Conference articles |
2017 |
Deterministic models remain the most common option for modeling gene regulatory networks even when the underlying assumptions of high copy numbers and fast promoter kinetics are unsatisfied. Here, we analyze a widely studied differentiation network motif known as the PU.1-GATA-1 circuit and we show that an ODE model of the biomolecular reactions consistent with known biology is incapable of exhibiting multistability, a defining behaviour for such a network. Thus, we consider the chemical master equation model of the same biomolecular reactions and using results recently developed by the authors, we analytically construct the stationary distribution. We show that this distribution is indeed capable of admitting a multitude of modes. We illustrate the results with a numerical example. |
2016 |
In this article, we show that scale-invariant systems, as well as systems invariant with respect to other input transformations, can realize nonlinear differential operators: when excited by inputs obeying functional forms characteristic for a given class of invariant systems, the systems' outputs converge to constant values directly quantifying the speed of the input. |
Combining in-vivo experiments with system identification methods, we determine a simple model of aerotaxis in B. subtilis, and we subsequently employ this model in order to compute the sequence of oxygen gradients needed in order to achieve set-point regulation with respect to a signal tracking the center of mass of the bacterial population. We then successfully validate both the model and the control scheme, by showing that in-vivo positioning control can be achieved via the application of the precomputed inputs in-vivo in an open-loop configuration. |
Applying Modular Response Analysis to a synthetic gene circuit, which was introduced in a recent paper by the authors, leads to the inference of a nontrivial "ghost" regulation edge which was not explicitly engineered into the network and which is, in fact, not immediately apparent from experimental measurements. One may thus hypothesize that this ghost regulatory effect is due to competition for resources. A mathematical model is proposed, and analyzed in closed form, that lends validation to this hypothesis. |
2015 |
This paper adopts a contraction approach to the analysis of the tracking properties of dynamical systems under high gain feedback when subject to inputs with bounded derivatives. It is shown that if the tracking error dynamics are contracting, then the system is input to output stable with respect to the input signal derivatives and the output tracking error. As an application, it iss hown that the negative feedback connection of plants composed of two strictly positive real LTI subsystems in cascade can follow external inputs with tracking errors that can be made arbitrarily small by applying a sufficiently large feedback gain. We utilize this result to design a biomolecular feedback for a synthetic genetic sensor to make it robust to variations in the availability of a cellular resource required for protein production. |
2014 |
Contraction theory provides an elegant way to analyze the behaviors of certain nonlinear dynamical systems. Under sometimes easy to check hypotheses, systems can be shown to have the incremental stability property that trajectories converge to each other. The present paper provides a self-contained introduction to some of the basic concepts and results in contraction theory, discusses applications to synchronization and to reaction-diffusion partial differential equations, and poses several open questions. |
In this paper, we sketch recent results for synchronization in a network of identical ODE models which are diffusively interconnected. In particular, 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. |
This conference paper (a) summarizes material from "A fundamental limitation to fold-change detection by biological systems with multiple time scales" (IET Systems Biology 2014) and presents additional remarks regarding (b) expansion techniques to compute FCD error and (c) stochastic adaptation and FCD |
This paper studies model-based estimation methods of a rate of a nonhomogeneous Poisson processes that describes events arising from modeling biological phenomena in which discrete events are measured. We describe an approach based on observers and Kalman filters as well as preliminary simulation results, and compare these to other methods (not model-based) in the literature. The problem is motivated by the question of identification of internal states from neural spikes and bacterial tumbling behavior. |
We introduce three forms of generalized contraction~(GC). Roughly speaking, these are motivated by allowing contraction to take place after small transients in time and/or amplitude. Indeed, contraction is usually used to prove asymptotic properties, like convergence to an attractor or entrainment to a periodic excitation, and allowing initial transients does not affect this asymptotic behavior. We provide sufficient conditions for GC, and demonstrate their usefulness using examples of systems that are not contractive, with respect to any norm, yet are~GC. |
2013 |
Recent experimental work has shown that transient E. coli chemotactic response is unchanged by a scaling of its ligand input signal (fold change detection, or FCD), and this is in agreement with earlier mathematical predictions. However, this prediction was based on certain particular assumptions on the structure of the chemotaxis pathway. In this work, we begin by showing that behavior similar to FCD can be obtained under weaker conditions on the system structure. Namely, we show that under relaxed conditions, a scaling of the chemotaxis system's inputs leads to a time scaling of the output response. We propose that this may be a contributing factor to the robustness of the experimentally observed FCD. We further show that FCD is a special case of this time scaling behavior for which the time scaling factor is unity. We then proceed to extend the conditions for output time scaling to more general adapting systems, and demonstrate this time scaling behavior on a published model of the chemotaxis pathway of the bacterium Rhodobacter sphaeroides. This work therefore provides examples of how robust biological behavior can arise from simple yet realistic conditions on the underlying system structure. |
We present conditions that guarantee spatial uniformity in diffusively-coupled systems. Diffusive coupling is a ubiquitous form of local interaction, arising in diverse areas including multiagent coordination and pattern formation in biochemical networks. The conditions we derive make use of the Jacobian matrix and Neumann eigenvalues of elliptic operators, and generalize and unify existing theory about asymptotic convergence of trajectories of reaction-diffusion partial differential equations as well as compartmental ordinary differential equations. We present numerical tests making use of linear matrix inequalities that may be used to certify these conditions. We discuss an example pertaining to electromechanical oscillators. The paper's main contributions are unified verifiable relaxed conditions that guarantee synchrony. |
2012 |
This paper presents techniques for finding out what type of solutions are compatible with a given sign pattern of interactions between state/input variables once the input behaviour is also known. By ``type'' of solutions we essentially refer to the sequence of upwards or downwards segments that variables can exhibit (essentially sign-patterns of variables derivatives) once input profiles are also specified. A concrete experimental example of how such techniques can invalidate models is also provided. |
Conference version of ``Stability certification of large scale stochastic systems using dissipativity of subsystems''. |
This is a conference version of ``A characterization of scale invariant responses in enzymatic networks. |
2011 |
This note introduces a small-gain result for interconnected MIMO orthant-monotone systems for which no matching condition is required between the partial orders in input and output spaces of the considered subsystems. 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 corresponded to positive-feedback or negative feedback cases. We relax those results by allowing arbitrary orthant orders. |
This paper studies invariance with respect to symmetries in sensory fields, a particular case of which, scale invariance, has recently been found in certain eukaryotic as well as bacterial cell signaling systems. We describe a necessary and sufficient characterization of symmetry invariance in terms of equivariant transformations, show how this characterization helps find all possible symmetries in standard models of biological adaptation, and discuss symmetry-invariant searches. |
2010 |
Preliminary conference version of ''A contraction approach to the hierarchical analysis and design of networked systems''. |
Summarized conference version of ``Modularity, retroactivity, and structural identification''. |
This paper presents a hierarchical principle for object recognition and its application to automatically classify developmental stages of C. elegans animals from a population of mixed stages. The system is in current use in a functioning C. elegans laboratory and has processed over two hundred thousand images for lab users. |
2009 |
This is a very summarized version ofthe first part of the paper "Persistence results for chemical reaction networks with time-dependent kinetics and no global conservation laws". |
See abstract and link to pdf in entry for Journal paper. |
See abstract and link to pdf in entry for Journal paper. |
2008 |
The proper function of many biological systems requires that external perturbations be detected, allowing the system to adapt to these environmental changes. It is now well established that this dual detection and adaptation requires that the system have an internal model in the feedback loop. In this paper we relax the requirement that the response of the system adapt perfectly, but instead allow regulation to within a neighborhood of zero. We show, in a nonlinear setting, that systems with the ability to detect input signals and approximately adapt require an approximate model of the input. We illustrate our results by analyzing a well-studied biological system. These results generalize previous work which treats the perfectly adapting case. |
Conference version of paper "Conditions for global stability of monotone tridiagonal systems with negative feedback" |
2007 |
This tutorial paper presents an introduction to systems and synthetic molecular biology. It provides an introduction to basic biological concepts, and describes some of the techniques as well as challenges in the analysis and design of biomolecular networks. |
For distributed systems with a cyclic interconnection structure, a global stability result is shown to hold if the secant criterion is satisfied. |
2006 |
This conference paper presented a version of an approximate internal model principle, for linear systems. A subsequent paper at the IFAC 2008 conference improved on this result by extending it to a class of nonlinear systems. |
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 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 structure (e.g., mass-action kinetics) of the dynamical equations involved, and relying only on stoichiometric constraints. The key idea is to find a suitable set of coordinates under which the resulting system is cooperative. 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 work is concerned with the study of the robustness and fragility of gene regulation networks to variability in the timescales of the distinct biological processes involved. It explores and compares two methods: introducing asynchronous updates in a Boolean model, or integrating the Boolean rules in a continuous, piecewise linear model. As an example, the segment polarity network of the fruit fly is analyzed. A theoretical characterization is given of the model's ability to predict the correct development of the segmented embryo, in terms of the specific timescales of the various regulation interactions. |
This paper deals with global convergence to equilibria, and in particular Hirsch's generic convergence theorem for strongly monotone systems, for singular perturbations of monotone systems. |
This paper deals with global convergence to equilibria, and in particular Hirsch's generic convergence theorem for strongly monotone systems, for singular perturbations of monotone systems. |
2005 |
2004 |
We show how certain properties of Goldbeter's original 1995 model for circadian oscillations can be proved mathematically. We establish global asymptotic stability, and in particular no oscillations, if the rate of transcription is somewhat smaller than that assumed by Goldbeter, but, on the other hand, this stability persists even under arbitrary delays in the feedback loop. We are mainly interested in illustrating certain mathematical techniques, including the use of theorems concerning tridiagonal cooperative systems and the recently developed theory of monotone systems with inputs and outputs. |
Monotone systems are dynamical systems for which the flow preserves a partial order. Some applications will be briefly reviewed in this paper. Much of the appeal of the class of monotone systems stems from the fact that roughly, most solutions converge to the set of equilibria. However, this usually requires a stronger monotonicity property which is not always satisfied or easy to check in applications. Following work of J.F. Jiang, we show that monotonicity is enough to conclude global attractivity if there is a unique equilibrium and if the state space satisfies a particular condition. The proof given here is self-contained and does not require the use of any of the results from the theory of monotone systems. We will illustrate it on a class of chemical reaction networks with monotone, but otherwise arbitrary, reaction kinetics. |
We investigate the problem of searching for a hidden target in a bounded region by an autonomous agent that is only able to use limited local sensory information. We propose 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. A solution to the original problem is then 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. |
In this paper we investigate 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. We formalize a discrete version of the problem as a "reward-collecting" path problem and provide efficient approximation algorithms for various cases. |
2003 |
2002 |
The fundamental Filippov--Wazwski Relaxation Theorem states that the solution set of an initial value problem for a locally Lipschitz inclusion is dense in the solution set of the same initial value problem for the corresponding relaxation inclusion on compact intervals. In a recent paper of ours, a complementary result was provided for inclusions with finite dimensional state spaces which says that the approximation can be carried out over non-compact or infinite intervals provided one does not insist on the same initial values. This note extends the infinite-time relaxation theorem to the inclusions whose state spaces are Banach spaces. To illustrate the motivations for studying such approximation results, we briefly discuss a quick application of the result to output stability and uniform output stability properties. |
For systems whose output is to be kept small (thought of as an error output), the notion of input to output stability (IOS) arises. Alternatively, when considering a system whose output is meant to provide information about the state (i.e. a measurement output), one arrives at the detectability notion of output to state stability (OSS). Combining these concepts, one may consider a system with two types of outputs, an error and a measurement. This leads naturally to a notion of partial detectability which we call measurement to error stability (MES). This property characterizes systems in which the error signal is detectable through the measurement signal. This paper provides a partial Lyapunov characterization of the MES property. A closely related property of stability in three measures (SIT) is introduced, which characterizes systems for which the error decays whenever it dominates the measurement. The SIT property is shown to imply MES, and the two are shown to be equivalent under an additional boundedness assumption. A nonsmooth Lyapunov characterization of the SIT property is provided, which yields the partial characterization of MES. The analysis is carried out on systems described by differential inclusions -- implicitly incorporating a disturbance input with compact value-set. |
2001 |
2000 |
Experimental data show that biological synapses are dynamic, i.e., their weight changes on a short time scale by several hundred percent in dependence of the past input to the synapse. In this article we explore the consequences that this synaptic dynamics entails for the computational power of feedforward neural networks. It turns out that even with just a single hidden layer such networks can approximate a surprisingly large large class of nonlinear filters: all filters that can be characterized by Volterra series. This result is robust with regard to various changes in the model for synaptic dynamics. Furthermore we show that simple gradient descent suffices to approximate a given quadratic filter by a rather small neural system with dynamic synapses. |
1999 |
This paper studies the input-to-state stability (ISS) property for discrete-time nonlinear systems. We show that many standard ISS results may be extended to the discrete-time case. More precisely, we provide a Lyapunov-like sufficient condition for ISS, and we show the equivalence between the ISS property and various other properties, as well as provide a small gain theorem. |
This paper continues the investigation of the recently introduced integral version of input-to-state stability (iISS). We study the problem of designing control laws that achieve iISS disturbance attenuation. The main contribution is an appropriate concept of control Lyapunov function (iISS-CLF), whose existence leads to an explicit construction of such a control law. The results are compared and contrasted with the ones available for the ISS case. |
1998 |
1997 |
We showned in another recent paper that any asymptotically controllable system can be stabilized by means of a certain type of discontinuous feedback. The feedback laws constructed in that work are robust with respect to actuator errors as well as to perturbations of the system dynamics. A drawback, however, is that they may be highly sensitive to errors in the measurement of the state vector. This paper addresses this shortcoming, and shows how to design a dynamic hybrid stabilizing controller which, while preserving robustness to external perturbations and actuator error, is also robust with respect to measurement error. This new design relies upon a controller which incorporates an internal model of the system driven by the previously constructed feedback. |
This paper deals with a notion of "input to output stability (IOS)", which formalizes the idea that outputs depend in an "aymptotically stable" manner on inputs, while internal signals remain bounded. When the output equals the complete state, one recovers the property of input to state stability (ISS). When there are no inputs, one has a generalization of the classical concept of partial stability. The main results provide Lyapunov-function characterizations of IOS. |
1996 |
Contains a proof of a technical step, which was omitted from the journal paper due to space constraints |
1995 |
We suggest that a very natural mathematical framework for the study of dissipation -in the sense of Willems, Moylan and Hill, and others- is that of indefinite quasimetric spaces. Several basic facts about dissipative systems are seen to be simple consequences of the properties of such spaces. Quasimetric spaces provide also one natural context for optimal control problems, and even for "gap" formulations of robustness. |
This paper deals with the computational complexity, and in some cases undecidability, of several problems in nonlinear control. The objective is to compare the theoretical difficulty of solving such problems to the corresponding problems for linear systems. In particular, the problem of null-controllability for systems with saturations (of a "neural network" type) is mentioned, as well as problems regarding piecewise linear (hybrid) systems. A comparison of accessibility, which can be checked fairly simply by Lie-algebraic methods, and controllability, which is at least NP-hard for bilinear systems, is carried out. Finally, some remarks are given on analog computation in this context. |
Invited talk at the 1994 ICM. Paper deals with the notion of observables for nonlinear systems, and their role in realization theory, minimality, and several control and path planning questions. |
It is shown that the existence of a continuous control-Lyapunov function (CLF) is necessary and sufficient for null asymptotic controllability of nonlinear finite-dimensional control systems. The CLF condition is expressed in terms of a concept of generalized derivative (upper contingent derivative). This result generalizes to the non-smooth case the theorem of Artstein relating closed-loop feedback stabilization to smooth CLF's. It relies on viability theory as well as optimal control techniques. A "non-strict" version of the results, analogous to the LaSalle Invariance Principle, is also provided. |
Previous characterizations of ISS-stability are shown to generalize without change to the case of stability with respect to sets. Some results on ISS-stabilizability are mentioned as well. |
1994 |
1993 |
This paper concerns recurrent networks x'=s(Ax+Bu), y=Cx, where s is a sigmoid, in both discrete time and continuous time. The paper establishes parameter identifiability under stronger assumptions on the activation than in "For neural networks, function determines form", but on the other hand deals with arbitrary (nonzero) initial states. |
We present a formula for a stabilizing feedback law under the assumption that a piecewise smooth control-Lyapunov function exists. The resulting feedback is continuous at the origin and smooth everywhere except on a hypersurface of codimension 1, assuming that certain transversality conditions are imposed there. |
This paper deals with analog circuits. It establishes the finiteness of VC dimension, teaching dimension, and several other measures of sample complexity which arise in learning theory. It also shows that the equivalence of behaviors, and the loading problem, are effectively decidable, modulo a widely believed conjecture in number theory. The results, the first ones that are independent of weight size, apply when the gate function is the "standard sigmoid" commonly used in neural networks research. The proofs rely on very recent developments in the elementary theory of real numbers with exponentiation. (Some weaker conclusions are also given for more general analytic gate functions.) Applications to learnability of sparse polynomials are also mentioned. |
This paper develops in detail an explicit design for control under saturation limits for the linearized equations of longitudinal flight control for an F-8 aircraft, and tests the obtained controller on the original nonlinear model. |
1992 |
A conference paper. Placed here because it was requested, but contains little that is not also contained in the survey on neural nets mentioned above. |
1991 |
This paper shows how to extend recent results of Colonius and Kliemann, regarding connections between chaos and controllability, from continuous to discrete time. The extension is nontrivial because the results all rely on basic properties of the accessibility Lie algebra which fail to hold in discrete time. Thus, this paper first develops further results in nonlinear accessibility, and then shows how a theorem can be proved, which while analogous to the one given in the work by Colonius and Klieman, also exhibits some important differences. A counterexample is used to show that the theorem given in continuous time cannot be generalized in a straightforward manner. |
This paper studies various types of input/output representations for nonlinear continuous time systems. The algebraic and analytic i/o equations studied in previous papers by the authors are generalized to integral and integro-differential equations, and an abstract notion is also considered. New results are given on generic observability, and these results are then applied to give conditions under which that the minimal order of an equation equals the minimal possible dimension of a realization, just as with linear systems but in contrast to the discrete time nonlinear theory. |
1990 |
Given a 2-coloring of the vertices of a regular n-gon P, how many parallel lines are needed to separate the vertices into monochromatic subsets? We prove that floor(n/2) is a tight upper bound, and also provide an O(n log n) time algorithm to determine the direction that gives the minimum number of lines. If the polygon is a non-regular convex polygon, then n-3 lines may be necessary, while n-2 lines always suffice. This problem arises in machine learning and has implications about the representational capabilities of some neural networks. |
This paper shows the existence of (nonlinear) smooth dynamic feedback stabilizers for linear time invariant systems under input constraints, assuming only that open-loop asymptotic controllability and detectability hold. |
1989 |
This paper describes how notions of input-to-state stabilization are useful when stabilizing cascades of systems. The simplest result along these lines is local, and it states that a cascade of two locally asymptotically stable systems is again asystable. A global result is obtained if both systems have the origin as a globally asymptotically stable state and the "converging input bounded state" property holds for the second system. Relations to input to state stability and the "bounded input bounded state" property as mentioned as well. |
This paper introduces a subclass of Hamiltonian control systems motivated by mechanical models. It deals with time-optimal control problems. The main results characterize regions of the state space where singular trajectories cannot exist, and provide high-order conditions for optimality. |
Coprime right fraction representations are obtained for nonlinear systems defined by differential equations, under assumptions of stabilizability and detectability. A result is also given on left (not necessarily coprime) factorizations. |
1988 |
It has been known for a long time that certain controllability properties are more difficult to verify than others. This article makes this fact precise, comparing controllability with accessibility, for a wide class of nonlinear continuous time systems. The original contribution is in formalizing this comparison in the context of computational complexity. (This paper placed here by special request.) |
1987 |
1986 |
This paper studies time-optimal control questions for a certain class of nonlinear systems. This class includes a large number of mechanical systems, in particular, rigid robotic manipulators with torque constraints. As nonlinear systems, these systems have many properties that are false for generic systems of the same dimensions. |
1985 |
We consider the problem of estimating a signal, which is known -- or assumed -- to be constant on each of the members of a partition of a square lattice into m unknown regions, from the observation of the signal plus Gaussian noise. This is a nonlinear estimation problem, for which it is not appropriate to use the conditional expectation as the estimate. We show that, at least in principle, the "maximum iikelihood estimator" (MLE) proposed by Geman and Geman lends itself to numerical computation using the annealing algorithm. We argue that the MLE by itself can be, under certain conditions (low signal to noise ratio), a very unsatisfactory estimator, in that it does worse than just deciding that the signal was zero. However, if combined with a rule which we propose, for deciding when to use and when to ignore it, the MLE can provide a reasonable suboptimal estimator. We then discuss preliminary numerical data obtained using the annealing method. These results indicate that: (a) the annealing algorithm performs remarkably well, and (b) a criterion can be formulated in terms of quantities computed from the observed image (without using a priori knowledge of the signal-to-noise ratio) for deciding when to keep the MLE. |
1984 |
In the context of realization theory, conditions are given for the possibility of simulating a given discrete time system, using immersion and/or feedback, by linear or state-affine systems. |
1983 |
1982 |
This note addresses the following problem: Find conditions under which a continuous-time (nonlinear) system gives rise, under constant rate sampling, to a discrete-time system which satisfies the accessibility property. |
1981 |
1980 |
We show that, in general, it is impossible to stabilize a controllable system by means of a continuous feedback, even if memory is allowed. No optimality considerations are involved. All state spaces are Euclidean spaces, so no obstructions arising from the state space topology are involved either. For one dimensional state and input, we prove that continuous stabilization with memory is always possible. (This is an old conference paper, never published in journal form but widely cited nonetheless. Warning: file is very large, since it was scanned.) |
1978 |
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