arXiv subjects

Michael Margaliot

Publications and source records attributed to Michael Margaliot.

At least 73 records · Page 4Linked to original sources

arXiv2017

A Polynomial-Time Algorithm for Solving the Minimal Observability Problem in Conjunctive Boolean Networks

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.

math.OC↗

arXiv2017

Entrainment in the Master Equation

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.

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arXiv2017

Ribosome Flow Model with Extended Objects

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.

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arXiv2017

Optimal Translation Along a Circular mRNA

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.

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arXiv2017

A Deterministic Model for One-Dimensional Excluded Flow with Local Interactions

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.

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arXiv2017

Controllability analysis and control synthesis for the ribosome flow model

The ribosomal density along the coding region of the mRNA molecule affect 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. We study this problem using a model for mRNA translation, called the ribosome flow model (RFM). In the RFM, the mRNA molecule is modeled as chain of n sites. The n state-variables describe the ribosomal density profile along the mRNA molecule, whereas the transition rates from each site to the next are controlled by n+1 positive constants. To study the problem of controlling the density profile, we consider some or all of the transition rates as time-varying controls. We consider the following problem: given an initial and a desired ribosomal density profile, determine the time-varying values of the transition rates that steer the RFM to this density profile, if they exist. Specifically, we consider two control problems. In the first, all transition rates can be regulated and the goal is to steer the ribosomal density profile and the protein production rate from a given initial value to a desired value. In the second, a single transition rate is controlled and the goal is to steer the production rate to a desired value. In the first case, we show that the system is controllable, i.e. the control is powerful enough to steer the RFM to any desired value, and we provide closed-form expressions for constant control functions (or transition rates) asymptotically steering the RFM to the desired value. For the second problem, we show that the production rate can be steered to any desired value in a feasible region determined by the other, constant transition rates. We discuss some of the biological implications of these results.

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arXiv2017

Minimal Controllability of Conjunctive Boolean Networks is NP-Complete

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.

cs.DS↗

arXiv2017

Approximating the Frequency Response of Contractive Systems

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.

eess.SY↗

arXiv2016

A Deterministic Mathematical Model for Bidirectional Excluded Flow with Langmuir Kinetics

In many important cellular processes, including mRNA translation, gene transcription, phosphotransfer, and intracellular transport, biological "particles" move along some kind of "tracks". The motion of these particles can be modeled as a one-dimensional movement along an ordered sequence of sites. The biological particles (e.g., ribosomes, RNAPs, phosphate groups, motor proteins) have volume and cannot surpass one another. In some cases, there is a preferred direction of movement along the track, but in general the movement may be two-directional, and furthermore the particles may attach or detach from various regions along the tracks (e.g. ribosomes may drop off the mRNA molecule before reaching a stop codon). We derive a new deterministic mathematical model for such transport phenomena that may be interpreted as the dynamic mean-field approximation of an important model from mechanical statistics called the asymmetric simple exclusion process (ASEP) with Langmuir kinetics. Using tools from the theory of monotone dynamical systems and contraction theory we show that the model admits a unique globally asymptotically stable equilibrium. This means that the occupancy in all the sites along the lattice converges to a steady-state value that depends on the parameters but not on the initial conditions. We also show that the model entrains (or phase locks) to periodic excitations in any of its forward, backward, attachment, or detachment rates. We demonstrate an application of this phenomenological transport model for analyzing the effect of ribosome drop off in mRNA translation. One may perhaps expect that drop off from a jammed site may increase the total flow by reducing congestion. Our results show that this is not true. Drop off has a substantial effect on the flow, yet always leads to a reduction in the steady-state protein production rate.

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arXiv2016

On the Ribosomal Density that Maximizes Protein Translation Rate

During mRNA translation, several ribosomes attach to the same mRNA molecule simultaneously translating it into a protein. This pipelining increases the protein production rate. A natural and important question is what ribosomal density maximizes the protein production rate. Using mathematical models of ribosome flow along both a linear and a circular mRNA molecule we prove that typically the steady-state production rate is maximized when the ribosomal density is one half of the maximal possible density. We discuss the implications of our results to endogenous genes under natural cellular conditions and also to synthetic biology.

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arXiv2016

Optimal Down Regulation of mRNA Translation

Down regulation of mRNA translation is an important problem in various bio-medical domains ranging from developing effective medicines for tumors and for viral diseases to developing attenuated virus strains that can be used for vaccination. Here, we study the problem of down regulation of mRNA translation using a mathematical model called the ribosome flow model (RFM). In the RFM, the mRNA molecule is modeled as a chain of $n$ sites. The flow of ribosomes between consecutive sites is regulated by $n+1$ transition rates. Given a set of feasible transition rates, that models the outcome of all possible mutations, we consider the problem of maximally down regulating the translation rate by altering the rates within this set of feasible rates. Under certain conditions on the feasible set, we show that an optimal solution can be determined efficiently. We also rigorously analyze two special cases of the down regulation optimization problem. Our results suggest that one must focus on the position along the mRNA molecule where the transition rate has the strongest effect on the protein production rate. However, this rate is not necessarily the slowest transition rate along the mRNA molecule. We discuss some of the biological implications of these results.

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arXiv2015

Analyzing Linear Communication Networks using the Ribosome Flow Model

The Ribosome Flow Model (RFM) describes the unidirectional movement of interacting particles along a one-dimensional chain of sites. As a site becomes fuller, the effective entry rate into this site decreases. The RFM has been used to model and analyze mRNA translation, a biological process in which ribosomes (the particles) move along the mRNA molecule (the chain), and decode the genetic information into proteins. Here we propose the RFM as an analytical framework for modeling and analyzing linear communication networks. In this context, the moving particles are data-packets, the chain of sites is a one dimensional set of ordered buffers, and the decreasing entry rate to a fuller buffer represents a kind of decentralized backpressure flow control. For an RFM with homogeneous link capacities, we provide closed-form expressions for important network metrics including the throughput and end-to-end delay. We use these results to analyze the hop length and the transmission probability (in a contention access mode) that minimize the end-to-end delay in a multihop linear network, and provide closed-form expressions for the optimal parameter values.

cs.NI↗

arXiv2015

Ribosome Flow Model on a Ring

The asymmetric simple exclusion process (ASEP) is an important model from statistical physics describing particles that hop randomly from one site to the next along an ordered lattice of sites, but only if the next site is empty. ASEP has been used to model and analyze numerous multiagent systems with local interactions including the flow of ribosomes along the mRNA strand. In ASEP with periodic boundary conditions a particle that hops from the last site returns to the first one. The mean field approximation of this model is referred to as the ribosome flow model on a ring (RFMR). The RFMR may be used to model both synthetic and endogenous gene expression regimes. We analyze the RFMR using the theory of monotone dynamical systems. We show that it admits a continuum of equilibrium points and that every trajectory converges to an equilibrium point. Furthermore, we show that it entrains to periodic transition rates between the sites. We describe the implications of the analysis results to understanding and engineering cyclic mRNA translation in-vitro and in-vivo.

q-bio.QM↗

arXiv2015

A Model for Competition for Ribosomes in the Cell

Large-scale simultaneous mRNA translation and the resulting competition for the available ribosomes has important implications to the cell's functioning and evolution. Developing a better understanding of the intricate correlations between these simultaneous processes, rather than focusing on the translation of a single isolated transcript, should help in gaining a better understanding of mRNA translation regulation and the way elongation rates affect organismal fitness. A model of simultaneous translation is specifically important when dealing with highly expressed genes, as these consume more resources. In addition, such a model can lead to more accurate predictions that are needed in the interconnection of translational modules in synthetic biology. We develop and analyze a general model for large-scale simultaneous mRNA translation and competition for ribosomes. This is based on combining several ribosome flow models (RFMs) interconnected via a pool of free ribosomes. 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 is more complicated than previously thought.

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arXiv2015

Contraction After Small Transients

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 consider three generalizations of contraction with respect to a norm that allow contraction to take place after small transients in time and/or amplitude. These generalized contractive systems (GCSs) are useful for several reasons. First, we show that there exist simple and checkable conditions guaranteeing that a system is a GCS, and demonstrate their usefulness using several models from systems biology. Second, allowing small transients does not destroy the important asymptotic properties of contractive systems like convergence to a unique equilibrium point, if it exists, and entrainment to a periodic excitation. Third, in some cases as we change the parameters in a contractive system it becomes a GCS just before it looses contractivity with respect to a norm. In this respect, generalized contractivity is the analogue of marginal stability in Lyapunov stability theory.

math.DS↗

arXiv2014

On the Structure of the Initiation and Elongation Rates that Maximize Protein Production in the Ribosome Flow Model

Translation is a crucial step in gene expression. During translation, macromolecules called ribosomes "read" the mRNA strand in a sequential manner and produce a corresponding protein. Translation is known to consume most of the cell's energy. Maximizing the protein production rate in mRNA translation, subject to the bounded biomolecullar budget, is thus an important problem in both biology and biotechnology. We consider this problem using a mathematical model for mRNA translation called the ribosome flow model (RFM). For an mRNA strand with $n$ sites the RFM includes $n$ state-variables that encode the normalized ribosomal density at each site, and $n+1$ positive parameters: the initiation rate and elongation rates along the chain. An affine constraint on these rates is used to model the bounded cellular budget. We show that for a homogeneous constraint the rates that maximize the steady-state protein production rate have a special structure. They are symmetric with respect to the middle of the chain, and monotonically increase as we move towards the center of the chain. The ribosomal densities corresponding to the optimal rates monotonically decrease along the chain. We discuss some of the biological implications of these results.

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arXiv2014

Sensitivity of mRNA Translation

Using the dynamic mean-field approximation of the totally asymmetric simple exclusion process (TASEP), we investigate the effect of small changes in the initiation, exit, and elongation rates along the mRNA strand on the steady state protein translation rate. We focus on two special cases where exact closed-form expressions for the translation rate sensitivity can be derived. We discuss the ramifications of our results in the context of functional genomics, molecular evolution, and synthetic biology.

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arXiv2014

Maximizing Protein Translation Rate in the Nonhomogeneous Ribosome Flow Model: A Convex Optimization Approach

Translation is an important stage in gene expression. During this stage, macro-molecules called ribosomes travel along the mRNA strand linking amino-acids together in a specific order to create a functioning protein. An important question is how to maximize protein production. Indeed, translation is known to consume most of the cell's energy and it is natural to assume that evolution shaped this process so that it maximizes the protein production rate. If this is indeed so then one can estimate various parameters of the translation machinery by solving an appropriate mathematical optimization problem. The same problem also arises in the context of synthetic biology, namely, re-engineer heterologous genes in order to maximize their translation rate in a host organism. We consider the problem of maximizing the protein production rate using a computational model for translation-elongation called the ribosome flow model (RFM). This model describes the flow of the ribosomes along an mRNA chain of length n using a set of n first-order nonlinear ODEs. It also includes n+1 positive parameters: the ribosomal initiation rate into the mRNA chain, and n elongation rates along the chain sites. We show that the steady-state translation rate in the RFM is a strictly concave function of its parameters. This means that the problem of maximizing the translation rate under a suitable constraint always admits a unique solution, and that this solution can be determined using highly-efficient algorithms for solving convex optimization problems even for large values of n. Furthermore, our analysis shows that the optimal translation rate can be computed based only on the optimal initiation rate and the elongation rate of the codons near the beginning of the ORF. We discuss some applications of the theoretical results to synthetic biology, molecular evolution, and functional genomics.

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