSs, i.e., the system partitioning and distributed optimization algorithms. The design of distributed model predictive control (DMPC) strategies with a system partitioning and by using density-dependent population games (DDPG) is presented.Peer ReviewedPostprint (author's final draft