In-Silico Proportional-Integral Moment Control of Stochastic Gene Expression

The problem of controlling the mean and the variance of a species of interest in a simple gene expression is addressed. It is shown that the protein mean level can be globally and robustly tracked to any desired value using a simple PI controller that satisfies certain sufficient conditions. Controlling both the mean and variance however requires an additional control input, e.g. the mRNA degradation rate, and local robust tracking of mean and variance is proved to be achievable using multivariable PI control, provided that the reference point satisfies necessary conditions imposed by the system. Even more importantly, it is shown that there exist PI controllers that locally, robustly and simultaneously stabilize all the equilibrium points inside the admissible region. The results are then extended to the mean control of a gene expression with protein dimerization. It is shown that the moment closure problem can be circumvented without invoking any moment closure technique. Local stabilization and convergence of the average dimer population to any desired reference value is ensured using a pure integral control law. Explicit bounds on the controller gain are provided and shown to be valid for any reference value. As a byproduct, an explicit upper-bound of the variance of the monomer species, acting on the system as unknown input due to the moment openness, is obtained. The results are illustrated by simulation.Comment: 28 pages; 9 Figures. arXiv admin note: substantial text overlap with arXiv:1207.4766, arXiv:1307.644

Dynamical pathway analysis

<p>Abstract</p> <p>Background</p> <p>Although a great deal is known about one gene or protein and its functions under different environmental conditions, little information is available about the complex behaviour of biological networks subject to different environmental perturbations. Observing differential expressions of one or more genes between normal and abnormal cells has been a mainstream method of discovering pertinent genes in diseases and therefore valuable drug targets. However, to date, no such method exists for elucidating and quantifying the differential dynamical behaviour of genetic regulatory networks, which can have greater impact on phenotypes than individual genes.</p> <p>Results</p> <p>We propose to redress the deficiency by formulating the functional study of biological networks as a control problem of dynamical systems. We developed mathematical methods to study the stability, the controllability, and the steady-state behaviour, as well as the transient responses of biological networks under different environmental perturbations. We applied our framework to three real-world datasets: the SOS DNA repair network in <it>E. coli </it>under different dosages of radiation, the GSH redox cycle in mice lung exposed to either poisonous air or normal air, and the MAPK pathway in mammalian cell lines exposed to three types of HIV type I Vpr, a wild type and two mutant types; and we found that the three genetic networks exhibited fundamentally different dynamical properties in normal and abnormal cells.</p> <p>Conclusion</p> <p>Difference in stability, relative stability, degrees of controllability, and transient responses between normal and abnormal cells means considerable difference in dynamical behaviours and different functioning of cells. Therefore differential dynamical properties can be a valuable tool in biomedical research.</p

A survey of recent advances in fractional order control for time delay systems

Several papers reviewing fractional order calculus in control applications have been published recently. These papers focus on general tuning procedures, especially for the fractional order proportional integral derivative controller. However, not all these tuning procedures are applicable to all kinds of processes, such as the delicate time delay systems. This motivates the need for synthesizing fractional order control applications, problems, and advances completely dedicated to time delay processes. The purpose of this paper is to provide a state of the art that can be easily used as a basis to familiarize oneself with fractional order tuning strategies targeted for time delayed processes. Solely, the most recent advances, dating from the last decade, are included in this review

Integration of process design and control: A review

There is a large variety of methods in literature for process design and control, which can be classified into two main categories. The methods in the first category have a sequential approach in which, the control system is designed, only after the details of process design are decided. However, when process design is fixed, there is little room left for improving the control performance. Recognizing the interactions between process design and control, the methods in the second category integrate some control aspects into process design. With the aim of providing an exploration map and identifying the potential areas of further contributions, this paper presents a thematic review of the methods for integration of process design and control. The evolution paths of these methods are described and the advantages and disadvantages of each method are explained. The paper concludes with suggestions for future research activities

Optimized state feedback regulation of 3DOF helicopter system via extremum seeking

In this paper, an optimized state feedback regulation of a 3 degree of freedom (DOF) helicopter is designed via extremum seeking (ES) technique. Multi-parameter ES is applied to optimize the tracking performance via tuning State Vector Feedback with Integration of the Control Error (SVFBICE). Discrete multivariable version of ES is developed to minimize a cost function that measures the performance of the controller. The cost function is a function of the error between the actual and desired axis positions. The controller parameters are updated online as the optimization takes place. This method significantly decreases the time in obtaining optimal controller parameters. Simulations were conducted for the online optimization under both fixed and varying operating conditions. The results demonstrate the usefulness of using ES for preserving the maximum attainable performance

Modeling and Estimation of Biological Plants

Estimating the state of a dynamic system is an essential task for achieving important objectives such as process monitoring, identification, and control. Unlike linear systems, no systematic method exists for the design of observers for nonlinear systems. Although many researchers have devoted their attention to these issues for more than 30 years, there are still many open questions. We envisage that estimation plays a crucial role in biology because of the possibility of creating new avenues for biological studies and for the development of diagnostic, management, and treatment tools. To this end, this thesis aims to address two types of nonlinear estimation techniques, namely, the high-gain observer and the moving-horizon estimator with application to three different biological plants. After recalling basic definitions of stability and observability of dynamical systems and giving a bird's-eye survey of the available state estimation techniques, we are interested in the high-gain observers. These observers may be used when the system dynamics can be expressed in specific a coordinate under the so-called observability canonical form with the possibility to assign the rate of convergence arbitrarily by acting on a single parameter called the high-gain parameter. Despite the evident benefits of this class of observers, their use in real applications is questionable due to some drawbacks: numerical problems, the peaking phenomenon, and high sensitivity to measurement noise. The first part of the thesis aims to enrich the theory of high-gain observers with novel techniques to overcome or attenuate these challenging performance issues that arise when implementing such observers. The validity and applicability of our proposed techniques have been shown firstly on a simple one-gene regulatory network, and secondly on an SI epidemic model. The second part of the thesis studies the problem of state estimation using the moving horizon approach. The main advantage of MHE is that information about the system can be explicitly considered in the form of constraints and hence improve the estimates. In this work, we focus on estimation for nonlinear plants that can be rewritten in the form of quasi-linear parameter-varying systems with bounded unknown parameters. Moving-horizon estimators are proposed to estimate the state of such systems according to two different formulations, i.e., "optimistic" and "pessimistic". In the former case, we perform estimation by minimizing the least-squares moving-horizon cost with respect to both state variables and parameters simultaneously. In the latter, we minimize such a cost with respect to the state variables after picking up the maximum of the parameters. Under suitable assumptions, the stability of the estimation error given by the exponential boundedness is proved in both scenarios. Finally, the validity of our obtained results has been demonstrated through three different examples from biological and biomedical fields, namely, an example of one gene regulatory network, a two-stage SI epidemic model, and Amnioserosa cell's mechanical behavior during Dorsal closure

Differential Dynamic Properties of Scleroderma Fibroblasts in Response to Perturbation of Environmental Stimuli

Diseases are believed to arise from dysregulation of biological systems (pathways) perturbed by environmental triggers. Biological systems as a whole are not just the sum of their components, rather ever-changing, complex and dynamic systems over time in response to internal and external perturbation. In the past, biologists have mainly focused on studying either functions of isolated genes or steady-states of small biological pathways. However, it is systems dynamics that play an essential role in giving rise to cellular function/dysfunction which cause diseases, such as growth, differentiation, division and apoptosis. Biological phenomena of the entire organism are not only determined by steady-state characteristics of the biological systems, but also by intrinsic dynamic properties of biological systems, including stability, transient-response, and controllability, which determine how the systems maintain their functions and performance under a broad range of random internal and external perturbations. As a proof of principle, we examine signal transduction pathways and genetic regulatory pathways as biological systems. We employ widely used state-space equations in systems science to model biological systems, and use expectation-maximization (EM) algorithms and Kalman filter to estimate the parameters in the models. We apply the developed state-space models to human fibroblasts obtained from the autoimmune fibrosing disease, scleroderma, and then perform dynamic analysis of partial TGF-β pathway in both normal and scleroderma fibroblasts stimulated by silica. We find that TGF-β pathway under perturbation of silica shows significant differences in dynamic properties between normal and scleroderma fibroblasts. Our findings may open a new avenue in exploring the functions of cells and mechanism operative in disease development

Design and analysis of genetic feedback architectures for synthetic biology

Synthetic Biology seeks to design and assemble novel biological systems with favourable properties. It allows us to comprehend and modify the fundamental mechanisms of life and holds significant promise in revolutionizing current technologies ranging from medicine and biomanufacturing to energy and environmental protection. Biological processes constitute remarkably complex dynamical systems operating impeccably well in messy and constantly changing environments. Their ability to do so is rooted in sophisticated molecular control architectures crafted by natural evolutionary innovation over billions of years. Such control architectures, often blended with human-engineering approaches, are the key to realizing efficient and reliable synthetic biological systems. Aiming to accelerate the development of the latter, the present thesis addresses some fundamental challenges in biomolecular systems and control design. We begin by elucidating biological mechanisms of temporal gradient computation, enabling cells to adjust their behaviour in response to anticipated environmental changes. Specifically, we introduce biomolecular motifs capable of functioning as highly tunable and accurate signal differentiators to input molecular signals around their nominal operation. We investigate strategies to deal with high-frequency input signal components which can be detrimental to the performance of most differentiators. We ascertain the occurrence of such motifs in natural regulatory networks and demonstrate the potential of synthetic experimental realizations. Our motifs can serve as reliable speed biosensors and can form the basis for derivative feedback control. Motivated by the pervasiveness of Proportional-Integral-Derivative (PID) controllers in modern technological applications, we present the realization of a PID controller via biomolecular reactions employing, among others, our differentiator motifs. This biomolecular architecture represents a PID control law with set point weighting and filtered derivative action, offering robust regulation of a single-output biological process with enhanced dynamic performance and low levels of stochastic noise. It is characterized by significant ease of tuning and can be of particular experimental interest in molecular programming applications. Finally, we investigate efficient regulation strategies for multi-output biological processes with internal coupling interactions, expanding previously established single-output control approaches. More specifically, we propose control schemes allowing for robust manipulation of the outputs in various ways, namely manipulation of their product/ratio, linear combinations of them as well as manipulation of each of the outputs independently. Our analysis is centered around two-output biological processes, yet the scalability of the proposed regulation strategies to processes with a higher number of outputs is highlighted. In parallel, their experimental implementability is explored in both in vivo and in vitro settings

Control Theory: On the Way to New Application Fields

Control theory is an interdisciplinary field that is located at the crossroads of pure and applied mathematics with systems engineering and the sciences. Recently, deep interactions are emerging with new application areas, such as systems biology, quantum control and information technology. In order to address the new challenges posed by the new application disciplines, a special focus of this workshop has been on the interaction between control theory and mathematical systems biology. To complement these more biology oriented focus, a series of lectures in this workshop was devoted to the control of networks of systems, fundamentals of nonlinear control systems, model reduction and identification, algorithmic aspects in control, as well as open problems in control