| Articles in journal or book chapters |
| 2024 |
| Numerical ``direct'' approaches to time-optimal control often fail to find solutions that are singular in the sense of the Pontryagin Maximum Principle. These approaches behave better when searching for saturated (bang-bang) solutions. In previous work by one of the authors, singular solutions were theoretically shown to exist for the time-optimal problem for two-link manipulators under hard torque constraints. The theoretical results gave explicit formulas, based on Lie theory, for singular segments of trajectories, but the global structure of solutions remains unknown. In this work, we show how to effectively combine these theoretically found formulas with the use of general-purpose optimal control softwares. By using the explicit formula given by theory in the intervals where the numerical solution enters a singular arcs, we not only obtain an algebraic expression for the control in that interval, but we are also able to remove artifacts present in the numerical solution. In this way, the best features of numerical algorithms and theory complement each other and provide a better picture of the global optimal structure. We showcase the technique on a 2 degrees of freedom robotic arm example, and also propose a way of extending the analyzed method to robotic arms with higher degrees of freedom through partial feedback linearization, assuming the desired task can be mostly performed by a few of the degrees of freedom of the robot and imposing some prespecified trajectory on the remaining joints. |
| In previous work, we have developed an approach to understanding the long-term dynamics of classes of chemical reaction networks, based on rate-dependent Lyapunov functions. In this paper, we show that stronger notions of convergence can be established by proving contraction with respect to non-standard norms. This enables us to show that such networks entrain to periodic inputs. We illustrate our theory with examples from signaling pathways and genetic circuits. |
| Biological systems have been widely studied as complex dynamic systems that evolve with time in response to the internal resources abundance and external perturbations due to their common features. Integration of systems and synthetic biology provides a consolidated framework that draws system-level connections among biology, mathematics, engineering, and computer sciences. One major problem in current synthetic biology research is designing and controlling the synthetic circuits to perform reliable and robust behaviors as they utilize common transcription and translational resources among the circuits and host cells. While cellular resources are often limited, this results in a competition for resources by different genes and circuits, which affect the behaviors of synthetic genetic circuits. The manner competition impacts behavior depends on the “bottleneck” resource. With knowledge of physics laws and underlying mechanisms, the dynamical behaviors of the synthetic circuits can be described by the first principle models, usually represented by a system of ordinary differential equations (ODEs). In this work, we develop the novel embedded PINN (ePINN), which is composed of two nested loss-sharing neural networks to target and improve the unknown dynamics prediction from quantitative time series data. We apply the ePINN approach to identify the mathematical structures of competition phenotypes. Firstly, we use the PINNs approach to infer the model parameters and hidden dynamics from partially known data (including a lack of understanding of the reaction mechanisms or missing experimental data). Secondly, we test how well the algorithms can distinguish and extract the unknown dynamics from noisy data. Thirdly, we study how the synthetic and competing circuits behave in various cases when different particles become a limited resource. |
| This paper studies the effect of perturbations on the gradient flow of a general constrained nonlinear programming problem, where the perturbation may arise from inaccurate gradient estimation in the setting of data-driven optimization. Under suitable conditions on the objective function, the perturbed gradient flow is shown to be small-disturbance input-to-state stable (ISS), which implies that, in the presence of a small-enough perturbation, the trajectory of the perturbed gradient flow must eventually enter a small neighborhood of the optimum. This work was motivated by the question of robustness of direct methods for the linear quadratic regulator problem, and specifically the analysis of the effect of perturbations caused by gradient estimation or round-off errors in policy optimization. Interestingly, we show small-disturbance ISS for three of the most common optimization algorithms: standard gradient flow, natural gradient flow, and Newton gradient flow. |
| This work studies relationships between monotonicity and contractivity, and applies the results to establish that many reaction networks are weakly contractive, and thus, under appropriate compactness conditions, globally convergent to equilibria. Verification of these properties is achieved through a novel algorithm that can be used to generate cones for an accompanying monotone system. The results given here allow a unified proof of global convergence for several classes of networks that had been previously studied in the literature. |
| There is growing recognition that phenotypic plasticity enables cancer cells to adapt to various environmental conditions. An example of this adaptability is the persistence of an initially sensitive population of cancer cells in the presence of therapeutic agents. Understanding the implications of this drug-induced resistance is essential for predicting transient and long-term tumor tumor dynamics subject to treatment. This paper introduces a mathematical model of this phenomenon of drug-induced resistance which provides excellent fits to time-resolved in vitro experimental data. From observational data of total numbers of cells, the model unravels the relative proportions of sensitive and resistance subpopulations, and quantifies their dynamics as a function of drug dose. The predictions are then validated using data on drug doses which were not used when fitting parameters. The model is then used, in conjunction with optimal control techniques, in order to discover dosing strategies that might lead to better outcomes as quantified by lower total cell volume. |
| Deep neural network autoencoders are routinely used computationally for model reduction. They allow recognizing the intrinsic dimension of data that lie in a k-dimensional subset K of an input Euclidean space $\R^n$. The underlying idea is to obtain both an encoding layer that maps $\R^n$ into $\R^k$ (called the bottleneck layer or the space of latent variables) and a decoding layer that maps $\R^k$ back into $\R^n$, in such a way that the input data from the set K is recovered when composing the two maps. This is achieved by adjusting parameters (weights) in the network to minimize the discrepancy between the input and the reconstructed output. Since neural networks (with continuous activation functions) compute continuous maps, the existence of a network that achieves perfect reconstruction would imply that K is homeomorphic to a k-dimensional subset of $\R^k$, so clearly there are topological obstructions to finding such a network. On the other hand, in practice the technique is found to "work" well, which leads one to ask if there is a way to explain this effectiveness. We show that, up to small errors, indeed the method is guaranteed to work. This is done by appealing to certain facts from differential geometry. A computational example is also included to illustrate the ideas. |
| Linear immersions (or Koopman eigenmappings) of a nonlinear system have wide applications in prediction and control. In this work, we study the non-existence of one-to-one linear immersions for nonlinear systems with multiple omega-limit sets. While previous research has indicated the possibility of discontinuous one-to-one linear immersions for such systems, it remained uncertain whether continuous one-to-one linear immersions are attainable. Under mild conditions, we prove that any continuous one-to-one immersion to a class of systems including linear systems cannot distinguish different omega-limit sets, and thus cannot be one-to-one. Furthermore, we show that this property is also shared by approximate linear immersions learned from data as sample size increases and sampling interval decreases. Multiple examples are studied to illustrate our results. |
| Powerful distributed computing can be achieved by communicating cells that individually perform simple operations. We have developed design software to divide a large genetic circuit across cells as well as the genetic parts to implement the subcircuits in their genomes. These tools were demonstrated using a 2-bit version of the MD5 hashing algorithm, an early predecessor to the cryptographic functions underlying cryptocurrency. One iteration requires 110 logic gates, which were partitioned across 66 strains of Escherichia coli, requiring the introduction of a total of 1.1 Mb of recombinant DNA into their genomes. The strains are individually experimentally verified to integrate their assigned input signals, process this information correctly, and propagate the result to the cell in the next layer. This work demonstrates the potential to obtain programmable control of multicellular biological processes. |
| Bispecific T Cell Engagers (BTC) constitute an exciting antibody design in immuno-oncology that acts to bypass antigen presentation and forms a direct link between cancer and immune cells in the tumor microenvironment (TME). By design, BTCs are efficacious only when the drug is bound to both immune and cancer cell targets, and therefore approaches to maximize drug-target trimer in the TME should maximize the drug's efficacy. In this study, we quantitatively investigate how the concentration of ternary complex and its distribution depend on both the targets' specific properties and the design characteristics of the BTC, and specifically on the binding kinetics of the drug to its targets. A simplified mathematical model of drug-target interactions is considered here, with insights from the "three-body" problem applied to the model. Parameter identifiability analysis performed on the model demonstrates that steady-state data, which is often available at the early pre-clinical stages, is sufficient to estimate the binding affinity of the BTC molecule to both targets. The model is used to analyze several existing antibodies that are either clinically approved or are under development, and to explore the common kinetic features. We conclude with a discussion of the limitations of the BTCs, such as the increased likelihood of cytokine release syndrome, and an assessment for a full quantitative pharmacology model that accounts for drug distribution into the peripheral compartment. |
| This paper defines antifragility for dynamical systems as convexity of a newly introduced "logarithmic rate" of dynamical systems. It shows how to compute this rate for positive linear systems, and it interprets antifragility in terms of pulsed alternations of extreme strategies in comparison to average uniform strategies. |
| Single-cell omics technologies can measure millions of cells for up to thousands of biomolecular features, which enables the data-driven study of highly complex biological networks. However, these high-throughput experimental techniques often cannot track individual cells over time, thus complicating the understanding of dynamics such as the time trajectories of cell states. These ``dynamical phenotypes'' are key to understanding biological phenomena such as differentiation fates. We show by mathematical analysis that, in spite of high-dimensionality and lack of individual cell traces, three timepoints of single-cell omics data are theoretically necessary and sufficient in order to uniquely determine the network interaction matrix and associated dynamics. Moreover, we show through numerical simulations that an interaction matrix can be accurately determined with three or more timepoints even in the presence of sampling and measurement noise typical of single-cell omics. Our results can guide the design of single-cell omics time-course experiments, and provide a tool for data-driven phase-space analysis. |
| Differentiation within multicellular organisms is a complex process that helps to establish spatial patterning and tissue formation within the body. Often, the differentiation of cells is governed by morphogens and intercellular signaling molecules that guide the fate of each cell, frequently using toggle-like regulatory components. Synthetic biologists have long sought to recapitulate patterned differentiation with engineered cellular communities, and various methods for differentiating bacteria have been invented. Here, we couple a synthetic corepressive toggle switch with intercellular signaling pathways to create a “quorum-sensing toggle”. We show that this circuit not only exhibits population-wide bistability in a well-mixed liquid environment but also generates patterns of differentiation in colonies grown on agar containing an externally supplied morphogen. If coupled to other metabolic processes, circuits such as the one described here would allow for the engineering of spatially patterned, differentiated bacteria for use in biomaterials and bioelectronics. |
| We develop some basic principles for the design and robustness analysis of a continuous-time bilinear dynamical network, where an attacker can manipulate the strength of the interconnections/edges between some of the agents/nodes. We formulate the edge protection optimization problem of picking a limited number of attack-free edges and minimizing the impact of the attack over the bilinear dynamical network. In particular, the H2-norm of bilinear systems is known to capture robustness and performance properties analogous to its linear counterpart and provides valuable insights for identifying which edges arem ost sensitive to attacks. The exact optimization problem is combinatorial in the number of edges, and brute-force approaches show poor scalability. However, we show that the H2-norm as a cost function is supermodular and, therefore, allows for efficient greedy approximations of the optimal solution. We illustrate and compare the effectiveness of our theoretical findings via numerical simulation |
| Motivated by the growing use of Artificial Intelligence (AI) tools in control design, this paper takes the first steps towards bridging the gap between results from Direct Gradient methods for the Linear Quadratic Regulator (LQR), and neural networks. More specifically, it looks into the case where one wants to find a Linear Feed-Forward Neural Network (LFFNN) feedback that minimizes a LQR cost. This paper starts by computing the gradient formulas for the parameters of each layer, which are used to derive a key conservation law of the system. This conservation law is then leveraged to prove boundedness and global convergence of solutions to critical points, and invariance of the set of stabilizing networks under the training dynamics. This is followed by an analysis of the case where the LFFNN has a single hidden layer. For this case, the paper proves that the training converges not only to critical points but to the optimal feedback control law for all but a set of measure-zero of the initializations. These theoretical results are followed by an extensive analysis of a simple version of the problem (the ``vector case''), proving the theoretical properties of accelerated convergence and robustness for this simpler example. Finally, the paper presents numerical evidence of faster convergence of the training of general LFFNNs when compared to traditional direct gradient methods, showing that the acceleration of the solution is observable even when the gradient is not explicitly computed but estimated from evaluations of the cost function. |
| 2023 |
| Synthetic gene circuits require cellular resources, which are often limited. This leads to competition for resources by different genes, which alter a synthetic genetic circuit's behavior. However, the manner in which competition impacts behavior depends on the identity of the "bottleneck" resource which might be difficult to discern from input-output data. In this paper, we aim at classifying the mathematical structures of resource competition in biochemical circuits. We find that some competition structures can be distinguished by their response to different competitors or resource levels. Specifically, we show that some response curves are always linear, convex, or concave. Furthermore, high levels of certain resources protect the behavior from low competition, while others do not. We also show that competition phenotypes respond differently to various interventions. Such differences can be used to eliminate candidate competition mechanisms when constructing models based on given data. On the other hand, we show that different networks can display mathematically equivalent competition phenotypes. |
| Single-cell -omics datasets are high-dimensional and difficult to visualize. A common strategy for exploring such data is to create and analyze 2D projections. Such projections may be highly nonlinear, and implementation algorithms are designed with the goal of preserving aspects of the original high-dimensional shape of data such as neighborhood relationships or metrics. However, important aspects of high-dimensional geometry are known from mathematical theory to have no equivalent representation in 2D, or are subject to large distortions, and will therefore be misrepresented or even invisible in any possible 2D representation. We show that features such as quantitative distances, relative positioning, and qualitative neighborhoods of high-dimensional data points will always be misrepresented in 2D projections. Our results rely upon concepts from differential geometry, combinatorial geometry, and algebraic topology. As an illustrative example, we show that even a simple single-cell RNA sequencing dataset will always be distorted, no matter what 2D projection is employed. We also discuss how certain recently developed computational tools can help describe the high-dimensional geometric features that will be necessarily missing from any possible 2D projections. |
| 2022 |
| Metastasis can occur after malignant cells transition from the epithelial phenotype to the mesenchymal phenotype. This transformation allows cells to migrate via the circulatory system and subsequently settle in distant organs after undergoing the reverse transition. The core gene regulatory network controlling these transitions consists of a system made up of coupled SNAIL/miRNA-34 and ZEB1/miRNA-200 subsystems. In this work, we formulate a mathematical model and analyze its long-term behavior. We start by developing a detailed reaction network with 24 state variables. Assuming fast promoter and mRNA kinetics, we then show how to reduce our model to a monotone four-dimensional system. For the reduced system, monotone dynamical systems theory can be used to prove generic convergence to the set of equilibria for all bounded trajectories. The theory does not apply to the full model, which is not monotone, but we briefly discuss results for singularly-perturbed monotone systems that provide a tool to extend convergence results from reduced to full systems, under appropriate time separation assumptions. |
| In order to control highly-contagious and prolonged outbreaks, public health authorities intervene to institute social distancing, lock-down policies, and other Non-Pharmaceutical Interventions (NPIs). Given the high social, educational, psychological, and economic costs of NPIs, authorities tune them, alternatively tightening up or relaxing rules, with the result that, in effect, a relatively flat infection rate results. For example, during the summer of 2020 in parts of the United States, daily COVID-19 infection numbers dropped to a plateau. This paper approaches NPI tuning as a control-theoretic problem, starting from a simple dynamic model for social distancing based on the classical SIR epidemics model. Using a singular-perturbation approach, the plateau becomes a Quasi-Steady-State (QSS) of a reduced two-dimensional SIR model regulated by adaptive dynamic feedback. It is shown that the QSS can be assigned and it is globally asymptotically stable. Interestingly, the dynamic model for social distancing can be interpreted as a nonlinear integral controller. Problems of data fitting and parameter identifiability are also studied for this model. This letter also discusses how this simple model allows for a meaningful study of the effect of population size, vaccinations, and the emergence of second waves. |
| The emergence of and transitions between distinct phenotypes in isogenic cells can be attributed to the intricate interplay of epigenetic marks, external signals, and gene regulatory elements. These elements include chromatin remodelers, histone modifiers, transcription factors, and regulatory RNAs. Mathematical models known as Gene Regulatory Networks (GRNs) are an increasingly important tool to unravel the workings of such complex networks. In such models, epigenetic factors are usually proposed to act on the chromatin regions directly involved in the expression of relevant genes. However, it has been well-established that these factors operate globally and compete with each other for targets genome-wide. Therefore, a perturbation of the activity of a regulator can redistribute epigenetic marks across the genome and modulate the levels of competing regulators. In this paper, we propose a conceptual and mathematical modeling framework that incorporates both local and global competition effects between antagonistic epigenetic regulators in addition to local transcription factors, and show the counter-intuitive consequences of such interactions. We apply our approach to recent experimental findings on the Epithelial-Mesenchymal Transition (EMT). We show that it can explain the puzzling experimental data as well provide new verifiable predictions. |
| This paper introduces a notion of non-oscillation, proposes a constructive method for its robust verification, and studies its application to biological interaction networks. The paper starts by revisiting Muldowney's result on non-existence of periodic solutions based on the study of the variational system of the second additive compound of the Jacobian of a nonlinear system. It then shows that exponential stability of the latter rules out limit cycles, quasi-periodic solutions, and broad classes of oscillatory behavior. The focus then turns ton nonlinear equations arising in biological interaction networks with general kinetics, the paper shows that the dynamics of the variational system can be embedded in a linear differential inclusion. This leads to algorithms for constructing piecewise linear Lyapunov functions to certify global robust non-oscillatory behavior. Finally, the paper applies the new techniques to study several regulated enzymatic cycles where available methods are not able to provide any information about their qualitative global behavior. |
| Internal models are nowadays customarily used in different domains of science and engineering to describe how living organisms or artificial computational units embed their acquired knowledge about recurring events taking place in the surrounding environment. This article reviews the internal model principle in control theory, bioengineering, and neuroscience, illustrating the fundamental concepts and theoretical developments of the last few decades of research. |
| Recent work on data-driven control and reinforcement learning has renewed interest in a relatively old field in control theory: model-free optimal control approaches which work directly with a cost function and do not rely upon perfect knowledge of a system model. Instead, an "oracle" returns an estimate of the cost associated to, for example, a proposed linear feedback law to solve a linear-quadratic regulator problem. This estimate, and an estimate of the gradient of the cost, might be obtained by performing experiments on the physical system being controlled. This motivates in turn the analysis of steepest descent algorithms and their associated gradient differential equations. This paper studies the effect of errors in the estimation of the gradient, framed in the language of input to state stability, where the input represents a perturbation from the true gradient. Since one needs to study systems evolving on proper open subsets of Euclidean space, a self-contained review of input to state stability definitions and theorems for systems that evolve on such sets is included. The results are then applied to the study of noisy gradient systems, as well as the associated steepest descent algorithms. |
| 2021 |
| A dynamical system entrains to a periodic input if its state converges globally to an attractor with the same period. In particular, for a constant input, the state converges to a unique equilibrium point for any initial condition. We consider the problem of maximizing a weighted average of the system's output along the periodic attractor. The gain of entrainment is the benefit achieved by using a non-constant periodic input relative to a constant input with the same time average. Such a problem amounts to optimal allocation of resources in a periodic manner. We formulate this problem as a periodic optimal control problem, which can be analyzed by means of the Pontryagin maximum principle or solved numerically via powerful software packages. We then apply our framework to a class of nonlinear occupancy models that appear frequently in biological synthesis systems and other applications. We show that, perhaps surprisingly, constant inputs are optimal for various architectures. This suggests that the presence of non-constant periodic signals, which frequently appear in biological occupancy systems, is a signature of an underlying time-varying objective functional being optimized. |
| 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. |
| This paper considers the following learning problem: given sample pairs of input and output signals generated by an unknown nonlinear system (which is not assumed to be causal or time-invariant), one wishes to find a continuous-time recurrent neural net, with activation function tanh, that approximately reproduces the underlying i/o behavior with high confidence. Leveraging earlier work concerned with matching derivatives up to a finite order of the input and output signals the problem is reformulated in familiar system-theoretic language and quantitative guarantees on the sup-norm risk of the learned model are derived, in terms of the number of neurons, the sample size, the number of derivatives being matched, and the regularity properties of the inputs, the outputs, and the unknown i/o map. |
| Long-term behaviors of biochemical reaction networks (BRNs) are described by steady states in deterministic models and stationary distributions in stochastic models. Unlike deterministic steady states, stationary distributions capturing inherent fluctuations of reactions are extremely difficult to derive analytically due to the curse of dimensionality. Here, we develop a method to derive analytic stationary distributions from deterministic steady states by transforming BRNs to have a special dynamic property, called complex balancing. Specifically, we merge nodes and edges of BRNs to match in- and out-flows of each node. This allows us to derive the stationary distributions of a large class of BRNs, including autophosphorylation networks of EGFR, PAK1, and Aurora B kinase and a genetic toggle switch. This reveals the unique properties of their stochastic dynamics such as robustness, sensitivity, and multimodality. Importantly, we provide a user-friendly computational package, CASTANET, that automatically derives symbolic expressions of the stationary distributions of BRNs to understand their long-term stochasticity. |
| The development of resistance to chemotherapy is a major cause of treatment failure in cancer. Intratumoral heterogeneity and phenotypic plasticity play a significant role in therapeutic resistance. Individual cell measurements such as flow and mass cytometry and single cell RNA sequencing (scRNA-seq) have been used to capture and analyze this cell variability. In parallel, longitudinal treatment-response data is routinely employed in order to calibrate mechanistic mathematical models of heterogeneous subpopulations of cancer cells viewed as compartments with differential growth rates and drug sensitivities. This work combines both approaches: single cell clonally-resolved transcriptome datasets (scRNA-seq, tagging individual cells with unique barcodes that are integrated into the genome and expressed as sgRNA's) and longitudinal treatment response data, to fit a mechanistic mathematical model of drug resistance dynamics for a MDA-MB-231 breast cancer cell line. The explicit inclusion of the transcriptomic information in the parameter estimation is critical for identification of the model parameters and enables accurate prediction of new treatment regimens. |
| Different epidemiological models, from the classical SIR system to more sophisticated ones involving population compartments for socially distanced, quarantined, infection aware, asymptomatic infected, and other individuals, share some remarkable dynamic characteristics when contact rates are subject to periodic or one-shot changes. In simple pulsed isolation policies, a linear relationship is found among optimal start time and duration for reduction of the infected peak. If a single interval social distancing starts too early or too late it will be ineffective with respect to decreasing the peak of infection. On the other hand, the nonlinearity of epidemic models leads to non-monotone behavior of the peak of infected population under periodic relaxation policies. This observation led us to hypothesize that an additional single interval social distancing at a proper time can significantly decrease the infected peak of periodic policies, and we verified this improvement. |
| Careful timing of NPIs (non-pharmaceutical interventions) such as social distancing may avoid high ``second waves'' of infections of COVID-19. This paper asks what should be the timing of a set of K complete-lockdowns of prespecified lengths (such as two weeks) so as to minimize the peak of the infective compartment. Perhaps surprisingly, it is possible to give an explicit and easily computable rule for when each lockdown should commence. Simulations are used to show that the rule remains fairly accurate even if lockdowns are not perfect. |
| 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/. |
| Exact analytical and closed-form solutions to a problem involving transient diffusion in a bi-layer membrane with external transfer resistance are presented. In addition to the solutions of the transient response, the lead and lag times that are often of importance in the characterization of membranes and arise from the analysis of the asymptotic behavior of the mass permeated through the membrane are also provided. The solutions presented here are also compared to previously derived limiting cases of the diffusion in a bi-layer with an impermeable wall and constant concentrations at the upstream and downstream boundaries. Analysis of the time lag shows that this membrane property is independent of the direction of flow. Finally, an outline is provided of how these solutions, which characterize the response to a step function increase in concentration, can be also used to derive more complex input conditions. Adequately handling boundary layer effects has a wide array of potential applications such as the study of bi-layer undergoing phenomena of heat convection, gas film resistance, and absorption/desorption. |
| Maintaining and limiting T cell responses to constant antigen stimulation is critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) induces signalling that activates T cells to produce cytokines and also leads to the downregulation of surface TCRs. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation that requires complete downregulation of the receptor or the ligand. However, this is not the case for the TCR, and therefore, precisely how TCR downregulation maintains or limits T cell responses is controversial. Here, we observed that in vitro expanded primary human T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR downregulation. By directly fitting a mechanistic model to the data, we show that TCR downregulation produces imperfect adaptation, but when coupled to a switch produces perfect adaptation in cytokine production. A pre diction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings highlight that even partial TCR downregulation can limit T cell responses by producing perfect adaptation rendering T cells dependent on costimulation for sustained responses. |
| Correspondence regarding circulating tumor cell detection |
| 2020 |
| The notion of input to state stability (ISS) qualitatively describes stability of the mapping from initial states and inputs to internal states (and more generally outputs). This encyclopedia-style article entry gives a brief introduction to the definition of ISS and a discussion of equivalent characterizations. It is an update of the article in the 2015 edition, including additional citations to recent PDE work. |
| The phenomenon of fold-change detection, or scale-invariance, is exhibited by a variety of sensory systems, in both bacterial and eukaryotic signaling pathways. This encyclopedia-style article gives a brief introduction to the subject. |
| An important goal of synthetic biology is to build biosensors and circuits with well-defined input-output relationships that operate at speeds found in natural biological systems. However, for molecular computation, most commonly used genetic circuit elements typically involve several steps from input detection to output signal production: transcription, translation, and post-translational modifications. These multiple steps together require up to several hours to respond to a single stimulus, and this limits the overall speed and complexity of genetic circuits. To address this gap, molecular frameworks that rely exclusively on post-translational steps to realize reaction networks that can process inputs at a time scale of seconds to minutes have been proposed. Here, we build mathematical models of fast biosensors capable of producing Boolean logic functionality. We employ protease-based chemical and light-induced switches, investigate their operation, and provide selection guidelines for their use as on-off switches. As a proof of concept, we implement a rapamycin-induced switch in vitro and demonstrate that its response qualitatively agrees with the predictions from our models. We then use these switches as elementary blocks, developing models for biosensors that can perform OR and XOR Boolean logic computation while using reaction conditions as tuning parameters. We use sensitivity analysis to determine the time-dependent sensitivity of the output to proteolytic and protein-protein binding reaction parameters. These fast protease-based biosensors can be used to implement complex molecular circuits with a capability of processing multiple inputs controllably and algorithmically. Our framework for evaluating and optimizing circuit performance can be applied to other molecular logic circuits. |
| This paper deals with the analysis of the dynamics of chemical reaction networks, developing a theoretical framework based only on graphical knowledge and applying regardless of the particular form of kinetics. This paper introduces a class of networks that are "structurally (mono) attractive", by which we mean that they are incapable of exhibiting multiple steady states, oscillation, or chaos by the virtue of their reaction graphs. These networks are characterized by the existence of a universal energy-like function which we call a Robust Lyapunov function (RLF). To find such functions, a finite set of rank-one linear systems is introduced, which form the extremals of a linear convex cone. The problem is then reduced to that of finding a common Lyapunov function for this set of extremals. Based on this characterization, a computational package, Lyapunov-Enabled Analysis of Reaction Networks (LEARN), is provided that constructs such functions or rules out their existence. An extensive study of biochemical networks demonstrates that LEARN offers a new unified framework. We study basic motifs, three-body binding, and transcriptional networks. We focus on cellular signalling networks including various post-translational modification cascades, phosphotransfer and phosphorelay networks, T-cell kinetic proofreading, ERK signaling, and the Ribosome Flow Model. |
| Starting in the early 2000s, sophisticated technologies have been developed for the rational construction of synthetic genetic networks that implement specified logical functionalities. Despite impressive progress, however, the scaling necessary in order to achieve greater computational power has been hampered by many constraints, including repressor toxicity and the lack of large sets of mutually-orthogonal repressors. As a consequence, a typical circuit contains no more than roughly seven repressor-based gates per cell. A possible way around this scalability problem is to distribute the computation among multiple cell types, which communicate among themselves using diffusible small molecules (DSMs) and each of which implements a small sub-circuit. Examples of DSMs are those employed by quorum sensing systems in bacteria. This paper focuses on systematic ways to implement this distributed approach, in the context of the evaluation of arbitrary Boolean functions. The unique characteristics of genetic circuits and the properties of DSMs require the development of new Boolean synthesis methods, distinct from those classically used in electronic circuit design. In this work, we propose a fast algorithm to synthesize distributed realizations for any Boolean function, under constraints on the number of gates per cell and the number of orthogonal DSMs. The method is based on an exact synthesis algorithm to find the minimal circuit per cell, which in turn allows us to build an extensive database of Boolean functions up to a given number of inputs. For concreteness, we will specifically focus on circuits of up to 4 inputs, which might represent, for example, two chemical inducers and two light inputs at different frequencies. Our method shows that, with a constraint of no more than seven gates per cell, the use of a single DSM increases the total number of realizable circuits by at least 7.58-fold compared to centralized computation. Moreover, when allowing two DSM's, one can realize 99.995\% of all possible 4-input Boolean functions, still with at most 7 gates per cell. The methodology introduced here can be readily adapted to complement recent genetic circuit design automation software. |
| Cell-fate networks are traditionally studied within the framework of gene regulatory networks. This paradigm considers only interactions of genes through expressed transcription factors and does not incorporate chromatin modification processes. This paper introduces a mathematical model that seamlessly combines gene regulatory networks and DNA methylation, with the goal of quantitatively characterizing the contribution of epigenetic regulation to gene silencing. The ``Basin of Attraction percentage'' is introduced as a metric to quantify gene silencing abilities. As a case study, a computational and theoretical analysis is carried out for a model of the pluripotent stem cell circuit as well as a simplified self-activating gene model. The results confirm that the methodology quantitatively captures the key role that methylation plays in enhancing the stability of the silenced gene state. |
| Motivated by the current COVID-19 epidemic, this work introduces an epidemiological model in which separate compartments are used for susceptible and asymptomatic "socially distant" populations. Distancing directives are represented by rates of flow into these compartments, as well as by a reduction in contacts that lessens disease transmission. The dynamical behavior of this system is analyzed, under various different rate control strategies, and the sensitivity of the basic reproduction number to various parameters is studied. One of the striking features of this model is the existence of a critical implementation delay in issuing separation mandates: while a delay of about four weeks does not have an appreciable effect, issuing mandates after this critical time results in a far greater incidence of infection. In other words, there is a nontrivial but tight "window of opportunity" for commencing social distancing. Different relaxation strategies are also simulated, with surprising results. Periodic relaxation policies suggest a schedule which may significantly inhibit peak infective load, but that this schedule is very sensitive to parameter values and the schedule's frequency. Further, we considered the impact of steadily reducing social distancing measures over time. We find that a too-sudden reopening of society may negate the progress achieved under initial distancing guidelines, if not carefully designed. |
| One of the most important factors limiting the success of chemotherapy in cancer treatment is the phenomenon of drug resistance. We have recently introduced a framework for quantifying the effects of induced and non-induced resistance to cancer chemotherapy. In this work, we expound on the details relating to an optimal control problem outlined in our previous paper (Greene et al., 2018). The control structure is precisely characterized as a concatenation of bang-bang and path-constrained arcs via the Pontryagin Maximum Principle and differential Lie algebraic techniques. A structural identifiability analysis is also presented, demonstrating that patient-specific parameters may be measured and thus utilized in the design of optimal therapies prior to the commencement of therapy. For completeness, a detailed analysis of existence results is also included. |
| 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". |
| It is well known that the presence of an incoherent feedforward loop (IFFL) in a network may give rise to a steady state non-monotonic dose response. This note shows that the converse implication does not hold. It gives an example of a three-dimensional system that has no IFFLs, yet its dose response is bell-shaped. It also studies under what conditions the result is true for two-dimensional systems, in the process recovering, in far more generality, a result given in the T-cell activation literature. |
| Metronomic chemotherapy can drastically enhance immunogenic tumor cell death. However, the responsible mechanisms are still incompletely understood. Here, we develop a mathematical model to elucidate the underlying complex interactions between tumor growth, immune system activation, and therapy-mediated immunogenic cell death. Our model is conceptually simple, yet it provides a surprisingly excellent fit to empirical data obtained from a GL261 mouse glioma model treated with cyclophosphamide on a metronomic schedule. The model includes terms representing immune recruitment as well as the emergence of drug resistance during prolonged metronomic treatments. Strikingly, a fixed set of parameters, not adjusted for individuals nor for drug schedule, excellently recapitulates experimental data across various drug regimens, including treatments administered at intervals ranging from 6 to 12 days. Additionally, the model predicts peak immune activation times, rediscovering experimental data that had not been used in parameter fitting or in model construction. The validated model was then used to make predictions about expected tumor-immune dynamics for novel drug administration schedules. Notably, the validated model suggests that immunostimulatory and immunosuppressive intermediates are responsible for the observed phenomena of resistance and immune cell recruitment, and thus for variation of responses with respect to different schedules of drug administration. |
| Circulating tumor cells (CTCs) are widely studied using liquid biopsy methods that analyze single, fractionally-small peripheral blood (PB) samples. However, little is known about fluctuations in CTC numbers that occur over short timescales in vivo, and how these may affect accurate enumeration from blood samples. Diffuse in vivo flow cytometry (DiFC) developed by the Niedre lab allows continuous, non-invasive counting of rare, green fluorescent protein expressing CTCs in large deeply-seated blood vessels in mice. Here, DiFC is used to study short-term changes in CTC numbers in multiple myeloma and Lewis lung carcinoma xenograft models. Both 35- to 50-minute data sets are analyzed, with intervals corresponding to approximately 1, 5, 10 and 20\% of the PB volume, as well as changes over 24-hour periods. For rare CTCs, the use of short DiFC intervals (corresponding to small PB samples) frequently resulted in no detections. For more abundant CTCs, CTC numbers frequently varied by an order of magnitude or more over the time-scales considered. This variability far exceeded that expected by Poisson statistics, and instead was consistent with rapidly changing mean numbers of CTCs in the PB. Because of these natural temporal changes, accurately enumerating CTCs from fractionally small blood samples is inherently problematic. The problem is likely to be compounded for multicellular CTC clusters or specific CTC subtypes. However, it is also shown that enumeration can be improved by averaging multiple samples, analysis of larger volumes, or development of new methods for enumeration of CTCs directly in vivo. |
| 2019 |
| 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. |
| In biological processes such as embryonic development, hematopoietic cell differentiation, and the arising of tumor heterogeneity and consequent resistance to therapy, mechanisms of gene activation and deactivation may play a role in the emergence of phenotypically heterogeneous yet genetically identical (clonal) cellular populations. Mathematically, the variability in phenotypes in the absence of genetic variation can be modeled through the existence of multiple metastable attractors in nonlinear systems subject with stochastic switching, each one of them associated to an alternative epigenetic state. An important theoretical and practical question is that of estimating the number and location of these states, as well as their relative probabilities of occurrence. This paper focuses on a rigorous analytic characterization of multiple modes under slow promoter kinetics, which is a feature of epigenetic regulation. It characterizes the stationary distributions of Chemical Master Equations for gene regulatory networks as a mixture of Poisson distributions. As illustrations, the theory is used to tease out the role of cooperative binding in stochastic models in comparison to deterministic models, and applications are given to various model systems, such as toggle switches in isolation or in communicating populations and a trans-differentiation network. |
| Resistance to chemotherapy is a major impediment to the successful treatment of cancer. Classically, resistance has been thought to arise primarily through random genetic mutations, after which mutated cells expand via Darwinian selection. However, recent experimental evidence suggests that the progression to resistance need not occur randomly, but instead may be induced by the therapeutic agent itself. This process of resistance induction can be a result of genetic changes, or can occur through epigenetic alterations that cause otherwise drug-sensitive cancer cells to undergo "phenotype switching". This relatively novel notion of resistance further complicates the already challenging task of designing treatment protocols that minimize the risk of evolving resistance. In an effort to better understand treatment resistance, we have developed a mathematical modeling framework that incorporates both random and drug-induced resistance. Our model demonstrates that the ability (or lack thereof) of a drug to induce resistance can result in qualitatively different responses to the same drug dose and delivery schedule. The importance of induced resistance in treatment response led us to ask if, in our model, one can determine the resistance induction rate of a drug for a given treatment protocol. Not only could we prove that the induction parameter in our model is theoretically identifiable, we have also proposed a possible in vitro experiment which could practically be used to determine a treatment's propensity to induce resistance. |
| A matrix is totally nonnegative (resp., totally positive) if all its minors are nonnegative (resp., positive). This paper draws connections between B. Schwarz's 1970 work on TN and TP matrices to Smillie's 1984 and Smith's 1991 work on stability of nonlinear tridiagonal cooperative systems, simplifying proofs in the later paper and suggesting new research questions. |
| Recent experimental results from the Zloza lab combined a mouse model of influenza A virus (IAV) infection (A/H1N1/PR8) and a highly aggressive model of infection-unrelated cancer, B16-F10 skin melanoma. This paper showed that acute influenza infection of the lung promotes distal melanoma growth in the dermis of the flank and leads to decreased host survival. Here, we proceed to ground the experimental observations in a mechanistic immunobiochemical model that incorporates the T cell receptor signaling pathway, various transcription factors, and a gene regulatory network (GRN). A core component of our model is a biochemical motif, which we call a Triple Incoherent Feed-Forward Loop (TIFFL), and which reflects known interactions between IRF4, Blimp-1, and Bcl-6. The different activity levels of the TIFFL components, as a function of the cognate antigen levels and the given inflammation context, manifest themselves in phenotypically distinct outcomes. Specifically, both the TIFFL reconstruction and quantitative estimates obtained from the model allowed us to formulate a hypothesis that it is the loss of the fundamental TIFFL-induced adaptation of the expression of PD-1 receptors on anti-melanoma CD8+ T cells that constitutes the essence of the previously unrecognized immunologic factor that promotes the experimentally observed distal tumor growth in the presence of acute non-ocogenic infection. We therefore hope that this work can further highlight the importance of adaptive mechanisms by which immune functions contribute to the balance between self and non-self immune tolerance, adaptive resistance, and the strength of TCR-induced activation, thus contributing to the understanding of a broader complexity of fundamental interactions between pathogens and tumors. |
| We consider a nonlinear SISO system that is a cascade of a scalar "bottleneck entrance" with a stable positive linear system. In response to any periodic inflow, all solutions converge to a unique periodic solution with the same period. We study the problem of maximizing the averaged throughput via controlled switching. We compare two strategies: 1) switching between a high and low value, and 2 ~using a constant inflow equal to the prescribed mean value. We show that no possible switching policy can outperform a constant inflow rate, though it can approach it asymptotically. We describe several potential applications of this problem in traffic systems, ribosome flow models, and scheduling at security checks. |
| The goal of many single-cell studies on eukaryotic cells is to gain insight into the biochemical reactions that control cell fate and state. This paper introduces the concept of effective stoichiometric space (ESS) to guide the reconstruction of biochemical networks from multiplexed, fixed time-point, single-cell data. In contrast to methods based solely on statistical models of data, the ESS method leverages the power of the geometric theory of toric varieties to begin unraveling the structure of chemical reaction networks (CRN). This application of toric theory enables a data-driven mapping of covariance relationships in single cell measurements into stoichiometric information, one in which each cell subpopulation has its associated ESS interpreted in terms of CRN theory. In the development of ESS we reframe certain aspects of the theory of CRN to better match data analysis. As an application of our approach we process cytomery- and image-based single-cell datasets and identify differences in cells treated with kinase inhibitors. Our approach is directly applicable to data acquired using readily accessible experimental methods such as Fluorescence Activated Cell Sorting (FACS) and multiplex immunofluorescence. |
| 2018 |
| The study of stochastic biomolecular networks is a key part of systems biology, as such networks play a central role in engineered synthetic biology constructs as well as in naturally occurring cells. This expository paper reviews in a unified way a pair of recent approaches to the finite computation of statistics for chemical reaction networks. |
| This paper is a review of systems and control problems in synthetic biology, focusing on past accomplishments and open problems. It is partially a report on the workshop "The Compositionality Problem in Synthetic Biology: New Directions for Control Theory" held on June 26-27, 2017 at MIT, and organized by D. Del Vecchio, R. M. Murray, and E. D. Sontag |
| What complicated dynamics can arise in the simplest biochemical systems, in response to a periodic input? This paper discusses two models that commonly appear as components of larger sensing and signal transduction pathways in systems biology: a simple two-species negative feedback loop, and a prototype nonlinear integral feedback. These systems have globally attracting steady states when unforced, yet, when subject to a periodic excitation, subharmonic responses and strange attractors can arise via period-doubling cascades. These behaviors are similar to those exhibited by classical forced nonlinear oscillators such as those described by van der Pol or Duffing equations. The lack of entrainment to external oscillations, in even the simplest biochemical networks, represents a level of additional complexity in molecular biology. |
| This paper deals with the design of promoters that maintain constant levels of expression, whether they are carried at single copy in the genome or on high-copy plasmids. The design is based on an incoherent feedforward loop (iFFL) with a perfectly non-cooperative repression. The circuits are implemented in E. coli using Transcription Activator Like Effectors (TALEs). The resulting stabilized promoters generate near identical expression across different genome locations and plasmid backbones (pSC101, p15a, ColE1, pUC), and also provide robustness to strain mutations and growth media. Further, their strength is tunable and can be used to maintain constant ratios between proteins. |
| The ribosomal density along the coding region of the mRNA molecule affects various fundamental intracellular phenomena including: protein production rates, organismal fitness, ribosomal drop off, and co-translational protein folding. Thus, regulating translation in order to obtain a desired ribosomal profile along the mRNA molecule is an important biological problem. This paper studies this problem formulated in the context of the ribosome flow model (RFM) in which one views the transition rates between site as controls. |
| 2017 |
| This is an expository paper, which compares in detail various alternative weak contraction ideas for nonlinear system stability. |
| This paper proposes a technique that combines experimental data, mathematical modeling, and statistical analyses for identifying optimal treatment protocols that are robust with respect to individual variability. Experimental data from a small sample population is amplified using bootstrapping to obtain a large number of virtual populations that statistically match the expected heterogeneity. Alternative therapies chosen from among a set of clinically-realizable protocols are then compared and scored according to coverage. As proof of concept, the method is used to evaluate a treatment with oncolytic viruses and dendritic cell vaccines in a mouse model of melanoma. The analysis shows that while every scheduling variant of an experimentally-utilized treatment protocol is fragile (non-robust), there is an alternative region of dosing space (lower oncolytic virus dose, higher dendritic cell dose) for which a robust optimal protocol exists. |
| Biochemical reaction networks in cells frequently consist of reactions with disparate timescales. Stochastic simulations of such multiscale BRNs are prohibitively slow due to the high computational cost incurred in the simulations of fast reactions. One way to resolve this problem is to replace fast species by their stationary conditional expectation values conditioned on slow species. While various approximations schemes for this quasi-steady state approximation have been developed, they often lead to considerable errors. This paper considers two classes of multiscale BRNs which can be reduced by through an exact QSS rather than approximations. Specifically, we assume that fast species constitute either a feedforward network or a complex balanced network. Exact reductions for various examples are derived, and the computational advantages of this approach are illustrated through simulations. |
| This paper introduces two generalizations of systems invariant with respect to continuous sets of input transformations, that is, systems whose output dynamics remain invariant when applying a transformation to the input and simultaneously adjusting the initial conditions. These generalizations concern systems invariant with respect to time-dependent input transformations with exponentially increasing or decreasing ``strength'', and systems invariant with respect to transformations of the "nonlinear derivatives" of the input. Interestingly, these two generalizations of invariant systems encompass linear time-invariant (LTI) systems with real transfer function zeros of arbitrary multiplicity. Furthermore, the zero-dynamics of systems possessing our generalized invariances show properties analogous to those of LTI systems with transfer function zeros, generalizing concepts like pole-zero cancellation, the rejection of ramps by Hurwitz LTI systems with a zero at the origin with multiplicity two, and (to a certain extend) the superposition principle with respect to inputs zeroing the output. |
| Aerotaxis, the directed migration along oxygen gradients, allows many microorganisms to locate favorable oxygen concentrations. Despite oxygen's fundamental role for life, even key aspects of aerotaxis remain poorly understood. In Bacillus subtilis, for example, there is conflicting evidence of whether migration occurs to the maximal oxygen concentration available or to an optimal intermediate one, and how aerotaxis can be maintained over a broad range of conditions. Using precisely controlled oxygen gradients in a microfluidic device, spanning the full spectrum of conditions from quasi-anoxic to oxic (60nM-1mM), we resolved B. subtilis' ``oxygen preference conundrum'' by demonstrating consistent migration towards maximum oxygen concentrations. Surprisingly, the strength of aerotaxis was largely unchanged over three decades in oxygen concentration (131nM-196mM). We discovered that in this range B. subtilis responds to the logarithm of the oxygen concentration gradient, a log-sensing strategy that affords organisms high sensitivity over a wide range of conditions. |
| Utilizing the synthetic transcription-translation (TX-TL) system, this paper studies the impact of nucleotide triphosphates (NTPs) and magnesium (Mg2+), on gene expression, in the context of the counterintuitive phenomenon of suppression of gene expression at high NTP concentration. Measuring translation rates for different Mg2+ and NTP concentrations, we observe a complex resource dependence. We demonstrate that translation is the rate-limiting process that is directly inhibited by high NTP concentrations. Additional Mg2+ can partially reverse this inhibition. In several experiments, we observe two maxima of the translation rate viewed as a function of both Mg2+ and NTP concentration, which can be explained in terms of an NTP-independent effect on the ribosome complex and an NTP- Mg2+ titration effect. The non-trivial compensatory effects of abundance of different vital resources signals the presence of complex regulatory mechanisms to achieve optimal gene expression. |
| Elucidating the structure of biological intracellular networks from experimental data remains a major challenge. This paper studies two types of ``response signatures'' to identify specific circuit motifs, from the observed response to periodic inputs. In particular, the objective is to distinguish negative feedback loops (NFLs) from incoherent feedforward loops (IFFLs), which are two types of circuits capable of producing exact adaptation. The theory of monotone systems with inputs is used to show that ``period skipping'' (non-harmonic responses) is ruled out in IFFL's, and a notion called ``refractory period stabilization'' is also analyzed. The approach is then applied to identify a circuit dominating cell cycle timing in yeast, and to uncover a calcium-mediated NFL circuit in \emph{C.elegans} olfactory sensory neurons. |
| This paper analizes a model for the initial stage of T cell activation. The state variables in the model are the concentrations of phosphorylation states of the T cell receptor complex and the phosphatase SHP-1 in the cell. It is shown that these quantities cannot approach zero, and that there is more than one positive steady state for certain values of the parameters; in addition, damped oscillations are possible. It is also shown that the chemical concentration which represents the degree of activation of the cell, represented by the maximally phosphorylated form of the T cell receptor complex, is in general a non-monotone function of the activating signal. In particular there are cases where there is a value of the dissociation constant of the ligand from the receptor which produces an optimal activation of the T cell. In this way the results of certain simulations in the literature have been confirmed rigorously and new features are discovered. |
| This paper describes a novel approach for characterization of chemosensitivity and prediction of clinical response in multiple myeloma. It relies upon a patient-specific computational model of clinical response, parameterized by a high-throughput ex vivo assay that quantifies sensitivity of primary MM cells to 31 agents or combinations, in a reconstruction of the tumor microenvironment. The mathematical model, which inherently accounts for intra-tumoral heterogeneity of drug sensitivity, combined with drug- and regimen-specific pharmacokinetics, produces patient-specific predictions of clinical response 5 days post-biopsy. |
| Since the early 1990s, many authors have independently suggested that self/nonself recognition by the immune system might be modulated by the rates of change of antigen challenges. This paper introduces an extremely simple and purely conceptual mathematical model that allows dynamic discrimination of immune challenges. The main component of the model is a motif which is ubiquitous in systems biology, the incoherent feedforward loop, which endows the system with the capability to estimate exponential growth exponents, a prediction which is consistent with experimental work showing that exponentially increasing antigen stimulation is a determinant of immune reactivity. Combined with a bistable system and a simple feedback repression mechanism, an interesting phenomenon emerges as a tumor growth rate increases: elimination, tolerance (tumor growth), again elimination, and finally a second zone of tolerance (tumor escape). This prediction from our model is analogous to the ``two-zone tumor tolerance'' phenomenon experimentally validated since the mid 1970s. Moreover, we provide a plausible biological instantiation of our circuit using combinations of regulatory and effector T cells. |
| A recent paper by Karin et al. introduced a mathematical notion called dynamical compensation (DC) of biological circuits. DC was shown to play an important role in glucose homeostasis as well as other key physiological regulatory mechanisms. Karin et al.\ went on to provide a sufficient condition to test whether a given system has the DC property. Here, we show how DC is a reformulation of a well-known concept in systems biology, statistics, and control theory -- that of parameter structural non-identifiability. Viewing DC as a parameter identification problem enables one to take advantage of powerful theoretical and computational tools to test a system for DC. We obtain as a special case the sufficient criterion discussed by Karin et al. We also draw connections to system equivalence and to the fold-change detection property. |
| Emergent responses of the immune system result from the integration of molecular and cellular networks over time and across multiple organs. High-content and high-throughput analysis technologies, concomitantly with data-driven and mechanistic modeling, hold promise for the systematic interrogation of these complex pathways. However, connecting genetic variation and molecular mechanisms to individual phenotypes and health outcomes has proven elusive. Gaps remain in data, and disagreements persist about the value of mechanistic modeling for immunology. This paper presents perspectives that emerged from the National Institute of Allergy and Infectious Disease (NIAID) workshop `Complex Systems Science, Modeling and Immunity' and subsequent discussions regarding the potential synergy of high-throughput data acquisition, data-driven modeling, and mechanistic modeling to define new mechanisms of immunological disease and to accelerate the translation of these insights into therapies. |
| This paper reports on the construction of a phosphorylation- and optically-responsive supramolecular complex of metabolic pathway enzymes for the biodegradation of an environmental pollutant. Fusing of enzymes led to an increase in pathway efficiency, and illustrates the possibility of spatio-temporal control over formation and functioning of a wide variety of synthetic biotransformations. |
| 2016 |
| This paper presents a condition which guarantees spatial uniformity for the asymptotic behavior of the solutions of a reaction diffusion partial differential equation (PDE) with Neumann boundary conditions in one dimension, using the Jacobian matrix of the reaction term and the first Dirichlet eigenvalue of the Laplacian operator on the given spatial domain. The estimates are based on logarithmic norms in non-Hilbert spaces, which allow, in particular for a class of examples of interest in biology, tighter estimates than other previously proposed methods. |
| 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. |
| Contraction theory is a powerful tool for proving asymptotic properties of nonlinear dynamical systems including convergence to an attractor and entrainment to a periodic excitation. We introduce three new forms of generalized contraction (GC) that are motivated by allowing contraction to take place after small transients in time and/or amplitude. These forms of GC are useful for several reasons. First, allowing small transients does not destroy the asymptotic properties provided by standard contraction. Second, in some cases as we change the parameters in a contractive system it becomes a GC just before it looses contractivity. In this respect, GC is the analogue of marginal stability in Lyapunov stability theory. We provide checkable sufficient conditions for GC, and demonstrate their usefulness using several models from systems biology that are not contractive, with respect to any norm, yet are GC. |
| Synthetic constructs in biotechnology, bio-computing, and proposed gene therapy interventions are often based on plasmids or transfected circuits which implement some form of on-off (toggle or flip-flop) switch. For example, the expression of a protein used for therapeutic purposes might be triggered by the recognition of a specific combination of inducers (e.g., antigens), and memory of this event should be maintained across a cell population until a specific stimulus commands a coordinated shut-off. The robustness of such a design is hampered by molecular (intrinsic) or environmental (extrinsic) noise, which may lead to spontaneous changes of state in a subset of the population and is reflected in the bimodality of protein expression, as measured for example using flow cytometry. In this context, a majority-vote correction circuit, which brings deviant cells back into the required state, is highly desirable. To address this concrete challenge, we have developed a new theoretical design for quorum-sensing (QS) synthetic toggles. QS provides a way for cells to broadcast their states to the population as a whole so as to facilitate consensus. Our design is endowed with strong theoretical guarantees, based on monotone dynamical systems theory, of global stability and no oscillations, and which leads to robust consensus states. |
| We develop and analyze a general model for large-scale simultaneous mRNA translation and competition for ribosomes. Such models are especially important when dealing with highly expressed genes, as these consume more resources. For our model, we prove that the compound system always converges to a steady-state and that it always entrains or phase locks to periodically time-varying transition rates in any of the mRNA molecules. We use this model to explore the interactions between the various mRNA molecules and ribosomes at steady-state. We show that increasing the length of an mRNA molecule decreases the production rate of all the mRNAs. Increasing any of the codon translation rates in a specific mRNA molecule yields a local effect: an increase in the translation rate of this mRNA, and also a global effect: the translation rates in the other mRNA molecules all increase or all decrease. These results suggest that the effect of codon decoding rates of endogenous and heterologous mRNAs on protein production might be more complicated than previously thought. |
| 2015 |
| The notion of input to state stability (ISS) qualitatively describes stability of the mapping from initial states and inputs to internal states (and more generally outputs). This entry focuses on the definition of ISS and a discussion of equivalent characterizations. |
| This letter discusses a paper in the same journal which reported a method for reconstructing network topologies. Here we show that the method is a variant of a previously published method, modular response analysis. We also demonstrate that the implementation of the algorithm in that paper using statistical similarity measures as a proxy for global network responses to perturbations is erroneous and its performance is overestimated. |
| Reverse engineering of biological pathways involves an iterative process between experiments, data processing, and theoretical analysis. In this work, we engineer synthetic circuits, subject them to perturbations, and then infer network connections using a combination of nonparametric single-cell data resampling and modular response analysis. Intriguingly, we discover that recovered weights of specific network edges undergo divergent shifts under differential perturbations, and that the particular behavior is markedly different between different topologies. Investigating topological changes under differential perturbations may address the longstanding problem of discriminating direct and indirect connectivities in biological networks. |
| The phenomenon of fold-change detection, or scale invariance, is exhibited by a variety of sensory systems, in both bacterial and eukaryotic signaling pathways. It has been often remarked in the systems biology literature that certain systems whose output variables respond at a faster time scale than internal components give rise to an approximate scale-invariant behavior, allowing approximate fold-change detection in stimuli. This paper establishes a fundamental limitation of such a mechanism, showing that there is a minimal fold-change detection error that cannot be overcome, no matter how large the separation of time scales is. To illustrate this theoretically predicted limitation, we discuss two common biomolecular network motifs, an incoherent feedforward loop and a feedback system, as well as a published model of the chemotaxis signaling pathway of Dictyostelium discoideum. |
| Chemical systems are inherently stochastic, as reactions depend on random (thermal) motion. This motivates the study of stochastic models, and specifically the Chemical Master Equation (CME), a discrete-space continuous-time Markov process that describes stochastic chemical kinetics. Exact studies using the CME are difficult, and several moment closure tools related to "mass fluctuation kinetics" and "fluctuation-dissipation" formulas can be used to obtain approximations of moments. This paper, in contrast, introduces a class of nonlinear chemical reaction networks for which exact computation is possible, by means of finite-dimensional linear differential equations. This class allows second and higher order reactions, but only under special assumptions on structure and/or conservation laws. |
| A formalism for the study of random dynamical systems with inputs and outputs (RDSIO) is introduced. An axiomatic framework and basic properties of RDSIO are developed, and a theorem is shown that guarantees the stability of interconnected systems. |
| 2014 |
| This paper gives conditions that guarantee spatial uniformity of the solutions of reaction-diffusion partial differential equations, stated in terms of the Jacobian matrix and Neumann eigenvalues of elliptic operators on the given spatial domain, and similar conditions for diffusively-coupled networks of ordinary differential equations. Also derived are numerical tests making use of linear matrix inequalities that are useful in certifying these conditions. |
| Contraction theory provides an elegant way to analyze the behavior of certain nonlinear dynamical systems. In this paper, we discuss the application of contraction to synchronization of diffusively interconnected components described by nonlinear differential equations. We provide estimates of convergence of the difference in states between components, in the cases of line, complete, and star graphs, and Cartesian products of such graphs. We base our approach on contraction theory, using matrix measures derived from norms that are not induced by inner products. Such norms are the most appropriate in many applications, but proofs cannot rely upon Lyapunov-like linear matrix inequalities, and different techniques, such as the use of the Perron-Frobenious Theorem in the cases of L1 or L-infinity norms, must be introduced. |
| This paper introduces a small-gain result for interconnected orthant-monotone systems for which no matching condition is required between the partial orders in input and output spaces. Previous results assumed that the partial orders adopted would be induced by positivity cones in input and output spaces and that such positivity cones should fulfill a compatibility rule: namely either be coincident or be opposite. Those two configurations correspond to positive feedback or negative feedback cases. We relax those results by allowing arbitrary orthant orders. |
| A recent biological study has demonstrated that the gene expression pattern entrains to a periodically varying abundance of tRNA molecules. This motivates developing mathematical tools for analyzing entrainment of translation elongation to intra-cellular signals such as tRNAs levels and other factors affecting translation. We consider a recent deterministic mathematical model for translation called the Ribosome Flow Model (RFM). We analyze this model under the assumption that the elongation rate of the tRNA genes and/or the initiation rate are periodic functions with a common period T. We show that the protein synthesis pattern indeed converges to a unique periodic trajectory with period T. The analysis is based on introducing a novel property of dynamical systems, called contraction after a short transient (CAST), that may be of independent interest. We provide a sufficient condition for CAST and use it to prove that the RFM is CAST, and that this implies entrainment. Our results support the conjecture that periodic oscillations in tRNA levels and other factors related to the translation process can induce periodic oscillations in protein levels, and suggest a new approach for engineering genes to obtain a desired, periodic, synthesis rate. |
| This paper describes a potential pitfall of perturbation-based approaches to network inference It is shows experimentally, and then explained mathematically, how even in the simplest signaling systems, perturbation methods may lead to paradoxical conclusions: for any given pair of two components X and Y, and depending upon the specific intervention on Y, either an activation or a repression of X could be inferred. The experiments are performed in an in vitro minimal system, thus isolating the effect and showing that it cannot be explained by feedbacks due to unknown intermediates; this system utilizes proteins from a pathway in mammalian (and other eukaryotic) cells that play a central role in proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis and is a perturbation target of contemporary therapies for various types of cancers. The results show that the simplistic view of intracellular signaling networks being made up of activation and repression links is seriously misleading, and call for a fundamental rethinking of signaling network analysis and inference methods. |
| A transcriptional system is built based on a 'resource allocator' that sets a core RNAP concentration, which is then shared by multiple sigma fragments, which provide specificity. Adjusting the concentration of the core sets the maximum transcriptional capacity available to a synthetic system. |
| This paper studies the direction of change of steady states to parameter perturbations in chemical reaction networks, and, in particular, to changes in conserved quantities. Theoretical considerations lead to the formulation of a computational procedure that provides a set of possible signs of such sensitivities. The procedure is purely algebraic and combinatorial, only using information on stoichiometry, and is independent of the values of kinetic constants. Two examples of important intracellular signal transduction models are worked out as an illustration. In these examples, the set of signs found is minimal, but there is no general guarantee that the set found will always be minimal in other examples. The paper also briefly discusses the relationship of the sign problem to the question of uniqueness of steady states in stoichiometry classes. |
| 2013 |
| This paper study systems with sign-definite interactions between variables, providing a sufficient condition to characterize the possible transitions between intervals of increasing and decreasing behavior. It also provides a discussion illustrating how our approach can help identify interactions in models, using information from time series of observations. |
| This work introduces a notion of random dynamical systems with inputs, providing several basic definitions and results on equilibria and convergence. It also presents a "converging input to converging state" result, a concept that plays a key role in the analysis of stability of feedback interconnections, for monotone systems. |
| This paper proves that ordinary differential equation systems that are contractive with respect to $L^p$ norms remain so when diffusion is added. Thus, diffusive instabilities, in the sense of the Turing phenomenon, cannot arise for such systems, and in fact any two solutions converge exponentially to each other. The key tools are semi-inner products and logarithmic Lipschitz constants in Banach spaces. An example from biochemistry is discussed, which shows the necessity of considering non-Hilbert spaces. An analogous result for graph-defined interconnections of systems defined by ordinary differential equations is given as well. |
| Complex networks of biochemical reactions, such as intracellular protein signaling pathways and genetic networks, are often conceptualized in terms of ``modules,'' semi-independent collections of components that perform a well-defined function and which may be incorporated in multiple pathways. However, due to sequestration of molecular messengers during interactions and other effects, collectively referred to as retroactivity, real biochemical systems do not exhibit perfect modularity. Biochemical signaling pathways can be insulated from impedance and competition effects, which inhibit modularity, through enzymatic ``futile cycles'' which consume energy, typically in the form of ATP. We hypothesize that better insulation necessarily requires higher energy consumption. We test this hypothesis through a combined theoretical and computational analysis of a simplified physical model of covalent cycles, using two innovative measures of insulation, as well as a new way to characterize optimal insulation through the balancing of these two measures in a Pareto sense. Our results indicate that indeed better insulation requires more energy. While insulation may facilitate evolution by enabling a modular ``plug and play'' interconnection architecture, allowing for the creation of new behaviors by adding targets to existing pathways, our work suggests that this potential benefit must be balanced against the metabolic costs of insulation necessarily incurred in not affecting the behavior of existing processes. |
| The chemotaxis pathway of the bacterium Rhodobacter sphaeroides has many similarities to that of Escherichia coli. It exhibits robust adaptation and has several homologues of the latter's chemotaxis proteins. Recent theoretical results have correctly predicted that, in response to a scaling of its ligand input signal, Escherichia coli exhibits the same output behavior, a property known as fold-change detection (FCD). In light of recent experimental results suggesting that R. sphaeroides may also show FCD, we present theoretical assumptions on the R. sphaeroides chemosensory dynamics that can be shown to yield FCD behavior. Furthermore, it is shown that these assumptions make FCD a property of this system that is robust to structural and parametric variations in the chemotaxis pathway, in agreement with experimental results. We construct and examine models of the full chemotaxis pathway that satisfy these assumptions and reproduce experimental time-series data from earlier studies. We then propose experiments in which models satisfying our theoretical assumptions predict robust FCD behavior where earlier models do not. In this way, we illustrate how transient dynamic phenotypes such as FCD can be used for the purposes of discriminating between models that reproduce the same experimental time-series data. |
| This work introduces an experimental platform customized for the development and verification of reverse engineering and pathway characterization algorithms in mammalian cells. Specifically, we stably integrate a synthetic gene network in human kidney cells and use it as a benchmark for validating reverse engineering methodologies. The network, which is orthogonal to endogenous cellular signaling, contains a small set of regulatory interactions that can be used to quantify the reconstruction performance. By performing successive perturbations to each modular component of the network and comparing protein and RNA measurements, we study the conditions under which we can reliably reconstruct the causal relationships of the integrated synthetic network. |
| This paper shows that metastatic breast cancer cells cooperatively invade a 3D collagen matrix while following a glucose gradient. The front cell leadership is dynamic, and invading cells act in a cooperative manner by exchanging leaders in the invading front. |
| This paper studies networks of components, and shows that a contraction property on the interconnection matrix, coupled with contractivity of the individual component subsystems, suffices to insure contractivity of the overall system. |
| Using synthetic circuits stably integrated in human kidney cells, we study the effect of negative feedback regulation on cell-wide (extrinsic) and gene-specific (intrinsic) sources of uncertainty. We develop a theoretical approach to extract the two noise components from experiments and show that negative feedback reduces extrinsic noise while marginally increasing intrinsic noise, resulting to significant total noise reduction. We compare the results to simple negative regulation, where a constitutively transcribed transcription factor represses a reporter protein. We observe that the control architecture also reduces the extrinsic noise but results in substantially higher intrinsic fluctuations. We conclude that negative feedback is the most efficient way to mitigate the effects of extrinsic fluctuations by a sole regulatory wiring. |
| 2012 |
| 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. |
| This paper deals with the stability of interconnections of nonlinear stochastic systems, using concepts of passivity and noise-to-state stability. |
| This paper studies a recently discovered remarkable feature that was shown in many adapting systems: scale invariance, which means that the initial, transient behavior stays approximately the same when the background signal level is scaled. Not every adapting system is scale-invariant: we investigate under which conditions a broadly used model of biochemical enzymatic networks will show scale invariant behavior. For all 3-node enzymatic networks, we performed a wide computational study to find candidates for scale invariance, among 16,038 possible topologies. This effort led us to discover a new necessary and sufficient mechanism that explains the behavior of all 3-node enzyme networks that have this property, which we call``uniform linearizations with fast output''. We also apply our theoretical results to a concrete biological example of order six, a model of the response of the chemotaxis signaling pathway of Dictyostelium discoideum to changes in chemoeffector cyclic adenosine monophosphate (cAMP). |
| Drugs are commonly used in combinations larger than two for treating bacterial infections. It is generally impossible to infer directly from the effects of individual drugs the net effect of a multi-drug combination. This paper describes an empirically derived mechanism-independent method for predicting the microbial growth response to combinations of more than two drugs, experimentally tested on both gram-negative (Escherichia coli) and grampositive (Staphylococcus aureus) bacteria. The method shows that for a wide range of drugs, the bacterial responses to drug pairs are sufficient to infer the effects of larger drug combinations, and provides a simple formula for the prediction. |
| 2011 |
| This is a short expository article describing how the species-reaction graph (SR graph) can be used to analyze both multistability and monotonicity of biochemical networks. |
| An encyclopedia-type article on foundations of ISS. |
| Many reverse-engineering techniques in systems biology rely upon data on steady-state (or dynamic) perturbations --obtained from siRNA, gene knock-down or overexpression, kinase and phosphatase inhibitors, or other interventions-- in order to understand the interactions between different ``modules'' in a network. This paper first reviews one such popular such technique, introduced by the author and collaborators, and focuses on why conclusions drawn from its use may be misleading due to ``retroactivity'' (impedance or load) effects. A theoretical result characterizing stoichiometric-induced steady-state retroactivity effects is given for a class of biochemical networks. |
| The problem of stabilization of equilibria is one of the central issues in control. In addition to its intrinsic interest, it represents a first step towards the solution of more complicated problems, such as the stabilization of periodic orbits or general invariant sets, or the attainment of other control objectives, such as tracking, disturbance rejection, or output feedback, all of which may be interpreted as requiring the stabilization of some quantity (typically, some sort of ``error'' signal). A very special case, when there are no inputs, is that of stability. This short and informal article provides an introduction to the subject. |
| An encyclopedia-type article on foundations of input/output stability. |
| In this paper, we introduce a topological redundancy measure for labeled directed networks that is formal, computationally efficient and applicable to a variety of directed networks such as cellular signaling, metabolic and social interaction networks. We demonstrate the computational efficiency of our measure by computing its value and statistical significance on a number of biological and social networks with up to several thousands of nodes and edges. Our results suggest a number of interesting observations: (1) social networks are more redundant that their biological counterparts, (2) transcriptional networks are less redundant than signaling networks, (3) the topological redundancy of the C. elegans metabolic network is largely due to its inclusion of currency metabolites, and (4) the redundancy of signaling networks is highly (negatively) correlated with monotonicity of their dynamics. |
| New checkable criteria for persistence of chemical reaction networks are proposed, which extend and complement existing ones. The new results allow the consideration of reaction rates which are time-varying, thus incorporating the effects of external signals, and also relax the assumption of existence of global conservation laws, thus allowing for inflows (production) and outflows (degradation). For time-invariant networks parameter-dependent conditions for persistence of certain classes of networks are provided. As an illustration, two networks arising in the systems biology literature are analyzed, namely a hypoxia and an apoptosis network. |
| Natural and synthetic biological networks must function reliably in the face of fluctuating stoichiometry of their molecular components. These fluctuations are caused in part by changes in relative expression efficiency and the DNA template amount of the network-coding genes. Gene product levels could potentially be decoupled from these changes via built-in adaptation mechanisms, thereby boosting network reliability. Here we show that a mechanism based on an incoherent feed-forward motif enables adaptive gene expression in mammalian cells. We modeled, synthesized, and tested transcriptional and post-transcriptional incoherent loops and found that in all cases the gene product adapts to changes in DNA template abundance. We also observed that the post-transcriptional form results in superior adaptation behavior, higher absolute expression levels, and lower intrinsic fluctuations. Our results support a previously-hypothesized endogenous role in gene dosage compensation for such motifs and suggest that their incorporation in synthetic networks will improve their robustness and reliability. |
| Biological signal transduction networks are commonly viewed as circuits that pass along in the process amplifying signals, enhancing sensitivity, or performing other signal-processing to transcriptional and other components. Here, we report on a "reverse-causality" phenomenon, which we call load-induced modulation. Through a combination of analytical and experimental tools, we discovered that signaling was modulated, in a surprising way, by downstream targets that receive the signal and, in doing so, apply what in physics is called a load. Specifically, we found that non-intuitive changes in response dynamics occurred for a covalent modification cycle when load was present. Loading altered the response time of a system, depending on whether the activity of one of the enzymes was maximal and the other was operating at its minimal rate or whether both enzymes were operating at submaximal rates. These two conditions, which we call "limit regime" and "intermediate regime," were associated with increased or decreased response times, respectively. The bandwidth, the range of frequency in which the system can process information, decreased in the presence of load, suggesting that downstream targets participate in establishing a balance between noise-filtering capabilities and a its ability to process high-frequency stimulation. Nodes in a signaling network are not independent relay devices, but rather are modulated by their downstream targets |
| Often, the ultimate goal of regulation is to maintain a narrow range of concentration levels of vital quantities (homeostasis, adaptation) while at the same time appropriately reacting to changes in the environment (signal detection or sensitivity). Much theoretical, modeling, and analysis effort has been devoted to the understanding of these questions, traditionally in the context of steady-state responses to constant or step-changing stimuli. In this paper, we present a new theorem that provides a necessary and sufficient characterization of invariance of transient responses to symmetries in inputs. A particular example of this property, scale invariance (a.k.a. "fold change detection"), appears to be exhibited by biological sensory systems ranging from bacterial chemotaxis pathways to signal transduction mechanisms in eukaryotes. The new characterization amounts to the solvability of an associated partial differential equation. It is framed in terms of a notion which considerably extends equivariant actions of compact Lie groups. For several simple system motifs that are recurrent in biology, the solvability criterion may be checked explicitly. |
| 2010 |
| We present a novel computational method, and related software, to synthesize signal transduction networks from single and double causal evidence. |
| Contraction theory provides an elegant way of analyzing the behaviors of systems subject to external inputs. Under sometimes easy to check hypotheses, systems can be shown to have the incremental stability property that all trajectories converge to a unique solution. This property is especially interesting when forcing functions are periodic (globally attracting limit cycles result), as well as in the context of establishing synchronization results. The present paper provides a self-contained introduction to some basic results, with a focus on contractions with respect to non-Euclidean metrics. |
| This paper derives new results for certain classes of chemical reaction networks, linking structural to dynamical properties. In particular, it investigates their monotonicity and convergence without making assumptions on the form of the kinetics (e.g., mass-action) of the dynamical equations involved, and relying only on stoichiometric constraints. The key idea is to find an alternative representation under which the resulting system is monotone. As a simple example, the paper shows that a phosphorylation/dephosphorylation process, which is involved in many signaling cascades, has a global stability property. |
| This paper addresses the problem of giving conditions for transcriptional systems to be globally entrained to external periodic inputs. By using contraction theory, a powerful tool from dynamical systems theory, it is shown that certain systems driven by external periodic signals have the property that all solutions converge to fixed limit cycles. General results are proved, and the properties are verified in the specific case of some models of transcriptional systems. |
| This paper provides synchronization conditions for networks of nonlinear systems, where each component of the network itself consists of subsystems represented as operators in the extended L2 space. The synchronization conditions are provided by combining the input-output properties of the subsystems with information about the structure of network. The paper also explores results for state-space models as well as biochemical applications. The work is motivated by cellular networks where signaling occurs both internally, through interactions of species, and externally, through intercellular signaling. |
| Certain cellular sensory systems display fold-change detection (FCD): a response whose entire shape, including amplitude and duration, depends only on fold-changes in input, and not on absolute changes. Thus, a step change in input from, say, level 1 to 2, gives precisely the same dynamical output as a step from level 2 to 4, since the steps have the same fold-change. We ask what is the benefit of FCD, and show that FCD is necessary and sufficient for sensory search to be independent of multiplying the input-field by a scalar. Thus the FCD search pattern depends only on the spatial profile of the input, and not on its amplitude. Such scalar symmetry occurs in a wide range of sensory inputs, such as source strength multiplying diffusing/convecting chemical fields sensed in chemotaxis, ambient light multiplying the contrast field in vision, and protein concentrations multiplying the output in cellular signaling-systems.Furthermore, we demonstrate that FCD entails two features found across sensory systems, exact adaptation and Weber's law, but that these two features are not sufficient for FCD. Finally, we present a wide class of mechanisms that have FCD, including certain non-linear feedback and feedforward loops.. We find that bacterial chemotaxis displays feedback within the present class, and hence is expected to show FCD. This can explain experiments in which chemotaxis searches are insensitive to attractant source levels. This study thus suggests a connection between properties of biological sensory systems and scalar symmetry stemming from physical properties of their input-fields. |
| This note studies feedforward circuits as models for perfect adaptation to step signals in biological systems. A global convergence theorem is proved in a general framework, which includes examples from the literature as particular cases. A notable aspect of these circuits is that they do not adapt to pulse signals, because they display a memory phenomenon. Estimates are given of the magnitude of this effect. |
| An edited set of articles about Rudolf Kalman's legacy through his Ph.D. students. |
| Multivariate Poisson random variables subject to linear integer constraints arise in several application areas, such as queuing and biomolecular networks. This note shows how to compute conditional statistics in this context, by employing WZ Theory and associated algorithms. A symbolic computation package has been developed and is made freely available. A discussion of motivating biomolecular problems is also provided. |
| This paper studies monotone tridiagonal systems with negative feedback. These systems possess the Poincar{\'e}-Bendixson property, which implies that, if orbits are bounded, if there is a unique steady state and this unique equilibrium is asymptotically stable, and if one can rule out periodic orbits, then the steady state is globally asymptotically stable. Different approaches are discussed to rule out period orbits. One is based on direct linearization, while the other uses the theory of second additive compound matrices. Among the examples that will illustrate our main theoretical results is the classical Goldbeter model of circadian rhythms. |
| 2009 |
| This is an expository paper about graph-theoretical properties of biochemical networks, discussing two approaches, one based on bipartite graphs and Petri net concepts, and another based on decompositions into order-preserving subsystems. Other papers on this website contain basically the same material. |
| This is an expository paper about certain aspects of Synthetic Biology, including a discussion of the issue of modularity (load effects from downstream components). |
| Attractors of cooperative dynamical systems are particularly simple; for example, a nontrivial periodic orbit cannot be an attractor. This paper provides characterizations of attractors for the wider class of systems defined by the property that all directed feedback loops are positive. Several new results for cooperative systems are obtained in the process. |
| Certain mass-action kinetics models of biochemical reaction networks, although described by nonlinear differential equations, may be partially viewed as state-dependent linear time-varying systems, which in turn may be modeled by convex compact valued positive linear differential inclusions. A result is provided on asymptotic stability of such inclusions, and applied to biochemical reaction networks with inflows and outflows. Included is also a characterization of exponential stability of general homogeneous switched systems |
| The concept of robustness of regulatory networks has been closely related to the nature of the interactions among genes, and the capability of pattern maintenance or reproducibility. Defining this robustness property is a challenging task, but mathematical models have often associated it to the volume of the space of admissible parameters. Not only the volume of the space but also its topology and geometry contain information on essential aspects of the network, including feasible pathways, switching between two parallel pathways or distinct/disconnected active regions of parameters. A method is presented here to characterize the space of admissible parameters, by writing it as a semi-algebraic set, and then theoretically analyzing its topology and geometry, as well as volume. This method provides a more objective and complete measure of the robustness of a developmental module. As a detailed case study, the segment polarity gene network is analyzed. |
| The concept of robustness of regulatory networks has received much attention in the last decade. One measure of robustness has been associated with the volume of the feasible region, namely, the region in the parameter space in which the system is functional. In recent work, we emphasized that topology and geometry matter, as well as volume. In this paper, and using the segment polarity gene network to illustrate our approach, we show that random walks in parameter space and how they exit the feasible region provide a rich perspective on the different modes of failure of a model. In particular, for the segment polarity network, we found that, between two alternative ways of activating Wingless, one is more robust. Our method provides a more complete measure of robustness to parameter variation. As a general modeling strategy, our approach is an interesting alternative to Boolean representation of biochemical networks. |
| A novel computational method (called p53HMM) is presented that utilizes Profile Hidden Markov Models (PHMM's) to estimate the relative binding affinities of putative p53 response elements (RE's), both p53 single-sites and cluster-sites. These models incorporate a novel ``Correlated Baum Welch'' training algorithm that provides increased predictive power by exploiting the redundancy of information found in the repeated, palindromic p53-binding motif. The predictive accuracy of these new models are compared against other predictive models, including position specic score matrices (PSSM's, or weight matrices). Finally, we provide experimental evidence that verifies a predicted p53-target site that regu- lates the CHMP4C gene. The P53HMM algorithm is available on-line from http://tools.csb.ias.edu. |
| This paper asks what classes of input signals are sufficient in order to completely identify the input/output behavior of generic bilinear systems. The main results are that step inputs are not sufficient, nor are single pulses, but the family of all pulses (of a fixed amplitude but varying widths) do suffice for identification. |
| During normal kidney function, there are are routinely wide swings in proximal tubule fluid flow and proportional changes in Na+ reabsorption across tubule epithelial cells. This "glomerulotubular balance" occurs in the absence of any substantial change in cell volume, and is thus a challenge to coordinate luminal membrane solute entry with peritubular membrane solute exit. In this work, linear optimal control theory is applied to generate a configuration of regulated transporters that could achieve this result. A previously developed model of rat proximal tubule epithelium is linearized about a physiologic reference condition; the approximate linear system is recast as a dynamical system; and a Riccati equation is solved to yield optimal linear feedback that stabilizes Na+ flux, cell volume, and cell pH. This optimal feedback control is largely consigned to three physiologic variables, cell volume, cell electrical potential, and lateral intercellular hydrostatic pressure. Transport modulation by cell volume stabilizes cell volume; transport modulation by electrical potential or interspace pressure act to stabilize Na+ flux and cell pH. This feedback control is utilized in a tracking problem, in which reabsorptive Na+ flux varies over a factor of two. The resulting control parameters consist of two terms, an autonomous term and a feedback term, and both terms include transporters on both luminal and peritubular cell membranes. Overall, the increase in Na+ flux is achieved with upregulation of luminal Na+/H+ exchange and Na+-glucose cotransport, with increased peritubular Na+-3HCO_3- and K+-Cl- cotransport, and with increased Na+,K+-ATPase activity. The configuration of activated transporters emerges as testable hypothesis of the molecular basis for glomerulotubular balance. It is suggested that the autonomous control component at each cell membrane could represent the cytoskeletal effects of luminal flow. |
| 2008 |
| In this expository paper, we provide a streamlined version of the key lemma on stability of interconnections due to Vidyasagar and Moylan and Hill, and then show how it its hypotheses may be verified for network structures of great interest in biology. |
| The transitive reduction problem is that of inferring a sparsest possible biological signal transduction network consistent with a set of experimental observations, with a goal to minimize false positive inferences even if risking false negatives. This paper provides computational complexity results as well as approximation algorithms with guaranteed performance. |
| In this note, we show how certain properties of Goldbeter's 1995 model for circadian oscillations can be proved mathematically, using techniques from the recently developed theory of monotone systems with inputs and outputs. The theory establishes global asymptotic stability, and in particular no oscillations, if the rate of transcription is somewhat smaller than that assumed by Goldbeter, based on the application of a tight small gain condition. This stability persists even under arbitrary delays in the feedback loop. On the other hand, when the condition is violated a Poincare'-Bendixson result allows to conclude existence of oscillations, for sufficiently high delays. |
| Strongly monotone systems of ordinary differential equations which have a certain translation-invariance property are shown to have the property that all projected solutions converge to a unique equilibrium. This result may be seen as a dual of a well-known theorem of Mierczynski for systems that satisfy a conservation law. As an application, it is shown that enzymatic futile cycles have a global convergence property. |
| This paper presents a stability test for a class of interconnected nonlinear systems motivated by biochemical reaction networks. One of the main results determines global asymptotic stability of the network from the diagonal stability of a "dissipativity matrix" which incorporates information about the passivity properties of the subsystems, the interconnection structure of the network, and the signs of the interconnection terms. This stability test encompasses the "secant criterion" for cyclic networks presented in our previous paper, and extends it to a general interconnection structure represented by a graph. A second main result allows one to accommodate state products. This extension makes the new stability criterion applicable to a broader class of models, even in the case of cyclic systems. The new stability test is illustrated on a mitogen activated protein kinase (MAPK) cascade model, and on a branched interconnection structure motivated by metabolic networks. Finally, another result addresses the robustness of stability in the presence of diffusion terms in a compartmental system made out of identical systems. |
| Modularity plays a fundamental role in the prediction of the behavior of a system from the behavior of its components, guaranteeing that the properties of individual components do not change upon interconnection. Just as electrical, hydraulic, and other physical systems often do not display modularity, nor do many biochemical systems, and specifically, genetic networks. Here, we study the effect of interconnections on the input/output dynamic characteristics of transcriptional components, focusing on a property, which we call "retroactivity," that plays a role analogous to non-zero output impedance in electrical systems. In transcriptional networks, retroactivity is large when the amount of transcription factor is comparable to, or smaller than, the amount of promoter binding sites, or when the affinity of such binding sites is high. In order to attenuate the effect of retroactivity, we propose a feedback mechanism inspired by the design of amplifiers in electronics. We introduce, in particular, a mechanism based on a phosphorylation/dephosphorylation cycle. This mechanism enjoys a remarkable insulation property, due to the fast time scales of the phosphorylation and dephosphorylation reactions. Such a mechanism, when viewed as a signal transduction system, has thus an inherent capacity to provide insulation and hence to increase the modularity of the system in which it is placed. |
| This paper generalizes the approach to bistability based on the existence of characteristics for open-loop monotone systems to the case when characteristics do not exist. A set-valued version is provided, instead. |
| A class of distributed systems with a cyclic interconnection structure is considered. These systems arise in several biochemical applications and they can undergo diffusion driven instability which leads to a formation of spatially heterogeneous patterns. In this paper, a class of cyclic systems in which addition of diffusion does not have a destabilizing effect is identified. For these systems global stability results hold if the "secant" criterion is satisfied. In the linear case, it is shown that the secant condition is necessary and sufficient for the existence of a decoupled quadratic Lyapunov function, which extends a recent diagonal stability result to partial differential equations. For reaction-diffusion equations with nondecreasing coupling nonlinearities global asymptotic stability of the origin is established. All of the derived results remain true for both linear and nonlinear positive diffusion terms. Similar results are shown for compartmental systems. |
| 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. |
| We find that three intracellular regulatory networks contain far more positive "sign-consistent" feedback and feed-forward loops than negative loops. Negative inconsistent loops can be more easily removed from real regulatory network topologies compared to removing negative loops from shuffled networks. The abundance of positive feed-forward loops and feedback loops in real networks emerges from the presence of hubs that are enriched with either negative or positive links, and from the non-uniform connectivity distribution. Boolean dynamics applied to the signaling network further support the stability of its topology. These observations suggest that the "close-to-monotone" structure of intracellular regulatory networks may contribute to the dynamical stability observed in cellular behavior. |
| The p53 protein regulates the transcription of many different genes in response to a wide variety of stress signals. Following DNA damage, p53 regulates key processes, including DNA repair, cell-cycle arrest, senescence and apoptosis, in order to suppress cancer. This Analysis article provides an overview of the current knowledge of p53-regulated genes in these pathways and others, and the mechanisms of their regulation. In addition, we present the most comprehensive list so far of human p53-regulated genes and their experimentally validated, functional binding sites that confer p53 regulation. |
| The ``reverse engineering problem'' in systems biology is that of unraveling of the web of interactions among the components of protein and gene regulatory networks, so as to map out the direct or local interactions among components. These direct interactions capture the topology of the functional network. An intrinsic difficulty in capturing these direct interactions, at least in intact cells, is that any perturbation to a particular gene or signaling component may rapidly propagate throughout the network, thus causing global changes which cannot be easily distinguished from direct effects. Thus, a major goal in reverse engineering is to use these observed global responses - such as steady-state changes in concentrations of active proteins, mRNA levels, or transcription rates - in order to infer the local interactions between individual nodes. One approach to solving this global-to-local problem is the ``Modular Response Analysis'' (MRA) method proposed in work of the author with Kholodenko et. al. (PNAS, 2002) and further elaborated in other papers. The basic method deals only with steady-state data. However, recently, quasi-steady state MRA has been used by Santos et. al. (Nature Cell Biology, 2007) for quantifying positive and negative feedback effects in the Raf/Mek/Erk MAPK network in rat adrenal pheochromocytoma (PC-12) cells. This paper presents an overview of the MRA technique, as well as a generalization of the algorithm to that quasi-steady state case. |
| Feedback loops play an important role in determining the dynamics of biological networks. In order to study the role of negative feedback loops, this paper introduces the notion of "distance to positive feedback (PF-distance)" which in essence captures the number of "independent" negative feedback loops in the network, a property inherent in the network topology. Through a computational study using Boolean networks it is shown that PF-distance has a strong influence on network dynamics and correlates very well with the number and length of limit cycles in the phase space of the network. To be precise, it is shown that, as the number of independent negative feedback loops increases, the number (length) of limit cycles tends to decrease (increase). These conclusions are consistent with the fact that certain natural biological networks exhibit generally regular behavior and have fewer negative feedback loops than randomized networks with the same numbers of nodes and connectivity. |
| This note studies the number of positive steady states in biomolecular reactions consisting of activation/deactivation futile cycles, such as those arising from phosphorylations and dephosphorylations at each level of a MAPK cascade. It is shown that: (1) for some parameter ranges, there are at least n+1 (if n is even) or n (if n is odd) steady states; (2) there never are more than 2n-1 steady states (so, for n=2, there are no more than 3 steady states); (3) for parameters near the standard Michaelis-Menten quasi-steady state conditions, there are at most n+1 steady states; and (4) for parameters far from the standard Michaelis-Menten quasi-steady state conditions, there is at most one steady state. |
| The theory of monotone dynamical systems has been found very useful in the modeling of some gene, protein, and signaling networks. In monotone systems, every net feedback loop is positive. On the other hand, negative feedback loops are important features of many systems, since they are required for adaptation and precision. This paper shows that, provided that these negative loops act at a comparatively fast time scale, the main dynamical property of (strongly) monotone systems, convergence to steady states, is still valid. An application is worked out to a double-phosphorylation "futile cycle" motif which plays a central role in eukaryotic cell signaling The workis heavily based on Fenichel-Jones geometric singular perturbation theory. |
| 2007 |
| This expository presentation, prepared for a summer course, addresses the precise formulation of questions of robustness with respect to disturbances, using the paradigm of input to state stability. It provides an intuitive and informal presentation of the main concepts. |
| See abstract and pdf for ``Monotone and near-monotone biochemical networks''. |
| The problem of stabilization of equilibria is one of the central issues in control. In addition to its intrinsic interest, it represents a first step towards the solution of more complicated problems, such as the stabilization of periodic orbits or general invariant sets, or the attainment of other control objectives, such as tracking, disturbance rejection, or output feedback, all of which may be interpreted as requiring the stabilization of some quantity (typically, some sort of ``error'' signal). A very special case, when there are no inputs, is that of stability. This short and informal article provides an introduction to the subject. |
| A result is presented showing the existence of inputs universal for observability, uniformly with respect to the class of all continuous-time analytic systems. This represents an ultimate generalization of a 1977 theorem, for bilinear systems, due to Alberto Isidori and Osvaldo Grasselli. |
| 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. |
| Persistency is the property, for differential equations in Rn, that solutions starting in the positive orthant do not approach the boundary. For chemical reactions and population models, this translates into the non-extinction property: provided that every species is present at the start of the reaction, no species will tend to be eliminated in the course of the reaction. This paper provides checkable conditions for persistence of chemical species in reaction networks, using concepts and tools from Petri net theory, and verifies these conditions on various systems which arise in the modeling of cell signaling pathways. |
| This paper studies a computational problem motivated by the modular response analysis method for reverse engineering of protein and gene networks. This set-cover problem is hard to solve exactly for large networks, but efficient approximation algorithms are given and their complexity is analyzed. |
| This paper investigates computational complexity aspects of a combinatorial problem that arises in the reverse engineering of protein and gene networks, showing relations to an appropriate set multicover problem with large "coverage" factor, and providing a non-trivial analysis of a simple randomized polynomial-time approximation algorithm for the problem. |
| A useful approach to the mathematical analysis of large-scale biological networks is based upon their decompositions into monotone dynamical systems. This paper deals with two computational problems associated to finding decompositions which are optimal in an appropriate sense. In graph-theoretic language, the problems can be recast in terms of maximal sign-consistent subgraphs. The theoretical results include polynomial-time approximation algorithms as well as constant-ratio inapproximability results. One of the algorithms, which has a worst-case guarantee of 87.9% from optimality, is based on the semidefinite programming relaxation approach of Goemans-Williamson. The algorithm was implemented and tested on a Drosophila segmentation network and an Epidermal Growth Factor Receptor pathway model. |
| This paper gives a theorem showing that a slow feedback adaptation, acting entirely analogously to the role of negative feedback for ordinary relaxation oscillations, leads to periodic orbits for bistable monotone systems. The proof is based upon a combination of i/o monotone systems theory and Conley Index theory. |
| It had previously been shown that generic cortical microcircuit models can perform complex real-time computations on continuous input streams, provided that these computations can be carried out with a rapidly fading memory. We investigate in this article the computational capability of such circuits in the more realistic case where not only readout neurons, but in addition a few neurons within the circuit have been trained for specific tasks. This is essentially equivalent to the case where the output of trained readout neurons is fed back into the circuit. We show that this new model overcomes the limitation of a rapidly fading memory. In fact, we prove that in the idealized case without noise it can carry out any conceivable digital or analog computation on time-varying inputs. But even with noise the resulting computational model can perform a large class of biologically relevant real-time computations that require a non-fading memory. |
| This paper provides an expository introduction to monotone and near-monotone biochemical network structures. Monotone systems respond in a predictable fashion to perturbations, and have very robust dynamical characteristics. This makes them reliable components of more complex networks, and suggests that natural biological systems may have evolved to be, if not monotone, at least close to monotone. In addition, interconnections of monotone systems may be fruitfully analyzed using tools from control theory. |
| We analyze certain chemical reaction networks and show that every solution converges to some steady state. The reaction kinetics are assumed to be monotone but otherwise arbitrary. When diffusion effects are taken into account, the conclusions remain unchanged. The main tools used in our analysis come from the theory of monotone dynamical systems. We review some of the features of this theory and provide a self-contained proof of a particular attractivity result which is used in proving our main result. |
| 2006 |
| The network topology of neurons in the brain exhibits an abundance of feedback connections, but the computational function of these feedback connections is largely unknown. We present a computational theory that characterizes the gain in computational power achieved through feedback in dynamical systems with fading memory. It implies that many such systems acquire through feedback universal computational capabilities for analog computing with a non-fading memory. In particular, we show that feedback enables such systems to process time-varying input streams in diverse ways according to rules that are implemented through internal states of the dynamical system. In contrast to previous attractor-based computational models for neural networks, these flexible internal states are high-dimensional attractors of the circuit dynamics, that still allow the circuit state to absorb new information from online input streams. In this way one arrives at novel models for working memory, integration of evidence, and reward expectation in cortical circuits. We show that they are applicable to circuits of conductance-based Hodgkin-Huxley (HH) neurons with high levels of noise that reflect experimental data on invivo conditions. |
| This paper considers a class of systems with a cyclic structure that arises, among other examples, in dynamic models for certain biochemical reactions. We first show that a criterion for local stability, derived earlier in the literature, is in fact a necessary and sufficient condition for diagonal stability of the corresponding class of matrices. We then revisit a recent generalization of this criterion to output strictly passive systems, and recover the same stability condition using our diagonal stability result as a tool for constructing a Lyapunov function. Using this procedure for Lyapunov construction we exhibit classes of cyclic systems with sector nonlinearities and characterize their global stability properties. |
| A commonly employed measure of the signal amplification properties of an input/output system is its induced L2 norm, sometimes also known as H-infinity gain. In general, however, it is extremely difficult to compute the numerical value for this norm, or even to check that it is finite, unless the system being studied is linear. This paper describes a class of systems for which it is possible to reduce this computation to that of finding the norm of an associated linear system. In contrast to linearization approaches, a precise value, not an estimate, is obtained for the full nonlinear model. The class of systems that we study arose from the modeling of certain biological intracellular signaling cascades, but the results should be of wider applicability. |
| As a discrete approach to genetic regulatory networks, Boolean models provide an essential qualitative description of the structure of interactions among genes and proteins. Boolean models generally assume only two possible states (expressed or not expressed) for each gene or protein in the network as well as a high level of synchronization among the various regulatory processes. In this paper, we discuss and compare two possible methods of adapting qualitative models to incorporate the continuous-time character of regulatory networks. The first method consists of introducing asynchronous updates in the Boolean model. In the second method, we adopt the approach introduced by L. Glass to obtain a set of piecewise linear differential equations which continuously describe the states of each gene or protein in the network. We apply both methods to a particular example: a Boolean model of the segment polarity gene network of Drosophila melanogaster. We analyze the dynamics of the model, and provide a theoretical characterization of the model's gene pattern prediction as a function of the timescales of the various processes. |
| 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. |
| Motivated by the theory of monotone i/o systems, this paper shows that certain finite and infinite dimensional semi-dynamical systems with negative feedback can be decomposed into a monotone open loop system with inputs and a decreasing output function. The original system is reconstituted by plugging the output into the input. By embedding the system into a larger symmetric monotone system, this paper obtains finer information on the asymptotic behavior of solutions, including existence of positively invariant sets and global convergence. An important new result is the extension of the "small gain theorem" of monotone i/o theory to reaction-diffusion partial differential equations: adding diffusion preserves the global attraction of the ODE equilibrium. |
| This paper further develops a method, originally introduced in a paper by Angeli and Sontag, for proving global attractivity of steady states in certain classes of dynamical systems. In this aproach, one views the given system as a negative feedback loop of a monotone controlled system. An auxiliary discrete system, whose global attractivity implies that of the original system, plays a key role in the theory, which is presented in a general Banach space setting. Applications are given to delay systems, as well as to systems with multiple inputs and outputs, and the question of expressing a given system in the required negative feedback form is addressed. |
| This paper shows that any globally asymptotically controllable system on any smooth manifold can be globally stabilized by a state feedback. Since discontinuous feedbacks are allowed, solutions are understood in the ``sample and hold'' sense introduced by Clarke-Ledyaev-Sontag-Subbotin (CLSS). This work generalizes the CLSS Theorem, which is the special case of our result for systems on Euclidean space. We apply our result to the input-to-state stabilization of systems on manifolds relative to actuator errors, under small observation noise. |
| Systems for which each constant input gives rise to a unique globally attracting equilibrium are considered. A counterexample is provided to show that inputs which are only asymptotically constant may not result in states converging to equilibria (failure of the converging-input converging state, or ``CICS'' property). |
| A generalization of the classical secant condition for the stability of cascades of scalar linear systems is provided for passive systems. The key is the introduction of a quantity that combines gain and phase information for each system in the cascade. For linear one-dimensional systems, the known result is recovered exactly. |
| The fundamental property of strongly monotone systems, and strongly cooperative systems in particular, is the limit set dichotomy due to Hirsch: if x < y, then either Omega(x) < Omega (y), or Omega(x) = Omega(y) and both sets consist of equilibria. We provide here a counterexample showing that this property need not hold for (non-strongly) cooperative systems. |
| We provide an almost-global stability result for a particular chemostat model, in which crowding effects are taken into consideration. The model can be rewritten as a negative feedback interconnection of two monotone i/o systems with well-defined characteristics, which allows the use of a small-gain theorem for feedback interconnections of monotone systems. This leads to a sufficient condition for almost-global stability, and we show that coexistence occurs in this model if the crowding effects are large enough. |
| We study a single species in a chemostat, limited by two nutrients, and separate nutrient uptake from growth. For a broad class of uptake and growth functions it is proved that a nontrivial equilibrium may exist. Moreover, if it exists it is unique and globally stable, generalizing a previous result by Legovic and Cruzado. |
| Biological complexity and limited quantitative measurements impose severe challenges to standard engineering methodologies for systems identification. This paper presents an approach, justified by the theory of universal inputs for distinguishability, based on replacing unmodeled dynamics by fictitious `dependent inputs'. The approach is particularly useful in validation experiments, because it allows one to fit model parameters to experimental data generated by a reference (wild-type) organism and then testing this model on data generated by a variation (mutant), so long as the mutations only affect the unmodeled dynamics that produce the dependent inputs. As a case study, this paper addresses the pathways that control the nitrogen uptake fluxes in baker's yeast Saccharomyces cerevisiae enabling it to optimally respond to changes in nitrogen availability. Well-defined perturbation experiments were performed on cells growing in steady-state. Time-series data of extracellular and intracellular metabolites were obtained, as well as mRNA levels. A nonlinear model was proposed, and shown to be structurally identifiable given input/output data. The identified model correctly predicted the responses of different yeast strains and different perturbations. |
| 2005 |
| One of the fundamental problems of cell biology is the understanding of complex regulatory networks. Such networks are ubiquitous in cells, and knowledge of their properties is essential for the understanding of cellular behavior. This paper studies the effect of experimental uncertainty on the accuracy of the inferred structure of the networks determined using the method in "Untangling the wires: a novel strategy to trace functional interactions in signaling and gene networks". |
| Interactions between genes and gene products give rise to complex circuits that enable cells to process information and respond to external signals. Theoretical studies often describe these interactions using continuous, stochastic, or logical approaches. Here we propose a framework for gene regulatory networks that combines the intuitive appeal of a qualitative description of gene states with a high flexibility in incorporating stochasticity in the duration of cellular processes. We apply our methods to the regulatory network of the segment polarity genes, thus gaining novel insights into the development of gene expression patterns. For example, we show that very short synthesis and decay times can perturb the wild type pattern. On the other hand, separation of timescales between pre- and post-translational processes and a minimal prepattern ensure convergence to the wild type expression pattern regardless of fluctuations. |
| For feedback loops involving single input, single output monotone systems with well-defined I/O characteristics, a previous paper provided an approach to determining the location and stability of steady states. A result on global convergence for multistable systems followed as a consequence of the technique. The present paper extends the approach to multiple inputs and outputs. A key idea is the introduction of a reduced system which preserves local stability properties. New results characterizing strong monotonicity of feedback loops involving cascades are also presented. |
| This paper proposes several definitions of observability for nonlinear systems and explores relationships among them. These observability properties involve the existence of a bound on the norm of the state in terms of the norms of the output and the input on some time interval. A Lyapunov-like sufficient condition for observability is also obtained. As an application, we prove several variants of LaSalle's stability theorem for switched nonlinear systems. These results are demonstrated to be useful for control design in the presence of switching as well as for developing stability results of Popov type for switched feedback systems. |
| This paper provides representations of switched systems described by controlled differential inclusions, in terms of perturbed control systems. The control systems have dynamics given by differential equations, and their inputs consist of the original controls together with disturbances that evolve in compact sets; their sets of maximal trajectories contain, as a dense subset, the set of maximal trajectories of the original system. Several applications to control theory, dealing with properties of stability with respect to inputs and of detectability, are derived as a consequence of the representation theorem. |
| This paper develops characterizations of various uniform stability properties of switched systems described by differential inclusions, and whose switchings are governed by a digraph. These characterizations are given in terms of stability properties of the system with restricted switchings and also in terms of Lyapunov functions. |
| This paper, prepared for a tutorial at the 2005 IEEE Conference on Decision and Control, presents an introduction to molecular systems biology and some associated problems in control theory. It provides an introduction to basic biological concepts, describes several questions in dynamics and control that arise in the field, and argues that new theoretical problems arise naturally in this context. A final section focuses on the combined use of graph-theoretic, qualitative knowledge about monotone building-blocks and steady-state step responses for components. |
| This paper deals with an almost global attractivity result for Lotka-Volterra systems with predator-prey interactions. These systems can be written as (negative) feedback systems. The subsystems of the feedback loop are monotone control systems, possessing particular input-output properties. We use a small-gain theorem, adapted to a context of systems with multiple equilibrium points to obtain the desired almost global attractivity result. It provides sufficient conditions to rule out oscillatory or more complicated behavior which is often observed in predator-prey systems. |
| 2004 |
| One of the key ideas in control theory is that of viewing a complex dynamical system as an interconnection of simpler subsystems, thus deriving conclusions regarding the complete system from properties of its building blocks. Following this paradigm, and motivated by questions in molecular biology modeling, the authors have recently developed an approach based on components which are monotone systems with respect to partial orders in state and signal spaces. This paper presents a brief exposition of recent results, with an emphasis on small gain theorems for negative feedback, and the emergence of multistability and associated hysteresis effects under positive feedback. |
| We discuss several issues related to the stabilizability of nonlinear systems. First, for continuously stabilizable systems, we review constructions of feedbacks that render the system input-to-state stable with respect to actuator errors. Then, we discuss a recent paper which provides a new feedback design that makes globally asymptotically controllable systems input-to-state stable to actuator errors and small observation noise. We illustrate our constructions using the nonholonomic integrator, and discuss a related feedback design for systems with disturbances. |
| Multistability is an important recurring theme in cell signaling, of particular relevance to biological systems that switch between discrete states, generate oscillatory responses, or "remember" transitory stimuli. Standard mathematical methods allow the detection of bistability in some very simple feedback systems (systems with one or two proteins or genes that either activate each other or inhibit each other), but realistic depictions of signal transduction networks are invariably much more complex than this. Here we show that for a class of feedback systems of arbitrary order, the stability properties of the system can be deduced mathematically from how the system behaves when feedback is blocked. Provided that this "open loop," feedback-blocked system is monotone and possesses a sigmoidal characteristic, the system is guaranteed to be bistable for some range of feedback strengths. We present a simple graphical method for deducing the stability behavior and bifurcation diagrams for such systems, and illustrate the method with two examples taken from recent experimental studies of bistable systems: a two-variable Cdc2/Wee1 system and a more complicated five-variable MAPK cascade. |
| We present new characterizations of input-output-to-state stability. This is a notion of detectability formulated in the ISS framework. Equivalent properties are presented in terms of asymptotic estimates of the state trajectories based on the magnitudes of the external input and output signals. These results provide a set of "separation principles" for input-output-to-state stability , characterizations of the property in terms of weaker stability notions. When applied to the closely related notion of integral ISS, these characterizations yield analogous results. |
| The stability of differential inclusions defined by locally Lipschitz compact valued maps is addressed. It is shown that if such a differential inclusion is globally asymptotically stable, then in fact it is uniformly globally asymptotically stable (with respect to initial states in compacts). This statement is trivial for differential equations, but here we provide the extension to compact (not necessarily convex) valued differential inclusions. The main result is presented in a context which is useful for control-theoretic applications: a differential inclusion with two outputs is considered, and the result applies to the property of global error detectability. |
| This paper studies the emergence of multistability and hysteresis in those systems that arise, under positive feedback, from monotone systems with well-defined steady-state responses. Such feedback configurations appear routinely in several fields of application, and especially in biology. The results are stated in terms of directly checkable conditions which do not involve explicit knowledge of basins of attractions of each equilibria. |
| A small-gain theorem is presented for almost global stability of monotone control systems which are open-loop almost globally stable, when constant inputs are applied. The theorem assumes "negative feedback" interconnections. This typically destroys the monotonicity of the original flow and potentially destabilizes the resulting closed-loop system. |
| Weakly activated signaling cascades can be modeled as linear systems. The input-to-output transfer function and the internal gain of a linear system, provide natural measures for the propagation of the input signal down the cascade and for the characterization of the final outcome. The most efficient design of a cascade for generating sharp signals, is obtained by choosing all the off rates equal, and a "universal" finite optimal length. |
| This paper studies aspects of the dynamics of a conventional mechanism of ligand-receptor interactions, with a focus on the stability and location of steady-states. A theoretical framework is developed, and, as an application, a minimal parametrization is provided for models for two- or multi-state receptor interaction with ligand. In addition, an "affinity quotient" is introduced, which allows an elegant classification of ligands into agonists, neutral agonists, and inverse agonists. |
| We prove the global asymptotic stability of a well-known delayed negative-feedback model of testosterone dynamics, which has been proposed as a model of oscillatory behavior. We establish stability (and hence the impossibility of oscillations) even in the presence of delays of arbitrary length. |
| This paper takes a computational learning theory approach to a problem of linear systems identification. It is assumed that input signals have only a finite number k of frequency components, and systems to be identified have dimension no greater than n. The main result establishes that the sample complexity needed for identification scales polynomially with n and logarithmically with k. |
| The main problem addressed in this paper is the design of feedbacks for globally asymptotically controllable (GAC) control affine systems that render the closed loop systems input to state stable with respect to actuator errors. Extensions for fully nonlinear GAC systems with actuator errors are also discussed. Our controllers have the property that they tolerate small observation noise as well. |
| This paper, addressed primarily to engineers and mathematicians with an interest in control theory, argues that entirely new theoretical problems arise naturally when addressing questions in the field of systems biology. Examples from the author's recent work are used to illustrate this point. |
| High-throughput technologies have facilitated the acquisition of large genomics and proteomics data sets. However, these data provide snapshots of cellular behavior, rather than help us reveal causal relations. Here, we propose how these technologies can be utilized to infer the topology and strengths of connections among genes, proteins, and metabolites by monitoring time-dependent responses of cellular networks to experimental interventions. We show that all connections leading to a given network node, e.g., to a particular gene, can be deduced from responses to perturbations none of which directly influences that node, e.g., using strains with knock-outs to other genes. To infer all interactions from stationary data, each node should be perturbed separately or in combination with other nodes. Monitoring time series provides richer information and does not require perturbations to all nodes. |
| 2003 |
| Monotone systems constitute one of the most important classes of dynamical systems used in mathematical biology modeling. The objective of this paper is to extend the notion of monotonicity to systems with inputs and outputs, a necessary first step in trying to understand interconnections, especially including feedback loops, built up out of monotone components. Basic definitions and theorems are provided, as well as an application to the study of a model of one of the cell's most important subsystems. |
| A new notion of input-to-state stability involving infinity norms of input derivatives up to a finite order k is introduced and characterized. An example shows that this notion of stability is indeed weaker than the usual ISS. Applications to the study of global asymptotic stability of cascaded nonlinear systems are discussed. |
| This paper addresses the time-optimal control problem for a class of control systems which includes controlled mechanical systems with possible dissipation terms. The Lie algebras associated with such mechanical systems enjoy certain special properties. These properties are explored and are used in conjunction with the Pontryagin maximum principle to determine the structure of singular extremals and, in particular, time-optimal trajectories. The theory is illustrated with an application to a time-optimal problem for a class of underwater vehicles. |
| The fundamental relaxation result for Lipschitz differential inclusions is the Filippov-Wazewski Relaxation Theorem, which provides approximations of trajectories of a relaxed inclusion on finite intervals. A complementary result is presented, which provides approximations on infinite intervals, but does not guarantee that the approximation and the reference trajectory satisfy the same initial condition. |
| Some biological systems operate at the critical point between stability and instability and this requires a fine-tuning of parameters. We bring together two examples from the literature that illustrate this: neural integration in the nervous system and hair cell oscillations in the auditory system. In both examples the question arises as to how the required fine-tuning may be achieved and maintained in a robust and reliable way. We study this question using tools from nonlinear and adaptive control theory. We illustrate our approach on a simple model which captures some of the essential features of neural integration. As a result, we propose a large class of feedback adaptation rules that may be responsible for the experimentally observed robustness of neural integration. We mention extensions of our approach to the case of hair cell oscillations in the ear. |
| This paper studies a feedback regulation problem that arises in at least two different biological applications. The feedback regulation problem under consideration may be interpreted as an adaptive control problem for tuning bifurcation parameters, and it has not been studied in the control literature. The goal of the paper is to formulate this problem and to present some preliminary results. |
| In the early embryonic cell cycle, Cdc2-cyclin B functions like an autonomous oscillator, at whose core is a negative feedback loop: cyclins accumulate and produce active mitotic Cdc2-cyclin B Cdc2 activates the anaphase-promoting complex (APC); the APC then promotes cyclin degradation and resets Cdc2 to its inactive, interphase state. Cdc2 regulation also involves positive feedback4, with active Cdc2-cyclin B stimulating its activator Cdc25 and inactivating its inhibitors Wee1 and Myt1. Under the correct circumstances, these positive feedback loops could function as a bistable trigger for mitosis, and oscillators with bistable triggers may be particularly relevant to biological applications such as cell cycle regulation. This paper examined whether Cdc2 activation is bistable, confirming that the response of Cdc2 to non-degradable cyclin B is temporally abrupt and switchlike, as would be expected if Cdc2 activation were bistable. It is also shown that Cdc2 activation exhibits hysteresis, a property of bistable systems with particular relevance to biochemical oscillators. These findings help establish the basic systems-level logic of the mitotic oscillator. |
| Suppose that an equilibrium is asymptotically stable when external inputs vanish. Then, every bounded trajectory which corresponds to a control which approaches zero and which lies in the domain of attraction of the unforced system, must also converge to the equilibrium. This "well-known" but hard-to-cite fact is proved and slightly generalized here. |
| This note provides a simple result showing, under suitable technical assumptions, that if a system S adapts to a class of external signals U, then S must necessarily contain a subsystem which is capable of generating all the signals in U. It is not assumed that regulation is robust, nor is there a prior requirement for the system to be partitioned into separate plant and controller components. Instead, a "signal detection" capability is imposed. These weaker assumptions make the result better applicable to cellular phenomena such as the adaptation of E-coli chemotactic tumbling rate to constant concentrations. |
| A construction is given of a globally asymptotically stable time-invariant system which can be destabilized by some integrable perturbation. Besides its intrinsic interest, this serves to provide counterexamples to an open question regarding Lyapunov functions. |
| 2002 |
| We analyze nonlinear cascades in which the driven subsystem is integral ISS, and characterize the admissible integral ISS gains for stability. This characterization makes use of the convergence speed of the driving subsystem, and allows a larger class of gain functions when the convergence is faster. We show that our integral ISS gain characterization unifies different approaches in the literature which restrict the nonlinear growth of the driven subsystem and the convergence speed of the driving subsystem. |
| This paper provides a necessary and sufficient condition for detectability, and an explicit construction of observers when this condition is satisfied, for chemical reaction networks of the Feinberg-Horn-Jackson zero deficiency type. |
| Emerging technologies have enabled the acquisition of large genomics and proteomics data sets. This paper proposes a novel quantitative method for determining functional interactions in cellular signaling and gene networks. It can be used to explore cell systems at a mechanistic level, or applied within a modular framework, which dramatically decreases the number of variables to be assayed. The topology and strength of network connections are retrieved from experimentally measured network responses to successive perturbations of all modules. In addition, the method can reveal functional interactions even when the components of the system are not all known, in which case some connections retrieved by the analysis will not be direct but correspond to the interaction routes through unidentified elements. The method is tested and illustrated using computer-generated responses of a modeled MAPK cascade and gene network. |
| We consider a new Lyapunov-type characterization of detectability for nonlinear systems without controls, in terms of lower-semicontinuous (not necessarily smooth, or even continuous) dissipation functions, and prove its equivalence to the GASMO (global asymptotic stability modulo outputs) and UOSS (uniform output-to-state stability) properties studied in previous work. The result is then extended to provide a construction of a discontinuous dissipation function characterization of the IOSS (input-to-state stability) property for systems with controls. This paper complements a recent result on smooth Lyapunov characterizations of IOSS. The utility of non-smooth Lyapunov characterizations is illustrated by application to a well-known transistor network example. |
| This paper introduces and studies a new definition of the minimum-phase property for general smooth nonlinear control systems. The definition does not rely on a particular choice of coordinates in which the system takes a normal form or on the computation of zero dynamics. In the spirit of the ``input-to-state stability'' philosophy, it requires the state and the input of the system to be bounded by a suitable function of the output and derivatives of the output, modulo a decaying term depending on initial conditions. The class of minimum-phase systems thus defined includes all affine systems in global normal form whose internal dynamics are input-to-state stable and also all left-invertible linear systems whose transmission zeros have negative real parts. As an application, we explain how the new concept enables one to develop a natural extension to nonlinear systems of a basic result from linear adaptive control. |
| We study nonlinear systems with both control and disturbance inputs. The main problem addressed in the paper is design of state feedback control laws that render the closed-loop system integral-input-to-state stable (iISS) with respect to the disturbances. We introduce an appropriate concept of control Lyapunov function (iISS-CLF), whose existence leads to an explicit construction of such a control law. The same method applies to the problem of input-to-state stabilization. Converse results and techniques for generating iISS-CLFs are also discussed. |
| The notions of asymptotic amplitude for signals, and Cauchy gain for input/output systems, and an associated small-gain principle, are introduced. These concepts allow the consideration of systems with multiple, and possibly feedback-dependent, steady states. A Lyapunov-like characterization allows the computation of gains for state-space systems, and the formulation of sufficient conditions insuring the lack of oscillations and chaotic behaviors in a wide variety of cascades and feedback loops. An application in biology (MAPK signaling) is worked out in detail. |
| errata for Structure and stability of certain chemical networks and applications to the kinetic proofreading model of T-cell receptor signal transduction |
| Given a set of differential equations whose description involves unknown parameters, such as reaction constants in chemical kinetics, and supposing that one may at any time measure the values of some of the variables and possibly apply external inputs to help excite the system, how many experiments are sufficient in order to obtain all the information that is potentially available about the parameters? This paper shows that the best possible answer (assuming exact measurements and real analiticity) is 2r+1 experiments, where r is the number of parameters. |
| A general ISS-type small-gain result is presented. It specializes to a small-gain theorem for ISS operators, and it also recovers the classical statement for ISS systems in state-space form. In addition, we highlight applications to incrementally stable systems, detectable systems, and to interconnections of stable systems. |
| 2001 |
| (This is an expository paper prepared for a plenary talk given at the Second Nonlinear Control Network Workshop, Paris, June 9, 2000.) The input to state stability (ISS) paradigm is motivated as a generalization of classical linear systems concepts under coordinate changes. A summary is provided of the main theoretical results concerning ISS and related notions of input/output stability and detectability. A bibliography is also included, listing extensions, applications, and other current work. |
| The area of hybrid systems concerns issues of modeling, computation, and control for systems which combine discrete and continuous components. The subclass of piecewise linear (PL) systems provides one systematic approach to discrete-time hybrid systems, naturally blending switching mechanisms with classical linear components. PL systems model arbitrary interconnections of finite automata and linear systems. Tools from automata theory, logic, and related areas of computer science and finite mathematics are used in the study of PL systems, in conjunction with linear algebra techniques, all in the context of a "PL algebra" formalism. PL systems are of interest as controllers as well as identification models. Basic questions for any class of systems are those of equivalence, and, in particular, if state spaces are equivalent under a change of variables. This paper studies this state-space equivalence problem for PL systems. The problem was known to be decidable, but its computational complexity was potentially exponential; here it is shown to be solvable in polynomial-time. |
| A measurable function x from a subset J of R into a metric space X is said to be C-meagre if C is non-empty subset of X and, for every closed subset K of X disjoint from C, the preimage of K under x has finite Lebesgue measure. This concept of meagreness, applied to trajectories, is shown to provide a unifying framework which facilitates a variety of characterizations, extensions or generalizations of diverse facts pertaining to asymptotic behaviour of dynamical systems. |
| This work explores Lyapunov characterizations of the input-output-to-state stability (IOSS) property for nonlinear systems. The notion of IOSS is a natural generalization of the standard zero-detectability property used in the linear case. The main contribution of this work is to establish a complete equivalence between the input-output-to-state stability property and the existence of a certain type of smooth Lyapunov function. As corollaries, one shows the existence of "norm-estimators", and obtains characterizations of nonlinear detectability in terms of relative stability and of finite-energy estimates. |
| This paper deals with the theory of structure, stability, robustness, and stabilization for an appealing class of nonlinear systems which arises in the analysis of chemical networks. The results given here extend, but are also heavily based upon, certain previous work by Feinberg, Horn, and Jackson, of which a self-contained and streamlined exposition is included. The theoretical conclusions are illustrated through an application to the kinetic proofreading model proposed by McKeithan for T-cell receptor signal transduction. |
| 2000 |
| Just as input to state stability (ISS) generalizes the idea of finite gains with respect to supremum norms, the new notion of integral input to state stability (IISS) generalizes the concept of finite gain when using an integral norm on inputs. In this paper, we obtain a necessary and sufficient characterization of the IISS property, expressed in terms of dissipation inequalities. |
| This paper continues the study of the integral input-to-state stability (IISS) property. It is shown that the IISS property is equivalent to one which arises from the consideration of mixed norms on states and inputs, as well as to the superposition of a ``bounded energy bounded state'' requirement and the global asymptotic stability of the unforced system. A semiglobal version of IISS is shown to imply the global version, though a counterexample shows that the analogous fact fails for input to state stability (ISS). The results in this note complete the basic theoretical picture regarding IISS and ISS. |
| It is shown that, for neutrally stable discrete-time linear systems subject to actuator saturation, finite gain lp stabilization can be achieved by linear output feedback, for all p>1. An explicit construction of the corresponding feedback laws is given. The feedback laws constructed also result in a closed-loop system that is globally asymptotically stable, and in an input-to-state estimate. |
| We analyze computations on temporal patterns and spatio-temporal patterns in formal network models whose temporal dynamics arises from empirically established quantitative models for short term dynamics at biological synapses. We give a complete characterization of all linear and nonlinear filters that can be approximated by such dynamic network models: it is the class of all filters that can be approximated by Volterra series. This characterization is shown to be rather stable with regard to changes in the model. For example it is shown that synaptic facilitation and one layer of neurons suffices for approximating arbitrary filters from this class. Our results provide a new complexity hierarchy for all filters that are approximable by Volterra series, which appears to be closer related to the actual cost of implementing such filters in neural hardware than preceding complexity measures. Our results also provide a new parameterization for approximations to such filters in terms of parameters that are arguable related to those that are tunable in biological neural systems. |
| This note provides explicit algebraic stabilizing formulas for clf's when controls are restricted to certain Minkowski balls in Euclidean space. Feedbacks of this kind are known to exist by a theorem of Artstein, but the proof of Artstein's theorem is nonconstructive. The formulas are obtained from a general feedback stabilization technique and are used to construct approximation solutions to some stabilization problems. |
| This paper deals with the regularity of solutions of the Hamilton-Jacobi Inequality which arises in H-infinity control. It shows by explicit counterexamples that there are gaps between existence of continuous and locally Lipschitz (positive definite and proper) solutions, and between Lipschitz and continuously differentiable ones. On the other hand, it is shown that it is always possible to smooth-out solutions, provided that an infinitesimal increase in gain is allowed. |
| This paper presents necessary and sufficient characterizations of several notions of input to output stability. Similar Lyapunov characterizations have been found to play a key role in the analysis of the input to state stability property, and the results given here extend their validity to the case when the output, but not necessarily the entire internal state, is being regulated. |
| 1999 |
| In this expository paper, we deal with several questions related to stability and stabilization of nonlinear finite-dimensional continuous-time systems. We review the basic problem of feedback stabilization, placing an emphasis upon relatively new areas of research which concern stability with respect to "noise" (such as errors introduced by actuators or sensors). The table of contents is as follows: Review of Stability and Asymptotic Controllability, The Problem of Stabilization, Obstructions to Continuous Stabilization, Control-Lyapunov Functions and Artstein's Theorem, Discontinuous Feedback, Nonsmooth CLF's, Insensitivity to Small Measurement and Actuator Errors, Effect of Large Disturbances: Input-to-State Stability, Comments on Notions Related to ISS. |
| This paper shows that, for time varying systems, global asymptotic controllability to a given closed subset of the state space is equivalent to the existence of a continuous control-Lyapunov function with respect to the set. |
| A finite-dimensional continuous-time system is forward complete if solutions exist globally, for positive time. This paper shows that forward completeness can be characterized in a necessary and sufficient manner by means of smooth scalar growth inequalities. Moreover, a version of this fact is also proved for systems with inputs, and a generalization is also provided for systems with outputs and a notion (unboundedness observability) of relative completeness. We apply these results to obtain a bound on reachable states in terms of energy-like estimates of inputs. |
| This paper shows that uniformly global asymptotic stability for a family of ordinary differential equations is equivalent to uniformly global exponential stability under a suitable nonlinear change of variables. The same is shown respectively for input-to-state stability, input-to-state exponential stability, and the property of finite square-norm gain ("nonlinear H-infty"). The results are shown for systems of any dimension not equal to 4 or 5. |
| One of the fundamental facts in control theory (Artstein's theorem) is the equivalence, for systems affine in controls, between continuous feedback stabilizability to an equilibrium and the existence of smooth control Lyapunov functions. This equivalence breaks down for general nonlinear systems, not affine in controls. One of the main results in this paper establishes that the existence of smooth Lyapunov functions implies the existence of (in general, discontinuous) feedback stabilizers which are insensitive to small errors in state measurements. Conversely, it is shown that the existence of such stabilizers in turn implies the existence of smooth control Lyapunov functions. Moreover, it is established that, for general nonlinear control systems under persistently acting disturbances, the existence of smooth Lyapunov functions is equivalent to the existence of (possibly) discontinuous) feedback stabilizers which are robust with respect to small measurement errors and small additive external disturbances. |
| We consider recurrent analog neural nets where the output of each gate is subject to Gaussian noise, or any other common noise distribution that is nonzero on a large set. We show that many regular languages cannot be recognized by networks of this type, and we give a precise characterization of those languages which can be recognized. This result implies severe constraints on possibilities for constructing recurrent analog neural nets that are robust against realistic types of analog noise. On the other hand we present a method for constructing feedforward analog neural nets that are robust with regard to analog noise of this type. |
| We provide an explicit KL stability or input-to-state stability (ISS) estimate for a sampled-data nonlinear system in terms of the KL estimate for the corresponding discrete-time system and a K function describing inter-sample growth. It is quite obvious that a uniform inter-sample growth condition, plus an ISS property for the exact discrete-time model of a closed-loop system, implies uniform ISS of the sampled-data nonlinear system; our results serve to quantify these facts by means of comparison functions. Our results can be used as an alternative to prove and extend results of Aeyels et al and extend some results by Chen et al to a class of nonlinear systems. Finally, the formulas we establish can be used as a tool for some other problems which we indicate. |
| This paper provides a precise result which shows that insensitivity to small measurement errors in closed-loop stabilization can be attained provided that the feedback controller ignores observations during small time intervals. |
| This paper studies controllability properties of recurrent neural networks. The new contributions are: (1) an extension of the result in "Complete controllability of continuous-time recurrent neural networks" to a slightly different model, where inputs appear in an affine form, (2) a formulation and proof of a necessary and sufficient condition, in terms of local-local controllability, and (3) a complete analysis of the 2-dimensional case for which the hypotheses made in previous work do not apply. |
| This paper deals with several related notions of output stability with respect to inputs (which may be thought of as disturbances). The main such notion is called input to output stability (IOS), and it reduces to input to state stability (ISS) when the output equals the complete state. For systems with no inputs, IOS provides a generalization of the classical concept of partial stability. Several variants, which formalize in different manners the transient behavior, are introduced. The main results provide a comparison among these notions |
| 1998 |
| This paper proposes a generally applicable technique for the control of analytic systems with no drift. The method is based on the generation of "nonsingular loops" that allow linearized controllability. One can then implement Newton and/or gradient searches in the search for a control. A general convergence theorem is proved. |
| The Vapnik-Chervonenkis (VC) dimension is an integer which helps to characterize distribution-independent learning of binary concepts from positive and negative samples. This paper, based on lectures delivered at the Isaac Newton Institute in August of 1997, presents a brief introduction, establishes various elementary results, and discusses how to estimate the VC dimension in several examples of interest in neural network theory. (It does not address the learning and estimation-theoretic applications of VC dimension, and the applications to uniform convergence theorems for empirical probabilities, for which many suitable references are available.) |
| This paper provides lower and upper bounds for the VC dimension of recurrent networks. Several types of activation functions are discussed, including threshold, polynomial, piecewise-polynomial and sigmoidal functions. The bounds depend on two independent parameters: the number w of weights in the network, and the length k of the input sequence. Ignoring multiplicative constants, the main results say roughly the following: 1. For architectures whose activation is any fixed nonlinear polynomial, the VC dimension is proportional to wk. 2. For architectures whose activation is any fixed piecewise polynomial, the VC dimension is between wk and w**2k. 3. For architectures with threshold activations, the VC dimension is between wlog(k/w) and the smallest of wklog(wk) and w**2+wlog(wk). 4. For the standard sigmoid tanh(x), the VC dimension is between wk and w**4 k**2. |
| This paper considers the problem of stabilization of linear systems for which only the magnitudes of outputs are measured. It is shown that, if a system is controllable and observable, then one can find a stabilizing controller, which is robust with respect to observation noise (in the ISS sense). |
| The following learning problem is considered, for continuous-time recurrent neural networks having sigmoidal activation functions. Given a ``black box'' representing an unknown system, measurements of output derivatives are collected, for a set of randomly generated inputs, and a network is used to approximate the observed behavior. It is shown that the number of inputs needed for reliable generalization (the sample complexity of the learning problem) is upper bounded by an expression that grows polynomially with the dimension of the network and logarithmically with the number of output derivatives being matched. |
| This note discusses two integral variants of the input-to-state stability (ISS) property, which represent nonlinear generalizations of L2 stability, in much the same way that ISS generalizes L-infinity stability. Both variants are equivalent to ISS for linear systems. For general nonlinear systems, it is shown that one of the new properties is strictly weaker than ISS, while the other one is equivalent to it. For bilinear systems, a complete characterization is provided of the weaker property. An interesting fact about functions of type KL is proved as well. |
| For analytic discrete-time systems, it is shown that uniform forward accessibility implies the generic existence of universal nonsingular control sequences. A particular application is given by considering forward accessible systems on compact manifolds. For general systems, it is proved that the complement of the set of universal sequences of infinite length is of the first category. For classes of systems satisfying a descending chain condition, and in particular for systems defined by polynomial dynamics, forward accessibility implies uniform forward accessibility. |
| 1997 |
| This paper provides an exposition of some recent results regarding system-theoretic aspects of continuous-time recurrent (dynamic) neural networks with sigmoidal activation functions. The class of systems is introduced and discussed, and a result is cited regarding their universal approximation properties. Known characterizations of controllability, observability, and parameter identifiability are reviewed, as well as a result on minimality. Facts regarding the computational power of recurrent nets are also mentioned. |
| It is shown that every asymptotically controllable system can be stabilized by means of some (discontinuous) feedback law. One of the contributions of the paper is in defining precisely the meaning of stabilization when the feedback rule is not continuous. The main ingredients in our construction are: (a) the notion of control-Lyapunov function, (b) methods of nonsmooth analysis, and (c) techniques from positional differential games. |
| 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. |
| This paper shows that neural networks which use continuous activation functions have VC dimension at least as large as the square of the number of weights w. This result settles the open question of whether whether the well-known O(w log w) bound, known for hard-threshold nets, also held for more general sigmoidal nets. Implications for the number of samples needed for valid generalization are discussed. |
| This paper suggests the use of Fourier-type activation functions in fully recurrent neural networks. The main theoretical advantage is that, in principle, the problem of recovering internal coefficients from input/output data is solvable in closed form. |
| For classes of concepts defined by certain classes of analytic functions depending on k parameters, there are nonempty open sets of samples of length 2k+2 which cannot be shattered. A slighly weaker result is also proved for piecewise-analytic functions. The special case of neural networks is discussed. |
| This paper presents a characterization of controllability for the class of control systems commonly called (continuous-time) recurrent neural networks. The characterization involves a simple condition on the input matrix, and is proved when the activation function is the hyperbolic tangent. |
| The notion of input-to-state stability (ISS) has proved to be useful in nonlinear systems analysis. This paper discusses a dual notion, output-to-state stability (OSS). A characterization is provided in terms of a dissipation inequality involving storage (Lyapunov) functions. Combining ISS and OSS there results the notion of input/output-to-state stability (IOSS), which is also studied and related to the notion of detectability, the existence of observers, and output injection. |
| This paper deals with the problem of global stabilization of linear discrete time systems by means of bounded feedback laws. The main result proved is an analog of one proved for the continuous time case by the authors, and shows that such stabilization is possible if and only if the system is stabilizable with arbitrary controls and the transition matrix has spectral radius less or equal to one. The proof provides in principle an algorithm for the construction of such feedback laws, which can be implemented either as cascades or as parallel connections (``single hidden layer neural networks'') of simple saturation functions. |
| 1996 |
| This paper summarizes the definitions and several of the main results of an approach to hybrid systems, which combines finite automata and linear systems, developed by the author in the early 1980s. Some related more recent results are briefly mentioned as well. |
| Shorter and more expository version of "Nonsmooth control-Lyapunov functions" |
| Recurrent perceptron classifiers generalize the usual perceptron model. They correspond to linear transformations of input vectors obtained by means of "autoregressive moving-average schemes", or infinite impulse response filters, and allow taking into account those correlations and dependences among input coordinates which arise from linear digital filtering. This paper provides tight bounds on sample complexity associated to the fitting of such models to experimental data. The results are expressed in the context of the theory of probably approximately correct (PAC) learning. |
| This paper presents a Converse Lyapunov Function Theorem motivated by robust control analysis and design. Our result is based upon, but generalizes, various aspects of well-known classical theorems. In a unified and natural manner, it (1) allows arbitrary bounded time-varying parameters in the system description, (2) deals with global asymptotic stability, (3) results in smooth (infinitely differentiable) Lyapunov functions, and (4) applies to stability with respect to not necessarily compact invariant sets. |
| This paper deals with (global) finite-gain input/output stabilization of linear systems with saturated controls. For neutrally stable systems, it is shown that the linear feedback law suggested by the passivity approach indeed provides stability, with respect to every Lp-norm. Explicit bounds on closed-loop gains are obtained, and they are related to the norms for the respective systems without saturation. These results do not extend to the class of systems for which the state matrix has eigenvalues on the imaginary axis with nonsimple (size >1) Jordan blocks, contradicting what may be expected from the fact that such systems are globally asymptotically stabilizable in the state-space sense; this is shown in particular for the double integrator. |
| This paper deals with nonlinear least-squares problems involving the fitting to data of parameterized analytic functions. For generic regression data, a general result establishes the countability, and under stronger assumptions finiteness, of the set of functions giving rise to critical points of the quadratic loss function. In the special case of what are usually called "single-hidden layer neural networks", which are built upon the standard sigmoidal activation tanh(x) or equivalently 1/(1+exp(-x)), a rough upper bound for this cardinality is provided as well. |
| We present new characterizations of the Input to State Stability property. As a consequence of these results, we show the equivalence between the ISS property and several (apparent) variations proposed in the literature. |
| 1995 |
| An encyclopedia-type article on foundations of input/output stability. |
| This paper discusses various continuity and incremental-gain properties for neutrally stable linear systems under linear feedback subject to actuator saturation. The results complement our previous ones, which applied to the same class of problems and provided finite-gain stability. |
| We consider the problem of characterizing possible supply functions for a given dissipative nonlinear system, and provide a result that allows some freedom in the modification of such functions. |
| Blum and Rivest showed that any possible neural net learning algorithm based on fixed architectures faces severe computational barriers. This paper extends their NP-completeness result, which applied only to nets based on hard threshold activations, to nets that employ a particular continuous activation. In view of neural network practice, this is a more relevant result to understanding the limitations of backpropagation and related techniques. |
| We deal with the question of obtaining explicit feedback control laws that stabilize a nonlinear system, under the assumption that a "control Lyapunov function" is known. In previous work, the case of unbounded controls was considered. Here we obtain results for bounded and/or positive controls. We also provide some simple preliminary remarks regarding a set stability version of the problem and a version for systems subject to disturbances. |
| This paper studies various stability issues for parameterized families of systems, including problems of stabilization with respect to sets. The study of such families is motivated by robust control applications. A Lyapunov-theoretic necessary and sufficient characterization is obtained for a natural notion of robust uniform set stability; this characterization allows replacing ad hoc conditions found in the literature by more conceptual stability notions. We then use these techniques to establish a result linking state space stability to ``input to state'' (bounded-input bounded-state) stability. In addition, the preservation of stabilizability under certain types of cascade interconnections is analyzed. |
| This paper deals with finite size networks which consist of interconnections of synchronously evolving processors. Each processor updates its state by applying a "sigmoidal" function to a rational-coefficient linear combination of the previous states of all units. We prove that one may simulate all Turing Machines by such nets. In particular, one can simulate any multi-stack Turing Machine in real time, and there is a net made up of 886 processors which computes a universal partial-recursive function. Products (high order nets) are not required, contrary to what had been stated in the literature. Non-deterministic Turing Machines can be simulated by non-deterministic rational nets, also in real time. The simulation result has many consequences regarding the decidability, or more generally the complexity, of questions about recursive nets. |
| This paper proposes a simple numerical technique for the steering of arbitrary analytic systems with no drift. It is based on the generation of "nonsingular loops" which allow linearized controllability along suitable trajetories. Once such loops are available, it is possible to employ standard Newton or steepest descent methods, as classically done in numerical control. The theoretical justification of the approach relies on recent results establishing the genericity of nonsingular controls, as well as a simple convergence lemma. |
| The "input to state stability" (ISS) property provides a natural framework in which to formulate notions of stability with respect to input perturbations. In this expository paper, we review various equivalent definitions expressed in stability, Lyapunov-theoretic, and dissipation terms. We sketch some applications to the stabilization of cascades of systems and of linear systems subject to control saturation. |
| We consider the problem of characterizing possible supply functions for a given dissipative nonlinear system, and provide a result that allows some freedom in the modification of such functions. |
| We show that the well-known Lyapunov sufficient condition for input-to-state stability is also necessary, settling positively an open question raised by several authors during the past few years. Additional characterizations of the ISS property, including one in terms of nonlinear stability margins, are also provided. |
| This paper deals with the orders of input/output equations satisfied by nonlinear systems. Such equations represent differential (or difference, in the discrete-time case) relations between high-order derivatives (or shifts, respectively) of input and output signals. It is shown that, under analyticity assumptions, there cannot exist equations of order less than the minimal dimension of any observable realization; this generalizes the known situation in the classical linear case. The results depend on new facts, themselves of considerable interest in control theory, regarding universal inputs for observability in the discrete case, and observation spaces in both the discrete and continuous cases. Included in the paper is also a new and simple self-contained proof of Sussmann's universal input theorem for continuous-time analytic systems. |
| 1994 |
| We examine the power of constant depth circuits with sigmoid threshold gates for computing boolean functions. It is shown that, for depth 2, constant size circuits of this type are strictly more powerful than constant size boolean threshold circuits (i.e. circuits with linear threshold gates). On the other hand it turns out that, for any constant depth d, polynomial size sigmoid threshold circuits with polynomially bounded weights compute exactly the same boolean functions as the corresponding circuits with linear threshold gates. |
| Controllability questions for discrete-time nonlinear systems are addressed in this paper. In particular, we continue the search for conditions under which the group-like notion of transitivity implies the stronger and semigroup-like property of forward accessibility. We show that this implication holds, pointwise, for states which have a weak Poisson stability property, and globally, if there exists a global "attractor" for the system. |
| This paper concerns recurrent networks x'=s(Ax+Bu), y=Cx, where s is a sigmoid, in both discrete time and continuous time. Our main result is that observability can be characterized, if one assumes certain conditions on the nonlinearity and on the system, in a manner very analogous to that of the linear case. Recall that for the latter, observability is equivalent to the requirement that there not be any nontrivial A-invariant subspace included in the kernel of C. We show that the result generalizes in a natural manner, except that one now needs to restrict attention to certain special "coordinate" subspaces. |
| In this paper, we present necessary and sufficient conditions for observability of the class of output-saturated systems. These are linear systems whose output passes through a saturation function before it can be measured. |
| We consider recurrent networks with real-valued weights. If allowed exponential time for computation, they turn out to have unbounded power. However, under polynomial-time constraints there are limits on their capabilities, though being more powerful than Turing Machines. Moreover, there is a precise correspondence between nets and standard non-uniform circuits with equivalent resources, and as a consequence one has lower bound constraints on what they can compute. We note that these networks are not likely to solve polynomially NP-hard problems, as the equality "P=NP" in our model implies the almost complete collapse of the standard polynomial hierarchy. We show that a large class of different networks and dynamical system models have no more computational power than this neural (first-order) model with real weights. The results suggest the following Church-like Thesis of Time-bounded Analog Computing: "Any reasonable analog computer will have no more power (up to polynomial time) than first-order recurrent networks." |
| We present two constructions of controllers that globally stabilize linear systems subject to control saturation. We allow essentially arbitrary saturation functions. The only conditions imposed on the system are the obvious necessary ones, namely that no eigenvalues of the uncontrolled system have positive real part and that the standard stabilizability rank condition hold. One of the constructions is in terms of a "neural-network type" one-hidden layer architecture, while the other one is in terms of cascades of linear maps and saturations. |
| 1993 |
| In this short expository survey, we sketch various known facts about uniqueness of weights in neural networks, including results about recurrent nets, and we provide a new and elementary complex-variable proof of a uniqueness result that applies in the single hidden layer case. |
| This paper has an expository introduction to two related topics: (a) Some mathematical results regarding "neural networks", and (b) so-called "neurocontrol" and "learning control" (each part can be read independently of the other). It was prepared for a short course given at the 1993 European Control Conference. |
| A basic open question for discrete-time nonlinear systems is that of determining when, in analogy with the classical continuous-time "positive form of Chow's Lemma", accessibility follows from transitivity of a natural group action. This paper studies the problem, and establishes the desired implication for analytic systems in several cases: (i) compact state space, (ii) under a Poisson stability condition, and (iii) in a generic sense. In addition, the paper studies accessibility properties of the "control sets" recently introduced in the context of dynamical systems studies. Finally, various examples and counterexamples are provided relating the various Lie algebras introduced in past work. |
| This paper shows that the weights of continuous-time feedback neural networks x'=s(Ax+Bu), y=Cx (where s is a sigmoid) are uniquely identifiable from input/output measurements. Under very weak genericity assumptions, the following is true: Assume given two nets, whose neurons all have the same nonlinear activation function s; if the two nets have equal behaviors as "black boxes" then necessarily they must have the same number of neurons and -except at most for sign reversals at each node- the same weights. Moreover, even if the activations are not a priori known to coincide, they are shown to be also essentially determined from the external measurements. |
| This paper deals with systems that are obtained from linear time-invariant continuous- or discrete-time devices followed by a function that just provides the sign of each output. Such systems appear naturally in the study of quantized observations as well as in signal processing and neural network theory. Results are given on observability, minimal realizations, and other system-theoretic concepts. Certain major differences exist with the linear case, and other results generalize in a surprisingly straightforward manner. |
| 1992 |
| This paper compares the representational capabilities of one hidden layer and two hidden layer nets consisting of feedforward interconnections of linear threshold units. It is remarked that for certain problems two hidden layers are required, contrary to what might be in principle expected from the known approximation theorems. The differences are not based on numerical accuracy or number of units needed, nor on capabilities for feature extraction, but rather on a much more basic classification into "direct" and "inverse" problems. The former correspond to the approximation of continuous functions, while the latter are concerned with approximating one-sided inverses of continuous functions - and are often encountered in the context of inverse kinematics determination or in control questions. A general result is given showing that nonlinear control systems can be stabilized using two hidden layers, but not in general using just one. |
| This paper deals with single-hidden-layer feedforward nets, studying various aspects of classification power and interpolation capability. In particular, a worst-case analysis shows that direct input to output connections in threshold nets double the recognition but not the interpolation power, while using sigmoids rather than thresholds allows doubling both. For other measures of classification, including the Vapnik-Chervonenkis dimension, the effect of direct connections or sigmoidal activations is studied in the special case of two-dimensional inputs. |
| For analytic systems satisfying the strong accessibility rank condition, generic inputs produce trajectories along which the linearized system is controllable. Applications to the steering of systems without drift are briefly mentioned. |
| It is shown that realizability of an input/output operators by a finite-dimensional continuous-time rational control system is equivalent to the existence of a high-order algebraic differential equation satisfied by the corresponding input/output pairs ("behavior"). This generalizes, to nonlinear systems, the classical equivalence between autoregressive representations and finite dimensional linear realizability. |
| This paper studies fundamental analytic properties of generating series for nonlinear control systems, and of the operators they define. It then applies the results obtained to the extension of facts, which relate realizability and algebraic input/output equations, to local realizability and analytic equations. |
| 1991 |
| This paper surveys recent work by the author on learning and representational capabilities of feedforward nets. The learning results show that, among two possible variants of the so-called backpropagation training method for sigmoidal nets, both of which variants are used in practice, one is a better generalization of the older perceptron training algorithm than the other. The representation results show that nets consisting of sigmoidal neurons have at least twice the representational capabilities of nets that use classical threshold neurons, at least when this increase is quantified in terms of classification power. On the other hand, threshold nets are shown to be more useful when approximating implicit functions, as illustrated with an application to a typical control problem. |
| This conference paper reviews various results relating state-space (Lyapunov) stabilization and exponential stabilization to several notions of input/output or bounded-input bounded-output stabilization. It also provides generalizations of some of these results to systems with saturating controls. Some of these latter results were not included in journal papers. |
| The notion of controllability was identified by Kalman as one of the central properties determining system behavior. His simple rank condition is ubiquitous in linear systems analysis. This article presents an elementary and expository overview of the generalizations of this test to a condition for testing accessibility of discrete and continuous time nonlinear systems. |
| We provide a formula for a stabilizing feedback law using a bounded control, under the assumption that an appropriate control-Lyapunov function is known. Such a feedback, smooth away from the origin and continuous everywhere, is known to exist via Artstein's Theorem. As in the unbounded-control case treated in a previous note, we provide an explicit and ``universal'' formula given by an algebraic function of Lie derivatives. In particular, we extend to the bounded case the result that the feedback can be chosen analytic if the Lyapunov function and the vector fields defining the system are analytic. |
| This paper shows the existence of a finite neural network, made up of sigmoidal neurons, which simulates a universal Turing machine. It is composed of less than 100,000 synchronously evolving processors, interconnected linearly. High-order connections are not required. (Note: this paper was placed here by special request. The results in this paper have been by now improved considerably: see the JCSS pape which among other aspects provides a polynomial time simulation. This paper, based on a unary encoding, results in an exponential slowdown). |
| Feedforward nets with sigmoidal activation functions are often designed by minimizing a cost criterion. It has been pointed out before that this technique may be outperformed by the classical perceptron learning rule, at least on some problems. In this paper, we show that no such pathologies can arise if the error criterion is of a threshold LMS type, i.e., is zero for values ``beyond'' the desired target values. More precisely, we show that if the data are linearly separable, and one considers nets with no hidden neurons, then an error function as above cannot have any local minima that are not global. In addition, the proof gives the following stronger result, under the stated hypotheses: the continuous gradient adjustment procedure is such that from any initial weight configuration a separating set of weights is obtained in finite time. This is a precise analogue of the Perceptron Learning Theorem. The results are then compared with the more classical pattern recognition problem of threshold LMS with linear activations, where no spurious local minima exist even for nonseparable data: here it is shown that even if using the threshold criterion, such bad local minima may occur, if the data are not separable and sigmoids are used. keywords = { neural networks , feedforward neural nets }, |
| 1990 |
| This paper surveys some well-known facts as well as some recent developments on the topic of stabilization of nonlinear systems. (NOTE: figures are not included in file; they were pasted-in.) |
| Results are given on the integrability of certain distributions which arise from smoothly parametrized families of diffeomorphisms acting on manifolds. Applications to control problems and in particular to the problem of sampling are discussed. Pages 42-50 apply the results to the control of continuous time systems; this is an exposition of some of the basic results of the Lie algebraic accessibility theory. |
| This paper presents a geometric study of controllability for discrete-time nonlinear systems. Various accessibility properties are characterized in terms of Lie algebras of vector fields. Some of the results obtained are parallel to analogous ones in continuous-time, but in many respects the theory is substantially different and many new phenomena appear. |
| Previous results about input to state stabilizability are shown to hold even for systems which are not linear in controls, provided that a more general type of feedback be allowed. Applications to certain stabilization problems and coprime factorizations, as well as comparisons to other results on input to state stability, are also briefly discussed.d local minima may occur, if the data are not separable and sigmoids are used. |
| We prove that for any family of n-dimensional controllable linear systems, continuously parameterized by up to three parameters, and for any continuous selection of n eigenvalues (in complex conjugate pairs), there is some dynamic controller of dimension 3n which is itself continuously parameterized and for which the closed-loop eigenvalues are these same eigenvalues, each counted 4 times. An analogous result holds also for smooth parameterizations. |
| 1989 |
| We investigate the effect of sampling on linearization for continuous time systems. It is shown that the discretized system is linearizable by state coordinate change for an open set of sampling times if and only if the continuous time system is linearizable by state coordinate change. Also, it is shown that linearizability via digital feedback imposes highly nongeneric constraints on the structure of the plant, even if this is known to be linearizable with continuous-time feedback. |
| This note presents an explicit proof of the theorem - due to Artstein - which states that the existence of a smooth control-Lyapunov function implies smooth stabilizability. Moreover, the result is extended to the real-analytic and rational cases as well. The proof uses a "universal" formula given by an algebraic function of Lie derivatives; this formula originates in the solution of a simple Riccati equation. |
| Every dichotomy on a 2k-point set in Rn can be implemented by a neural net with a single hidden layer containing k sigmoidal neurons. If the neurons were of a hardlimiter (Heaviside) type, 2k-1 would be in general needed. |
| This paper shows that coprime right factorizations exist for the input to state mapping of a continuous time nonlinear system provided that the smooth feedback stabilization problem be solvable for this system. In particular, it follows that feedback linearizable systems admit such factorizations. In order to establish the result a Lyapunov-theoretic definition is proposed for bounded input bounded output stability. The main technical fact proved relates the notion of stabilizability studied in the state space nonlinear control literature to a notion of stability under bounded control perturbations analogous to those studied in operator theoretic approaches to systems; it states that smooth stabilization implies smooth input-to-state stabilization. (Note: This is the original ISS paper, but the ISS results have been much improved in later papers. The material on coprime factorizations is still of interest, but the 89 CDC paper has some improvements and should be read too.) |
| We give an example of a neural net without hidden layers and with a sigmoid transfer function, together with a training set of binary vectors, for which the sum of the squared errors, regarded as a function of the weights, has a local minimum which is not a global minimum. The example consists of a set of 125 training instances, with four weights and a threshold to be learnt. We do not know if substantially smaller binary examples exist. |
| We prove that the angular velocity equations can be smoothly stabilized with a single torque controller for bodies having an axis of symmetry. This complements a recent result of Aeyels and Szafranski. |
| This note establishes a result linking algebraically coprime factorizations of transfer matrices of delay systems to approximately coprime factorizations in the sense of distributions. The latter have been employed by the second author in the study of function-space controllability for such systems. |
| This paper establishes the equality of the observation spaces defined by means of piecewise constant controls with those defined in terms of differentiable controls. |
| 1988 |
| This paper studies accessibility (weak controllability) of bilinear systems under constant sampling rates. It is shown that the property is preserved provided that the sampling period satisfies a condition related to the eigenvalues of the autonomous dynamics matrix. This condition generalizes the classical Kalman-Ho-Narendra criterion which is well known in the linear case, and which, for observability, results in the classical Nyquist theorem. |
| This paper provides further results about the equilinearization method of control design recently introduced by the author. A simplified derivation of the controller is provided, as well as a theorem on local stabilization along reference trajectories. |
| For continuous time analytic input/output maps, the existence of a singular differential equation relating derivatives of controls and outputs is shown to be equivalent to bilinear realizability. A similar result holds for the problem of immersion into bilinear systems. The proof is very analogous to that of the corresponding, and previously known, result for discrete time. |
| The present article compares the difficulties of deciding controllability and accessibility. These are standard properties of control systems, but complete algebraic characterizations of controllability have proved elusive. We show in particular that for subsystems of bilinear systems, accessibility can be decided in polynomial time, but controllability is NP-hard. |
| This paper concerns itself with the existence of open-loop control generators for nonlinear (continuous-time) systems. The main result is that, under relatively mild assumptions on the original system, and for each fixed compact subset of the state space, there always exists one such generator. This is a new system with the property that the controls it produces are sufficiently rich to preserve complete controllability along nonsingular trajectories. General results are also given on the continuity and differentiability of the input to state mapping for various p-norms on controls, as well as a comparison of various nonlinear controllability notions. |
| 1987 |
| Explicit equations are given for the moduli space of framed instantons as a quasi-affine variety, based on the representation theory of noncommutative power series, or equivalently, the minimal realization theory of bilinear systems. |
| A nonlinear controllable plant, under mild technical conditions, admits a precompensator with the following property: along control trajectories joining pairs of states, the composite system (precompensator plus plant) is, up to first order, isomorphic to a parallel connection of integrators. |
| A book review which also provides a quick introduction to questions of stability and positivity of multivariable polynomials for 2D and spatially-distributed systems. |
| 1986 |
| This paper proposes a notion of smooth action on a manifold, and establishes a general integrability result for certain associated distributions. As corollaries, various classical and new results on manifold structures of orbits are established, and the main theorem on preservation of transitivity under sampling is shown to be a simple consequence. |
| New results are given on the pole-shifting problem for commutative rings, and these are then applied to conclude that rings of continuous, smooth, or real-analytic functions on a manifold X are PA rings if and only if X is one-dimensional. |
| Weak controllability of bilinear systems is preserved under sampling provided that the sampling period satisfies a condition related to the eigenvalues of the autonomous dynamics matrix. This condition generalizes the classical Kalman-Ho-Narendra criterion which is well known in the linear case. |
| We present various comments on a question about systems over rings posed in a recent note by Sharma, proving that a ring R is pole-assignable if and only if, for every reachable system (F,G), G contains a rank-one summand of the state space. We also provide a generalization to deal with dynamic feedback. |
| A controller is shown to exist, universal for the family of all systems of fixed dimension n, and m controls, which stabilizes those systems that are stabilizable, if certain gains are large enough. The controller parameters are continuous, in fact polynomial, functions of the entries of the plant. As a consequence, a result is proved on polynomial stabilization of families of systems. |
| 1985 |
| This paper provides an introduction to definitions and known facts relating to the stabilization of parametrized families of linear systems using static and dynamic controllers. New results are given in the rational and polynomial cases. |
| Let Ul, U2, ... be a sequence of observed random variables and (T1(U1),T2(Ul,U2),...) be a corresponding sequence of sufficient statistics (a sufficient sequence). Under certain regularity conditions, the sufficient sequence defines the input/output map of a time-varying, discrete-time nonlinear system. This system provides a recursive way of updating the sufficient statistic as new observations are made. Conditions are provided assuring that such a system evolves in a state space of minimal dimension. Several examples are provided to illustrate how this notion of dimensional minimality is related to other properties of sufficient sequences. The results can be used to verify the form of the minimum dimension (discrete-time) nonlinear filter associated with the autoregressive parameter estimation problem. |
| The k-th alternation level of the theory of real numbers under addition and order is log-complete for the k-th level of the polynomial hierarchy. |
| 1984 |
| We continue here our investigation into the preservation of structural properties under the sampling of nonlinear systems. The main new result is that, under minimal hypothesis, a controllable system always satisfies a strong type of approximate sampled controllability. |
| In this paper we are concerned with the theory of second order (linear) innovations for discrete random processes. We show that of existence of a finite dimensional linear filter realizing the mapping from a discrete random process to its innovations is equivalent to a certain semiiseparable structure of the covariance sequence of the process. We also show that existence of a finite dimensional realization (linear or nonlinear) of the mapping from a process to its innovations implies that the process have this serniseparable covariance sequence property. In particular, for a stationary random process, the spectral density function must be rational. |
| A notion of local observability, which is natural in the context of nonlinear input/output regulation. is introduced. A simple characterization is provided, a comparison is made with other local nonlinear observability definitions. and its behavior under constant-rate sampling is analyzed. |
| In this note we present an algebraic approach to the proof that a linear system with matrices (A,B) is null-controllable using bounded inputs iff it is null-controllable (with unbounded inputs) and all eigenvalues of A have nonpositive real parts (continuous time) or magnitude not greater than one (discrete time). We also give the analogous results for the asymptotic case. Finally, we give an interpretation of these results in the context of local nonlinear controllability. |
| A polynomially parametrized family of continuous-time controllable linear systems is always stabilizable by polynomially parametrized feedback. |
| 1983 |
| This note studies the preservation of controllability (and other properties) under sampling of a nonlinear system. More detailed results are obtained in the cases of analytic systems and of systems with finite dimensional Lie algebras. |
| Given a continuous-time family of finite dimensional single input linear systems, parametrized polynomially, such that each of the systems in the family is controllable, there exists a polynomially parametrized control law making each of the systems in the family stable. |
| It is shown that a control system in Rn is asymptotically controllable to the origin if and only if there exists a positive definite continuous functional of the states whose derivative can be made negative by appropriate choices of controls. |
| 1982 |
| This paper was a conference version of the SIAM paper that introduced the idea of control-Lyapunov functions for arbitrary nonlinear systems. (The journal paper was submitted in 1981 but only published in 1983.) |
| Various types of transfer matrix factorizations are of interest when designing regulators for generalized types of linear systems (delay differential. 2-D, and families of systems). This paper studies the existence of stable and of stable proper factorizations, in the context of the thery of systems over rings. Factorability is related to stabilizability and detectability properties of realizations of the transfer matrix. The original formulas for coprime factorizations (which are valid, in particular, over the field of reals) were given in this paper. |
| Algebraic study of functions defined by piecewise linear (generally discontinuous) equations. File obtained by scanning a reprint. |
| 1981 |
| Problems that appear in trying to extend linear control results to systems over rings R have attracted considerable attention lately. This interest has been due mainly to applications-oriented motivations (in particular, dealing with delay-differential equations), and partly to a purely algebraic interest. Given a square n-matrix F and an n-row matrix G. pole-shifting problems consist in obtaining more or less arbitrary characteristic polynomials for F+GK, for suitable ("feedback") matrices K. A review of known facts is given, various partial results are proved, and the case n=2 is studied in some detail. |
| A paper that introduces a separation principle for general finite dimensional analytic continuous-time systems, proving the equivalence between existence of an output regulator (which is an abstract dynamical system) and certain "0-detectability" and asymptotic controllability assumptions. |
| Development of an approach to nonlinear control based on mixtures of linear systems and finite automata. File obtained by scanning. |
| 1980 |
| This paper proposes an approach to the problem of establishing the existence of observers for deterministic dynamical systems. This approach differs from the standard one based on Luenberger observers in that the observation error is not required to be Markovian given the past input and output data. A general abstract result is given, which special- izes to new results for parametrized families of linear systems, delay systems and other classes of systems. Related problems of feedback control and regulation are also studied. |
| Necessary and sufficient conditions are given for a matrix over a ring to admit a Moore-Penrose generalized inverse in a weak sense. (Attached is also a Math Review with additional comments on strong inverses.) |
| The family of m-input, n-dimensional linear systems can be globally Identified with a generic input sequence of length 2mn. This bound is the best possible. A best bound is proved also for a corresponding local identification problem. |
| 1979 |
| This paper studies the problem of obtaining minimal realizations of linear input/output maps defined over rings. In particular, it is shown that, contrary to the case of systems over fields, it is in general impossible to obtain realizations whose dimiension equals the rank of the Hankel matrix. A characterization is given of those (Noetherian) rings over which realizations of such dimensions can he always obtained, and the result is applied to delay-differential systems. |
| An abstract operator approach is introduced, permitting a unified study of discrete- and continuous-time linear control systems. As an application, an algorithm is given for deciding if a linear system can be built from any fixed set of linear components. Finally, a criterion is given for reachability of the abstract systems introduced, giving thus a unified proof of known reachability results for discrete-time, continuous-time, and delay-differential systems. |
| Different notions of observability are compared for systems defined by polynomial difference equations. The main result states that, for systems having the standard property of (multiple-experiment initial-state) observability, the response to a generic input sequence is sufficient for final-state determination. Some remarks are made on results for nonpolynomial and/or continuous-time systems. An identifiability result is derived from the above. |
| A state-space realization theory is presented for a wide class of discrete time input/output behaviors. Although In many ways restricted, this class does include as particular cases those treated in the literature (linear, multilinear, internally bilinear, homogeneous), as well as certain nonanalytic nonlinearities. The theory is conceptually simple, and matrix-theoretic algorithms are straightforward. Finite-realizability of these behaviors by state-affine systems is shown to be equivalent both to the existence of high-order input/output equations and to realizability by more general types of systems. |
| 1978 |
| The inner rank of an m x n matrix A over a ring is defined as the least integer r such that A can be expressed as the product of an m x r and an r x n matrix. For example, over a (skew) field this concept coincides with the usual notion of rank. This notion is studied in this paper, and is related to Sylvester's law of nullity and work by P.M. Cohn. |
| A construction is given to obtain first-order equation representations of a multidimensional filter, whose dimension is of the order of the degree of the transfer function. |
| This paper deals with observability properties of realizations of linear response maps defined over commutative rings. A characterization is given for those maps which admit realizations which are simultaneously reachable and observable in a strong sense. Applications are given to delay-differential systems. |
| 1977 |
| A lattice characterization is given for the class of minimal-rank realizations of a linear response map defined over a (commutative) Noetherian integral domain. As a corollary, it is proved that there are only finitely many nonisomorphic minimal-rank realizations of a response map over the integers, while for delay -differential systems these are classified by a lattice of subspaces of a finite-dimensional real vector space. |
| It is well known that principal rings are strong Fatou rings. We construct here a more general type of strong Fatou rings. We also prove that the monoid of divisor classes of a noetherian strong Fatou ring contains only the zero element, and that the dimension of such a ring is at most two. |
| 1976 |
| An elementary presentation is given of some of the main motivations and known results on linear systems over rings, including questions of realization and control. The analogies and differences with the more standard case of systems over fields are emphasized throughout. |
| Two classes of rings which occur in linear system theory are introduced and compared. Characterizations of one of them are given in terms, of integral extensions (every finite extension of R is integral) and Cayley--Hamilton type matrix condition. A comparison is made in the case of no zero-divisors with Ore domains. |
| Considered here are a type of discrete-time systems which have algebraic constraints on their state set and for which the state transitions are given by (arbitrary) polynomial functions of the inputs and state variables. The paper studies reachability in bounded time, the problem of deciding whether two systems have the same external behavior by applying finitely many inputs, the fact that finitely many inputs (which can be chosen quite arbitrarily) are sufficient to separate those states of a system which are distinguishable, and introduces the subject of realization theory for this class of systems. |
| 1975 |
| This paper studies some problems appearing in the extension of the theory of linear dynamical systems to the case in which parameters are taken from noncommutative rings. Purely algebraic statements of some of the problems are also obtained. Through systems defined by operator rings, the theory of linear systems over rings may be applied to other areas of automata and control theory; several such applications are outlined. |
| Some results are given in the theory of rational power series over a broad class of semirings. In particular, it is shown that for unambiguous sets the notion of rationality is independent of the semiring over which representations are defined. The undecidability of the rationality of probabilistic word functions is also established. |
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