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At least 685 records · Page 38Linked to original sources
PubMed2003

Potent side-chain to side-chain cyclized dermorphin analogues containing a carbonyl bridge.

A new family of cyclic opioid peptide analogues related to the 1-4 sequence of dermorphin/deltorphin (Tyr-D-Aaa2-Phe-Aaa4-NH2) has been synthesized. The synthesis of the linear precursor peptides was accomplished by the solid-phase method and ring formation was achieved via a ureido group incorporating the side chain amino functions of D-Aaa2 (D-Lys, D-Orn) and Aaa4 (Lys, Orn, Dab, Dap). The peptides were tested in the guinea-pig ileum (GPI) and mouse vas deferens (MVD) assays. Most showed very high agonist potency in the GPI assay. The peptide containing D-Lys in position 2 and Dab in position 4 was 210 times more active than enkephalin, and that containing Orn and Dab, respectively, was 150 times more active than enkephalin. The latter peptide was also very active in the MVD assay, and showed an IC50 MVD/GPI ratio of 0.816. NMR spectra of selected peptides were recorded, and structural parameters were determined. The conformational space of the peptides was examined using the electrostatically driven Monte Carlo method. With the help of the NMR spectra each peptide was described as an ensemble of conformations. The conformations have been interpreted with regard to the opioid activities, and comparisons have been made with a model proposed earlier for enkephalin analogues.

Analgesics, Opioid↗
PubMed1997

Detecting chaos in HRV signals in human cardiac transplant recipients.

A statistical approach to chaos identification in time series is presented. The method is applied to numerical data generated by chaotic systems and to heart rate variability (HRV) signals of normal subjects and heart transplant recipients. This method compares the short-term predictability for a given time series to an ensemble of random data which has the same Fourier spectrum as the original time series. The short-term prediction error is computed as a discriminating statistic for performing statistical hypothesis testing. The results suggest that HRV signals of the transplant recipients recorded 3 months after the transplantations show the same signature of chaos as that of the HRV signals for normal subjects.

Algorithms↗
PubMed1989

Spectro-temporal interpretation of activity patterns of auditory neurons.

Sensory receptors transform an external sensory stimulus into an internal neural activity pattern. This mapping is studied through its inverse. An earlier paper showed that within the context of a neuron model composed of a linear filter followed by an exponential pulse generator and a Gaussian stimulus ensemble a unique "most plausible" first-order stimulus estimate can be constructed. This method, applicable only to neurons showing phase-lock, is extended to neurons without phase-lock. In this situation second-order spectro-temporal stimulus estimates are produced; examples are given from simulation. The method is applied to activity of neurons in the auditory system of the frog.

Acoustic Stimulation↗
PubMed1997

Multi-unit mapping of acoustic stimuli in gerbil inferior colliculus.

Multi-unit peristimulus time (MU-PST) histograms were recorded in the gerbil inferior colliculus (IC) in response to tone burst stimuli. Histograms were collected every 100 microns as the recording electrode was advanced along the tonotopic axis of the central nucleus of the IC. Space/time maps of neural activity were constructed from these data. In most of our sample the pattern of response changed systematically as the stimulating frequency was increased in octave steps. At low frequencies (< 500 Hz) the pattern of response was broadly distributed spatially and phase-locked to the stimulus frequency. At higher frequencies (> 1 kHz) the pattern of response was more localized and showed no evidence of phase locking. The location of the maximum response to tones from 1 to 32 kHz moved ventrally along the tonotopic axis at an approximate rate of 230 microns/stimulus octave. The patterns of response were localized near stimulus threshold and spread over a larger region as level increased. This method of collecting and displaying multi-unit response maps provides an overview of ensemble activity that allows concurrent observation of spatial and temporal variations in activity patterns. The quantitative analysis of components of MU-PST Maps are consistent with trends illustrated with single-unit tuning and level functions. This perspective of IC activity suggests potential processing mechanisms that are congruent with single-unit reconstructions.

Acoustic Stimulation↗
PubMed2006

Enhanced fluorescence of Cy5-labeled DNA tethered to silver island films: fluorescence images and time-resolved studies using single-molecule spectroscopy.

Methods that increase the total emission per fluorophore would provide increased sensitivity and a wider dynamic range for chemical analysis, medical diagnostics, and in vivo molecular imaging. The use of fluorophore-metal interactions has the potential to dramatically increase the detectability of single fluorophores for bioanalytical monitoring. The fabrication and single-molecule analysis of fluorophore-labeled DNA molecules tethered to silver island films are described in this article. The single-molecule spectroscopic method reveals some insightful information on the behaviors of single molecules, rather than an ensemble of molecules. Analysis of fluorescence images, intensity profiles, total emitted photons, and lifetime distributions reveals some of sample heterogeneities. Investigations of time-dependent emission characteristics of single molecules indicate that the total number of emitted photons on the silvered surface is more than 10 times greater than on free labeled DNA molecules on a glass substrate. In addition, time-correlated single-photon counting results reveal the reduced lifetimes of single molecules tethered to silver island films.

Carbocyanines↗
PubMed2006

Enzyme dynamics and tunneling enhanced by compression in the hydrogen abstraction catalyzed by soybean lipoxygenase-1.

A fully microscopical simulation of the rate-limiting hydrogen abstraction catalyzed by soybean lipoxygenase-1 (SLO-1) has been carried out. This enzyme exhibits the largest, and weakly temperature dependent, experimental H/D kinetic isotope effect (KIE) reported for a biological system. The theoretical model used here includes the complete enzyme with a solvation shell of water molecules, the Fe(III)-OH- cofactor, and the linoleic acid substrate. We have used a hybrid QM(PM3/d-SRP)/MM method to describe the potential energy surface of the whole system, and the ensemble-averaged variational transition-state theory with multidimensional tunneling (EA-VTST/MT) to calculate the rate constant and the primary KIE. The computational results show that the compression of the wild-type active site enzyme results in the huge contribution of tunneling (99%) to the rate of the hydrogen abstraction. Importantly, the active site becomes more flexible in the Ile553Ala mutant reactant complex simulation (for which a markedly temperature dependent KIE has been experimentally determined), thus justifying the proposed key role of the gating promoting mode in the reaction catalyzed by SLO-1. Finally, the results indicate that the calculated KIE for the wild-type enzyme has an important dependence on the barrier width.

Binding Sites↗
PubMed2004

Trajectory approach to dissipative quantum phase space dynamics: Application to barrier scattering.

The Caldeira-Leggett master equation, expressed in Lindblad form, has been used in the numerical study of the effect of a thermal environment on the dynamics of the scattering of a wave packet from a repulsive Eckart barrier. The dynamics are studied in terms of phase space trajectories associated with the distribution function, W(q,p,t). The equations of motion for the trajectories include quantum terms that introduce nonlocality into the motion, which imply that an ensemble of correlated trajectories needs to be propagated. However, use of the derivative propagation method (DPM) allows each trajectory to be propagated individually. This is achieved by deriving equations of motion for the partial derivatives of W(q,p,t) that appear in the master equation. The effects of dissipation on the trajectories are studied and results are shown for the transmission probability. On short time scales, decoherence is demonstrated by a swelling of trajectories into momentum space. For a nondissipative system, a comparison is made of the DPM with the "exact" transmission probability calculated from a fixed grid calculation.

Journal Article↗
PubMed2004

Dynamics of the two-dimensional gonihedric spin model.

In this paper, we study dynamical aspects of the two-dimensional (2D) gonihedric spin model using both numerical and analytical methods. This spin model has vanishing microscopic surface tension and it actually describes an ensemble of loops living on a 2D surface. The self-avoidance of loops is parametrized by a parameter kappa . The kappa=0 model can be mapped to one of the six-vertex models discussed by Baxter, and it does not have critical behavior. We have found that allowing for kappa not equal 0 does not lead to critical behavior either. Finite-size effects are rather severe, and in order to understand these effects, a finite-volume calculation for non-self-avoiding loops is presented. This model, like his 3D counterpart, exhibits very slow dynamics, but a careful analysis of dynamical observables reveals nonglassy evolution (unlike its 3D counterpart). We find, also in this kappa=0 case, the law that governs the long-time, low-temperature evolution of the system, through a dual description in terms of defects. A power, rather than logarithmic, law for the approach to equilibrium has been found.

Journal Article↗
PubMedDate not supplied

Molecular cytometry.

The first flow cytometric analyses were of total cellular DNA or protein content. The advent of labeled antibodies, first polyclonal and then monoclonal, led to the analysis of cellular content of specific antigen molecules and a myriad of immunological applications. Although, strictly speaking, it is incorrect to use the word "cytometry" for anything that does not refer to cellular measurements, the term has been used for a variety of non-cellular measurements such as chromosome analysis and solution molecular measurements. In recent years, there has been an increase in the development of methods to analyze molecules and their properties in solution. These analyses have ranged from ensemble measurements, primarily fluorescence-based immunoassays, to single molecule detection with applications in DNA analysis.

DNA↗
PubMed1990

[Rumpelstilzchen on the couch--an ensemble of shame, identity and father themes].

The fairy-tale "Rumpelstiltsken" is investigated as to its hidden meaning. A method, already described in the literature, is applied which allows conclusions about the hidden meaning to be drawn on the basis of the fairy-tale's place and handling with the history of literature. The hidden meaning found for "Rumpelstiltsken" lies in the question as to how individuation is possible in a symbiotic mother-child relationship. The answer is given in the fairy-tale in that a third person is introduced, who is, however, not involved in the symbiosis. A metapsychological concept of shame is then formulated on the basis of this understanding of "Rumpelstiltsken".

Child↗
PubMed1998

Tertiary structure prediction of mixed alpha/beta proteins via energy minimization.

We describe an improved algorithm for protein structure prediction, assuming that the location of secondary structural elements is known, with particular focus on prediction for proteins containing beta-strands. Hydrogen bonding terms are incorporated into the potential function, supplementing our previously developed residue-residue potential which is based on a combination of database statistics and an excluded volume term. Two small mixed alpha/beta proteins, 1-CTF and BPTI, are studied. In order to obtain native-like structures, it is necessary to allow the beta-strands in BPTI to distort substantially from an ideal geometry, and an automated algorithm to carry this out efficiently is presented. Simulated annealing Monte Carlo methods, which contain a genetic algorithm component as well, are used to produce an ensemble of low-energy structures. For both proteins, a cluster of structures with low RMS deviation from the native structure is generated and the energetic ranking of this cluster is in the top 2 or 3 clusters obtained from simulations. These results are encouraging with regard to the possibility of constructing a robust procedure for tertiary folding which is applicable to beta-strand containing proteins.

Algorithms↗
PubMed2002

Prediction of coordination number and relative solvent accessibility in proteins.

Knowing the coordination number and relative solvent accessibility of all the residues in a protein is crucial for deriving constraints useful in modeling protein folding and protein structure and in scoring remote homology searches. We develop ensembles of bidirectional recurrent neural network architectures to improve the state of the art in both contact and accessibility prediction, leveraging a large corpus of curated data together with evolutionary information. The ensembles are used to discriminate between two different states of residue contacts or relative solvent accessibility, higher or lower than a threshold determined by the average value of the residue distribution or the accessibility cutoff. For coordination numbers, the ensemble achieves performances ranging within 70.6-73.9% depending on the radius adopted to discriminate contacts (6A-12A). These performances represent gains of 16-20% over the baseline statistical predictor, always assigning an amino acid to the largest class, and are 4-7% better than any previous method. A combination of different radius predictors further improves performance. For accessibility thresholds in the relevant 15-30% range, the ensemble consistently achieves a performance above 77%, which is 10-16% above the baseline prediction and better than other existing predictors, by up to several percentage points. For both problems, we quantify the improvement due to evolutionary information in the form of PSI-BLAST-generated profiles over BLAST profiles. The prediction programs are implemented in the form of two web servers, CONpro and ACCpro, available at http://promoter.ics.uci.edu/BRNN-PRED/.

Amino Acids↗
PubMed2004

A novel method reveals that solvent water favors polyproline II over beta-strand conformation in peptides and unfolded proteins: conditional hydrophobic accessible surface area (CHASA).

In aqueous solution, the ensemble of conformations sampled by peptides and unfolded proteins is largely determined by their interaction with water. It has been a long-standing goal to capture these solute-water energetics accurately and efficiently in calculations. Historically, accessible surface area (ASA) has been used to estimate these energies, but this method breaks down when applied to amphipathic peptides and proteins. Here we introduce a novel method in which hydrophobic ASA is determined after first positioning water oxygens in hydrogen-bonded orientations proximate to all accessible peptide/protein backbone N and O atoms. This conditional hydrophobic accessible surface area is termed CHASA. The CHASA method was validated by predicting the polyproline-II (P(II)) and beta-strand conformational preferences of non-proline residues in the coil library (i.e., non-alpha-helix, non-beta-strand, non-beta-turn library derived from X-ray elucidated structures). Further, the method successfully rationalizes the previously unexplained solvation energies in polyalanyl peptides and compares favorably with published experimentally determined P(II) residue propensities. We dedicate this paper to Frederic M. Richards.

Hydrogen Bonding↗
PubMed2003

Method for quantitative imaging of the macromolecular 1H fraction in tissues.

A new method was developed for mapping the relative density of the macromolecular protons involved in magnetization transfer (MT). This method employs a stimulated echo preparation scheme in order to modulate the phase distribution within a spin ensemble. This labeled spin ensemble is then used as an intrinsic indicator, which is diluted due to magnetization exchange with macromolecular protons. A pulse sequence is presented which compensates for longitudinal relaxation, allows observation of the dilution effect only, and provides for calculation of parameter maps using indicator dilution theory. Compared to other quantitative MT techniques, neither additional relaxation time measurements nor knowledge regarding the lineshape of the macromolecular proton pool are required. Moreover, the inherent low specific absorption rate and the low sensitivity for B(1) errors make this method favorable in a clinical setting. This sequence was used to measure the macromolecular proton density in cross-linked bovine serum albumin. Using a navigated echo planar readout, the sequence was also employed to visualize the macromolecular content of human brain in vivo.

Animals↗
PubMedDate not supplied

25 + 1 channel pulsed ultrasound Doppler velocity meter for quantitative flow measurements and turbulence analysis.

A multichannel pulsed ultrasound Doppler instrument designed to measure velocity and volume flow rate quantitatively has been applied for turbulence detection. A 7-MHz transmitting frequency and a phase locked loop technique for the frequency to velocity conversion have been used to obtain high temporal resolution in the single channel mode. To provide for reliable positioning of the single gate within the arterial lumen the device could first be operated in the multichannel mode measuring the velocity profiles with zero crossing detection methods. Measurements of the velocity in the center of the lumen of the common and internal carotid arteries have been recorded on a beat to beat basis. An ensemble average of 16 consecutive pulses was determined. Thereafter, the root mean square of the differences between ensemble average and individual velocity pulses was computed, and a disturbance index was defined by dividing the disturbance velocity by the mean velocity. First clinical results show that the method presented is a valuable complement to the analysis of flow pulse patterns in the transcutaneous examination of carotid arteries.

Acoustics↗
PubMed2005

Improved prediction of bacterial transcription start sites.

MOTIVATION: Identifying bacterial promoters is an important step towards understanding gene regulation. In this paper, we address the problem of predicting the location of promoters and their transcription start sites (TSSs) in Escherichia coli. The accepted method for this problem is to use position weight matrices (PWMs), which define conserved motifs at the sigma-factor binding site. However this method is known to result in large numbers of false positive predictions. RESULTS: Our approaches to TSS prediction are based upon an ensemble of support vector machines (SVMs) employing a variant of the mismatch string kernel. This classifier is subsequently combined with a PWM and a model based on distribution of distances from TSS to gene start. We investigate the effect of different scoring techniques and quantify performance using area under a detection-error tradeoff curve. When tested on a biologically realistic task, our method provides performance comparable with or superior to the best reported for this task. False positives are significantly reduced, an improvement of great significance to biologists. AVAILABILITY: The trained ensemble-SVM model with instructions on usage can be downloaded from http://eresearch.fit.qut.edu.au/downloads

Algorithms↗
PubMed2004

Refinement of NMR structures using implicit solvent and advanced sampling techniques.

NMR biomolecular structure calculations exploit simulated annealing methods for conformational sampling and require a relatively high level of redundancy in the experimental restraints to determine quality three-dimensional structures. Recent advances in generalized Born (GB) implicit solvent models should make it possible to combine information from both experimental measurements and accurate empirical force fields to improve the quality of NMR-derived structures. In this paper, we study the influence of implicit solvent on the refinement of protein NMR structures and identify an optimal protocol of utilizing these improved force fields. To do so, we carry out structure refinement experiments for model proteins with published NMR structures using full NMR restraints and subsets of them. We also investigate the application of advanced sampling techniques to NMR structure refinement. Similar to the observations of Xia et al. (J.Biomol. NMR 2002, 22, 317-331), we find that the impact of implicit solvent is rather small when there is a sufficient number of experimental restraints (such as in the final stage of NMR structure determination), whether implicit solvent is used throughout the calculation or only in the final refinement step. The application of advanced sampling techniques also seems to have minimal impact in this case. However, when the experimental data are limited, we demonstrate that refinement with implicit solvent can substantially improve the quality of the structures. In particular, when combined with an advanced sampling technique, the replica exchange (REX) method, near-native structures can be rapidly moved toward the native basin. The REX method provides both enhanced sampling and automatic selection of the most native-like (lowest energy) structures. An optimal protocol based on our studies first generates an ensemble of initial structures that maximally satisfy the available experimental data with conventional NMR software using a simplified force field and then refines these structures with implicit solvent using the REX method. We systematically examine the reliability and efficacy of this protocol using four proteins of various sizes ranging from the 56-residue B1 domain of Streptococcal protein G to the 370-residue Maltose-binding protein. Significant improvement in the structures was observed in all cases when refinement was based on low-redundancy restraint data. The proposed protocol is anticipated to be particularly useful in early stages of NMR structure determination where a reliable estimate of the native fold from limited data can significantly expedite the overall process. This refinement procedure is also expected to be useful when redundant experimental data are not readily available, such as for large multidomain biomolecules and in solid-state NMR structure determination.

Bacterial Proteins↗
PubMed2006

Multiple pathways in conformational transitions of the alanine dipeptide: an application of dynamic importance sampling.

We present multiple dynamic transition pathways on the two-dimensional dihedral plane between conformational states of the alanine dipeptide. The method used in this study is dynamic importance sampling (DIMS). To perform DIMS, unbiased molecular dynamic simulations are used to generate equilibrium ensembles for the alanine dipeptide within different states. Free energy surfaces on the dihedral plane are calculated from the equilibrium simulations, and four energy minima defined from the surface are used as the starting and ending points for DIMS dynamics. The DIMS method represents an important step towards finding multiple transition pathways within complex biomolecular systems.

Alanine↗