Semi-classical statistical description of Fröhlich condensation

Fröhlich’s model equations describing phonon condensation in open systems of biological relevance are reinvestigated within a semi-classical statistical framework. The main assumptions needed to deduce Fröhlich’s rate equations are identified and it is shown how they lead us to write an appropriate form for the corresponding master equation. It is shown how solutions of the master equation can be numerically computed and can highlight typical features of the condensation effect. Our approach provides much more information compared to the existing ones as it allows to investigate the time evolution of the probability density function instead of following single averaged quantities. The current work is also motivated, on the one hand, by recent experimental evidences of long-lived excited modes in the protein structure of hen-egg white lysozyme, which were reported as a consequence of the condensation effect, and, on the other hand, by a growing interest in investigating long-range effects of electromagnetic origin and their influence on the dynamics of biochemical reactions.     

Characterizing rare-event property distributions via replicate molecular dynamics simulations of proteins

As computational resources increase, molecular dynamics simulations of biomolecules are becoming an increasingly informative complement to experimental studies. In particular, it has now become feasible to use multiple initial molecular configurations to generate an ensemble of replicate production-run simulations that allows for more complete characterization of rare events such as ligand-receptor unbinding. However, there are currently no explicit guidelines for selecting an ensemble of initial configurations for replicate simulations. Here, we use clustering analysis and steered molecular dynamics simulations to demonstrate that the configurational changes accessible in molecular dynamics simulations of biomolecules do not necessarily correlate with observed rare-event properties. This informs selection of a representative set of initial configurations. We also employ statistical analysis to identify the minimum number of replicate simulations required to sufficiently sample a given biomolecular property distribution. Together, these results suggest a general procedure for generating an ensemble of replicate simulations that will maximize accurate characterization of rare-event property distributions in biomolecules.     

A stochastic analysis of first-order reaction networks

A stochastic model for a general system of first-order reactions in which each reaction may be either a conversion reaction or a catalytic reaction is derived. The governing master equation is formulated in a manner that explicitly separates the effects of network topology from other aspects, and the evolution equations for the first two moments are derived. We find the surprising, and apparently unknown, result that the time evolution of the second moments can be represented explicitly in terms of the eigenvalues and projections of the matrix that governs the evolution of the means. The model is used to analyze the effects of network topology and the reaction type on the moments of the probability distribution. In particular, it is shown that for an open system of first-order conversion reactions, the distribution of all the system components is a Poisson distribution at steady state. Two different measures of the noise have been used previously, and it is shown that different qualitative and quantitative conclusions can result, depending on which measure is used. The effect of catalytic reactions on the variance of the system components is also analyzed, and the master equation for a coupled system of first-order reactions and diffusion is derived. All authors contributed equally to this work.     

Understanding evolutionary and ecological dynamics using a continuum limit

Continuum limits in the form of stochastic differential equations are typically used in theoretical population genetics to account for genetic drift or more generally, inherent randomness of the model. In evolutionary game theory and theoretical ecology, however, this method is used less frequently to study demographic stochasticity. Here, we review the use of continuum limits in ecology and evolution. Starting with an individual‐based model, we derive a large population size limit, a (stochastic) differential equation which is called continuum limit. By example of the Wright–Fisher diffusion, we outline how to compute the stationary distribution, the fixation probability of a certain type, and the mean extinction time using the continuum limit. In the context of the logistic growth equation, we approximate the quasi‐stationary distribution in a finite population.     

Analytical and Simulation Results for Stochastic Fitzhugh-Nagumo Neurons and Neural Networks

An analytical approach is presented for determining the response of a neuron or of the activity in a network of connected neurons, represented by systems of nonlinear ordinary stochastic differential equations—the Fitzhugh-Nagumo system with Gaussian white noise current. For a single neuron, five equations hold for the first- and second-order central moments of the voltage and recovery variables. From this system we obtain, under certain assumptions, five differential equations for the means, variances, and covariance of the two components. One may use these quantities to estimate the probability that a neuron is emitting an action potential at any given time. The differential equations are solved by numerical methods. We also perform simulations on the stochastic Fitzugh-Nagumo system and compare the results with those obtained from the differential equations for both sustained and intermittent deterministic current inputs withsuperimposed noise. For intermittent currents, which mimic synaptic input, the agreement between the analytical and simulation results for the moments is excellent. For sustained input, the analytical approximations perform well for small noise as there is excellent agreement for the moments. In addition, the probability that a neuron is spiking as obtained from the empirical distribution of the potential in the simulations gives a result almost identical to that obtained using the analytical approach. However, when there is sustained large-amplitude noise, the analytical method is only accurate for short time intervals. Using the simulation method, we study the distribution of the interspike interval directly from simulated sample paths. We confirm that noise extends the range of input currents over which (nonperiodic) spike trains may exist and investigate the dependence of such firing on the magnitude of the mean input current and the noise amplitude. For networks we find the differential equations for the means, variances, and covariances of the voltage and recovery variables and show how solving them leads to an expression for the probability that a given neuron, or given set of neurons, is firing at time t. Using such expressions one may implement dynamical rules for changing synaptic strengths directly without sampling. The present analytical method applies equally well to temporally nonhomogeneous input currents and is expected to be useful for computational studies of information processing in various nervous system centers.     

A stochastic Markov chain model to describe lung cancer growth and metastasis

A stochastic Markov chain model for metastatic progression is developed for primary lung cancer based on a network construction of metastatic sites with dynamics modeled as an ensemble of random walkers on the network. We calculate a transition matrix, with entries (transition probabilities) interpreted as random variables, and use it to construct a circular bi-directional network of primary and metastatic locations based on postmortem tissue analysis of 3827 autopsies on untreated patients documenting all primary tumor locations and metastatic sites from this population. The resulting 50 potential metastatic sites are connected by directed edges with distributed weightings, where the site connections and weightings are obtained by calculating the entries of an ensemble of transition matrices so that the steady-state distribution obtained from the long-time limit of the Markov chain dynamical system corresponds to the ensemble metastatic distribution obtained from the autopsy data set. We condition our search for a transition matrix on an initial distribution of metastatic tumors obtained from the data set. Through an iterative numerical search procedure, we adjust the entries of a sequence of approximations until a transition matrix with the correct steady-state is found (up to a numerical threshold). Since this constrained linear optimization problem is underdetermined, we characterize the statistical variance of the ensemble of transition matrices calculated using the means and variances of their singular value distributions as a diagnostic tool. We interpret the ensemble averaged transition probabilities as (approximately) normally distributed random variables. The model allows us to simulate and quantify disease progression pathways and timescales of progression from the lung position to other sites and we highlight several key findings based on the model.     

Strengthening forecasts of climate change impacts with multi‐model ensemble averaged projections using MAGICC/SCENGEN 5.3

Climate output from general circulation models (GCMs) is being used with increasing frequency to explore potential climate change impacts on species’ distributional range shifts and extinction probability. However, different GCMs do not perform equally well in their ability to hindcast the key climatic factors that potentially influence species distributions. Previous research has demonstrated that multi‐model ensemble forecasts perform better than any single GCM in simulating observed conditions at a global scale. MAGICC/SCENGEN 5.3 is a freeware climate model ‘emulator’ that generates multi‐model ensemble forecasts, conditional on regional and/or global performance, for up to twenty GCMs. In combination with a new application ‘M/SGridder’, this software can be used to produce down‐scaled ensemble forecasts, which minimize climate‐model‐related uncertainty, for a range of ecological problems.     

A stochastic model of the dynamics of host-pathogen systems with mutation

In this paper a stochastic model of the dynamics of host-pathogen systems with mutation is constructed. In previous works deterministic models of host-pathogen systems with no mutation were considered. The evolution of the pathogen population in any generation of the host is formulated as a multidimensional birth and death process, while the evolution of genotypic frequencies in successive generations of the host is described by a solution of a nonlinear vector difference equation. A general solution of the differential equations of the multidimensional birth and death process is presented and expressions for the stationary distribution, whenever it exists, and the mean time to extinction, when absorbing states are present, are derived. Some answers to questions raised in the discussion of a previous paper (Mode, 1962) are also contained in this paper. The research reported in this paper was supported by the United States Atomic Energy Comission, Division of Biology and Medicine Project AT(45-1)-1729.     

Steady states in random nets: I

A neural net is taken to consist of a semi-infinite chain of neurons with connections distributed according to a certain probability frequency of the lengths of the axones. If an input of excitation is “fed” into the net from an outside source, the statistical properties of the net determine a certain steady state output. The general functional relation between the input and the output is derived as an integral equation. For a certain type of probability distribution of connections, this equation is reducible to a differential equation. The latter can be solved by elementary methods for the output in terms of the input in general and for the input in terms of the output in special cases.     

The most likely voltage path and large deviations approximations for integrate-and-fire neurons

We develop theory and numerical methods for computing the most likely subthreshold voltage path of a noisy integrate-and-fire (IF) neuron, given observations of the neuron’s superthreshold spiking activity. This optimal voltage path satisfies a second-order ordinary differential (Euler-Lagrange) equation which may be solved analytically in a number of special cases, and which may be solved numerically in general via a simple “shooting” algorithm. Our results are applicable for both linear and nonlinear subthreshold dynamics, and in certain cases may be extended to correlated subthreshold noise sources. We also show how this optimal voltage may be used to obtain approximations to (1) the likelihood that an IF cell with a given set of parameters was responsible for the observed spike train; and (2) the instantaneous firing rate and interspike interval distribution of a given noisy IF cell. The latter probability approximations are based on the classical Freidlin-Wentzell theory of large deviations principles for stochastic differential equations. We close by comparing this most likely voltage path to the true observed subthreshold voltage trace in a case when intracellular voltage recordings are available in vitro. Action Editor: Peter Latham     

Random effects in population models with hereditary effects

This paper discusses the influence of environmental noise on the dynamics of single species population models with hereditary effects. A detailed analysis is carried out for the logistic equation with discrete delay in the resource limitation term (Hutchinson's equation). When the system undergoes Hopf bifurcation, we find the stationary probability density distribution for the amplitude of the periodic solution by means of an averaged Fokker-Planck equation. Finally, we estimate the persistence time of the species when the population density has a lower bound beyond which it goes extinct.     

Incorporation of variability into the modeling of viral delays in HIV infection dynamics

We consider classes of functional differential equation models which arise in attempts to describe temporal delays in HIV pathogenesis. In particular, we develop methods for incorporating arbitrary variability (i.e., general probability distributions) for these delays into systems that cannot readily be reduced to a finite number of coupled ordinary differential equations (as is done in the method of stages). We discuss modeling from first principles, introduce several classes of non-linear models (including discrete and distributed delays) and present a discussion of theoretical and computational approaches. We then use the resulting methodology to carry out simulations and perform parameter estimation calculations, fitting the models to a set of experimental data. Results obtained confirm the statistical significance of the presence of delays and the importance of including delays in validating mathematical models with experimental data. We also show that the models are quite sensitive to the mean of the distribution which describes the delay in viral production, whereas the variance of this distribution has relatively little impact.     

A dynamical approach to chemical kinetics: Mass-action laws as generalized Riccati equations

It is shown how the fundamental laws of chemical kinetics for either open or closed systems with an arbitrarily large number of reactants can be represented as a system of Riccati-like differential equations. Through the use of a concise tensor notation, it is shown when and how the differential system is exactly reducible to linear form, a reduction without approximation that parallels the well-known similar reduction of a single simle Riccati equation. An example is worked out to show how open kinetics can lead to oscillatory chemical concentrations of the Change-Higgins type. The biologically central problem of great chemical speciation is discussed from the viewpoint of Gibbs ensemble theory within the linearized kinetics and, approximately, within the starting nonlinear kinetics where it is shown roughly how to estimate, from an overall temperature-like parameter characterizing the whole system, mean chemical levels and mean frequencies of oscillation, and where a gross oscillation of the total mass is estimated in terms of an anharmonic oscillator whose general structure is fixed from the structure of the chemical kinetic laws.     

Structural forecasting of species persistence under changing environments

The persistence of a species in a given place not only depends on its intrinsic capacity to consume and transform resources into offspring, but also on how changing environmental conditions affect its growth rate. However, the complexity of factors has typically taken us to choose between understanding and predicting the persistence of species. To tackle this limitation, we propose a probabilistic approach rooted on the statistical concepts of ensemble theory applied to statistical mechanics and on the mathematical concepts of structural stability applied to population dynamics models – what we call structural forecasting. We show how this new approach allows us to estimate a probability of persistence for single species in local communities; to understand and interpret this probability conditional on the information we have concerning a system; and to provide out‐of‐sample predictions of species persistence as good as the best experimental approaches without the need of extensive amounts of data.     

The frequency-dependent Wright–Fisher model: diffusive and non-diffusive approximations

We study a class of processes that are akin to the Wright–Fisher model, with transition probabilities weighted in terms of the frequency-dependent fitness of the population types. By considering an approximate weak formulation of the discrete problem, we are able to derive a corresponding continuous weak formulation for the probability density. Therefore, we obtain a family of partial differential equations for the evolution of the probability density, and which will be an approximation of the discrete process in the joint large population, small time-steps and weak selection limit. If the fitness functions are sufficiently regular, we can recast the weak formulation in a more standard formulation, without any boundary conditions, but supplemented by a number of conservation laws. The equations in this family can be purely diffusive, purely hyperbolic or of convection–diffusion type, with frequency dependent convection. The particular outcome will depend on the assumed scalings. The diffusive equations are of the degenerate type; using a duality approach, we also obtain a frequency dependent version of the Kimura equation without any further assumptions. We also show that the convective approximation is related to the replicator dynamics and provide some estimate of how accurate is the convective approximation, with respect to the convective-diffusion approximation. In particular, we show that the mode, but not the expected value, of the probability distribution is modelled by the replicator dynamics. Some numerical simulations that illustrate the results are also presented.     

Similarity Measures for Protein Ensembles

Analyses of similarities and changes in protein conformation can provide important information regarding protein function and evolution. Many scores, including the commonly used root mean square deviation, have therefore been developed to quantify the similarities of different protein conformations. However, instead of examining individual conformations it is in many cases more relevant to analyse ensembles of conformations that have been obtained either through experiments or from methods such as molecular dynamics simulations. We here present three approaches that can be used to compare conformational ensembles in the same way as the root mean square deviation is used to compare individual pairs of structures. The methods are based on the estimation of the probability distributions underlying the ensembles and subsequent comparison of these distributions. We first validate the methods using a synthetic example from molecular dynamics simulations. We then apply the algorithms to revisit the problem of ensemble averaging during structure determination of proteins, and find that an ensemble refinement method is able to recover the correct distribution of conformations better than standard single-molecule refinement.     

Dynamics of Competition between Subnetworks of Spiking Neuronal Networks in the Balanced State

We explore and analyze the nonlinear switching dynamics of neuronal networks with non-homogeneous connectivity. The general significance of such transient dynamics for brain function is unclear; however, for instance decision-making processes in perception and cognition have been implicated with it. The network under study here is comprised of three subnetworks of either excitatory or inhibitory leaky integrate-and-fire neurons, of which two are of the same type. The synaptic weights are arranged to establish and maintain a balance between excitation and inhibition in case of a constant external drive. Each subnetwork is randomly connected, where all neurons belonging to a particular population have the same in-degree and the same out-degree. Neurons in different subnetworks are also randomly connected with the same probability; however, depending on the type of the pre-synaptic neuron, the synaptic weight is scaled by a factor. We observed that for a certain range of the “within” versus “between” connection weights (bifurcation parameter), the network activation spontaneously switches between the two sub-networks of the same type. This kind of dynamics has been termed “winnerless competition”, which also has a random component here. In our model, this phenomenon is well described by a set of coupled stochastic differential equations of Lotka-Volterra type that imply a competition between the subnetworks. The associated mean-field model shows the same dynamical behavior as observed in simulations of large networks comprising thousands of spiking neurons. The deterministic phase portrait is characterized by two attractors and a saddle node, its stochastic component is essentially given by the multiplicative inherent noise of the system. We find that the dwell time distribution of the active states is exponential, indicating that the noise drives the system randomly from one attractor to the other. A similar model for a larger number of populations might suggest a general approach to study the dynamics of interacting populations of spiking networks.     

On mathematical theory of selection: continuous time population dynamics

Mathematical theory of selection is developed within the frameworks of general models of inhomogeneous populations with continuous time. Methods that allow us to study the distribution dynamics under natural selection and to construct explicit solutions of the models are developed. All statistical characteristics of interest, such as the mean values of the fitness or any trait can be computed effectively, and the results depend in a crucial way on the initial distribution. The developed theory provides an effective method for solving selection systems; it reduces the initial complex model to a special system of ordinary differential equations (the escort system). Applications of the method to the Price equations are given; the solutions of some particular inhomogeneous Malthusian, Ricker and logistic-like models used but not solved in the literature are derived in explicit form.