The Moments of Stochastic Integrals and the Distribution of Sojourn Times

For a single diallelic locus in a finite population with any time-independent selection scheme, using the diffusion approximation, a formula is derived in terms of sojourn times for the moments of the integral of an arbitrary function of gene frequency along sample paths. Irreversible mutation and conditioned and unconditioned processes without mutation are treated. From this expression, the differential equation satisfied by the moments follows directly, and the exact probability distribution of sojourn times is deduced. An independent probabilistic proof of the last result based on the properties of time-homogeneous Markov processes is presented.     

A Local Equation for Differential Diagnosis of β-Thalassemia Trait and Iron Deficiency Anemia by Logistic Regression Analysis in Southeast Iran

The most common differential diagnosis of β-thalassemia (β-thal) trait is iron deficiency anemia. Several red blood cell equations were introduced during different studies for differential diagnosis between β-thal trait and iron deficiency anemia. Due to genetic variations in different regions, these equations cannot be useful in all population. The aim of this study was to determine a native equation with high accuracy for differential diagnosis of β-thal trait and iron deficiency anemia for the Sistan and Baluchestan population by logistic regression analysis. We selected 77 iron deficiency anemia and 100 β-thal trait cases. We used binary logistic regression analysis and determined best equations for probability prediction of β-thal trait against iron deficiency anemia in our population. We compared diagnostic values and receiver operative characteristic (ROC) curve related to this equation and another 10 published equations in discriminating β-thal trait and iron deficiency anemia. The binary logistic regression analysis determined the best equation for best probability prediction of β-thal trait against iron deficiency anemia with area under curve (AUC) 0.998. Based on ROC curves and AUC, Green & King, England & Frazer, and then Sirdah indices, respectively, had the most accuracy after our equation. We suggest that to get the best equation and cut-off in each region, one needs to evaluate specific information of each region, specifically in areas where populations are homogeneous, to provide a specific formula for differentiating between β-thal trait and iron deficiency anemia.     

A stochastic spectral analysis of transcriptional regulatory cascades

The past decade has seen great advances in our understanding of the role of noise in gene regulation and the physical limits to signaling in biological networks. Here, we introduce the spectral method for computation of the joint probability distribution over all species in a biological network. The spectral method exploits the natural eigenfunctions of the master equation of birth – death processes to solve for the joint distribution of modules within the network, which then inform each other and facilitate calculation of the entire joint distribution. We illustrate the method on a ubiquitous case in nature: linear regulatory cascades. The efficiency of the method makes possible numerical optimization of the input and regulatory parameters, revealing design properties of, e.g., the most informative cascades. We find, for threshold regulation, that a cascade of strong regulations converts a unimodal input to a bimodal output, that multimodal inputs are no more informative than bimodal inputs, and that a chain of up-regulations outperforms a chain of down-regulations. We anticipate that this numerical approach may be useful for modeling noise in a variety of small network topologies in biology.     

Subnets of scale-free networks are not scale-free: sampling properties of networks

Most studies of networks have only looked at small subsets of the true network. Here, we discuss the sampling properties of a network's degree distribution under the most parsimonious sampling scheme. Only if the degree distributions of the network and randomly sampled subnets belong to the same family of probability distributions is it possible to extrapolate from subnet data to properties of the global network. We show that this condition is indeed satisfied for some important classes of networks, notably classical random graphs and exponential random graphs. For scale-free degree distributions, however, this is not the case. Thus, inferences about the scale-free nature of a network may have to be treated with some caution. The work presented here has important implications for the analysis of molecular networks as well as for graph theory and the theory of networks in general.     

An information theory model of hydrophobic interactions

A molecular model of poorly understood hydrophobic effects is heuristically developed using the methods of information theory. Because primitive hydrophobic effects can be tied to the probability of observing a molecular-sized cavity in the solvent, the probability distribution of the number of solvent centers in a cavity volume is modeled on the basis of the two moments available from the density and radial distribution of oxygen atoms in liquid water. The modeled distribution then yields the probability that no solvent centers are found in the cavity volume. This model is shown to account quantitatively for the central hydrophobic phenomena of cavity formation and association of inert gas solutes. The connection of information theory to statistical thermodynamics provides a basis for clarification of hydrophobic effects. The simplicity and flexibility of the approach suggest that it should permit applications to conformational equilibria of nonpolar solutes and hydrophobic residues in biopolymers.     

Effect of temporal fluctuation of selection coefficient on gene frequency in a population.

The diffusion equations describing the change of gene frequencies are extended to indlude the effect of temporal fluctuation of selection coefficient that may persist for some generations. The equilibrium distribution of gene frequencies and the fixation probability of a mutant gene are obtained from the extended equations. Comparison is made with the experimental data on protein polymorphism. A possible bearing of the fluctuation of selection coefficient on the problem of molecular evolution is discussed in relation to the neutral theory.     

Anomalous yet Brownian

We describe experiments using single-particle tracking in which mean-square displacement is simply proportional to time (Fickian), yet the distribution of displacement probability is not Gaussian as should be expected of a classical random walk but, instead, is decidedly exponential for large displacements, the decay length of the exponential being proportional to the square root of time. The first example is when colloidal beads diffuse along linear phospholipid bilayer tubes whose radius is the same as that of the beads. The second is when beads diffuse through entangled F-actin networks, bead radius being less than one-fifth of the actin network mesh size. We explore the relevance to dynamic heterogeneity in trajectory space, which has been extensively discussed regarding glassy systems. Data for the second system might suggest activated diffusion between pores in the entangled F-actin networks, in the same spirit as activated diffusion and exponential tails observed in glassy systems. But the first system shows exceptionally rapid diffusion, nearly as rapid as for identical colloids in free suspension, yet still displaying an exponential probability distribution as in the second system. Thus, although the exponential tail is reminiscent of glassy systems, in fact, these dynamics are exceptionally rapid. We also compare with particle trajectories that are at first subdiffusive but Fickian at the longest measurement times, finding that displacement probability distributions fall onto the same master curve in both regimes. The need is emphasized for experiments, theory, and computer simulation to allow definitive interpretation of this simple and clean exponential probability distribution.     

Random walk theory of a trap-controlled hopping transport process

A random walk theory of hopping motion in the presence of a periodic distribution of traps is presented. The solution of the continuous-time random walk equations is exact and valid for arbitrary intersite interactions and trap concentration. The treatment is shown to be equivalent to an exact solution of the master equation for this trapping problem. These interactions can be a general function of electric field and are not restricted to nearest neighbors. In particular, with the inclusion of trap-to-trap interactions, as well as trap-to-host interactions, an exact treatment of the change from one hopping channel to another has been obtained. The trap-modulated propagator has been derived in terms of a type of Green's function that is introduced. The results are specialized to spatial moments of the propagator, from which expressions for the drift velocity and diffusion coefficient are obtained. Numerical results for the drift velocity are presented and shown to account for the change in hopping channels in recent transport measurements in mixed molecularly doped polymers.     

Probability landscape of heritable and robust epigenetic state of lysogeny in phage lambda

Computational studies of biological networks can help to identify components and wirings responsible for observed phenotypes. However, studying stochastic networks controlling many biological processes is challenging. Similar to Schrödinger’s equation in quantum mechanics, the chemical master equation (CME) provides a basic framework for understanding stochastic networks. However, except for simple problems, the CME cannot be solved analytically. Here we use a method called discrete chemical master equation (dCME) to compute directly the full steady-state probability landscape of the lysogeny maintenance network in phage lambda from its CME. Results show that wild-type phage lambda can maintain a constant level of repressor over a wide range of repressor degradation rate and is stable against UV irradiation, ensuring heritability of the lysogenic state. Furthermore, it can switch efficiently to the lytic state once repressor degradation increases past a high threshold by a small amount. We find that beyond bistability and nonlinear dimerization, cooperativity between repressors bound to O_R1 and O_R2 is required for stable and heritable epigenetic state of lysogeny that can switch efficiently. Mutants of phage lambda lack stability and do not possess a high threshold. Instead, they are leaky and respond to gradual changes in degradation rate. Our computation faithfully reproduces the hair triggers for UV-induced lysis observed in mutants and the limitation in robustness against mutations. The landscape approach computed from dCME is general and can be applied to study broad issues in systems biology.     

An effective kinetic representation of fluctuation-driven neuronal networks with application to simple and complex cells in visual cortex

A coarse-grained representation of neuronal network dynamics is developed in terms of kinetic equations, which are derived by a moment closure, directly from the original large-scale integrate-and-fire (I&F) network. This powerful kinetic theory captures the full dynamic range of neuronal networks, from the mean-driven limit (a limit such as the number of neurons N --> infinity, in which the fluctuations vanish) to the fluctuation-dominated limit (such as in small N networks). Comparison with full numerical simulations of the original I&F network establishes that the reduced dynamics is very accurate and numerically efficient over all dynamic ranges. Both analytical insights and scale-up of numerical representation can be achieved by this kinetic approach. Here, the theory is illustrated by a study of the dynamical properties of networks of various architectures, including excitatory and inhibitory neurons of both simple and complex type, which exhibit rich dynamic phenomena, such as, transitions to bistability and hysteresis, even in the presence of large fluctuations. The implication for possible connections between the structure of the bifurcations and the behavior of complex cells is discussed. Finally, I&F networks and kinetic theory are used to discuss orientation selectivity of complex cells for "ring-model" architectures that characterize changes in the response of neurons located from near "orientation pinwheel centers" to far from them.     

On the law of the iterated logarithm

The law of the iterated logarithm provides a family of bounds all of the same order such that with probability one only finitely many partial sums of a sequence of independent and identically distributed random variables exceed some members of the family, while for others infinitely many do so. In the former case, the total number of such excesses has therefore a proper probability distribution, and it is shown here that whenever the law applies this distribution possesses no moments of positive order. This result further elucidates the celebrated precision of this law of probability concerning fluctuations of sums of random variables.     

Superstatistics in nanoscale electrochemical systems

Stochastic electrochemical reaction steps on nanosized electrodes are non-Markovian when externally driven by an applied voltage. We show that, compared to the Markovian case (when external driving is absent), nanoscale electrochemical systems obey a superstatistics characterized by a superposition of Tsallis' q indices. The distribution of Tsallis' q indices along stochastic trajectories can be calculated from the electrochemical master equation and normal distributions from Boltzmann-Gibbs thermostatistics are recovered in the thermodynamic limit (the infinite electrode size limit). Although on the nanoscale the external control makes intricate correlations between the microstates, in the superstatistical frame one can still address the microstates as if they were uncorrelated. The resulting superstatistical entropic form is additive in this frame and Tsallis' indices have on the time-average values ≤ 1, which is, indeed, an example of a superstatistical system where no ad hoc distribution has to be assumed for the fluctuations; rather, the distribution is directly calculated from a mesoscopic master equation without freely adjustable parameters.     

Global epidemiology of HIV infection in men who have sex with men

Epidemics of HIV in men who have sex with men (MSM) continue to expand in most countries. We sought to understand the epidemiological drivers of the global epidemic in MSM and why it continues unabated. We did a comprehensive review of available data for HIV prevalence, incidence, risk factors, and the molecular epidemiology of HIV in MSM from 2007 to 2011, and modelled the dynamics of HIV transmission with an agent-based simulation. Our findings show that the high probability of transmission per act through receptive anal intercourse has a central role in explaining the disproportionate disease burden in MSM. HIV can be transmitted through large MSM networks at great speed. Molecular epidemiological data show substantial clustering of HIV infections in MSM networks, and higher rates of dual-variant and multiple-variant HIV infection in MSM than in heterosexual people in the same populations. Prevention strategies that lower biological transmission and acquisition risks, such as approaches based on antiretrovirals, offer promise for controlling the expanding epidemic in MSM, but their potential effectiveness is limited by structural factors that contribute to low health-seeking behaviours in populations of MSM in many parts of the world.     

Traffic-driven epidemic spreading in finite-size scale-free networks

The study of complex networks sheds light on the relation between the structure and function of complex systems. One remarkable result is the absence of an epidemic threshold in infinite-size, scale-free networks, which implies that any infection will perpetually propagate regardless of the spreading rate. The vast majority of current theoretical approaches assumes that infections are transmitted as a reaction process from nodes to all neighbors. Here we adopt a different perspective and show that the epidemic incidence is shaped by traffic-flow conditions. Specifically, we consider the scenario in which epidemic pathways are defined and driven by flows. Through extensive numerical simulations and theoretical predictions, it is shown that the value of the epidemic threshold in scale-free networks depends directly on flow conditions, in particular on the first and second moments of the betweenness distribution given a routing protocol. We consider the scenarios in which the delivery capability of the nodes is bounded or unbounded. In both cases, the threshold values depend on the traffic and decrease as flow increases. Bounded delivery provokes the emergence of congestion, slowing down the spreading of the disease and setting a limit for the epidemic incidence. Our results provide a general conceptual framework for the understanding of spreading processes on complex networks.     

Universal distribution of protein evolution rates as a consequence of protein folding physics

The hypothesis that folding robustness is the primary determinant of the evolution rate of proteins is explored using a coarse-grained off-lattice model. The simplicity of the model allows rapid computation of the folding probability of a sequence to any folded conformation. For each robust folder, the network of sequences that share its native structure is identified. The fitness of a sequence is postulated to be a simple function of the number of misfolded molecules that have to be produced to reach a characteristic protein abundance. After fixation probabilities of mutants are computed under a simple population dynamics model, a Markov chain on the fold network is constructed, and the fold-averaged evolution rate is computed. The distribution of the logarithm of the evolution rates across distinct networks exhibits a peak with a long tail on the low rate side and resembles the universal empirical distribution of the evolutionary rates more closely than either distribution resembles the log-normal distribution. The results suggest that the universal distribution of the evolutionary rates of protein-coding genes is a direct consequence of the basic physics of protein folding.