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 Articles in journal or book chapters
1. T. Chen, M. Ali Al-Radhawi, C.A. Voigt, and E.D. Sontag. A synthetic distributed genetic multi-bit counter. iScience, 24:103526, 2021. [PDF] Keyword(s): counters, synthetic biology, transcriptional networks, gene networks, boolean circuits, boolean gates, systems biology.
Abstract:
 A design for genetically-encoded counters is proposed via repressor-based circuits. An N-bit counter reads sequences of input pulses and displays the total number of pulses, modulo $2^N$. The design is based on distributed computation, with specialized cell types allocated to specific tasks. This allows scalability and bypasses constraints on the maximal number of circuit genes per cell due to toxicity or failures due to resource limitations. The design starts with a single-bit counter. The N-bit counter is then obtained by interconnecting (using diffusible chemicals) a set of N single-bit counters and connector modules. An optimization framework is used to determine appropriate gate parameters and to compute bounds on admissible pulse widths and relaxation (inter-pulse) times, as well as to guide the construction of novel gates. This work can be viewed as a step toward obtaining circuits that are capable of finite-automaton computation, in analogy to digital central processing units.

2. A.P. Tran, M. Ali Al-Radhawi, E. Ernst, and E.D. Sontag. Optimization of heuristic logic synthesis by iteratively reducing circuit substructures using a database of optimal implementations. 2021. Note: Submitted. Keyword(s): Heuristic logic minimizer, Boolean circuit reduction, optimal synthesis, logic optimization, synthetic biology.
Abstract:
 Minimal synthesis of Boolean functions is an NP-hard problem, and heuristic approaches typically give suboptimal circuits. However, in the emergent field of synthetic biology, genetic logic designs that use even a single additional Boolean gate can render a circuit unimplementable in a cell. This has led to a renewed interest in the field of optimal multilevel Boolean synthesis. For small numbers (1-4) of inputs, an exhaustive search is possible, but this is impractical for large circuits. In this work, we demonstrate that even though it is challenging to build a database of optimal implementations for anything larger than 4-input Boolean functions, a database of 4-input optimal implementations can be used to greatly reduce the number of logical gates required in larger heuristic logic synthesis implementations. The proposed algorithm combines the heuristic results with an optimal implementation database and yields average improvements of 5.16% for 5-input circuits and 4.54% for 6-input circuits on outputs provided by the logic synthesis tool extit{ABC}. In addition to the gains in the efficiency of the implemented circuits, this work also attests to the importance and practicality of the field of optimal synthesis, even if it cannot directly provide results for larger circuits. The focus of this work is on circuits made exclusively of 2-input NOR gates but the presented results are readily applicable to 2-input NAND circuits as well as (2-input) AND/NOT circuits. In addition, the framework proposed here is likely to be adaptable to other types of circuits. An implementation of the described algorithm, HLM (Hybrid Logic Minimizer), is available at https://github.com/sontaglab/HLM/.

3. J. Miller, M.A. Al-Radhawi, and E.D. Sontag. Mediating ribosomal competition by splitting pools. IEEE Control Systems Letters, 5:1555-1560, 2020. [PDF] Keyword(s): systems biology, synthetic biology, ribosomes, RFM, ribosome flow model.
Abstract:
 Synthetic biology constructs often rely upon the introduction of "circuit" genes into host cells, in order to express novel proteins and thus endow the host with a desired behavior. The expression of these new genes "consumes" existing resources in the cell, such as ATP, RNA polymerase, amino acids, and ribosomes. Ribosomal competition among strands of mRNA may be described by a system of nonlinear ODEs called the Ribosomal Flow Model (RFM). The competition for resources between host and circuit genes can be ameliorated by splitting the ribosome pool by use of orthogonal ribosomes, where the circuit genes are exclusively translated by mutated ribosomes. In this work, the RFM system is extended to include orthogonal ribosome competition. This Orthogonal Ribosomal Flow Model (ORFM) is proven to be stable through the use of Robust Lyapunov Functions. The optimization problem of maximizing the weighted protein translation rate by adjusting allocation of ribosomal species is formulated and implemented. Note: publsihed Nov 2020, even though journal reprint says "Nov 2021".

4. D.K. Agrawal, R. Marshall, V. Noireaux, and E.D. Sontag. In vitro implementation of robust gene regulation in a synthetic biomolecular integral controller. Nature Communications, 10:1-12, 2019. [PDF] Keyword(s): tracking, synthetic biology, integral feedback, TX/TL, systems biology, dynamical systems, adaptation, internal model principle, identifiability.
Abstract:
 Cells respond to biochemical and physical internal as well as external signals. These signals can be broadly classified into two categories: (a) actionable'' or reference'' inputs that should elicit appropriate biological or physical responses such as gene expression or motility, and (b) disturbances'' or perturbations'' that should be ignored or actively filtered-out. These disturbances might be exogenous, such as binding of nonspecific ligands, or endogenous, such as variations in enzyme concentrations or gene copy numbers. In this context, the term robustness describes the capability to produce appropriate responses to reference inputs while at the same time being insensitive to disturbances. These two objectives often conflict with each other and require delicate design trade-offs. Indeed, natural biological systems use complicated and still poorly understood control strategies in order to finely balance the goals of responsiveness and robustness. A better understanding of such natural strategies remains an important scientific goal in itself and will play a role in the construction of synthetic circuits for therapeutic and biosensing applications. A prototype problem in robustly responding to inputs is that of robust tracking'', defined by the requirement that some designated internal quantity (for example, the level of expression of a reporter protein) should faithfully follow an input signal while being insensitive to an appropriate class of perturbations. Control theory predicts that a certain type of motif, called integral feedback, will help achieve this goal, and this motif is, in fact, a necessary feature of any system that exhibits robust tracking. Indeed, integral feedback has always been a key component of electrical and mechanical control systems, at least since the 18th century when James Watt employed the centrifugal governor to regulate steam engines. Motivated by this knowledge, biological engineers have proposed various designs for biomolecular integral feedback control mechanisms. However, practical and quantitatively predictable implementations have proved challenging, in part due to the difficulty in obtaining accurate models of transcription, translation, and resource competition in living cells, and the stochasticity inherent in cellular reactions. These challenges prevent first-principles rational design and parameter optimization. In this work, we exploit the versatility of an Escherichia coli cell-free transcription-translation (TXTL) to accurately design, model and then build, a synthetic biomolecular integral controller that precisely controls the expression of a target gene. To our knowledge, this is the first design of a functioning gene network that achieves the goal of making gene expression track an externally imposed reference level, achieves this goal even in the presence of disturbances, and whose performance quantitatively agrees with mathematical predictions.

5. J.A. Ascensao, P. Datta, B. Hancioglu, E.D. Sontag, M.L. Gennaro, and O.A. Igoshin. Non-monotonic response dynamics of glyoxylate shunt genes in Mycobacterium tuberculosis. PLoS Computational Biology, 12:e1004741, 2016. [PDF] Keyword(s): cell signaling, monotone systems, monotone systems, systems biology.
Abstract:
 Understanding how dynamical responses of biological networks are constrained by underlying network topology is one of the fundamental goals of systems biology. Here we employ monotone systems theory to formulate a theorem stating necessary conditions for non-monotonic time-response of a biochemical network to a monotonic stimulus. We apply this theorem to analyze the non-monotonic dynamics of the sigmaB-regulated glyoxylate shunt gene expression in Mycobacterium tuberculosis cells exposed to hypoxia. We first demonstrate that the known network structure is inconsistent with observed dynamics. To resolve this inconsistency we employ the formulated theorem, modeling simulations and optimization along with follow-up dynamic experimental measurements. We show a requirement for post-translational modulation of sigmaB activity in order to reconcile the network dynamics with its topology. The results of this analysis make testable experimental predictions and demonstrate wider applicability of the developed methodology to a wide class of biological systems.

6. M. Miller, M. Hafner, E.D. Sontag, N. Davidsohn, S. Subramanian, P. E. M. Purnick, D. Lauffenburger, and R. Weiss. Modular design of artificial tissue homeostasis: robust control through synthetic cellular heterogeneity. PLoS Computational Biology, 8:e1002579-, 2012. [PDF] Keyword(s): systems biology, homeostasis, stem cells, synthetic biology.
Abstract:
 Synthetic biology efforts have largely focused on small engineered gene networks, yet understanding how to integrate multiple synthetic modules and interface them with endogenous pathways remains a challenge. Here we present the design, system integration, and analysis of several large scale synthetic gene circuits for artificial tissue homeostasis. Diabetes therapy represents a possible application for engineered homeostasis, where genetically programmed stem cells maintain a steady population of beta-cells despite continuous turnover. We develop a new iterative process that incorporates modular design principles with hierarchical performance optimization targeted for environments with uncertainty and incomplete information. We employ theoretical analysis and computational simulations of multicellular reaction/diffusion models to design and understand system behavior, and find that certain features often associated with robustness (e.g., multicellular synchronization and noise attenuation) are actually detrimental for tissue homeostasis. We overcome these problems by engineering a new class of genetic modules for 'synthetic cellular heterogeneity' that function to generate beneficial population diversity. We design two such modules (an asynchronous genetic oscillator and a signaling throttle mechanism), demonstrate their capacity for enhancing robust control, and provide guidance for experimental implementation with various computational techniques. We found that designing modules for synthetic heterogeneity can be complex, and in general requires a framework for non-linear and multifactorial analysis. Consequently, we adapt a 'phenotypic sensitivity analysis' method to determine how functional module behaviors combine to achieve optimal system performance. We ultimately combine this analysis with Bayesian network inference to extract critical, causal relationships between a module's biochemical rate-constants, its high level functional behavior in isolation, and its impact on overall system performance once integrated.

7. S. Kachalo, R. Zhang, E.D. Sontag, R. Albert, and B. Dasgupta. NET-SYNTHESIS: A software for synthesis, inference and simplification of signal transduction networks. Bioinformatics, 24:293 - 295, 2008. [PDF] Keyword(s): systems biology, biochemical networks, algorithms, signal transduction networks, graph algorithms.
Abstract:
 This paper presents a software tool for inference and simplification of signal transduction networks. The method relies on the representation of observed indirect causal relationships as network paths, using techniques from combinatorial optimization to find the sparsest graph consistent with all experimental observations. We illustrate the biological usability of our software by applying it to a previously published signal transduction network and by using it to synthesize and simplify a novel network corresponding to activation-induced cell death in large granular lymphocyte leukemia.

8. R. Albert, B. DasGupta, R. Dondi, S. Kachalo, E.D. Sontag, A. Zelikovsky, and K. Westbrooks. A novel method for signal transduction network inference from indirect experimental evidence. Journal of Computational Biology, 14:927-949, 2007. [PDF] Keyword(s): systems biology, biochemical networks, algorithms, signal transduction networks, graph algorithms.
Abstract:
 This paper introduces a new method of combined synthesis and inference of biological signal transduction networks. The main idea lies in representing observed causal relationships as network paths, and using techniques from combinatorial optimization to find the sparsest graph consistent with all experimental observations. The paper formalizes the approach, studies its computational complexity, proves new results for exact and approximate solutions of the computationally hard transitive reduction substep of the approach, validates the biological applicability by applying it to a previously published signal transduction network by Li et al., and shows that the algorithm for the transitive reduction substep performs well on graphs with a structure similar to those observed in transcriptional regulatory and signal transduction networks.

9. B. DasGupta, J.P. Hespanha, J. Riehl, and E.D. Sontag. Honey-pot constrained searching with local sensory information. Nonlinear Analysis, 65:1773-1793, 2006. [PDF] Keyword(s): search problems, algorithms, computational complexity.
Abstract:
 This paper investigates the problem of searching for a hidden target in a bounded region of the plane by an autonomous robot which is only able to use limited local sensory information. It proposes an aggregation-based approach to solve this problem, in which the continuous search space is partitioned into a finite collection of regions on which we define a discrete search problem and a solution to the original problem is obtained through a refinement procedure that lifts the discrete path into a continuous one. The resulting solution is in general not optimal but one can construct bounds to gauge the cost penalty incurred. The discrete version is formalized and an optimization problem is stated as a `reward-collecting' bounded-length path problem. NP-completeness and efficient approximation algorithms for various cases of this problem are discussed.

10. M. J. Donahue, L. Gurvits, C. Darken, and E.D. Sontag. Rates of convex approximation in non-Hilbert spaces. Constr. Approx., 13(2):187-220, 1997. [PDF] Keyword(s): machine learning, neural networks, optimization, approximation theory.
Abstract:
 This paper deals with sparse approximations by means of convex combinations of elements from a predetermined "basis" subset S of a function space. Specifically, the focus is on the rate at which the lowest achievable error can be reduced as larger subsets of S are allowed when constructing an approximant. The new results extend those given for Hilbert spaces by Jones and Barron, including in particular a computationally attractive incremental approximation scheme. Bounds are derived for broad classes of Banach spaces. The techniques used borrow from results regarding moduli of smoothness in functional analysis as well as from the theory of stochastic processes on function spaces.

 Conference articles
1. A.C.B de Olivera, M. Siami, and E.D. Sontag. Bilinear dynamical networks under malicious attack: an efficient edge protection method. In Proc. 2021 Automatic Control Conference, pages 1210-1216, 2021. [PDF] Keyword(s): Bilinear systems, adversarial attacks, robustness measures, supermodular optimization.
Abstract:
 In large-scale networks, agents and links are often vulnerable to attacks. This paper focuses on continuous-time bilinear networks, where additive disturbances model attacks or uncertainties on agents/states (node disturbances), and multiplicative disturbances model attacks or uncertainties on couplings between agents/states (link disturbances). It investigates network robustness notion in terms of the underlying digraph of the network, and structure of exogenous uncertainties and attacks. Specifically, it defines a robustness measure using the $\mathcal H_2$-norm of the network and calculates it in terms of the reachability Gramian of the bilinear system. The main result is that under certain conditions, the measure is supermodular over the set of all possible attacked links. The supermodular property facilitates the efficient solution finding of the optimization problem. Examples illustrate how different structures can make the system more or less vulnerable to malicious attacks on links.

2. D. K. Agrawal, R. Marshall, M. Ali Al-Radhawi, V. Noireaux, and E. D. Sontag. Some remarks on robust gene regulation in a biomolecular integral controller. In Proc. 2019 IEEE Conf. Decision and Control, pages 2820-2825, 2019. [PDF] Keyword(s): adaptation, biological adaptation, perfect adaptation, tracking, synthetic biology, integral feedback, TX/TL, systems biology, dynamical systems, adaptation, internal model principle, systems biology.
Abstract:
 Integral feedback can help achieve robust tracking independently of external disturbances. Motivated by this knowledge, biological engineers have proposed various designs of biomolecular integral feedback controllers to regulate biological processes. In this paper, we theoretically analyze the operation of a particular synthetic biomolecular integral controller, which we have recently proposed and implemented experimentally. Using a combination of methods, ranging from linearized analysis to sum-of-squares (SOS) Lyapunov functions, we demonstrate that, when the controller is operated in closed-loop, it is capable of providing integral corrections to the concentration of an output species in such a manner that the output tracks a reference signal linearly over a large dynamic range. We investigate the output dependency on the reaction parameters through sensitivity analysis, and quantify performance using control theory metrics to characterize response properties, thus providing clear selection guidelines for practical applications. We then demonstrate the stable operation of the closed-loop control system by constructing quartic Lyapunov functions using SOS optimization techniques, and establish global stability for a unique equilibrium. Our analysis suggests that by incorporating effective molecular sequestration, a biomolecular closed-loop integral controller that is capable of robustly regulating gene expression is feasible.

3. C. Darken, M.J. Donahue, L. Gurvits, and E.D. Sontag. Rate of approximation results motivated by robust neural network learning. In COLT '93: Proceedings of the sixth annual conference on Computational learning theory, New York, NY, USA, pages 303-309, 1993. ACM Press. [doi:http://doi.acm.org/10.1145/168304.168357] Keyword(s): machine learning, neural networks, optimization problems, approximation theory.

4. E.D. Sontag and H.J. Sussmann. Image restoration and segmentation using the annealing algorithm. In Proc. IEEE Conf. Dec. and Control, 1985, pages 768-773, 1985. [PDF] Keyword(s): image processing, optimization.
Abstract:
 We consider the problem of estimating a signal, which is known -- or assumed -- to be constant on each of the members of a partition of a square lattice into m unknown regions, from the observation of the signal plus Gaussian noise. This is a nonlinear estimation problem, for which it is not appropriate to use the conditional expectation as the estimate. We show that, at least in principle, the "maximum iikelihood estimator" (MLE) proposed by Geman and Geman lends itself to numerical computation using the annealing algorithm. We argue that the MLE by itself can be, under certain conditions (low signal to noise ratio), a very unsatisfactory estimator, in that it does worse than just deciding that the signal was zero. However, if combined with a rule which we propose, for deciding when to use and when to ignore it, the MLE can provide a reasonable suboptimal estimator. We then discuss preliminary numerical data obtained using the annealing method. These results indicate that: (a) the annealing algorithm performs remarkably well, and (b) a criterion can be formulated in terms of quantities computed from the observed image (without using a priori knowledge of the signal-to-noise ratio) for deciding when to keep the MLE.

 Internal reports
1. E.D. Sontag and H.J. Sussmann. Optimization algorithms for image restoration and segmentation. Technical report 34, Rutgers Center for Computer Aids for Industrial Productivity, 1987.

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