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PubMed2006

Single chain in mean field simulations: quasi-instantaneous field approximation and quantitative comparison with Monte Carlo simulations.

The description of fluctuations by single chain in mean field (SCMF) simulations is discussed and the results of this particle-based self-consistent field technique are quantitatively compared to Monte Carlo simulations of the same discretized Edwards-Hamiltonian providing exact reference data. In SCMF simulations one studies a large ensemble of noninteracting molecules subjected to real, external fields by Monte Carlo simulations. The external fields approximate nonbonded, instantaneous interactions between molecules. In the self-consistent mean field theory the external fields are static and fluctuation effects are ignored. In SCMF simulations, the external fields fluctuate since they are frequently recalculated from the instantaneous density distribution of the ensemble of molecules. In the limit of infinitely high density or instantaneous update of the external fields, the SCMF simulation method accurately describes long-wavelength fluctuations. At high but finite updating frequency the accuracy depends on the discretization of the model. The accuracy is illustrated by studying the single chain structure and intermolecular correlations in polymer melts, and fluctuation effects on the order-disorder transition of symmetric diblock copolymers.

Journal Article↗
PubMed2002

Right ventricular diastolic relaxation in conscious dog models of pressure overload, volume overload, and ischemia.

OBJECTIVE: Limitations in clinical understanding of right ventricular relaxation can be attributed to the paucity of information from basic studies in animal models of right ventricular disease. This study examined, in the conscious state, right ventricular relaxation dynamics under normal conditions (n = 15) and in subacute (2-5 weeks) canine models of right ventricular pressure overload (n = 6), volume overload (n = 7), and free wall ischemia (n = 7). METHODS: Right-heart micromanometric measurements were obtained by using multisensor catheters. A new algorithm was developed to obtain representative ensemble averages of hemodynamic waveform data sets. Right ventricular relaxation was analyzed by using an exponential model with 3 parameters: P(0), tau, and P(b). Significant changes versus control values were determined by means of analysis of variance and the Student unpaired t test with Bonferroni's adjustment. RESULTS: In the state of pressure overload, right ventricular pressure decay exhibits an increased P(0) (56.2 +/- 19.1 vs 13.1 +/- 5.1 mm Hg [mean +/- SD]) and prolonged tau (57.1 +/- 2.8 vs 27.8 +/- 3.9 ms); there is also a decreased P(b) (-7.9 +/- 1.5 vs 0.28 +/- 1.8 mm Hg). The only significant change in volume overload is an increased asymptote, P(b) (5.3 +/- 2.9 mm Hg). In right ventricular ischemia, prolongation of tau (41.4 +/- 13.0 ms) and decreased P(b) (-1.95 +/- 1.1 mm Hg) attain high significance. CONCLUSIONS: Distinctive abnormalities in right ventricular relaxation dynamics accompany pressure overload, volume overload, and ischemia and may contribute to clinical right ventricular dysfunction.

Animals↗
PubMed2003

Evolutionary algorithms for finding optimal gene sets in microarray prediction.

MOTIVATION: Microarray data has been shown recently to be efficacious in distinguishing closely related cell types that often appear in different forms of cancer, but is not yet practical clinically. However, the data might be used to construct a minimal set of marker genes that could then be used clinically by making antibody assays to diagnose a specific type of cancer. Here a replication algorithm is used for this purpose. It evolves an ensemble of predictors, all using different combinations of genes to generate a set of optimal predictors. RESULTS: We apply this method to the leukemia data of the Whitehead/MIT group that attempts to differentially diagnose two kinds of leukemia, and also to data of Khan et al. to distinguish four different kinds of childhood cancers. In the latter case we were able to reduce the number of genes needed from 96 to less than 15, while at the same time being able to classify all of their test data perfectly. We also apply this method to two other cases, Diffuse large B-cell lymphoma data (Shipp et al., 2002), and data of Ramaswamy et al. on multiclass diagnosis of 14 common tumor types. AVAILABILITY: http://stravinsky.ucsc.edu/josh/gesses/.

Algorithms↗
PubMed2002

A genetic algorithm for the identification of conformationally invariant regions in protein molecules.

Understanding macromolecular function often relies on the comparison of different structural models of a molecule. In such a comparative analysis, the identification of the part of the molecule that is conformationally invariant with respect to a set of conformers is a critical step, as the corresponding subset of atoms constitutes the reference for subsequent analysis for example by least-squares superposition. A method is presented that categorizes atoms in a molecule as either conformationally invariant or flexible by automatic analysis of an ensemble of conformers (e.g. crystal structures from different crystal forms or molecules related by non-crystallographic symmetry). Different levels of coordinate precision, both for different models and for individual atoms, are taken explicitly into account via a modified form of Cruickshank's DPI [Cruickshank (1999), Acta Cryst. D55, 583-601] and are propagated into error-scaled difference distance matrices [Schneider (2000), Acta Cryst. D56, 715-721]. All pairwise error-scaled difference distance matrices are then analysed simultaneously using a genetic algorithm. The algorithm has been tested on several well known examples and has been found to converge rapidly to reasonable results using a standard set of parameters. In addition to the description of the algorithm, a criterion is suggested for testing the identity of two three-dimensional models within experimental error without any explicit superposition.

Algorithms↗
PubMed1996

Somatic voltage-gated potassium currents of rat hippocampal pyramidal cells in organotypic slice cultures.

1. The dominant voltage-gated K+ currents in the somatic membrane of CA3 pyramidal cells from hippocampal slice cultures were characterized using the cell-attached configuration of the patch-clamp recording method. The kinetics, the voltage dependence of activation and inactivation, and the pharmacological properties of the current were determined from ensemble averages of large numbers of episodes from multichannel patches. 2. Steady-state analysis revealed that this current was half-inactivated at the resting membrane potential (Vr), and fully inactivated when patches were held 40 mV positive to Vr. Inactivation was removed when patches were hyperpolarized by 50 mV from Vr. Inactivation was well described by the Boltzmann equation with a slope factor of 12.6 mV. Removal of inactivation of the peak outward current could be described by a time-dependent monoexponential function with a time constant of the order of 100 ms. In contrast, the time course of inactivation was very slow: a +40 mV depolarization relative to Vr of several seconds was required for complete inactivation of the total outward current. 3. When steady-state inactivation was removed by hyperpolarization, the outward current activated with a threshold 10 mV positive to Vr and was half-activated at a potential 57 mV positive to Vr. The conductance can be described in terms of a single Boltzmann equation with a slope factor of 13.5 mV. Activation and inactivation properties of the somatic conductance produce a small window current between +10 and +20 mV relative to Vr. 4. The outward current activated in a voltage-dependent manner in less than 10 ms with 500 ms depolarizing steps. A kinetic analysis of its decay revealed at least three components, with the following time constants: a fast (17 ms), a slowly (approximately 150 ms), and a very slowly inactivating component (in the range of seconds). 5. External application of 4-aminopyridine (4-AP) induced a dose-dependent block of the peak outward current with an IC50 of 28 microM. The inhibitory effect of 4-AP saturated at a concentration of 200 microM which blocked 80% of the total current. The slowly and very slowly inactivating components of the current were not observed with 20 mM tetraethylammonium (TEA) in the pipette solution. A fast transient ensemble current (mean decay time constant, 24 ms) persisted in the presence of extracellular TEA in 29% of the patches. 6. In summary, at least two distinct voltage-gated K+ currents were present at the somatic level of hippocampal pyramidal cells. The dominant one, which we named IK(AT), is sensitive to micromolar concentrations of 4-AP and millimolar concentrations of TEA, and contributes three kinetic components to the total outward current. The second is TEA insensitive, and contributes only a fast transient component of outward current probably corresponding to the classic A-type K+ current. Intracellular recordings in CA3 pyramidal cells showed that IK(AT) plays an important role in regulating the duration of the action potential.

4-Aminopyridine↗
PubMed1974

Distributed relaxation processes in sensory adaptation.

Dynamic description of most receptors, even in their near-linear ranges, has not led to understanding of the underlying physical events-in many instances because their curious transfer functions are not found in the usual repertoire of integral-order control-system analysis. We have described some methods, borrowed from other fields, which allow one to map any linear frequency response onto a putative weighting over an ensemble of simpler relaxation processes. One can then ask whether the resultant weighting of such processes suggests a corresponding plausible distribution of values for an appropriate physical variable within the sensory transducer. To illustrate this approach, we have chosen the fractional-order low-frequency response of Limulus lateral-eye photoreceptors. We show first that the current "adapting-bump" hypothesis for the generator potential can be formulated in terms of local first-order relaxation processes in which local light flux, the cross section of rhodopsin for photon capture, and restoration rate of local conductance-changing capability play specific roles. A representative spatial distribution for one of these parameters, which just accounts for the low-frequency response of the receptor, is then derived and its relation to cellular properties and recent experiments is examined. Finally, we show that for such a system, nonintegral-order dynamics are equivalent to nonhyperbolic statics, and that the efficacy distribution derived to account for the small-signal dynamics in fact predicts several decades of near-logarithmic response in the steady state. Encouraged by the result that one plausible proposal can account approximately for both the low-frequency dynamics (the transfer function s(k)) and the range-compressing statics (the Weber-Fechner relationship) measured in this photoreceptor, we have described some formally similar applications of these distributed effects to the vertebrate retina and to analogous properties of mechanoreceptors and chemoreceptors.

Action Potentials↗
PubMed2004

M-CGH: analysing microarray-based CGH experiments.

BACKGROUND: Microarray-based comparative genomic hybridisation (array CGH) is a technique by which variation in relative copy numbers between two genomes can be analysed by competitive hybridisation to DNA microarrays. This technology has most commonly been used to detect chromosomal amplifications and deletions in cancer. Dedicated tools are needed to analyse the results of such experiments, which include appropriate visualisation, and to take into consideration the physical relation in the genome between the probes on the array. RESULTS: M-CGH is a MATLAB toolbox with a graphical user interface designed specifically for the analysis of array CGH experiments, with multiple approaches to ratio normalization. Specifically, the distributions of three classes of DNA copy numbers (gains, normal and losses) can be estimated using a maximum likelihood method. Amplicon boundaries are computed by either the fuzzy K-nearest neighbour method or a wavelet approach. The program also allows linking each genomic clone with the corresponding genomic information in the Ensembl database http://www.ensembl.org. CONCLUSIONS: M-CGH, which encompasses the basic tools needed for analysing array CGH experiments, is freely available for academics http://www.uio.no/~junbaiw/mcgh, and does not require any other MATLAB toolbox.

Chromosomes, Artificial, Bacterial↗
PubMed2006

Oriented ensembles in ultrafast electron diffraction.

Electron scattering expressions are presented which are applicable to very general conditions of implementation of anisotropic ultrafast electron diffraction (UED) experiments on the femto- and picosecond time scale. "Magic angle" methods for extracting from the experimental diffraction patterns both the isotropic scalar contribution (population dynamics) and the angular (orientation-dependent) contribution are described. To achieve this result, the molecular scattering intensity is given as an expansion in terms of the moments of the transition-dipole distribution created by the linearly polarized excitation laser pulse. The isotropic component (n=0 moment) depends only on population and scalar internuclear separations, and the higher moments reflect bond angles and evolve in time due to rotational motion of the molecules. This clear analytical separation facilitates assessment of the role of experimental variables in determining the influence of anisotropic orientational distributions of the molecular ensembles on the measured diffraction patterns. Practical procedures to separate the isotropic and anisotropic components of experimental data are evaluated and demonstrated with application to reactions. The influence of vectorial properties (bond angles and rotational dynamics) on the anisotropic component adds a new dimension to UED, arising through the imposition of spatial order on otherwise randomly oriented ensembles.

Journal Article↗
PubMedDate not supplied

Prediction of n-octanol/water partition coefficients from PHYSPROP database using artificial neural networks and E-state indices.

A new method, ALOGPS v 2.0 (http://www.lnh.unil.ch/~itetko/logp/), for the assessment of n-octanol/water partition coefficient, log P, was developed on the basis of neural network ensemble analysis of 12 908 organic compounds available from PHYSPROP database of Syracuse Research Corporation. The atom and bond-type E-state indices as well as the number of hydrogen and non-hydrogen atoms were used to represent the molecular structures. A preliminary selection of indices was performed by multiple linear regression analysis, and 75 input parameters were chosen. Some of the parameters combined several atom-type or bond-type indices with similar physicochemical properties. The neural network ensemble training was performed by efficient partition algorithm developed by the authors. The ensemble contained 50 neural networks, and each neural network had 10 neurons in one hidden layer. The prediction ability of the developed approach was estimated using both leave-one-out (LOO) technique and training/test protocol. In case of interseries predictions, i.e., when molecules in the test and in the training subsets were selected by chance from the same set of compounds, both approaches provided similar results. ALOGPS performance was significantly better than the results obtained by other tested methods. For a subset of 12 777 molecules the LOO results, namely correlation coefficient r(2)= 0.95, root mean squared error, RMSE = 0.39, and an absolute mean error, MAE = 0.29, were calculated. For two cross-series predictions, i.e., when molecules in the training and in the test sets belong to different series of compounds, all analyzed methods performed less efficiently. The decrease in the performance could be explained by a different diversity of molecules in the training and in the test sets. However, even for such difficult cases the ALOGPS method provided better prediction ability than the other tested methods. We have shown that the diversity of the training sets rather than the design of the methods is the main factor determining their prediction ability for new data. A comparative performance of the methods as well as a dependence on the number of non-hydrogen atoms in a molecule is also presented.

Journal Article↗
PubMed1981

A posteriori time-varying filtering of averaged evoked potentials. I. Introduction and conceptual basis.

This paper forms a preface and introduction to a new method for the estimation of evoked potentials: a posteriori time-varying filtering. A simple evoked potential model, consisting of a transient signal and additive noise, is discussed and the underlying assumptions explicitly formulated. Assuming this model, the problem of estimating the signal from an ensemble is considered from the statistical and communication engineering point of view, along with a brief survey of he pertinent literature. It is explained why ensemble averaging, in general, does not provide the best estimate in the mean-square error sense. After a summary of the controversial aspects of time-invariant "a posteriori "Wiener' filtering", it is indicated how that method can be generalized to a time-varying counterpart, which is able to handle the essentially transient character of evoked potential waveforms. Finally, the new method is presented on a conceptual level and its application illustrated by examples.

Brain↗
PubMed2005

HOPE: a homotopy optimization method for protein structure prediction.

We use a homotopy optimization method, HOPE, to minimize the potential energy associated with a protein model. The method uses the minimum energy conformation of one protein as a template to predict the lowest energy structure of a query sequence. This objective is achieved by following a path of conformations determined by a homotopy between the potential energy functions for the two proteins. Ensembles of solutions are produced by perturbing conformations along the path, increasing the likelihood of predicting correct structures. Successful results are presented for pairs of homologous proteins, where HOPE is compared to a variant of Newton's method and to simulated annealing.

Algorithms↗
PubMed2005

SWIFT (sequence-wide investigation with Fourier transform): a software tool for identifying proteins of a given class from the unannotated genome sequence.

BACKGROUND: The ever increasing number of sequenced genomes calls for new analysis techniques, which can benefit from the methodologies developed in the field of signal processing. METHODS: The present paper addresses the question of searching a pattern of amino acids (not necessarily completely specified) by means of the cross-correlation of complex sequences, obtained after suitable coding of the original amino acid sequence. Subsequently, the proposed algorithm provides a flexible strategy in setting the border between the accepted and rejected ORFs, by means of the k-means clustering of the candidate ORFs. The search for the class of proteins specified by the pattern is carried out from the most basic level, i.e. the DNA sequence, without sifting through an ensemble of previously determined ORFs. Thus, an exhaustive examination of all the occurrences of the pattern in the genome is performed. RESULTS: The application of the method to the search of surface proteins in Gram-positive bacteria witnesses its efficacy, in terms of both sensitivity and specificity. The comparison with the usual (and somewhat arbitrary) choice of setting a fixed value for the threshold length of the putative ORF confirms the validity of the proposed approach.

Algorithms↗
PubMed2004

Folding of the villin headpiece subdomain from random structures. Analysis of the charge distribution as a function of pH.

The structure of the 36 residue villin headpiece subdomain is investigated with the electrostatically driven Monte Carlo method. The ECEPP/3 (Empirical Conformational Energy Program for Peptides) force field, plus two different continuum solvation models, were used to describe the conformational energy of the chain with both blocked and unblocked N and C termini. A statistical analysis of an ensemble of ab initio generated conformations was carried out, based on a comparison with a set of ten native-like structures derived from published experimental data, by using rigid geometry and NMR-derived constraints obtained at pH 3.7. The ten native-like structures satisfy the NMR-derived constraints. The whole ensemble of conformations of the terminally unblocked villin headpiece sub-domain, generated by using ECEPP/3 with a continuum solvation model, were subsequently evaluated at pH 3.7 with a potential function that includes ECEPP/3 combined with a fast multigrid boundary element method. At pH 3.7, the lowest-energy conformation found during the conformational search satisfies approximately 70% of both the distance and the dihedral-angle constraints, and possesses the characteristic packing of three phenylalanine residues that constitute the main part of the hydrophobic core of the molecule. On the other hand, computations at pH 3.7 and pH 7.0 for the ten native-like structures satisfying the NMR-derived constraints indicate a substantial change in the charge distribution for each type of amino acid residue with the change in pH. The results of this study provide a basis to understand the effect of the interactions, such as hydrophobicity, charge-charge interaction and solvent polarization, on the stability of this small alpha-helical protein.

Carrier Proteins↗
PubMed1980

Signal statistics in objective auditory evoked potential (AEP) detection by the phase spectral method.

This paper reports on statistical aspects relevant to the use of the phase spectrum of post-stimulus EEG, in objective detection of the auditory evoked potential. The sampling statistics of two statistical estimators are discussed: the mean phase vector magnitude, and the standard deviation of an ensemble of post-stimulus EEG phases. These two estimators are circular statistics, and subject to strong sample size bias. Their confidence intervals have been derived empirically for sample sizes routinely used in clinical audiometry. A trial example illustrates the use of the objective phase statistics developed here; it is noted that the method may also be more efficient than the visual scoring of averaged responses.

Adult↗
PubMed2005

Direct calculation of solid-liquid coexistence points of a binary mixture by thermodynamic integration.

We present a new thermodynamic integration method that directly connects the liquid and the solid phases of a binary mixture by a reversible path. The states along the path are simulated in the isothermal-isobaric semigrand canonical ensemble, in which temperature, pressure, the total number of particles, and the fugacity fractions of the components are held fixed. The thermodynamic integration yields the chemical-potential difference between the two phases for one of the components and this information is then used to locate the solid-liquid coexistence points. The melting temperatures predicted by our method agree well with those predicted by the Gibbs-Duhem integration for a truncated and shifted Lennard-Jones system with a cutoff radius of 2.5sigma.

Journal Article↗
PubMed2004

Measure profile surrogates: a method to validate the performance of epileptic seizure prediction algorithms.

In a growing number of publications it is claimed that epileptic seizures can be predicted by analyzing the electroencephalogram (EEG) with different characterizing measures. However, many of these studies suffer from a severe lack of statistical validation. Only rarely are results passed to a statistical test and verified against some null hypothesis H0 in order to quantify their significance. In this paper we propose a method to statistically validate the performance of measures used to predict epileptic seizures. From measure profiles rendered by applying a moving-window technique to the electroencephalogram we first generate an ensemble of surrogates by a constrained randomization using simulated annealing. Subsequently the seizure prediction algorithm is applied to the original measure profile and to the surrogates. If detectable changes before seizure onset exist, highest performance values should be obtained for the original measure profiles and the null hypothesis. "The measure is not suited for seizure prediction" can be rejected. We demonstrate our method by applying two measures of synchronization to a quasicontinuous EEG recording and by evaluating their predictive performance using a straightforward seizure prediction statistics. We would like to stress that the proposed method is rather universal and can be applied to many other prediction and detection problems.

Algorithms↗
PubMed1996

Neural ensemble coding of target identity in echolocating bats.

Most insectivorous bats use echolocation to determine the identity of flying insects. Among the many target features that are so extracted, the insect's wingbeat pattern and frequency appear to serve as useful cues for identification. Biosonar pulses impinging on the fluttering wings of an insect are returned as echoes whose amplitudes vary with time, thus providing a characteristic signature of the insect. It has been shown previously that neurons in the inferior colliculus, a midbrain auditory nucleus, of the little brown bat respond to sound stimuli that mimic echoes from fluttering targets. To examine the manner in which target identity is represented in the inferior colliculus, an ensemble coding analysis using a filter-based approach was undertaken. The analysis indicates that a discrete subset of neurons in the inferior colliculus, the onset units, are strongly tuned to wingbeat frequencies of targets that the bat hunts, and that ensemble response reaches a maximum at a distinct phase of the prey capture maneuver: the late approach stage. On the basis of the analysis it is hypothesized that inferior colliculus neurons may play an important role in target detection-identification processing. Although ensemble coding of temporally sequenced information has not been analyzed in the auditory system so far, this study indicates that this method of coding may provide the information necessary to detect and identify targets during prey capture.

Acoustic Stimulation↗
PubMed2006

Flexible protein-protein docking.

Predicting the structure of protein-protein complexes using docking approaches is a difficult problem whose major challenges include identifying correct solutions, and properly dealing with molecular flexibility and conformational changes. Flexibility can be addressed at several levels: implicitly, by smoothing the protein surfaces or allowing some degree of interpenetration (soft docking) or by performing multiple docking runs from various conformations (cross or ensemble docking); or explicitly, by allowing sidechain and/or backbone flexibility. Although significant improvements have been achieved in the modeling of sidechains, methods for the explicit inclusion of backbone flexibility in docking are still being developed. A few novel approaches have emerged involving collective degrees of motion, multicopy representations and multibody docking, which should allow larger conformational changes to be modeled.

Binding Sites↗