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PubMed2002

Tip-tilt error for extremely large segmented telescopes: detailed theoretical point-spread-function analysis and numerical simulation results.

We present an analysis of point-spread functions for segmented mirrors affected by random tip-tilt errors on each segment. In addition to Strehl ratio evaluation, this analysis considers key characteristics such as the intensity and the location of speckles and secondary peaks and the relative energy distribution between these features. We develop a method to describe the shape of a nonaveraged point-spread function and deduce the final expressions for ensemble-averaged characteristics. Based on Keck-type hexagonal segmentation geometry, our study is extended to an arbitrary number of segments, and we describe qualitatively the transition from the case of a mirror with few segments to that of a mirror with several hundred segments--prototype of the next generation of Extremely Large Telescopes.

Journal Article↗
PubMedDate not supplied

[Role of rapid movement of spin labels in interpreting EPR spectra for spin-labelled macromolecules].

The method of spin labeling was used to monitor quick movements of side residues in protein monocrystals. The EPR spectra of monocrystals of spin-labeled lysozyme at different orientations of the tetrahonal crystal relative to the direction of the magnetic field were interpreted using the molecular dynamics method. A simple model was proposed, which enables one to calculate the trajectory of movements of the spin label by the molecular dynamic method over a relatively short period of time. The entire "frozen" protein molecule and a "defrozen" spin-labeled amino acid residue were considered in the framework of the model. To calculate the trajectories in vacuum, a model of spin-labeled lysozyme was constructed, and the parameters of force potentials for the atoms of the protein molecule and the spin label were specified. It follows from the calculations that the protein environment sterically hinders the range of eventual angular reorientations of the reporter NO-group of nitroxyl incorporated into the spin label, thereby affecting the shape of the EPR spectrum. However, the scatter in the positions of the reporter group in the angular space turned out to correspond to the Gauss distribution. Using the atomic coordinates of the spin label, obtained in a chosen time interval by the method of molecular dynamics, and taking into account the distribution of the states of the spin label in the ensemble of spin-labeled macromolecules in the crystal, we simulated the EPR spectra of monocrystals of spin-labeled lysozyme. The theoretical EPR spectra coincide well with the experimental.

Electron Spin Resonance Spectroscopy↗
PubMed1996

Bayesian reconstruction of PET images: methodology and performance analysis.

We describe a practical statistical methodology for the reconstruction of PET images. Our approach is based on a Bayesian formulation of the imaging problem. The data are modelled as independent Poisson random variables and the image is modelled using a Markov random field smoothing prior. We describe a sequence of calibration procedures which are performed before reconstruction: (i) calculation of accurate attenuation correction factors from re-projected Bayesian reconstructions of the transmission image; (ii) estimation of the mean of the randoms component in the data; and (iii) computation of the scatter component in the data using a Klein-Nishina-based scatter estimation method. The Bayesian estimate of the PET image is then reconstructed using a pre-conditioned conjugate gradient method. We performed a quantitation study with a multi-compartment chest phantom in a Siemens/CTI ECAT931 system. Using 40 1 min frames, we computed the ensemble mean and variance over several regions of interest from images reconstructed using the Bayesian and a standard filtered backprojection (FBP) protocol. The values for the region of interest were compared with well counter data for each compartment. These results show that the Bayesian protocol can produce substantial improvements in relative quantitation over the standard FBP protocol, particularly when short transmission scans are used. An example showing the application of the method to a clinical chest study is also given.

Algorithms↗
PubMed1999

Transient nonlinear dielectric relaxation and dynamic Kerr effect from sudden changes of a strong dc electric field: polar and polarizable molecules.

The nonlinear transient response of polar and polarizable particles (macromolecules) diluted in a nonpolar solvent to a sudden change both in magnitude and in direction of a strong external dc field is considered. By averaging the underlying Langevin equation, the infinite hierarchy of differential-recurrence equations for ensemble averages of the spherical harmonics is derived for an assembly of polar and anisotropically polarizable molecules pertaining to the noninertial rotational Brownian motion. On solving this hierarchy, the relaxation functions and relaxation times appropriate to the transient dynamic Kerr effect and nonlinear dielectric relaxation are calculated. The calculations are accomplished using the matrix continued fraction method, which allows us to express exactly the solution of the infinite hierarchy of differential-recurrence relations for the first- and second-order transient responses of the ensemble averages of the spherical harmonics (relaxation functions). The results are then compared with available experimental data and solutions previously obtained for various particular cases.

Journal Article↗
PubMed2002

Interaction of dihydrofolate reductase with methotrexate: ensemble and single-molecule kinetics.

The thermodynamics and kinetics of the interaction of dihydrofolate reductase (DHFR) with methotrexate have been studied by using fluorescence, stopped-flow, and single-molecule methods. DHFR was modified to permit the covalent addition of a fluorescent molecule, Alexa 488, and a biotin at the N terminus of the molecule. The fluorescent molecule was placed on a protein loop that closes over methotrexate when binding occurs, thus causing a quenching of the fluorescence. The biotin was used to attach the enzyme in an active form to a glass surface for single-molecule studies. The equilibrium dissociation constant for the binding of methotrexate to the enzyme is 9.5 nM. The stopped-flow studies revealed that methotrexate binds to two different conformations of the enzyme, and the association and dissociation rate constants were determined. The single-molecule investigation revealed a conformational change in the enzyme-methotrexate complex that was not observed in the stopped-flow studies. The ensemble averaged rate constants for this conformation change in both directions is about 2-4 s(-1) and is attributed to the opening and closing of the enzyme loop over the bound methotrexate. Thus the mechanism of methotrexate binding to DHFR involves multiple steps and protein conformational changes.

Base Sequence↗
PubMed2005

Ensembling local learners through multimodal perturbation.

Ensemble learning algorithms train multiple component learners and then combine their predictions. In order to generate a strong ensemble, the component learners should be with high accuracy as well as high diversity. A popularly used scheme in generating accurate but diverse component learners is to perturb the training data with resampling methods, such as the bootstrap sampling used in bagging. However, such a scheme is not very effective on local learners such as nearest-neighbor classifiers because a slight change in training data can hardly result in local learners with big differences. In this paper, a new ensemble algorithm named Filtered Attribute Subspace based Bagging with Injected Randomness (FASBIR) is proposed for building ensembles of local learners, which utilizes multimodal perturbation to help generate accurate but diverse component learners. In detail, FASBIR employs the perturbation on the training data with bootstrap sampling, the perturbation on the input attributes with attribute filtering and attribute subspace selection, and the perturbation on the learning parameters with randomly configured distance metrics. A large empirical study shows that FASBIR is effective in building ensembles of nearest-neighbor classifiers, whose performance is better than that of many other ensemble algorithms.

Algorithms↗
PubMed1997

A computational approach to modeling nucleic acid hairpin structures.

Hairpin is a structural motif frequently observed in both RNA and DNA molecules. This motif is involved specifically in various biological functions (e.g., gene expression and regulation). To understand how these hairpin motifs perform their functions, it is important to study their structures. Compared to protein structural motifs, structures of nucleic acid hairpins are less known. Based on a set of reduced coordinates for describing nucleic acid structures and a sampling algorithm that equilibrates structures using Metropolis Monte Carlo simulation, we developed a method to model nucleic acid hairpin structures. This method was used to predict the structure of a DNA hairpin with a single-guanosine loop. The lowest energy structure from the ensemble of 200 sampled structures has a RMSD of < 1.5 A, from the structure determined using NMR. Additional constraints for the loop bases were introduced for modeling an RNA hairpin with two nucleotides in the loop. The modeled structure of this RNA hairpin has extensive base stacking and an extra hydrogen bond (between the CYT in the loop and a phosphate oxygen), as observed in the NMR structure.

Algorithms↗
PubMed2003

Ensemble averaging and multiple statistical testing of EMG activities of cyclically repeated body motions. A tool for muscle function analysis in experimental and clinical orthopaedics.

Coupled with suitable computerized signal recording and processing methods surface electromyography can be a powerful tool for the analysis of muscle activity in specific body movements. It can be used for this purpose in experimental and in clinical diagnostic orthopaedics as well as in physiotherapy. We describe in this paper a motion analysis system comprising this feature. It has been employed for the diagnosis of the basic angular kinematics and muscle function in human gait and other cyclically repeatable movements of the human locomotive system. Changes in the temporal characteristics of the movements and the muscle activity due to changed physical or experimental conditions can be systematically investigated this way. Such changes can be the result of surgical and/or conservative orthopaedic therapy, a long term physiotherapeutic program, or modified walking conditions as in experimental orthopaedics. They are displayed and validated by signal ensemble averaging and subsequent multiple statistical testing (e.g. by a suitably adapted Bonferroni criterion). The efficiency of the system is demonstrated by an exemplary gait analysis of selected kinematic and muscular effects caused by an experimental simulation of a leg length inequality.

Algorithms↗
PubMedDate not supplied

Method for assessing the need for case-specific hemodynamics: application to the distribution of vascular permeability.

A common approach to understanding the role of hemodynamics in atherogenesis is to seek relationships between parameters of the hemodynamic environment, and the distribution of tissue variables thought to be indicative of early disease. An important question arising in such investigations is whether the distributions of tissue variables are sufficiently similar among cases to permit them to be described by an ensemble average distribution. If they are, the hemodynamic environment needs be determined only once, for a nominal representative geometry; if not, the hemodynamic environment must be obtained for each case. A method for classifying distributions from multiple cases to answer this question is proposed and applied to the distributions of the uptake of Evans blue dye labeled albumin by the external iliac arteries of swine in response to a step increase in flow. It is found that the uptake patterns in the proximal segment of the arteries, between the aortic trifurcation and the ostium of the circumflex iliac artery, show considerable case-to-case variability. In the distal segment, extending to the deep femoral ostium, many cases show very little spatial variation, and the patterns in those that do are similar among the cases. Thus the response of the distal segment may be understood with fewer simulations, but the proximal segment has more information to offer.

Animals↗
PubMed2006

Calculation of absorption spectra for light-harvesting systems using non-Markovian approaches as well as modified Redfield theory.

For an ensemble of B850 rings of the light-harvesting system LH2 of purple bacteria the linear absorption spectrum is calculated. Using different Markovian and non-Markovian, time-dependent and time-independent methods based on second-order perturbation theory in the coupling between the excitonic system and its surrounding environment as well as the modified Redfield theory, the influence of the shape of the spectral density on the linear absorption spectrum is demonstrated for single samples and in the ensemble average. For long bath correlation times non-Markovian effects clearly show up in the static absorption line shapes. Among the different spectral densities studied is one of the purple bacterium Rhodospirillum molischianum obtained by a molecular-dynamics simulation earlier. The effect of static disorder on its line shapes in the ensemble average is analyzed and the results of the present calculations are compared to experimental data.

Journal Article↗
PubMed1999

Validation of NMR side-chain conformations by packing calculations.

The precision and accuracy of protein structures determined by nuclear magnetic resonance (NMR) spectroscopy depend on the completeness of input experimental data set. Typically, rather than a single structure, an ensemble of up to 20 equally representative conformers is generated and routinely deposited in the Protein Database. There are substantially more experimentally derived restraints available to define the main-chain coordinates than those of the side chains. Consequently, the side-chain conformations among the conformers are more variable and less well defined than those of the backbone. Even when a side chain is determined with high precision and is found to adopt very similar orientations among all the conformers in the ensemble, it is possible that its orientation might still be incorrect. Thus, it would be helpful if there were a method to assess independently the side-chain orientations determined by NMR. Recently, homology modeling by side-chain packing algorithms has been shown to be successful in predicting the side-chain conformations of the buried residues for a protein when the main-chain coordinates and sequence information are given. Since the main-chain coordinates determined by NMR are consistently more reliable than those of the side-chains, we have applied the side-chain packing algorithms to predict side-chain conformations that are compatible with the NMR-derived backbone. Using four test cases where the NMR solution structures and the X-ray crystal structure of the same protein are available, we demonstrate that the side-chain packing method can provide independent validation for the side-chain conformations of NMR structures. Comparison of the side-chain conformations derived by side-chain packing prediction and by NMR spectroscopy demonstrates that when there is agreement between the NMR model and the predicted model, on average 78% of the time the X-ray structure also concurs. While the side-chain packing method can confirm the reliable residue conformations in NMR models, more importantly, it can also identify the questionable residue conformations with an accuracy of 60%. This validation method can serve to increase the confidence level for potential users of structural models determined by NMR.

Animals↗
PubMed2000

Force Spectroscopy of Molecular Systems-Single Molecule Spectroscopy of Polymers and Biomolecules.

How do molecules interact with each other? What happens if a neurotransmitter binds to a ligand-operated ion channel? How do antibodies recognize their antigens? Molecular recognition events play a pivotal role in nature: in enzymatic catalysis and during the replication and transcription of the genome; it is also important for the cohesion of cellular structures and in numerous metabolic reactions that molecules interact with each other in a specific manner. Conventional methods such as calorimetry provide very precise values of binding enthalpies; these are, however, average values obtained from a large ensemble of molecules without knowledge of the dynamics of the molecular recognition event. Which forces occur when a single molecular couple meets and forms a bond? Since the development of the scanning force microscope and force spectroscopy a couple of years ago, tools have now become available for measuring the forces between interfaces with high precision-starting from colloidal forces to the interaction of single molecules. The manipulation of individual molecules using force spectroscopy is also possible. In this way, the mechanical properties on a molecular scale are measurable. The study of single molecules is not an exclusive domain of force spectroscopy; it can also be performed with a surface force apparatus, laser tweezers, or the micropipette technique. Regardless of these techniques, force spectroscopy has been proven as an extraordinary versatile tool. The intention of this review article is to present a critical evaluation of the actual development of static force spectroscopy. The article mainly focuses on experiments dealing with inter- and intramolecular forces-starting with "simple" electrostatic forces, then ligand-receptor systems, and finally the stretching of individual molecules.

Journal Article↗
PubMed2003

Refinement of protein structures in explicit solvent.

We present a CPU efficient protocol for refinement of protein structures in a thin layer of explicit solvent and energy parameters with completely revised dihedral angle terms. Our approach is suitable for protein structures determined by theoretical (e.g., homology modeling or threading) or experimental methods (e.g., NMR). In contrast to other recently proposed refinement protocols, we put a strong emphasis on consistency with widely accepted covalent parameters and computational efficiency. We illustrate the method for NMR structure calculations of three proteins: interleukin-4, ubiquitin, and crambin. We show a comparison of their structure ensembles before and after refinement in water with and without a force field energy term for the dihedral angles; crambin was also refined in DMSO. Our results demonstrate the significant improvement of structure quality by a short refinement in a thin layer of solvent. Further, they show that a dihedral angle energy term in the force field is beneficial for structure calculation and refinement. We discuss the optimal weight for the energy constant for the backbone angle omega and include an extensive discussion of meaning and relevance of the calculated validation criteria, in particular root mean square Z scores for covalent parameters such as bond lengths.

Dimethyl Sulfoxide↗
PubMed1979

Estimation of signal and noise spectra by special averaging techniques with application to a posteriori "Wiener" filtering.

This paper deals with the problem of separating the spectra of signal and noise in ensembles where the signal can be considered as an invariant component and the noise as a stationary additive background. Several methods are discussed and compared on the basis of a statistical analysis of the first two moments of the estimators for signal and noise spectra. As a consequence a procedure is proposed which provides a flexible compromise between estimation accuracy and computational effort. The application of this procedure to a posteriori "Wiener" filtering is compared with a more common, but time consuming, technique.

Electronics, Medical↗
PubMed2005

Adaptive signal enhancement of somatosensory evoked potential for spinal cord compression detection: an experimental study.

The objective of this study was to assess the efficacy of adaptive signal enhancement (ASE) as a means of indicating intraoperative spinal cord impingement. ASE technique was used to determine the changes in the somatosensory evoked potential (SEP) elicited from eighteen rats with varying levels of spinal cord compression. ASE technique was found to be able to effectively extract SEP signals for the detection of spinal cord injury. Furthermore, while the traditional ensemble averaging (EA) technique requires more than 500 trials for meaningful signal processing in severe noisy SEP recordings, the ASE method required only 50 trials to provide similar information. Because of its fast and reliable SEP detection, the ASE method is ideal for spinal cord monitoring in the clinical setting.

Algorithms↗
PubMed1983

Brain systems and long-term memory.

This paper focuses mainly on those findings derived from lesion studies on the rat which help to identify ensembles of neural structures concerned with the expression of previously learned responses. At the outset, the use of the lesion method in the search for those neurological circuits underlying memory is defended. This is followed by an evaluation of neocortical and subcortical systems in long-term memory. Subsequently, a modest list of tentative functional neural "complexes" involved in the maintenance of certain classes of learned responses is given, based largely upon the author's own research. It is concluded that the key to the understanding of the neurological substrates of long-term memory lies in the identification of those subcortical sites which interact with neocortical sites in the performance of complex learned tasks. The most likely subcortical sites involved in this interaction appear to inhabit the regions of the basal ganglia, limbic midbrain area, and ventral portions of the brainstem reticular formation.

Animals↗
PubMed2004

Conformational analysis of drug-like molecules bound to proteins: an extensive study of ligand reorganization upon binding.

This paper describes a large-scale study on the nature and the energetics of the conformational changes drug-like molecules experience upon binding. Ligand strain energies and conformational reorganization were analyzed with different computational methods on 150 crystal structures of pharmaceutically relevant protein-ligand complexes. The common knowledge that ligands rarely bind in their lowest calculated energy conformation was confirmed. Additionally, we found that over 60% of the ligands do not bind in a local minimum conformation. While approximately 60% of the ligands were calculated to bind with strain energies lower than 5 kcal/mol, strain energies over 9 kcal/mol were calculated in at least 10% of the cases regardless of the method used. A clear correlation was found between acceptable strain energy and ligand flexibility, while there was no correlation between strain energy and binding affinity, thus indicating that expensive conformational rearrangements can be tolerated in some cases without overly penalizing the tightness of binding. On the basis of the trends observed, thresholds for the acceptable strain energies of bioactive conformations were defined with consideration of the impact of ligand flexibility. An analysis of the degree of folding of the bound ligands confirmed the general tendency of small molecules to bind in an extended conformation. The results suggest that the unfolding of hydrophobic ligands during binding, which exposes hydrophobic surfaces to contact with protein residues, could be one of the factors accounting for high reorganization energies. Finally, different methods for conformational analysis were evaluated, and guidelines were defined to maximize the prevalence of bioactive conformations in computationally generated ensembles.

Drug Design↗
PubMed2003

The remarkable difference between surface and step atoms in the magnetic anisotropy of two-dimensional nanostructures.

The original magnetic properties of nanometre-sized particles are due to the distinct contributions of volume, surface and step atoms. To disentangle these contributions is an ongoing challenge of materials science. Here we introduce a method enabling the identification of the remarkably different contributions of surface and perimeter atoms to the magnetic anisotropy energy of two-dimensional nanostructures. Our method uses the generally nonlinear relationship between perimeter length and surface area. Atomic-scale characterization of the morphology of ensembles of polydisperse nanostructures, combined with in situ measurements of their temperature-dependent magnetic susceptibility, gives access to the role played by the differently coordinated atoms. We show for Co nanostructures on a Pt(111) surface that their uniaxial out-of-plane magnetization is entirely caused by edge atoms having 20 times more anisotropy energy than their bulk and surface counterparts. Identification of the role of perimeter and surface atoms opens up unprecedented opportunities for materials engineering. As an example, we separately tune magnetic hardness and moment in bimetallic core-shell nanostructures.

Anisotropy↗