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PubMedDate not supplied

Fluoroscopic performance tests using a portable computer/frame grabber: Wiener spectra measurements.

Currently, routine tests of fluoroscopic image quality in common use are highly subjective. As part of an effort to develop more quantitative routine tests of fluoroscopic image quality, a method was developed to quickly and easily measure Wiener spectra (WS) of TV-viewed fluoroscopic systems that considers both spatial and temporal noise correlations. A PC-mounted frame grabber captures images at the TV frame rate to form a three-dimensional (3-D) array of pixels. Scans of a "two-dimensional slit" are then synthesized from which a one-dimensional central section of a 3-D WS is calculated. To avoid errors due to coarse (8-bit) quantization, a video amplifier is used to expand a portion of the signal to the full digitizer range. A reference signal (2 mm of aluminum) is then used to normalize image contrast. Ensemble averages of 250 spectra were obtained in approximately 1 min, including all processing. Results are presented to demonstrate reproducibility, sensitivity, and behavior of the WS. The eventual goal of this work is to use this method in conjunction with measurements of an MTF to calculate fundamental descriptors of image quality, such as SNR and NEQ.

Computer Simulation↗
PubMed2001

Reproducing the conformations of protein-bound ligands: a critical evaluation of several popular conformational searching tools.

Several programs (Catalyst, Confort, Flo99, MacroModel, and Omega) that are commonly used to generate conformational ensembles have been tested for their ability to reproduce bioactive conformations. The ligands from thirty-two different ligand-protein complexes determined by high-resolution (< 2.0 A) X-ray crystallography have been analyzed. The Low-Mode Conformational Search method (with AMBER* and the GB/SA hydration model), as implemented in MacroModel, was found to perform better than the other algorithms. The rule-based method Omega, which is orders of magnitude faster than the other methods, also gave reasonable results but were found to be dependent on the input structure. The methods supporting diverse sampling (Catalyst, Confort) performed least well. For the seven ligands in the set having eight or more rotatable bonds, none of the bioactive conformations were ever found, save for one exception (Flo99). These ligands do not bind in a local minimum conformation according to AMBER*\GB/SA. Taking these last two observations together, it is clear that geometrically similar structures should be collected in order to increase the probability of finding the bioactive conformation among the generated ensembles. Factors influencing bioactive conformational retrieval have been identified and are discussed.

Algorithms↗
PubMed1998

A robust method for determining the magnitude of the fully asymmetric alignment tensor of oriented macromolecules in the absence of structural information.

It has recently been shown that the degree of alignment of macromolecules in an aqueous dilute liquid crystalline medium of bicelles is sufficient to permit accurate values of residual 15N-1H, 13C-1H, and 13Calpha-C' dipolar couplings to be obtained on a routine basis, thereby providing potentially unique long-range structural information. To make use of this information in macromolecular structure determination, the magnitude of the axial and rhombic components of the molecular alignment tensor must be determined. This can be achieved by taking advantage of the fact that different, fixed-distance internuclear vector types are differently distributed relative to the alignment tensor. A histogram of the ensemble of normalized residual dipolar couplings for several such vector types approximates a powder pattern from which the magnitude of the axial and rhombic components are readily extracted in the absence of any prior structural information. The applicability of this method is demonstrated using synthetic data derived from four proteins representative of different sizes, topologies, and secondary structures, and experimental data measured on the small protein ubiquitin.

Carbon↗
PubMed1997

Consciousness and cognition may be mediated by multiple independent coherent ensembles.

Short-term or working memory (WM) provides temporary storage of information in the brain after an experience and is associated with conscious awareness. Neurons sensitive to the multiple stimulus attributes comprising an experience are distributed within many brain regions. Such distributed cell assemblies, activated by an event, are the most plausible system to represent the WM of that event. Studies with a variety of imaging technologies have implicated widespread brain regions in the mediation of WM for different categories of information. Each kind of WM may thus be expected to involve many brain regions rather than a local, uniquely dedicated set of cells. Neurons in a distributed "cell assembly" may be self-selected by their temporally coherent activations. The process by which this fragmented representation of the recent past is reassembled to accomplish essentially automatic and reliable recognition of a recurrent event constitutes an important problem. One plausible mechanism to achieve the identification of past with previous events would require that the representational system mediating WM must coexist in spatial extent and somehow overlap in temporal activation with cell ensembles registering input from subsequent events. The detection of such a postulated mechanism required an experimental approach which would focus upon spatial patterns of coherent activation while information about different events was stored in WM and retrieved, rather than focusing upon the temporal sequences of activation in localized regions of interest. For this purpose, the familiar delayed matching from sample (DMS) task was modified. A series of information-free flashes, or "noncontingent probes," was presented before an initial series of visual information items, the Priming Sample, which were to be held in WM during a Delay Period. A second series of visual information items were then presented, the Matching Sample. The task required detection of any item in the second series which had been absent from the initial series. Thirty such trials with a particular category of visual information constituted a single task. Several DMS tasks with this standardized design, but with different categories of visual information, were presented within each test session. The information categories included letters of the alphabet, single digit numbers, or faces from a school yearbook. Event-related potentials (ERPs), were computed from 21 standardized electrode placements, separately for information-free probes and for information items in each interval of the trials within a task. Because each electrode is particularly sensitive to coherent activation of neurons in the immediately underlying brain regions, topographic maps were constructed and interpolated across the surface of the scalp. The momentary fluctuations of the resulting voltage "landscapes" throughout the task were then subjected to quantitative analysis. Distinctive landscapes sometimes persisted for prolonged periods, implying sustained engagement of very large populations of neurons. "Difference landscapes" were constructed by subtraction of topographic maps evoked by noncontingent probes during the Delay Period from maps of probe ERPs before the presentation of the initial information in the Priming Sample. Such probe difference landscapes displayed recurrent high similarity to momentary landscapes elicited during subsequent presentation of the information items in the Matching Sample. It seemed as if the distributed cell assembly continuously engaged by mediation of WM of the diverse attributes of the initial stimuli was being dynamically compared to the ensembles engaged by registration of the subsequent stimuli. Spatial Principal Component Analysis was applied to the sequences of momentary voltage landscapes observed throughout trials of each task. This method sought a small number of spatial patterns with which these large sets of inhomogeneous spatial distributions of voltage co

Adult↗
PubMed1982

An analytical approach to single photon emission computed tomography with the attenuation effect.

The problem of transverse plane reconstruction from an ensemble of projections is considered in its general formulation and an analytically exact solution to the attenuated tomographic operator is proposed. Such a technique, called the regularizing iterative method (RIM), allows the introduction of a priori knowledge on the size and shape of the activity distribution and in principle on the exact attenuation distribution. The relaxation factor used is so named because it provides noise filtering for a small number of iterations. The effectiveness of RIM was studied in the single photon emission computed tomography (SPECT) problem with the aim of correcting for attenuation before quantitative study. Its application involves the use of a rotating scintillation camera connected to a mini-computer system. Various mathematical and physical phantoms were studied, and a satisfactory attenuation correction was always obtained in the final image with an improvement in the contrast and signal-to-noise ratio. Preliminary clinical studies on liver transverse sections seems to indicate an improvement in deep lesion detectability, compared with images obtained by the filtered (Ramp) back projection technique.

Models, Structural↗
PubMed1994

An evaluation of least-squares fits to COSY spectra as a means of estimating proton-proton coupling constants. II. Applications to polypeptides.

A new computational method for simultaneously estimating all the proton-proton coupling constants in a molecule from COSY spectra [Yang, J.-X. and Havel, T.F. (1994) J. Biomol. NMR, 4, 807-826] is applied to experimental data from two polypeptides. The first of these is a cyclic hexapeptide denoted as VDA (-D-Ala1-Phe2-Trp3-Lys(Z)4-Val5-Phe6-), in deuterated DMSO, while the second is a 39-residue protein, called decorsin, in aqueous solution. The effect of different data processing strategies and different initial parameter values on the accuracy of the coupling constants was explored. In the case of VDA, most of the coupling constants did not depend strongly on the initial values chosen for the optimization or on how the data were processed. This, together with our previous experience using simulated data, implies strongly that these values are accurate estimates of the coupling constants. They also differ by an average of only 0.36 Hz from the values of the 14 coupling constants that could be measured independently by established methods. In the case of decorsin, many of the coupling constants exhibited a moderate dependence on their initial values and a strong dependence on how the data were processed. With the most successful data processing strategy, the amide-alpha coupling constants differed by an average of 1.11 Hz from the 21 values that could be measured by established methods, while two thirds of the three-bond coupling constants fell within 1.0 Hz of the ranges obtained by applying the Karplus relation to an independently computed ensemble of distance geometry structures. The averages of the coupling constants over multiple optimizations using random initial values were computed in order to obtain the best possible estimates of the coupling constants. Most clearly incorrect averages can be identified by large standard deviations in the coupling constants or the associated line widths and chemical shifts, and can be explained by strong coupling and/or overlap with the water signal, the diagonal peaks or other cross peaks.

Amino Acid Sequence↗
PubMed2003

Combining inference from evolution and geometric probability in protein structure evaluation.

Starting from the hypothesis that evolutionarily important residues form a spatially limited cluster in a protein's native fold, we discuss the possibility of detecting a non-native structure based on the absence of such clustering. The relevant residues are determined using the Evolutionary Trace method. We propose a quantity to measure clustering of the selected residues on the structure and show that the exact values for its average and variance over several ensembles of interest can be found. This enables us to study the behavior of the associated z-scores. Since our approach rests on an analytic result, it proves to be general, customizable, and computationally fast. We find that clustering is indeed detectable in a large representative protein set. Furthermore, we show that non-native structures tend to achieve lower residue-clustering z-scores than those attained by the native folds. The most important conclusion that we draw from this work is that consistency between structural and evolutionary information, manifested in clustering of key residues, imposes powerful constraints on the conformational space of a protein.

Evolution, Molecular↗
PubMed2002

Inducible differentiation and morphogenesis of bipotential liver cell lines from wild-type mouse embryos.

This work shows that hepatic cell lines reproducibly can be derived from E14 embryos of many mouse inbred strains. These bipotential mouse embryonic liver (BMEL) cell lines present a mixed morphology, containing both epithelial and palmate-like cells, and an uncoupled phenotype, expressing hepatocyte transcription factors (HNF1alpha, HNF4alpha, GATA4) but not functions (apolipoproteins, albumin). BMEL cells are bipotential: under inducing conditions they express hepatocyte and bile duct functions. In addition, they can undergo morphogenesis in Matrigel culture to form bile duct units. When returned to basal culture conditions, the differentiated cells revert, within a few days, to an undifferentiated state. The ensemble of markers expressed by BMEL cells implies that they originate from hepatoblasts, the endodermal precursors of the liver. In conclusion, the establishment of a simple and reproducible method to isolate from any mouse embryo bipotential hepatic cell lines that exhibit the properties of transit stem cells provides a novel paradigm for investigation of hepatic cell lineage relationships.

Animals↗
PubMed2004

An empirical charge transfer potential with correct dissociation limits.

The empirical valence bond (EVB) method [J. Chem. Phys. 52, 1262 (1970)] has always embodied charge transfer processes. The mechanism of that behavior is examined here and recast for use as a new empirical potential energy surface for large-scale simulations. A two-state model is explored. The main features of the model are: (1) explicit decomposition of the total system electron density is invoked; (2) the charge is defined through the density decomposition into constituent contributions; (3) the charge transfer behavior is controlled through the resonance energy matrix elements which cannot be ignored; and (4) a reference-state approach, similar in spirit to the EVB method, is used to define the resonance state energy contributions in terms of "knowable" quantities. With equal validity, the new potential energy can be expressed as a nonthermal ensemble average with a nonlinear but analytical charge dependence in the occupation number. Dissociation to neutral species for a gas-phase process is preserved. A variant of constrained search density functional theory is advocated as the preferred way to define an energy for a given charge.

Journal Article↗
PubMed2006

Finite-size effects in dissipative particle dynamics simulations.

We have performed dissipative particle dynamics (DPD) simulations to evaluate the effect that finite size of transversal area has on stress anisotropy and interfacial tension. The simulations were carried out in one phase and two phases in parallelepiped cells. In one-phase simulations there is no finite-size effect on stress anisotropy when the simulation is performed using repulsive forces. However, an oscillatory function of stress anisotropy is found for attractive-repulsive interactions. In the case of liquid-liquid interfaces with repulsive interaction between molecules, there is only a small effect of surface area on interfacial tension when the simulations are performed using the Monte Carlo method at constant temperature and normal pressure. An important but artificial finite-size effect of interfacial area on surface tension is found in simulations in the canonical ensemble. Reliable results of interfacial tension from DPD simulations can be obtained using small systems, less than 2000 particles, when they interact exclusively with repulsive forces.

Journal Article↗
PubMed2002

Agent-based modeling as organizational and public policy simulators.

Agent-based models are an increasingly powerful tool for simulating social systems because they can represent important phenomenon difficult to capture in other mathematical formalisms. But, agent-based models have provided only limited support for policy-making because their distinctive abilities are often most useful in situations where the future is unpredictable. In such situations, the traditional analytic methods for applying simulation models to support decision-making are least effective. Fortunately, new analytic approaches for decision-making under conditions of deep uncertainty--emphasizing large ensembles of model-created scenarios and adaptive policies evaluated with the criteria of robustness, rather than with optimality or efficiency--can unleash the full potential of agent-based policy simulators.

Journal Article↗
PubMed2001

Intrinsic viscosity and the electrical polarizability of arbitrarily shaped objects.

The problem of calculating the electric polarizability tensor alpha(e) of objects of arbitrary shape has been reformulated in terms of path integration and implemented computationally. The method simultaneously yields the electrostatic capacity C and the equilibrium charge density. These functionals of particle shape are important in many materials science applications, including the conductivity and viscosity of filled materials and suspensions. The method has been validated through comparison with exact results (for the sphere, the circular disk, touching spheres, and tori), it has been found that 10(6) trajectories yield an accuracy of about four and three significant figures for C and alpha(e), respectively. The method is fast: For simple objects, 10(6) trajectories require about 1 min on a PC. It is also versatile: Switching from one object to another is easy. Predictions have also been made for regular polygons, polyhedra, and right circular cylinders, since these shapes are important in applications and since numerical calculations of high stated accuracy are available. Finally, the path-integration method has been applied to estimate transport properties of both linear flexible polymers (random walk chains of spheres) and lattice model dendrimer molecules. This requires probing of an ensemble of objects. For linear chains, the distribution function of C and of the trace (alpha(e)), are found to be universal in a size coordinate reduced by the chain radius of gyration. For dendrimers, these distribution functions become increasingly sharp with generation number. It has been found that C and alpha(e) provide important information about the distribution of molecular size and shape and that they are important for estimating the Stokes friction and intrinsic viscosity of macromolecules.

Journal Article↗
PubMed2004

Linearity of cortical receptive fields measured with natural sounds.

How do cortical neurons represent the acoustic environment? This question is often addressed by probing with simple stimuli such as clicks or tone pips. Such stimuli have the advantage of yielding easily interpreted answers, but have the disadvantage that they may fail to uncover complex or higher-order neuronal response properties. Here, we adopt an alternative approach, probing neuronal responses with complex acoustic stimuli, including animal vocalizations. We used in vivo whole-cell methods in the rat auditory cortex to record subthreshold membrane potential fluctuations elicited by these stimuli. Most neurons responded robustly and reliably to the complex stimuli in our ensemble. Using regularization techniques, we estimated the linear component, the spectrotemporal receptive field (STRF), of the transformation from the sound (as represented by its time-varying spectrogram) to the membrane potential of the neuron. We find that the STRF has a rich dynamical structure, including excitatory regions positioned in general accord with the prediction of the classical tuning curve. However, whereas the STRF successfully predicts the responses to some of the natural stimuli, it surprisingly fails completely to predict the responses to others; on average, only 11% of the response power could be predicted by the STRF. Therefore, most of the response of the neuron cannot be predicted by the linear component, although the response is deterministically related to the stimulus. Analysis of the systematic errors of the STRF model shows that this failure cannot be attributed to simple nonlinearities such as adaptation to mean intensity, rectification, or saturation. Rather, the highly nonlinear response properties of auditory cortical neurons must be attributable to nonlinear interactions between sound frequencies and time-varying properties of the neural encoder.

Acoustic Stimulation↗
PubMed1991

A role for protein kinase C in associative learning.

Recent work suggests that protein kinase C (PKC), an enzyme that has a critical role in the regulation of cell growth and differentiation, also participates in the sequence of molecular events that underlie learning and memory. By means of electrophysiological, biochemical, and neuro-imaging methods it has been demonstrated that, in the brain, the distribution of PKC changes as a result of memory storage. The changes in distribution occur within the same ensembles of nerve cells that are necessary for the acquisition and performance of various learning tasks in several species. Here we review the data pertaining to a model that has been proposed to account for the participation of PKC as a molecular signal for cotemporal synaptic input during associative learning.

Alzheimer Disease↗
PubMed2005

Processing multimode binding situations in simulation-based prediction of ligand-macromolecule affinities.

The linear response (LR) approximation and similar approaches belong to practical methods for estimation of ligand-receptor binding affinities. The approaches correlate experimental binding affinities with the changes upon binding of the ligand electrostatic and van der Waals energies and of solvation characteristics. These attributes are expressed as ensemble averages that are obtained by conformational sampling of the protein-ligand complex and of the free ligand by molecular dynamics or Monte Carlo simulations. We observed that outliers in the LR correlations occasionally exhibit major conformational changes of the complex during sampling. We treated the situation as a multimode binding case, for which the observed association constant is the sum of the partial association constants of individual states/modes. The resulting nonlinear expression for the binding affinities contains all the LR variables for individual modes that are scaled by the same two to four adjustable parameters as in the one-mode LR equation. The multimode method was applied to inhibitors of a matrix metalloproteinase, where this treatment improved the explained variance in experimental activity from 75% for the unimode case to about 85%. The predictive ability scaled accordingly, as verified by extensive cross-validations.

Computer Simulation↗
PubMed2005

Adaptive importance sampling Monte Carlo simulation of rare transition events.

We develop a general theoretical framework for the recently proposed importance sampling method for enhancing the efficiency of rare-event simulations [W. Cai, M. H. Kalos, M. de Koning, and V. V. Bulatov, Phys. Rev. E 66, 046703 (2002)], and discuss practical aspects of its application. We define the success/fail ensemble of all possible successful and failed transition paths of any duration and demonstrate that in this formulation the rare-event problem can be interpreted as a "hit-or-miss" Monte Carlo quadrature calculation of a path integral. The fact that the integrand contributes significantly only for a very tiny fraction of all possible paths then naturally leads to a "standard" importance sampling approach to Monte Carlo (MC) quadrature and the existence of an optimal importance function. In addition to showing that the approach is general and expected to be applicable beyond the realm of Markovian path simulations, for which the method was originally proposed, the formulation reveals a conceptual analogy with the variational MC (VMC) method. The search for the optimal importance function in the former is analogous to finding the ground-state wave function in the latter. In two model problems we discuss practical aspects of finding a suitable approximation for the optimal importance function. For this purpose we follow the strategy that is typically adopted in VMC calculations: the selection of a trial functional form for the optimal importance function, followed by the optimization of its adjustable parameters. The latter is accomplished by means of an adaptive optimization procedure based on a combination of steepest-descent and genetic algorithms.

Journal Article↗
PubMed2006

Predicting protein subcellular location by fusing multiple classifiers.

One of the fundamental goals in cell biology and proteomics is to identify the functions of proteins in the context of compartments that organize them in the cellular environment. Knowledge of subcellular locations of proteins can provide key hints for revealing their functions and understanding how they interact with each other in cellular networking. Unfortunately, it is both time-consuming and expensive to determine the localization of an uncharacterized protein in a living cell purely based on experiments. With the avalanche of newly found protein sequences emerging in the post genomic era, we are facing a critical challenge, that is, how to develop an automated method to fast and reliably identify their subcellular locations so as to be able to timely use them for basic research and drug discovery. In view of this, an ensemble classifier was developed by the approach of fusing many basic individual classifiers through a voting system. Each of these basic classifiers was trained in a different dimension of the amphiphilic pseudo amino acid composition (Chou [2005] Bioinformatics 21: 10-19). As a demonstration, predictions were performed with the fusion classifier for proteins among the following 14 localizations: (1) cell wall, (2) centriole, (3) chloroplast, (4) cytoplasm, (5) cytoskeleton, (6) endoplasmic reticulum, (7) extracellular, (8) Golgi apparatus, (9) lysosome, (10) mitochondria, (11) nucleus, (12) peroxisome, (13) plasma membrane, and (14) vacuole. The overall success rates thus obtained via the resubstitution test, jackknife test, and independent dataset test were all significantly higher than those by the existing classifiers. It is anticipated that the novel ensemble classifier may also become a very useful vehicle in classifying other attributes of proteins according to their sequences, such as membrane protein type, enzyme family/sub-family, G-protein coupled receptor (GPCR) type, and structural class, among many others. The fusion ensemble classifier will be available at www.pami.sjtu.edu.cn/people/hbshen.

Amino Acids↗
PubMed1997

Factors affecting the ability of energy functions to discriminate correct from incorrect folds.

Eighteen low and medium resolution empirical energy functions were tested for their ability to distinguish correct from incorrect folds from three test sets of decoy protein conformations. The energy functions included 13 pairwise potentials of mean force, covering a wide range of functional forms and methods of parameterization, four potentials that attempt to detect properly formed hydrophobic cores, and one environment-based potential. the first of the three test sets consists of large ensembles of plausible conformations for eight small proteins, all of which have correct native secondary structure and are reasonably compact. The second is the set of all subconformations in a database of known protein structures applied to the sequences in that database (ungapped threading). The third is a set of ensembles of 1000 conformations each for seven small proteins taken from molecular dynamics simulations at 298 K and 498 K. Our results show that there are functions effective for each challenge set; moreover, success in one test is no guarantee of success in another. We examine the factors that seem to be important for accurate discrimination of correct structures in each of the test sets, and note that extremely simple functions are often as effective as more complex functions.

Chemical Phenomena↗