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At least 505 records · Page 28Linked to original sources
PubMed1999

Three-dimensional kinematics of the forefoot, rearfoot, and leg without the function of tibialis posterior in comparison with normals during stance phase of walking.

BACKGROUND: Many studies have shown that lack of functional activity of tibialis posterior leads to changes in the longitudinal arch and affects the motion of the foot. A quantitative description of the affects on the motion of the foot in detail has not been reported. OBJECTIVE: To describe three-dimensional motion of the leg, rearfoot and forefoot with tibialis posterior dysfunction during stance phase of walking in comparison with normals. This study compared one case without the function of tibialis posterior with the ensemble average of 10 normals (five males, five females). METHODS: Subjects with 10, 12 mm retroreflective markers placed on their right leg, rearfoot and forefoot, performed five trials of walking at self-selected speed on a 10 m walkway. A four-camera three-dimensional motion analysis system and a synchronized force platform were used to record three-dimensional motions of the segments and force variables during stance phase of walking. RESULTS: The patterns and range of motion of the rearfoot relative to the leg, and the forefoot relative to the rearfoot demonstrated some differences between the tibialis posterior dysfunction case and normals. Most of the major differences occurred from just prior to heel-off through to toe-off, the period when a stable arch would be required. CONCLUSION: The observed differences in the three-dimensional foot motions of the tibialis posterior dysfunction case compared with normals during walking were consistent with the expected mechanical consequences of a foot without the function of tibialis posterior. The one exception was the inversion of the rearfoot which remained normal. RELEVANCE: Tibialis posterior dysfunction has been recognized as one of the significant impairments of the musculoskeletal system which affects normal walking. Dynamic investigation adds an understanding of how the muscle controls the foot during walking which is essential information for the diagnosis and the adjustment of treatment and rehabilitation for a tibialis posterior dysfunction case.

Adult↗
PubMedDate not supplied

Considerations in compound database preparation--"hidden" impact on virtual screening results.

Structure-based virtual screening (SBVS) utilizing docking algorithms has become an essential tool in the drug discovery process, and significant progress has been made in successfully applying the technique to a wide range of receptor targets. In silico validation of virtual screening protocols before application to a receptor target using a corporate or commercially available compound collection is key to establishing a successful process. Ultimately, retrieval of a set of active compounds from a database of inactives is required, and the metric of enrichment (E) is habitually used to discern the quality of separation of the two. Numerous reports have addressed the performance of docking algorithms with regard to the quality of binding mode prediction and the issue of postprocessing "hit lists" of docked ligands. However, the impact of ligand database preprocessing has yet to be examined in the context of virtual screening and prioritization of compounds for biological evaluation. We provide an insight into the implications of cheminformatic preprocessing of a validation database of compounds where multiple protonated, tautomeric, stereochemical, and conformational states have been enumerated. Several commonly used methods for the generation of ligand conformations and conformational ensembles are examined, paired with an exhaustive rigid-body algorithm for the docking of different "multimeric" compound representations to the ligand binding site of the human estrogen receptor alpha. Chemgauss, a shapegaussian scoring function with intrinsic chemical knowledge, was combined with PLP as a consensus-scoring scheme to rank output from the docking protocol and enrichment rates calculated for each screen. The overheads of CPU consumption and the effect on relative database size (disk requirement) for each of the protocols employed are considered. Assessment of these parameters indicates that SBVS enrichments are highly dependent on the initial cheminformatic treatment(s) used in database construction. The interplay of SMILES representations, stereochemical information, protonation state enumeration, and ligand conformation ensembles are critical in achieving optimum enrichment rates in such screening.

Computer Simulation↗
PubMedDate not supplied

Bayesian model based clustering analysis: application to a molecular dynamics trajectory of the HIV-1 integrase catalytic core.

This work describes the application of a Bayesian method for clustering protein conformations sampled during a molecular dynamics simulation of the HIV-1 integrase catalytic core. A clustering analysis is carried out under the assumption of normal distribution without fixing the number of clusters in advance. Some performance measures, such as posterior probability and class cross entropy, are used to determine the most probable set of clusters. The Bayesian clustering method results in meaningful groups identifying transitions between conformational ensembles. The dihedral angles involved in such transitions are also examined in detail. The conformations in high dimensional space are projected into 3D space employing a multidimensional scaling technique to provide a visual inspection.

Algorithms↗
PubMed2005

Cages, baskets, ladders, and tubes: conformational studies of polyhedral oligomeric silsesquioxanes.

The conformational flexibility of a series of cage, basket, ladder, and tube polyhedral oligomeric silsesquioxanes (POSS) has been examined using the Low Mode:Monte Carlo conformational search method in conjunction with the MM3/GBSA(CHCl3) surface. An ensemble of low energy structures was generated and used to explore the molecular shape and flexibility of each system. The results indicate that, except for the ladder molecule, the incompletely condensed systems that are studied are relatively rigid. Even in cases where the molecule is able to adopt numerous low energy conformations, the overall shape remains cage-like and the conformations differ only by small angles or substituent orientations. The ladder molecule is the most flexible and this ensemble clusters into two families: one that is cage-like and the other that is more open and ladder-like. The conformational flexibilities in the gas and solvent phases, as approximated using the GBSA continuum solvent model, are very similar.

Journal Article↗
PubMed2006

Monte carlo computer simulation of chain formation from nanoparticles.

Spontaneous assembly of long chains of nanoparticles (NPs) has been experimentally observed for many different materials including nanocolloids of semiconductors, metal oxides, and metals. While the origin of dipole moment in various colloids can be different, a universal explanation of chain assembly can be provided by the hypothesis of dipole-dipole attraction of nanocolloids. In this paper, we describe the application of the Monte Carlo method for modeling of self-organization of large ensembles of NPs. As the first approximation, the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory provides an adequate description of self-organization of several hundreds of NPs. Unlike microscale colloids that served as a classical model for DLVO, we used a distance-dependent media dielectric constant. The simulated chains are morphologically and geometrically similar to those observed experimentally. This establishes the fundamentally important ability of NPs to self-assemble due to their intrinsic anisotropy. Thermodynamic analysis of Monte Carlo results reveals the role of partial removal of the stabilizer shell in CdTe nanocolloids necessary for reduction of interparticle repulsion. Analysis of the field distribution around short chains demonstrates that the growth of linear agglomerates is kinetically controlled by a high activation barrier for NPs approaching from all of the directions except one end of the chain. The presented algorithm can be applied to other interparticle interactions, such as induced dipoles, which can stimulate chain formation in the absence of permanent dipole moment. It can also serve as a theoretical foundation for the understanding of the large complex superstructures forming from anisotropic and anisometric NPs. Monte Carlo simulation of nanoscale dipoles can also be extended to the interactions of NP with proteins, and related biological systems important for a variety of applications in medicine.

Journal Article↗
PubMed2005

Generalized density functional theory for degenerate states.

An extension of density functional theory is proposed for degenerate states. There are suitably selected basic variables beyond the subspace density. Generalized Kohn-Sham equations are derived. A direct method is proposed to ensure the fixed value of ensemble quantities. Then the Kohn-Sham equations are similar to the conventional Kohn-Sham equations. But the Kohn-Sham potential is different for different ensembles. A simple local expression is proposed for the correlation energy.

Journal Article↗
PubMed1995

Occurrence, solution structure and stability of DNA hairpins stabilized by a GA/CG helix unit.

The occurrence and NMR solution structure of a class of biloop hairpins containing the sequence 5'-CGXYAG are presented. These hairpins, which are variations on a sequence found in the reverse transcript of the human T-cell leukemia virus 2 (HLV2), show elevated melting points and high chemical stability toward denaturation by urea. Hairpins with the 5'-CGXYAG configuration have melting points 18-20 degrees higher than hairpins with 5'-CAXYGG or 5'-GGXYAC configurations. The identities of the looping bases, X and Y above, play a negligible role in determining the stability of this DNA hairpin stability. This is very different from G-A based loops in RNA, where the third base must be a purine for high stability [the GNRA loops; V.P. Antao, S.Y. Lai and I. Tinoco, Jr (1991) Nucleic Acids Res., 19, 5901-5905]. We show that these properties are associated with a four base helix unit that contains both a sheared GA base pair and a Watson-Crick CG base pair upon which it is stacked. As an understanding of the significance of AG base pairs has become increasingly important in the structural biology of nucleic acids, we compute an 0.7-0.9 A precision ensemble of NMR solution structures using iterative relaxation matrix methods. Calculations performed on NMR-derived structures indicate that neither base-base electrostatic interactions, nor base-solvent dispersive interactions, are significant factors in determining the observed differences in hairpin stability. Thus the stability of the 5'-CGXYAG configuration would appear to derive from favorable base-base London/van der Waals interactions.

Base Composition↗
PubMed2005

Fine structure of distributions and central limit theorem in diffusive billiards.

We investigate deterministic diffusion in periodic billiard models, in terms of the convergence of rescaled distributions to the limiting normal distribution required by the central limit theorem; this is stronger than the usual requirement that the mean-square displacement grow asymptotically linearly in time. The main model studied is a chaotic Lorentz gas where the central limit theorem has been rigorously proved. We study one-dimensional position and displacement densities describing the time evolution of statistical ensembles in a channel geometry, using a more refined method than histograms. We find a pronounced oscillatory fine structure, and show that this has its origin in the geometry of the billiard domain. This fine structure prevents the rescaled densities from converging pointwise to Gaussian densities; however, demodulating them by the fine structure gives new densities which seem to converge uniformly. We give an analytical estimate of the rate of convergence of the original distributions to the limiting normal distribution, based on the analysis of the fine structure, which agrees well with simulation results. We show that using a Maxwellian (Gaussian) distribution of velocities in place of unit speed velocities does not affect the growth of the mean-square displacement, but changes the limiting shape of the distributions to a non-Gaussian one. Using the same methods, we give numerical evidence that a nonchaotic polygonal channel model also obeys the central limit theorem, but with a slower convergence rate.

Journal Article↗
PubMed2004

Automated protein classification using consensus decision.

We propose a novel technique for automatically generating the SCOP classification of a protein structure with high accuracy. High accuracy is achieved by combining the decisions of multiple methods using the consensus of a committee (or an ensemble) classifier. Our technique is rooted in machine learning which shows that by judicially employing component classifiers, an ensemble classifier can be constructed to outperform its components. We use two sequence- and three structure-comparison tools as component classifiers. Given a protein structure, using the joint hypothesis, we first determine if the protein belongs to an existing category (family, superfamily, fold) in the SCOP hierarchy. For the proteins that are predicted as members of the existing categories, we compute their family-, superfamily-, and fold-level classifications using the consensus classifier. We show that we can significantly improve the classification accuracy compared to the individual component classifiers. In particular, we achieve error rates that are 3-12 times less than the individual classifiers' error rates at the family level, 1.5-4.5 times less at the superfamily level, and 1.1-2.4 times less at the fold level.

Algorithms↗
PubMed2004

Atomic force microscopy study of DNA deposited on poly L-ornithine-coated mica.

Analyses of individual biomolecules, like DNA, or DNA-protein complexes, via atomic force microscopy, require 'gentle' methods to immobilize DNA on surfaces, which allow the ensemble of molecules to adopt conformations dictated primarily by their physical characteristics, and which possibly permit the use of a wide selection of buffers. We show that poly-L-ornithine-coated mica is a good substrate for fast, reliable deposition of DNA for wet or dry imaging. The surface firmly secures DNA, which retains the B-form helical rise (0.34 nm bp(-1)). The conformations of DNA that result are reminiscent of three-dimensional random coils projected on to a plane. The contrast is good, especially in solution, and buffers with physiological concentrations of salt with or without divalent cations may be used. This is important for comparison of scanning probe microscopy results with those obtained by different techniques.

Aluminum Silicates↗
PubMed2005

Characterization of the molten globule state of retinol-binding protein using a molecular dynamics simulation approach.

Retinol-binding protein transports retinol, and circulates in the plasma as a macromolecular complex with the protein transthyretin. Under acidic conditions retinol-binding protein undergoes a transition to the molten globule state, and releases the bound retinol ligand. A biased molecular dynamics simulation method has been used to generate models for the ensemble of conformers populated within this molten globule state. Simulation conformers, with a radius of gyration at least 1.1 A greater than that of the native state, contain on average 37%beta-sheet secondary structure. In these conformers the central regions of the two orthogonal beta-sheets that make up the beta-barrel in the native protein are highly persistent. However, there are sizable fluctuations for residues in the outer regions of the beta-sheets, and large variations in side chain packing even in the protein core. Significant conformational changes are seen in the simulation conformers for residues 85-104 (beta-strands E and F and the E-F loop). These changes give an opening of the retinol-binding site. Comparisons with experimental data suggest that the unfolding in this region may provide a mechanism by which the complex of retinol-binding protein and transthyretin dissociates, and retinol is released at the cell surface.

Computer Simulation↗
PubMed2005

Decision tree based information integration for automated protein classification.

We propose a novel technique for automatically generating the SCOP classification of a protein structure with high accuracy. We achieve accurate classification by combining the decisions of multiple methods using the consensus of a committee (or an ensemble) classifier. Our technique, based on decision trees, is rooted in machine learning which shows that by judicially employing component classifiers, an ensemble classifier can be constructed to outperform its components. We use two sequence- and three structure-comparison tools as component classifiers. Given a protein structure and using the joint hypothesis, we first determine if the protein belongs to an existing category (family, superfamily, fold) in the SCOP hierarchy. For the proteins that are predicted as members of the existing categories, we compute their family-, superfamily-, and fold-level classifications using the consensus classifier. We show that we can significantly improve the classification accuracy compared to the individual component classifiers. In particular, we achieve error rates that are 3-12 times less than the individual classifiers' error rates at the family level, 1.5-4.5 times less at the superfamily level, and 1.1-2.4 times less at the fold level.

Algorithms↗
PubMed1975

A modified measurement of respiratory resistance by forced oscillation during normal breathing.

We have modified the measurements of the resistance of the respiratory system, Rrs, by the forced oscillation technique and we have developed equipment to automatically compute Rrs. Flow rate and mouth pressure are treated by selective averaging filters that remove the interference of the subject's respiratory flow on the imposed oscillations. The filtered mean Rrs represents a weighted ensemble average computer over both inspiration and expiration. This method avoids aberrant Rrs values, decreases the variability, and yields an unbiased mean Rrs. Rrs may be measured during slow or rapid spontaneous breathing, in normals and in obstructive patients, over a range of 3-9 Hz. A good reproducibility of Rrs at several days' interval was demonstrated. Frequency dependence of Rrs was found in patients with obstructive lung disease but not in healthy nonsmokers.

Airway Resistance↗
PubMed1991

Frequency domain analysis of ventilation and gas exchange kinetics in hypoxic exercise.

The kinetics of O2 up-take (VO2), CO2 output (VCO2), ventilation (VE), and heart rate (HR) were studied during exercise in normoxia and hypoxia [inspired O2 fraction (FIO2) 0.14]. Eight male subjects each completed 6 on- and off-step transitions in work rate (WR) from low (25 W) to moderate (100-125 W) levels and a pseudorandom binary sequence (PRBS) exercise test in which WR was varied between the same WRs. Breath-by-breath data were linearly interpolated to yield 1-s values. After the first PRBS cycle had been omitted as a warm-up, five cycles were ensemble-averaged before frequency domain analysis by standard Fourier methods. The step data were fit by a two-component (three for HR) exponential model to estimate kinetic parameters. In the steady state of low and moderate WRs, each value of VO2, VCO2, VE, and HR was significantly greater during hypoxic than normoxic exercise (P less than 0.05) with the exception of VCO2 (low WR). Hypoxia slowed the kinetics of VO2 and HR in on- and off-step transitions and speeded up the kinetics of VCO2 and VE in the on-transition and of VE in the off-transition. Frequency domain analysis confined to the range of 0.003-0.019 Hz for the PRBS tests indicated reductions in amplitude and greater phase shifts in the hypoxic tests for VO2 and HR at specific frequencies, whereas amplitude tended to be greater with little change in phase shift for VCO2 and VE during hypoxic tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Dual controls, p-value plots, and the multiple testing issue in carcinogenicity studies.

The interpretation of statistically significant findings in a carcinogenicity study is difficult, in part because of the large number of statistical tests conducted. Some scientists who believe that the false positive rates in these experiments are unreasonably large often suggest that the use of multiple control groups will provide important insight into the operational false positive rates. The purpose of this paper is 2-fold: to present results from two carcinogenicity studies with dual control groups, and to present and illustrate a new graphical technique potentially useful in the analysis and interpretation of tumor data from carcinogenicity studies. The experimental data analyzed show that statistically significant differences between identically treated groups will occur with regular frequency. Such data, however, do not provide strong evidence of extrabinomial variation in tumor rates. The p-value plot is advocated as a graphical method that can be used to assess visually the ensemble of p values for neoplasm data from an entire study. This technique is then illustrated using several examples. Through computer simulation, we present p-value plots generated with and without treatment effects present. On average, the plots look substantially different depending on the presence or absence of an effect. We also evaluate decision rules motivated by the p-value plots. Such rules appear to have good power to detect treatment effects (i.e., have low false negative rates) while still controlling false positive rates.

Animals↗
PubMed2003

The effect of straining maneuvers on G-protection during assisted pressure breathing.

INTRODUCTION: Pilots flying high-performance aircraft increase their acceleration tolerance by using straining maneuvers and anti-G suits. Recently, assisted positive pressure breathing has been added in some aircraft systems. This study assessed the effect of anti-G straining maneuvers on the G-protective properties of one such system, the AGE-39 anti-G ensemble used in the Swedish JAS 39 Gripen aircraft. METHODS: Ten subjects were studied in a centrifuge using each of the following: 1) the AGE-39 in combination with anti-G straining maneuvers (AGSM) throughout each high-G exposure (full maneuver; FM); 2) the AGE-39 in combination with AGSM only during the initial part of each high-G exposure (reduced maneuver; RM). G-tolerance was established during exposures to rapid onset rate (ROR) G profiles with plateau levels ranging from 6.5 to 9.0 G. RESULTS: Mean G-tolerance was > or = 8.8 G (range: 8.5 to > or = 9.0 G) in the RM condition and > or = 9.0 G in all subjects in the FM condition. Mean arterial pressure was 30-50 mm Hg higher (p < 0.001) in the FM than in the RM condition at any given ROR G-load. CONCLUSIONS: AGE-39 in combination with a brief period of straining provide efficient G-protection as illustrated by the finding that all subjects could tolerate 8.5 G while performing AGSM during the initial part of the high-G exposures. However, at 9.0 G, 40% of the subjects had to perform AGSM throughout the duration of the G-exposure. That arterial pressure was only 30-50 mm Hg higher in the FM than RM condition suggests that in the presence of straining maneuvers, pressure breathing makes only a minute contribution to the arterial-pressure response.

Adult↗
PubMed2002

Distribution of molecular size within an unfolded state ensemble using small-angle X-ray scattering and pulse field gradient NMR techniques.

The size distribution of molecules within an unfolded state of the N-terminal SH3 domain of drk (drkN SH3) has been studied by small-angle X-ray scattering (SAXS) and pulsed-field-gradient NMR (PFG-NMR) methods. An empirical model to describe this distribution in the unfolded state ensemble has been proposed based on (i) the ensemble-averaged radius of gyration and hydrodynamic radius derived from the SAXS and PFG-NMR data, respectively, and (ii) a histogram of the size distribution of structures obtained from preliminary analyses of structural parameters recorded on the unfolded state. Results show that this unfolded state, U(exch), which exists in equilibrium with the folded state, F(exch), under non-denaturing conditions, is relatively compact, with the average size of conformers within the unfolded state ensemble only 30-40% larger than the folded state structure. In addition, the model predicts a significant overlap in the size range of structures comprising the U(exch) state with those in a denatured state obtained by addition of 2 M guanidinium chloride.

Animals↗
PubMed2005

Controlling bursting in cortical cultures with closed-loop multi-electrode stimulation.

One of the major modes of activity of high-density cultures of dissociated neurons is globally synchronized bursting. Unlike in vivo, neuronal ensembles in culture maintain activity patterns dominated by global bursts for the lifetime of the culture (up to 2 years). We hypothesize that persistence of bursting is caused by a lack of input from other brain areas. To study this hypothesis, we grew small but dense monolayer cultures of cortical neurons and glia from rat embryos on multi-electrode arrays and used electrical stimulation to substitute for afferents. We quantified the burstiness of the firing of the cultures in spontaneous activity and during several stimulation protocols. Although slow stimulation through individual electrodes increased burstiness as a result of burst entrainment, rapid stimulation reduced burstiness. Distributing stimuli across several electrodes, as well as continuously fine-tuning stimulus strength with closed-loop feedback, greatly enhanced burst control. We conclude that externally applied electrical stimulation can substitute for natural inputs to cortical neuronal ensembles in transforming burst-dominated activity to dispersed spiking, more reminiscent of the awake cortex in vivo. This nonpharmacological method of controlling bursts will be a critical tool for exploring the information processing capacities of neuronal ensembles in vitro and has potential applications for the treatment of epilepsy.

Action Potentials↗