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We present a new sufficient condition for finite-gain $L_2$ input-to-output stability of a networked system. The condition requires a matrix, that combines information on the $L_2$ gains of the sub-systems and their interconnections, to be discrete-time diagonally stable (DTDS). We show that the new result generalizes the standard small gain theorem for the negative feedback connection of two sub-systems. An important advantage of the new result is that known sufficient conditions for DTDS can be applied to derive sufficient conditions for networked input-to-output stability. We demonstrate this using several examples. We also derive a new necessary and sufficient condition for a matrix that is a rank one perturbation of a Schur diagonal matrix to be DTDS.

Multistationarity - the existence of multiple equilibrium points - is a common phenomenon in dynamical systems from a variety of fields, including neuroscience, opinion dynamics, systems biology, and power systems. A recently proposed generalization of contraction theory, called $k$-contraction, is a promising approach for analyzing the asymptotic behaviour of multistationary systems. In particular, all bounded trajectories of a time-invariant 2-contracting system converge to an equilibrium point, but the system may have multiple equilibrium points where more than one is locally stable. An important challenge is to study $k$-contraction in large-scale interconnected systems. Inspired by a recent small-gain theorem for 2-contraction by Angeli et al., we derive a new sufficient condition for 2-contraction of a feedback interconnection of two nonlinear dynamical systems. Our condition is based on (i) deriving new formulas for the 2-multiplicative [2-additive] compound of block matrices using block Kronecker products [sums], (ii) a hierarchical approach for proving standard contraction, and (iii) a network small-gain theorem for Metzler matrices. We demonstrate our results by deriving a simple sufficient condition for 2-contraction in a network of FitzHugh-Nagumo neurons.

The flow of a $k$-cooperative system maps the set of vectors with up to~$(k-1)$ sign variations to itself. In particular, $1$-cooperative systems are just cooperative systems. Strongly $2$-cooperative systems satisfy a strong \Poincare-Bendixson property: any bounded solution that evolves in a compact set containing no equilibria converges to a periodic orbit. For $3$-dimensional strongly $2$-cooperative nonlinear systems, we provide a sufficient condition that guarantees the existence of an invariant compact set in the state space that includes an attracting periodic orbit. We show that our theoretical results unify and generalize known results on the existence of a periodic solution in two well-known models in biochemistry, a 3D Goodwin oscillator model and the 3D Field-Noyes ordinary-differential-equation (ODE) model for the Belousov-Zhabotinskii reaction, while simplifying the proofs.

Given a time-series of noisy measured outputs of a dynamical system z[k], k=1...N, the Identifying Regulation with Adversarial Surrogates (IRAS) algorithm aims to find a non-trivial first integral of the system, namely, a scalar function g() such that g(z[i]) = g(z[j]), for all i,j. IRAS has been suggested recently and was used successfully in several learning tasks in models from biology and physics. Here, we give the first rigorous analysis of this algorithm in a specific setting. We assume that the observations admit a linear first integral and that they are contaminated by Gaussian noise. We show that in this case the IRAS iterations are closely related to the self-consistent-field (SCF) iterations for solving a generalized Rayleigh quotient minimization problem. Using this approach, we derive several sufficient conditions guaranteeing local convergence of IRAS to the correct first integral.

The totally asymmetric simple exclusion process (TASEP) is a stochastic model for the unidirectional dynamics of interacting particles on a $1$D-lattice that is much used in systems biology and statistical physics. Its master equation describes the evolution of the probability distribution on the state space. The size of the master equation grows exponentially with the length of the lattice. It is known that the complexity of the system may be reduced using mean field approximations. We provide a rigorous derivation and a stochastic interpretation of these approximations and present numerical results on their accuracy for a number of relevant cases.

Compound matrices play an important role in many fields of mathematics and have recently found new applications in systems and control theory. However, the explicit formulas for these compounds are non-trivial and not always easy to use. Here, we derive new formulas for the multiplicative and additive compounds of a matrix using Kronecker products and sums. This provides a new approach to matrix compounds based on the well-known and powerful theory of Kronecker products and sums. We demonstrate several applications of these new formulas, including deriving a new expression for the additive compound of the product of two matrices.

We consider a continuous-time linear time-invariant dynamical system that admits an invariant cone. For the case of a self-dual and homogeneous cone we show that if the system is asymptotically stable then it admits a quadratic Lyapunov function with a special structure. The complexity of this Lyapuonv function scales linearly with the dimension of the dynamical system. In the particular case when the cone is the nonnegative orthant this reduces to the well-known and important result that a positive system admits a diagonal Lyapunov function. We demonstrate our theoretical results by deriving a new special quadratic Lyapunov function for systems that admit the ice-cream cone as an invariant set.

We derive a sufficient condition for $k$-contraction in a generalized Lurie system~(GLS), that is, the feedback connection of a nonlinear dynamical system and a memoryless nonlinear function. For $k=1$, this reduces to a sufficient condition for standard contraction. For $k=2$, this condition implies that every bounded solution of the GLS converges to an equilibrium, which is not necessarily unique. We demonstrate the theoretical results by analyzing $k$-contraction in a biochemical control circuit with nonlinear dissipation terms.

We consider a class of bilinear weakly contractive systems that entrain to periodic excitations. Entrainment is important in many natural and artificial processes. For example, in order to function properly synchronous generators must entrain to the frequency of the electrical grid, and biological organisms must entrain to the 24h solar day. A dynamical system has a positive gain of entrainment (GOE) if entrainment also yields a larger output, on average. This property is important in many applications from the periodic operation of bioreactors to the periodic production of proteins during the cell cycle division process. We derive a closed-form formula for the GOE to first-order in the control perturbation. This is used to show that in the class of systems that we consider the GOE is always a higher-order phenomenon. We demonstrate the theoretical results using two applications: the master equation and a model from systems biology called the ribosome flow model, both with time-varying and periodic transition rates.

We derive a sufficient condition guaranteeing that a singularly perturbed linear time-varying system is strongly monotone with respect to a matrix cone $C$ of rank $k$. This implies that the singularly perturbed system inherits the asymptotic properties of systems that are strongly monotone with respect to $C$, which include convergence to the set of equilibria when $k=1$, and a Poincar\'e-Bendixson property when $k=2$. We extend this result to singularly perturbed nonlinear systems with a compact and convex state-space. We demonstrate our theoretical results using a simple numerical example.

A Lurie system is the interconnection of a linear time-invariant system and a nonlinear feedback function. We derive a new sufficient condition for $k$-contraction of a Lurie system. For $k=1$, our sufficient condition reduces to the standard stability condition based on the bounded real lemma and a small gain condition. However, Lurie systems often have more than a single equilibrium and are thus not contractive with respect to any norm. For $k=2$, our condition guarantees a well-ordered asymptotic behaviour of the closed-loop system: every bounded solution converges to an equilibrium, which is not necessarily unique. We demonstrate our results by deriving a sufficient condition for $k$-contraction of a general networked system, and then applying it to guarantee $k$-contraction in a Hopfield neural network, a nonlinear opinion dynamics model, and a 2-bus power system., Comment: arXiv admin note: substantial text overlap with arXiv:2211.05696

We consider a Lurie system obtained via a connection of a linear time-invariant system and a nonlinear feedback function. Such systems often have more than a single equilibrium and are thus not contractive with respect to any norm. We derive a new sufficient condition for $k$-contraction of a Lurie system. For $k=1$, our sufficient condition reduces to the standard stability condition based on the bounded real lemma and a small gain condition. For $k=2$, our condition guarantees well-ordered asymptotic behaviour of the closed-loop system: every bounded solution converges to an equilibrium, which is not necessarily unique. We apply our results to derive a sufficient condition for $k$-contractivity of a networked system., Comment: To appear in IFAC World Congress 2023

The ribosome flow model (RFM) is a phenomenological model for the flow of particles along a 1D chain of $n$ sites. It has been extensively used to study ribosome flow along the mRNA molecule during translation. When the transition rates along the chain are time-varying and jointly $T$-periodic the RFM entrains, i.e., every trajectory of the RFM converges to a unique $T$-periodic solution that depends on the transition rates, but not on the initial condition. In general, entrainment to periodic excitations like the 24h solar day or the 50Hz frequency of the electric grid is important in numerous natural and artificial systems. An interesting question, called the gain of entrainment (GOE) in the RFM, is whether proper coordination of the periodic translation rates along the mRNA can lead to a larger average protein production rate. Analyzing the GOE in the RFM is non-trivial and partial results exist only for the RFM with dimensions $n=1,2$. We use a new approach to derive several results on the GOE in the general $n$-dimensional RFM. Perhaps surprisingly, we rigorously characterize several cases where there is no GOE, so to maximize the average production rate in these cases, the best choice is to use constant transition rates all along the chain.

Compound matrices have found applications in many fields of science including systems and control theory. In particular, a sufficient condition for $k$-contraction is that a logarithmic norm (also called matrix measure) of the $k$-additive compound of the Jacobian is uniformly negative. However, this may be difficult to check in practice because the $k$-additive compound of an $n\times n$ matrix has dimensions $\binom{n}{k}\times \binom{n}{k}$. For an $n\times n$ matrix $A$, we prove a duality relation between the $k$ and $(n-k)$ compounds of $A$. We use this duality relation to derive a sufficient condition for $k$-contraction that does not require the computation of any $k$-compounds. We demonstrate our results by deriving a sufficient condition for $k$-contraction of an $n$-dimensional Hopfield network that does not require to compute any compounds. In particular, for $k=2$ this sufficient condition implies that the network is $2$-contracting and this implies a strong asymptotic property: every bounded solution of the network converges to an equilibrium point, that may not be unique. This is relevant, for example, when using the Hopfield network as an associative memory that stores patterns as equilibrium points of the dynamics.

The multiplicative and additive compounds of a matrix play an important role in several fields of mathematics including geometry, multi-linear algebra, combinatorics, and the analysis of nonlinear time-varying dynamical systems. There is a growing interest in applications of these compounds, and their generalizations, in systems and control theory. The goal of this tutorial paper is to provide a gentle and self-contained introduction to these topics with an emphasis on the geometric interpretation of the compounds, and to describe some of their recent applications including several non-trivial generalizations of positive systems, cooperative systems, contracting systems, and more., Comment: arXiv admin note: text overlap with arXiv:2103.15097

We consider the problem of making a networked system contracting by designing minimal effort local controllers. Our method combines a hierarchical contraction characterization and a matrix-balancing approach to stabilizing a Metzler matrix via minimal diagonal perturbations. We demonstrate our approach by designing local controllers that render contractive a network of FitzHugh-Nagumo neurons with a general topology of interactions.

The multiplicative and additive compounds of a matrix have important applications in geometry, linear algebra, and the analysis of dynamical systems. In particular, the $k$-compounds allow to build a $k$-compound dynamical system that tracks the evolution of $k$-dimensional parallelotopes along the original dynamics. This has recently found many applications in the analysis of non-linear systems described by ODEs and difference equations. Here, we introduce the $k$-compound system corresponding to a differential-algebraic system, and describe several applications to the analysis of discrete-time dynamical systems described by difference-algebraic equations., Comment: Accepted for publication in Automatica

A matrix is called a P-matrix if all its principal minors are positive. P-matrices have found important applications in functional analysis, mathematical programming, and dynamical systems theory. We introduce a new class of real matrices denoted~$\EP$. A matrix is in~$\EP$ if and only if its matrix exponential is a P-matrix for all positive times. In other words, $A\in \EP$ if and only if the transition matrix of the linear system~$\dot x=Ax$ is a P-matrix for any positive time~$t$. We analyze the properties of this new class of matrices and describe an application of our theoretical results to opinion dynamics.

The flow of contracting systems contracts 1-dimensional parallelotopes, i.e., line segments, at an exponential rate. One reason for the usefulness of contracting systems is that many interconnections of contracting sub-systems yield an overall contracting system. A generalization of contracting systems is $k$-contracting systems, where $k\in\{1,\dots,n\}$. The flow of such systems contracts the volume of $k$-dimensional parallelotopes at an exponential rate, and in particular they reduce to contracting systems when $k=1$. It was shown by Muldowney and Li that time-invariant $2$-contracting systems have a well-ordered asymptotic behaviour: all bounded trajectories converge to the set of equilibria. Here, we derive a sufficient condition guaranteeing that the system obtained from the series interconnection of two sub-systems is $k$-contracting. This is based on a new formula for the $k$th multiplicative and additive compounds of a block-diagonal matrix, which may be of independent interest. As an application, we find conditions guaranteeing that $2$-contracting systems with an exponentially decaying input retain the well-ordered behaviour of time-invariant 2-contracting systems.

The flow of contracting systems contracts 1-dimensional polygons (i.e. lines) at an exponential rate. One reason for the usefulness of contracting systems is that many interconnections of contracting sub-systems yield an overall contracting system. A recent generalization of contracting systems is called $k$-contracting systems, where $k\in\{1,\dots,n\}$. The flow of such systems contracts $k$-dimensional polygons at an exponential rate, and in particular they reduce to contracting systems when $k=1$. Here, we analyze serial interconnections of $1$-contracting and $2$-contracting systems. We provide conditions guaranteeing that such interconnections have a well-ordered asymptotic behaviour, and demonstrate the theoretical results using several examples.

The multiplicative and additive compounds of a matrix play an important role in several fields of mathematics including geometry, multi-linear algebra, combinatorics, and the analysis of nonlinear time-varying dynamical systems. There is a growing interest in applications of these compounds, and their generalizations, in systems and control theory. This tutorial paper provides a gentle introduction to these topics with an emphasis on the geometric interpretation of the compounds, and surveys some of their recent applications.

A linear dynamical system is called $k$-positive if its dynamics maps the set of vectors with up to $k-1$ sign variations to itself. For $k=1$, this reduces to the important class of positive linear systems. Since stable positive linear time-invariant (LTI) systems always admit a diagonal quadratic Lyapunov function, i.e. they are diagonally stable, we may expect that this holds also for stable $k$-positive systems. We show that, in general, this is not the case both in the continuous-time (CT) and discrete-time (DT) case. We then focus on DT $k$-positive linear systems and introduce the new notion of DT $k$-diagonal stability. It is shown that this is a necessary condition for standard DT diagonal stability. We demonstrate an application of this new notion to the analysis of a class of DT nonlinear systems., Comment: arXiv admin note: text overlap with arXiv:2003.09679

A time-varying nonlinear dynamical system is called a totally positive differential system (TPDS) if its Jacobian admits a special sign pattern: it is tri-diagonal with positive entries on the super- and sub-diagonals. If the vector field of a TPDS is T-periodic then every bounded trajectory converges to a T-periodic solution. In particular, when the vector field is time-invariant every bounded trajectory of a TPDS converges to an equlbrium. Here, we use the spectral theory of oscillatory matrices to analyze the behavior near a periodic solution of a TPDS. This yields information on the perturbation directions that lead to the fastest and slowest convergence to or divergence from the periodic solution. We demonstrate the theoretical results using a model from systems biology called the ribosome flow model.

The $k$ multiplicative and $k$ additive compounds of a matrix play an important role in geometry, multi-linear algebra, the asymptotic analysis of nonlinear dynamical systems, and in bounding the Hausdorff dimension of fractal sets. These compounds are defined for integer values of $k$. Here, we introduce generalizations called the $\alpha$ multiplicative and $\alpha$ additive compounds of a square matrix, with $\alpha$ real. We study the properties of these new compounds and demonstrate an application in the context of the Douady and Oesterl\'{e} Theorem. This leads to a generalization of contracting systems to $\alpha$ contracting systems, with $\alpha$ real. Roughly speaking, the dynamics of such systems contracts any set with Hausdorff dimension larger than $\alpha$. For $\alpha=1$ they reduce to standard contracting systems.

The rate of mRNA translation depends on the initiation, elongation, and termination rates of ribosomes along the mRNA. These rates depend on many "local" factors like the abundance of free ribosomes and tRNA molecules in the vicinity of the mRNA molecule. All these factors are stochastic and their experimental measurements are also noisy. An important question is how protein production in the cell is affected by this considerable variability. We develop a new theoretical framework for addressing this question by modeling the rates as identically and independently distributed random variables and using tools from random matrix theory to analyze the steady-state production rate. The analysis reveals a principle of universality: the average protein production rate depends only on the of the set of possible values that the random variable may attain. This explains how total protein production can be stabilized despite the overwhelming stochasticticity underlying cellular processes., Comment: Accepted to Scientific Reports - Nature

We consider $k$-positive linear systems, that is, systems that map the set of vectors with up to $k-1$ sign variations to itself. For $k=1$, this reduces to positive linear systems. It is well-known that stable positive linear time invariant (LTI) systems admit a diagonal Lyapunov function. This property has many important implications. A natural question is whether stable $k$-positive systemsalso admit a diagonal Lyapunov function. This paper shows that, in general, the answer is no. However, for both continuous-time and discrete-time $n$-dimensional systems that are $(n-1)$-positive we provide a sufficient condition for diagonal stability., Comment: We have updated this paper with a new title. Pls see search the new one titled as "Diagonal Stability of Discrete-time $k$-Positive linear Systems with Applications to Nonlinear Systems"

A linear dynamical system is called positive if its flow maps the non-negative orthant to itself. More precisely, it maps the set of vectors with zero sign variations to itself. A linear dynamical system is called $k$-positive if its flow maps the set of vectors with up to $k-1$ sign variations to itself. A nonlinear dynamical system is called $k$-cooperative if its variational system, which is a time-varying linear dynamical system, is $k$-positive. These systems have special asymptotic properties. For example, it was recently shown that strongly $2$-cooperative systems satisfy a strong Poincar\'{e}-Bendixson property. Positivity and~$k$-positivity are easy to verify in terms of the sign-pattern of the matrix in the dynamics. However, these sign conditions are not invariant under a coordinate transformation. A natural question is to determine if a given~$n$-dimensional system is $k$-positive up to a coordinate transformation. We study this problem for two special kinds of transformations: permutations and scaling by a signature matrix. For any $n\geq 4$ and~$k\in\{2,\dots, n-2\}$, we provide a graph-theoretical necessary and sufficient condition for $k$-positivity up to such coordinate transformations. We describe an application of our results to a specific class of Lotka-Volterra systems.

The totally asymmetric simple exclusion process (TASEP) is a basic model of statistical mechanics that has found numerous applications. We consider the case of TASEP with a finite chain where particles may enter from the left and leave to the right at prescribed rates. This model can be formulated as a Markov process with a finite number of states. Due to the irreducibility of the process it is well-known that the probability distribution on the states is globally attracted to a unique equilibrium distribution. We extend this result to the more detailed level of individual trajectories. To do so we formulate TASEP as a random dynamical system. Our main result is that the trajectories from all possible initial conditions contract to each other yielding the existence of a random attractor that consists of a single trajectory almost surely. This implies that in the long run TASEP ``filters out'' any perturbation that changes the state of the particles along the chain. In order to prove our main result we first establish that any random dynamical system on a finite state space possesses both a global random pullback attractor and a global random forward attractor. This observation appears to be missing in the literature. We then provide sufficient and necessary conditions for these attractors to be singletons. Finally, we show that TASEP satisfies one of these conditions.

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 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.

Oscillatory matrices were introduced in the seminal work of Gantmacher and Krein. An $n\times n$ matrix $A$ is called oscillatory if all its minors are nonnegative and there exists a positive integer $k$ such that all minors of $A^k$ are positive. The smallest $k$ for which this holds is called the exponent of the oscillatory matrix $A$. Gantmacher and Krein showed that the exponent is always smaller than or equal to $n-1$. An important and nontrivial problem is to determine the exact value of the exponent. Here we use the successive elementary bidiagonal factorization of oscillatory matrices, and its graph-theoretic representation, to derive an explicit expression for the exponent of several classes of oscillatory matrices, and a nontrivial upper-bound on the exponent for several other classes.

Positive systems play an important role in systems and control theory and have found many applications in multi-agent systems, neural networks, systems biology, and more. Positive systems map the nonnegative orthant to itself (and also the nonpositive orthant to itself). In other words, they map the set of vectors with zero sign variations to itself. In this note, discrete-time linear systems that map the set of vectors with up to $k-1$ sign variations to itself are introduced. For the special case $k=1$ these reduce to discrete-time positive linear systems. Properties of these systems are analyzed using tools from the theory of sign-regular matrices. In particular, it is shown that almost every solution of such systems converges to the set of vectors with up to $k-1$ sign variations. Also, the operation of such systems on $k$-dimensional parallelotopes are studied.

We consider a nonlinear SISO system that is a cascade of a scalar "bottleneck entrance" and an arbitrary Hurwitz positive linear system. This system entrains i.e. in response to a $T$-periodic inflow every solution converges to a unique $T$-periodic solution of the system. We study the problem of maximizing the averaged throughput via controlled switching. The objective is to choose a periodic inflow rate with a given mean value that maximizes the averaged outflow rate of the system. 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 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.

A matrix $A$ is called totally positive (TP) if all its minors are positive, and totally nonnegative (TN) if all its minors are nonnegative. A square matrix $A$ is called oscillatory if it is TN and some power of $A$ is TP. A linear time-varying system is called an oscillatory discrete-time system (ODTS) if the matrix defining its evolution at each time $k$ is oscillatory. We analyze the properties of $n$-dimensional time-varying nonlinear discrete-time systems whose variational system is an ODTS, and show that they have a well-ordered behavior. More precisely, if the nonlinear system is time-varying and $T$-periodic then any trajectory either leaves any compact set or converges to an $(n-1)T$-periodic trajectory, that is, a subharmonic trajectory. These results hold for any dimension $n$. The analysis of such systems requires establishing that a line integral of the Jacobian of the nonlinear system is an oscillatory matrix. This is non-trivial, as the sum of two oscillatory matrices is not necessarily oscillatory, and this carries over to integrals. We derive several new sufficient conditions guaranteeing that the line integral of a matrix is oscillatory, and demonstrate how this yields interesting classes of discrete-time nonlinear systems that admit a well-ordered behavior.

We introduce and analyze two general dynamical models for unidirectional movement of particles along a circular chain and an open chain of sites. The models include a soft version of the simple exclusion principle, that is, as the density in a site increases the effective entry rate into this site decreases. This allows to model and study the evolution of "traffic jams" of particles along the chain. A unique feature of these two new models is that each site along the chain can have a different size. Although the models are nonlinear, they are amenable to rigorous asymptotic analysis. In particular, we show that the dynamics always converges to a steady-state, and that the steady-state densities along the chain and the steady-state output flow rate from the chain can be derived from the spectral properties of a suitable matrix, thus eliminating the need to numerically simulate the dynamics until convergence. This spectral representation also allows for powerful sensitivity analysis, i.e. understanding how a change in one of the parameters in the models affects the steady-state. We show that the site sizes and the transition rates from site to site play different roles in the dynamics, and that for the purpose of maximizing the steady-state output (or production) rate the site sizes are more important than the transition rates. We also show that the problem of finding parameter values that maximize the production rate is tractable. We believe that the models introduced here can be applied to study various natural and artificial processes including ribosome flow during mRNA translation, the movement of molecular motors along filaments of the cytoskeleton, pedestrian and vehicular traffic, evacuation dynamics, and more.

The dynamics of linear positive systems map the positive orthant to itself. In other words, it maps a set of vectors with zero sign variations to itself. This raises the following question: what linear systems map the set of vectors with $k$ sign variations to itself? We address this question using tools from the theory of cooperative dynamical systems and the theory of totally positive matrices. This yields a generalization of positive linear systems called $k$-positive linear systems, that reduces to positive systems for $k=1$. We describe applications of this new type of systems to the analysis of nonlinear dynamical systems. In particular, we show that such systems admit certain explicit invariant sets, and for the case $k=2$ establish the Poincar\'{e}-Bendixson property for any bounded trajectory.

The ribosome flow model with input and output (RFMIO) is a deterministic dynamical system that has been used to study the flow of ribosomes during mRNA translation. The RFMIO and its variants encapsulate important properties that are relevant to modeling ribosome flow such as the possible evolution of "traffic jams" and non-homogeneous elongation rates along the mRNA molecule, and can also be used for studying additional intracellular processes such as transcription, transport, and more. Here we consider networks of interconnected RFMIOs as a fundamental tool for modeling, analyzing and re-engineering the complex mechanisms of protein production. In these networks, the output of each RFMIO may be divided, using connection weights, between several inputs of other RFMIOs. We show that under quite general feedback connections the network has two important properties: (1) it admits a unique steady-state and every trajectory converges to this steady-state, and (2) the problem of how to determine the connection weights so that the network steady-state output is maximized is a convex optimization problem. These mathematical properties make these networks highly suitable as models of various phenomena: property (1) means that the behavior is predictable and ordered, and property (2) means that determining the optimal weights is numerically tractable even for large-scale networks. For the specific case of a feed-forward network of RFMIOs we prove an additional useful property, namely, that there exists a spectral representation for the network steady-state, and thus it can be determined without any numerical simulations of the dynamics. We describe the implications of these result to several fundamental biological phenomena and biotechnological objectives.

A matrix is called strictly sign-regular of order $k$ (denoted by $SSR_k$) if all its $k\times k$ minors are non-zero and have the same sign. For example, totally positive matrices, i.e., matrices with all minors positive, are $SSR_k$ for all $k$. Another important subclass are those that are $SSR_k$ for all odd $k$. Such matrices have interesting sign variation diminishing properties, and it has been recently shown that they play an important role in the analysis of certain nonlinear cooperative dynamical systems. In this paper, the spectral properties of nonsingular matrices that are $SSR_k$ for a specific value $k$ are studied. One of the results is that the product of the first $k$ eigenvalues is real and of the same sign as the $k\times k$ minors, and that linear combinations of certain eigenvectors have specific sign patterns. It is then shown how known results for matrices that are $SSR_k$ for several values of $k$ can be derived from these spectral properties. Using these theoretical results, the notion of a totally positive discrete-time system (TPDTS) is introduced. This may be regarded as the discrete-time analogue of the important notion of a totally positive differential system, introduced by Schwarz in 1970. The asymptotic behavior of time-invariant and time-varying TPDTSs is analyzed, and it is shown that every trajectory of a periodic time-varying TPDTS converges to a periodic solution.

Smillie (1984) proved an interesting result on the stability of nonlinear, time-invariant, strongly cooperative, and tridiagonal dynamical systems. This result has found many applications in models from various fields including biology, ecology, and chemistry. Smith (1991) has extended Smillie's result and proved entrainment in the case where the vector field is time-varying and periodic. We use the theory of linear totally nonnegative differential systems developed by Schwarz (1970) to give a generalization of these two results. This is based on weakening the requirement for strong cooperativity to cooperativity, and adding an additional observability-type condition., Comment: arXiv admin note: text overlap with arXiv:1802.09590

Using a graph-theoretic approach, we derive a new sufficient condition for observability of a Boolean control network (BCN). Based on this condition, we describe two algorithms: the first selects a set of nodes so that observing this set makes the BCN observable. The second algorithm builds an observer for the observable BCN. Both algorithms are sub-optimal, as they are based on a sufficient but not necessary condition for observability. Yet their time-complexity is linear in the length of the description of the BCN, rendering them feasible for large-scale networks. We discuss how these results can be used to provide a sub-optimal yet polynomial-complexity algorithm for the minimal observability problem in BCNs. Some of the theoretical results are demonstrated using a BCN model of the core network regulating the mammalian cell cycle., Comment: arXiv admin note: text overlap with arXiv:1706.04072

Several studies analyzed certain nonlinear dynamical systems by showing that the cyclic number of sign variations in the vector of derivatives is an integer-valued Lyapunov function. These results are based on direct analysis of the dynamical equation satisfied by the vector of derivatives, i.e. the variational system. However, it is natural to assume that they follow from the fact that the transition matrix in the variational system satisfies a variation diminishing property (VDP) with respect to the cyclic number of sign variations in a vector. Motivated by this, we develop the theoretical framework of linear time-varying systems whose solution satisfies a VDP with respect to the cyclic number of sign variations. This provides an analogue of the work of Schwarz on totally positive differential systems, i.e. linear time-varying systems whose solution satisfies a VDP with respect to the standard (non-cyclic) number of sign variations.

A matrix is called totally nonnegative (TN) if all its minors are nonnegative, and totally positive (TP) if all its minors are positive. Multiplying a vector by a TN matrix does not increase the number of sign variations in the vector. In a largely forgotten paper, Schwarz (1970) considered matrices whose exponentials are TN or TP. He also analyzed the evolution of the number of sign changes in the vector solutions of the corresponding linear system. In a seemingly different line of research, Smillie (1984), Smith (1991), and others analyzed the stability of nonlinear tridiagonal cooperative systems by using the number of sign variations in the derivative vector as an integer-valued Lyapunov function. We provide a tutorial on these fascinating research topics and show that they are intimately related. This allows to derive generalizations of the results by Smillie (1984) and Smith (1991) while simplifying the proofs. It also opens the door to many new and interesting research directions.

The master equation plays an important role in many scientific fields including physics, chemistry, systems biology, physical finance, and sociodynamics. We consider the master equation with periodic transition rates. This may represent an external periodic excitation like the 24h solar day in biological systems or periodic traffic lights in a model of vehicular traffic. Using tools from systems and control theory, we prove that under mild technical conditions every solution of the master equation converges to a periodic solution with the same period as the rates. In other words, the master equation entrains (or phase locks) to periodic excitations. We describe two applications of our theoretical results to important models from statistical mechanics and epidemiology.

Many complex systems in biology, physics, and engineering include a large number of state-variables, and measuring the full state of the system is often impossible. Typically, a set of sensors is used to measure part of the state-variables. A system is called observable if these measurements allow to reconstruct the entire state of the system. When the system is not observable, an important and practical problem is how to add a \emph{minimal} number of sensors so that the system becomes observable. This minimal observability problem is practically useful and theoretically interesting, as it pinpoints the most informative nodes in the system. We consider the minimal observability problem for an important special class of Boolean networks, called conjunctive Boolean networks (CBNs). Using a graph-theoretic approach, we provide a necessary and sufficient condition for observability of a CBN with $n$ state-variables, and an efficient~$O(n^2)$-time algorithm for solving the minimal observability problem. We demonstrate the usefulness of these results by studying the properties of a class of random CBNs., Comment: Revised version. Date: Dec 6, 2017

The ribosome flow model on a ring (RFMR) is a deterministic model for translation of a circularized mRNA. We derive a new spectral representation for the optimal steady-state production rate and the corresponding optimal steady-state ribosomal density in the RFMR. This representation has several important advantages. First, it provides a simple and numerically stable algorithm for determining the optimal values even in very long rings. Second, it enables efficient computation of the sensitivity of the optimal production rate to small changes in the transition rates along the mRNA. Third, it implies that the optimal steady-state production rate is a strictly concave function of the transition rates. Thus maximizing the optimal steady-state production rate with respect to the rates, under an affine constraint on the rates becomes a convex optimization problem that admits a unique solution, which can be determined numerically using highly efficient algorithms. This optimization problem is important, for example, when re-engineering heterologous genes in a host organism. We describe the implications of our results to this and other aspects of translation.

We study a deterministic mechanistic model for the flow of ribosomes along the mRNA molecule, called the ribosome flow model with extended objects (RFMEO). This model encapsulates many realistic features of translation including non-homogeneous transition rates along the mRNA, the fact that every ribosome covers several codons, and the fact that ribosomes cannot overtake one another. The RFMEO is a mean-field approximation of an important model from statistical mechanics called the totally asymmetric simple exclusion process with extended objects (TASEPEO). We demonstrate that the RFMEO describes biophysical aspects of translation better than previous mean-field approximations, and that its predictions correlate well with those of TASEPEO. However, unlike TASEPEO, the RFMEO is amenable to rigorous analysis using tools from systems and control theory. We show that the ribosome density profile along the mRNA in the RFMEO converges to a unique steady-state density that depends on the length of the mRNA, the transition rates along it, and the number of codons covered by every ribosome, but not on the initial density of ribosomes along the mRNA. In particular, the protein production rate also converges to a unique steady-state. Furthermore, if the transition rates along the mRNA are periodic with a common period T then the ribosome density along the mRNA and the protein production rate converge to a unique periodic pattern with period T, that is, the model entrains to periodic excitations in the transition rates. We believe that the RFMEO could be useful for modeling, understanding, and re-engineering translation as well as other important biological processes.

Natural phenomena frequently involve a very large number of interacting molecules moving in confined regions of space. Cellular transport by motor proteins is an example of such collective behavior. We derive a deterministic compartmental model for the unidirectional flow of particles along a one-dimensional lattice of sites with nearest-neighbor interactions between the particles. The flow between consecutive sites is governed by a soft simple exclusion principle and by attracting or repelling forces between neighboring particles. Using tools from contraction theory, we prove that the model admits a unique steady-state and that every trajectory converges to this steady-state. Analysis and simulations of the effect of the attracting and repelling forces on this steady-state highlight the crucial role that these forces may play in increasing the steady-state flow, and reveal that this increase stems from the alleviation of traffic jams along the lattice. Our theoretical analysis clarifies microscopic aspects of complex multi-particle dynamic processes.

Given a conjunctive Boolean network (CBN) with $n$ state-variables, we consider the problem of finding a minimal set of state-variables to directly affect with an input so that the resulting conjunctive Boolean control network (CBCN) is controllable. We give a necessary and sufficient condition for controllability of a CBCN; an $O(n^2)$-time algorithm for testing controllability; and prove that nonetheless the minimal controllability problem for CBNs is NP-hard.

We consider contractive systems whose trajectories evolve on a compact and convex state-space. It is well-known that if the time-varying vector field of the system is periodic then the system admits a unique globally asymptotically stable periodic solution. Obtaining explicit information on this periodic solution and its dependence on various parameters is important both theoretically and in numerous applications. We develop an approach for approximating such a periodic trajectory using the periodic trajectory of a simpler system (e.g. an LTI system). Our approximation includes an error bound that is based on the input-to-state stability property of contractive systems. We show that in some cases this error bound can be computed explicitly. We also use the bound to derive a new theoretical result, namely, that a contractive system with an additive periodic input behaves like a low pass filter. We demonstrate our results using several examples from systems biology.