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An efficient stochastic diffusion algorithm for modeling second messengers in dendrites and spines.

Intracellular signaling pathways, which encompass both biochemical reactions and second messenger diffusion, interact non-linearly with neuronal membrane properties in their role as essential intermediaries for synaptic plasticity and neuromodulation. Computational modeling is a productive approach for investigating these phenomena; however, most current strategies for modeling neurons exclude signaling pathways. To overcome this deficiency, a new algorithm is presented to simulate stochastic diffusion in a highly efficient manner. The gain in speed is obtained by considering collections of molecules, instead of tracking the movement of individual molecules. The probability of a molecule leaving a spatially discrete compartment is used to create a lookup table that stores the probability of k(m) molecules leaving the compartment as a function of the total number of molecules in the compartment. During the simulation, the number of molecules leaving the compartment is determined using a uniform random number as an index into the lookup table. Simulations illustrate the accuracy of this algorithm by comparing it with the theoretical solution for deterministic diffusion. Additional simulations show how spines on a dendritic branch compartmentalize diffusible molecules. The efficiency of the algorithm is sufficient to allow simulation of second messenger pathways in a multitude of spines on an entire neuron.

Algorithms↗

On the resolution and feasibility of genome scanning approaches.

Before contemplating a genome scan to identify the map position of disease-predisposing genes, an investigator should have prior evidence of the genes' existence. It is therefore logically consistent to evaluate a genome scan experiment as an estimation problem, rather than as a hypothesis-testing problem, since absent prior evidence of the existence of disease genes, it is probably unwise to conduct the experiment at all. Recombination in a single meiosis can be modeled as a point process along the chromosome, and linkage or linkage disequilibrium (LD) mapping statistics are a simple function of the superposition of the recombination processes occurring in all meioses under study. Thus, multipoint lod scores are shown to be step functions, in the absence of ambiguity about the inheritance of chromosomal segments. The ability to map a disease gene is a function of how well the ascertained phenotypes predict the underlying trait locus genotypes. This chapter presents a thorough investigation of the properties of the multipoint lod score and uses results from renewal theory to examine the effects of deviations from a deterministic phenotype-genotype relationship. The quality of estimated gene locations is assessed through computing the mean and variance of the length of the expected 3-lod-unit support interval around the maximum likelihood estimate. The more deterministic the model, the smaller this interval is. A more exact quantification of details of this effect is used to describe the statistical properties of such genome scanning experiments from the perspective of estimation, with appropriately little regard to hypothesis testing. Hypothesis testing, however, is discussed as an appropriate context to describe linkage and LD analysis in situations where candidate genes are being screened, since only there does one have definable null and alternative hypotheses that have not been rejected before the beginning of the experiment. By contrast, it is hoped that the null hypothesis "there is no gene affecting this phenotype" has been rejected by other means before an expensive genome scan is even contemplated (though that this is often not done is probably the main problem!).

Chromosome Mapping↗

The effect of host heterogeneity and parasite intragenomic interactions on parasite population structure.

Understanding the processes that shape the genetic structure of parasite populations and the functional consequences of different parasite genotypes is critical for our ability to predict how an infection can spread through a host population and for the design of effective vaccines to combat infection and disease. Here, we examine how the genetic structure of parasite populations responds to host genetic heterogeneity. We consider the well-characterized molecular specificity of major histocompatibility complex binding of antigenic peptides to derive deterministic and stochastic models. We use these models to ask, firstly, what conditions favour the evolution of generalist parasite genotypes versus specialist parasite genotypes? Secondly, can parasite genotypes coexist in a population? We find that intragenomic interactions between parasite loci encoding antigenic peptides are pivotal in determining the outcome of evolution. Where parasite loci interact synergistically (i.e. the recognition of additional antigenic peptides has a disproportionately large effect on parasite fitness), generalist parasite genotypes are favoured. Where parasite loci act multiplicatively (have independent effects on fitness) or antagonistically (have diminishing effects on parasite fitness), specialist parasite genotypes are favoured. A key finding is that polymorphism is not stable and that, with respect to functionally important antigenic peptides, parasite populations are dominated by a single genotype.

Animals↗

Analysis of convergence of an evolutionary algorithm with self-adaptation using a stochastic Lyapunov function.

This paper analyses the convergence of evolutionary algorithms using a technique which is based on a stochastic Lyapunov function and developed within the martingale theory. This technique is used to investigate the convergence of a simple evolutionary algorithm with self-adaptation, which contains two types of parameters: fitness parameters, belonging to the domain of the objective function; and control parameters, responsible for the variation of fitness parameters. Although both parameters mutate randomly and independently, they converge to the "optimum" due to the direct (for fitness parameters) and indirect (for control parameters) selection. We show that the convergence velocity of the evolutionary algorithm with self-adaptation is asymptotically exponential, similar to the velocity of the optimal deterministic algorithm on the class of unimodal functions. Although some martingale inequalities have not be proved analytically, they have been numerically validated with 0.999 confidence using Monte-Carlo simulations.

Adaptation, Biological↗

The diagnostic path, a useful visualisation tool in virtual microscopy.

BACKGROUND: The Virtual Microscopy based on completely digitalised histological slide. Concerning this digitalisation many new features in mircoscopy can be processed by the computer. New applications are possible or old, well known techniques of image analyses can be adapted for routine use. AIMS: A so called diagnostic path observes in the way of a professional sees through a histological virtual slide combined with the text information of the dictation process. This feature can be used for image retrieval, quality assurance or for educational purpose. MATERIALS AND METHODS: The diagnostic path implements a metadata structure of image information. It stores and processes the different images seen by a pathologist during his "slide viewing" and the obtained image sequence ("observation path"). Contemporary, the structural details of the pathology reports were analysed. The results were transferred into an XML structure. Based on this structure, a report editor and a search function were implemented. The report editor compiles the "diagnostic path", which is the connection from the image viewing sequence ("observation path") and the oral report sequence of the findings ("dictation path"). The time set ups of speech and image viewing serve for the link between the two sequences. The search tool uses the obtained diagnostic path. It allows the user to search for particular histological hallmarks in pathology reports and in the corresponding images. RESULTS: The new algorithm was tested on 50 pathology reports and 74 attached histological images. The creation of a new individual diagnostic path is automatically performed during the routine diagnostic process. The test prototype experienced an insignificant prolongation of the diagnosis procedure (oral case description and stated diagnosis by the pathologist) and a fast and reliable retrieval, especially useful for continuous education and quality control of case description and diagnostic work. DISCUSSION: The Digital Virtual Microscope has been designed to handle 1000 images per day in the daily routine work of a pathology institution. It implies the necessity of an automatic mechanism of image meta dating. The non - deterministic correlation between the oral statements (case report) and image information content guides the image meta dating. The presented software opens up new possibilities for a content oriented search in a virtual slide, and can successfully support medical education and diagnostic quality assurance.

Journal Article↗

[Mathematical models in epidemiology: Study on viral hepatitis in Italy (author's transl)].

In this paper a mathematical approach to the epidemics is proposed. The method is based upon a model able to describe any time-depending phenomena using the following elements: "class", "transition" and "related probability". The solution of the differential equations describing the model are obtained: first, by numerical techniques; second, by a Montecarlo simulation method. Deterministic and stochastic solutions which have been obtained, by applying the model to the study of viral hepatitis in Italy during 1960--1970, have been compared each other, to improve the model itself.

Carrier State↗

A two-stage model for childhood acute lymphoblastic leukemia: application to hereditary and nonhereditary leukemogenesis.

A differential equation model is developed to represent a two-stage mutational process leading to childhood acute lymphoblastic leukemia (ALL). Leukemogenesis is modeled as transformation of target stem cells that initially grow rapidly in the embryo but plateau and then decline in postnatal childhood. Inheritance of the first of two leukemogenic mutations is allowed as a possibility in a small minority of leukemic patients who would characteristically develop leukemia at an early age. The model is shown to be capable of providing good fits to incidence data for childhood ALL; these fits allow estimation of some parameters of the model. The analysis shows that individuals inheriting one of the two mutations necessary for ALL would be likely to experience "multiclonal leukemogenesis"; that is, the parallel development of several leukemic clones arising from multiple independent leukemic events. The model suggests that between two and ten such clones would typically have developed in such individuals by the time of diagnosis. The main conclusions of the deterministic investigation were confirmed by stochastic modeling. The existence of multiclonal leukemogenesis is in principle testable by molecular biological methods (clonality analysis) that rely on the random inactivation of one of two X-chromosomes in normal female subjects. It is expected that the mathematical methods developed here will also be useful for more general (N-stage) models of malignant transformation of stem cell populations undergoing growth or decline.

Aging↗

Wet weather water quality modelling of a Portuguese urban catchment: difficulties and benefits.

This paper discusses the use of water quality deterministic modelling together with an integrated approach to assess the impact of urban stormwater discharges into ephemeral watercourses, based on the study of a Portuguese catchment. The description of the main aspects, difficulties and benefits found during data collection and model calibration and verification is presented, and the associated uncertainties and errors discussed. Experimental results showed a strong short- and long-term impact of sewer discharges on rivers, and confirmed deposition, resuspension and transport of pollutants as important processes for the water quality. However, the resuspension of riverbed sediment pollutants during storms was probably more significant than the direct impact of the urban discharges. The HydroWorks model was used since it allows for the calculation of pollutant build-up on catchment surfaces and in gully pots, their wash-off, and the deposition and erosion of sediments in sewers. However, it uses several constants, which could not be independently calibrated, increasing the uncertainty already associated with the data. River flows have quite different magnitude from the sewer system overflows, which, together with the difficulties in evaluating river flow rates, makes the integrated modelling approach rather complex and costly.

Cities↗

Stochastic models of neuronal dynamics.

Cortical activity is the product of interactions among neuronal populations. Macroscopic electrophysiological phenomena are generated by these interactions. In principle, the mechanisms of these interactions afford constraints on biologically plausible models of electrophysiological responses. In other words, the macroscopic features of cortical activity can be modelled in terms of the microscopic behaviour of neurons. An evoked response potential (ERP) is the mean electrical potential measured from an electrode on the scalp, in response to some event. The purpose of this paper is to outline a population density approach to modelling ERPs. We propose a biologically plausible model of neuronal activity that enables the estimation of physiologically meaningful parameters from electrophysiological data. The model encompasses four basic characteristics of neuronal activity and organization: (i) neurons are dynamic units, (ii) driven by stochastic forces, (iii) organized into populations with similar biophysical properties and response characteristics and (iv) multiple populations interact to form functional networks. This leads to a formulation of population dynamics in terms of the Fokker-Planck equation. The solution of this equation is the temporal evolution of a probability density over state-space, representing the distribution of an ensemble of trajectories. Each trajectory corresponds to the changing state of a neuron. Measurements can be modelled by taking expectations over this density, e.g. mean membrane potential, firing rate or energy consumption per neuron. The key motivation behind our approach is that ERPs represent an average response over many neurons. This means it is sufficient to model the probability density over neurons, because this implicitly models their average state. Although the dynamics of each neuron can be highly stochastic, the dynamics of the density is not. This means we can use Bayesian inference and estimation tools that have already been established for deterministic systems. The potential importance of modelling density dynamics (as opposed to more conventional neural mass models) is that they include interactions among the moments of neuronal states (e.g. the mean depolarization may depend on the variance of synaptic currents through nonlinear mechanisms).Here, we formulate a population model, based on biologically informed model-neurons with spike-rate adaptation and synaptic dynamics. Neuronal sub-populations are coupled to form an observation model, with the aim of estimating and making inferences about coupling among sub-populations using real data. We approximate the time-dependent solution of the system using a bi-orthogonal set and first-order perturbation expansion. For didactic purposes, the model is developed first in the context of deterministic input, and then extended to include stochastic effects. The approach is demonstrated using synthetic data, where model parameters are identified using a Bayesian estimation scheme we have described previously.

Bayes Theorem↗

[New standards for radiation safety and effective dose].

The scientific bases and the peculiarities of the new radiation safety standards (RSS) implemented in Russia in april 1996 are considered. A comparison is made of the merits and shortcomings of both conceptions of standardization--by means of setting dose limits for the critical organs or by means of limiting the effective dose as a measure of the total radiation risk of late effects. The application of the effective dose to practice gives unquestionable advantages for assessing the sufficiency of arrangements providing radiation safety of personnel or public protection against radiation. However the use of the effective dose for individual dose monitoring is often not good (especially in the case of internal irradiation) due to wide variation caused by oversimplifications in the applied models. Essential shortcomings of the RSS-96 are also the absence of the permissible body burden of radionuclides among the derived standards and the regulation of the mean annual (unmeasurable) values of their concentration in air. It is proposed in addition to the effective dose which limits the risk of stochastic effects to reserve in the RSS the limits of equivalent doses for the main body organs (lungs, liver). This would eliminate the deterministic effects and give the possibility of differential evaluation of the irradiation pattern. It is also proposed to replace the reglamentation of mean annual concentrations of radionuclides in air by the reglamentation of their permissible concentration in the working zone.

Humans↗

Linking spatial processes to life-history evolution of insect parasitoids.

Understanding the evolutionary transition from solitary to group living in animals is a profound challenge to evolutionary ecologists. A special case is found in insect parasitoids, where a tolerant gregarious larval lifestyle evolved from an intolerant solitary ancestor. The conditions for this transition are generally considered to be very stringent. Recent studies have aimed to identify conditions that facilitate the spread of a gregarious mutant. However, until now, ecological factors have not been included. Host distributions and life-history trade-offs affect the distribution of parasitoids in space and thus should determine the evolution of gregariousness. We add to current theory by using deterministic models to analyze the role of these ecological factors in the evolution of gregariousness. Our results show that gregariousness is facilitated through inversely density-dependent patch exploitation. In contrast, host density dependence in parasitoid distribution and patch exploitation impedes gregariousness. Numerical solutions show that an aggressive gregarious form can more easily invade a solitary population than can a tolerant form. Solitary forms can more easily invade a gregarious, tolerant population than vice versa. We discuss our results in light of exploitation of multitrophic chemical cues by searching parasitoids and aggregative and defensive behavior in herbivorous hosts.

Animals↗

Evidence of chaotic mood variation in bipolar disorder.

BACKGROUND: Using long-term daily mood records obtained from patients with bipolar disorder and normal subjects, we sought to determine the temporal pattern of mood in bipolar disorder. METHODS: Time series of 1.0 to 2.5 years from seven rapid-cycling patients with bipolar disorder and 28 normal controls were obtained. These were evaluated with several techniques to identify whether the temporal pattern of mood originates from a periodic, a random, or a deterministic source. RESULTS: True cyclicity was not apparent in the power spectra of either the normal subjects or the patients with bipolar disorder. Instead, spectra with a broadband "l/f" shape were observed in both groups, and these spectra were significantly flatter in normal subjects (P = .02). Correlation dimension estimates are a measure of nonlinear deterministic structure, and convergent estimates could be obtained for six of the seven patients with bipolar disorder and none of the normal subjects (P < .001). Additional findings are consistent with these results. CONCLUSIONS: These studies indicate that mood in patients with bipolar disorder is not truly cyclic for extended periods. Nonetheless, self-rated mood in bipolar disorder is significantly more organized than self-rated mood in normal subjects and can be characterized as a low-dimensional chaotic process. This characterization of the dynamics of bipolar disorder provides a unitary theoretical framework that can accommodate neurobiologic and psychosocial data and can reconcile existing models for the pathogenesis of the disorder. Furthermore, consideration of the dynamical structure of bipolar disorder may lead to new methods for predicting and controlling pathologic mood.

Adult↗

Estimation of the dimensionality of sleep-EEG data in schizophrenics.

Deterministic chaos could be regarded as a healthy flexibility of the human brain necessary for correct neuronal operations. Several investigations have demonstrated that in healthy subjects the dimensionality of REM sleep is much higher than that of slow wave sleep (SWS). We investigated the sleep-EEG of schizophrenic patients with methods from nonlinear system theory in order to estimate the dynamic properties of CNS. We hypothesized that schizophrenics would reveal alterations of their dynamic EEG features indicating impaired information processing. In 11 schizophrenic patients, the EEG's dimensionality during sleep stages II and REM was reduced. We suggest that such lower dimensional chaotic processes might be associated with an overloading of neuronal networks during sleep and therefore the psychopathology of schizophrenics might be due to impaired complexity of their EEG's dynamics.

Adult↗

A decision-tree to optimise control measures during the early stage of a foot-and-mouth disease epidemic.

A decision-tree was developed to support decision making on control measures during the first days after the declaration of an outbreak of foot-and-mouth disease (FMD). The objective of the tree was to minimise direct costs and export losses of FMD epidemics under several scenarios based on livestock and herd density in the outbreak region, the possibility of airborne spread, and the time between first infection and first detection. The starting point of the tree was an epidemiological model based on a deterministic susceptible-infectious-recovered approach. The effect of four control strategies on FMD dynamics was modelled. In addition to the standard control strategy of stamping out and culling of high-risk contact herds, strategies involving ring culling within 1 km of an infected herd, ring-vaccination within 1 km of an infected herd, and ring-vaccination within 3 km of an infected herd were assessed. An economic model converted outbreak and control effects of farming and processing operations into estimates of direct costs and export losses. Ring-vaccination is the economically optimal control strategy for densely populated livestock areas whereas ring culling is the economically optimal control strategy for sparsely populated livestock areas.

Animal Husbandry↗

Decision rules in the perception and categorization of multidimensional stimuli.

This article examines decision processes in the perception and categorization of stimuli constructed from one or more components. First, a general perceptual theory is used to formally characterize large classes of existing decision models according to the type of decision boundary they predict in a multidimensional perceptual space. A new experimental paradigm is developed that makes it possible to accurately estimate a subject's decision boundary in a categorization task. Three experiments using this paradigm are reported. Three conclusions stand out: (a) Subjects adopted deterministic decision rules, that is, for a given location in the perceptual space, most subjects always gave the same response; (b) subjects used decision rules that were nearly optimal; and (c) the only constraint on the type of decision bound that subjects used was the amount of cognitive capacity it required to implement. Subjects were not constrained to make independent decisions on each component or to attend to the distance to each prototype.

Attention↗

Dynamics of moments of FitzHugh-Nagumo neuronal models and stochastic bifurcations.

For the study of the behavior of noisy neuronal models, Rodriguez and Tuckwell have introduced an elegant and systematic method which consists of replacing the system of stochastic differential equations with a system of deterministic equations representing the dynamics of the means, variances, and covariance of the state variables [R. Rodriguez and H.C. Tuckwell, Phys. Rev. E 54, 5585 (1996)]. In this work, we first report a modification of their method in the case of the FitzHugh-Nagumo model which enhances the accuracy of the approximation without including higher order moments. This method is then combined with a self-consistency argument in order to better characterize the behavior of the underlying stochastic processes through the computation of approximate auto- and cross-correlation functions of the state variables. Finally, we argue that the moments' equations can also reveal the existence of stochastic bifurcations, i.e., qualitative changes in the dynamics of stochastic systems.

Action Potentials↗

Bridging rate coding and temporal spike coding by effect of noise.

It is controversial whether temporal spike coding or rate coding is dominant in the information processing of the brain. We show by a two-layered neural network model with noise that, when noise is small, cortical neurons fire synchronously and intervals of synchronous firing robustly encode the signal information, but that the neurons desynchronize with moderately strong noise to encode waveforms of the signal more accurately. Further increase of noise just deteriorates the encoding. A positive role of noise in the brain is suggested in a meaning different from stochastic resonance, coherence resonance, and deterministic chaos.

Action Potentials↗

Power spectral analysis of the shape of fMLP-stimulated granulocytes. A tool for the study of cytoskeletal organization under normal and pathological conditions.

fMLP (N-formyl-methionyl-leucyl-phenylalanine) is a powerful activator of granulocytes, eliciting different metabolic responses, such as generation of reactive oxygen species, production of arachidonic acid metabolites, and release of lysosomal enzymes. fMLP determines also a dramatic rearrangement of the actin cytoskeleton; under non-gradient conditions this entails characteristic alterations in cell shape (chemokinesis), while under gradient conditions it is instrumental in promoting cell migration up the gradient (chemotaxis). Here we analyze mathematically the cell contour of fMLP-stimulated human granulocytes stimulated with fMLP under non-gradient conditions, using the methods for study of stochastic series. The cell contours were drawn and divided into 200 segments of equal linear length and the angles between consecutive segments were computed. The derived series of angles were examined for autocorrelations and from the autocorrelation function the power spectrum was calculated. Our results show that the pattern of lamellipodial extensions of the cell membrane is not entirely randomly-designed, but it is partly regulated by deterministic components, as revealed by the presence of statistically significant periodicities. Soon after fMLP stimulation, the power spectrum of the cell contours exhibits a single distinct peak at frequency 0.07, indicating a prevalence of prominent lamellipodia, each one covering in the average 1/15 of the linearized cell contour. Some 30 min after fMLP stimulation the power spectrum becomes flatter (indicating a general decrement of the deterministic component), but still presents one single peak; the latter is shifted to the right (frequency 0.13), indicating the prevalence of less prominent and regular, but more numerous, protrusions, each one covering 1/20 to 1/30 of the cell contour.

Cytoskeleton↗