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PubMed1993

Reduced representation model of protein structure prediction: statistical potential and genetic algorithms.

A reduced representation model, which has been described in previous reports, was used to predict the folded structures of proteins from their primary sequences and random starting conformations. The molecular structure of each protein has been reduced to its backbone atoms (with ideal fixed bond lengths and valence angles) and each side chain approximated by a single virtual united-atom. The coordinate variables were the backbone dihedral angles phi and psi. A statistical potential function, which included local and nonlocal interactions and was computed from known protein structures, was used in the structure minimization. A novel approach, employing the concepts of genetic algorithms, has been developed to simultaneously optimize a population of conformations. With the information of primary sequence and the radius of gyration of the crystal structure only, and starting from randomly generated initial conformations, I have been able to fold melittin, a protein of 26 residues, with high computational convergence. The computed structures have a root mean square error of 1.66 A (distance matrix error = 0.99 A) on average to the crystal structure. Similar results for avian pancreatic polypeptide inhibitor, a protein of 36 residues, are obtained. Application of the method to apamin, an 18-residue polypeptide with two disulfide bonds, shows that it folds apamin to native-like conformations with the correct disulfide bonds formed.

Algorithms↗
PubMed1994

A simplified amino acid potential for use in structure predictions of proteins.

A simplified description and a corresponding force field for polypeptides is introduced. Each amino acid residue is reduced to one interaction site, representing the backbone, and one or two side chain sites depending on its size and complexity. Site-site interactions are parameterized after a hydrophobicity criterium. The treatment of backbone sites is in addition designed to reproduce typical polypeptide hydrogen bonding patterns, as well as yielding conformations in accord with the allowed phi and psi angles through an effective angle potential. There are no explicit charges in the model. The derived energy functions, which are based on thermodynamic data and sterical consideration of allowed backbone conformations, correspond to the introduction of an effective potential. The model is tested on two small proteins, avian pancreatic polypeptide and a parathyroid hormone-related protein, by simulating folding from an initially extended state using Monte Carlo methods. The reduced amino acid description is able to satisfactorily reproduce the experimentally determined native structures.

Amino Acids↗
PubMed1990

Principles, problems and a paradox with the measurement of energy expenditure of free-living subjects using doubly-labelled water.

Many aspects of the study of human nutrition would benefit from the ability to measure the energy which is expended by subjects as they go about their normal activities. The doubly-labelled water technique is a method which allows such measures to be made. The technique depends on the principle that a measure of carbon dioxide production is possible from the difference in the rates at which isotopic labels of hydrogen and oxygen are eliminated from the body. This simple explanation however conceals a host of assumptions. Several issues have emerged as important in the application of the technique to humans. These issues include first, the use of two samples (an initial and final sample) or multiple samples to estimate the rates of isotope elimination, and secondly the appropriate use of dilution spaces. This paper reviews the current status of the debates concerning these two issues. Paradoxically, improvements in our understanding of the technique, in the methods for calculating carbon dioxide production and in the accuracy of mass spectrometry, have not led to improvements in the accuracy of the technique. The mean deviation of estimates of carbon dioxide production using the technique from estimates made by conventional methods averages 7 per cent.

Animals↗
PubMed1993

Antigen-antibody binding and mass transport by convection and diffusion to a surface: a two-dimensional computer model of binding and dissociation kinetics.

The kinetics of binding and dissociation between a soluble analyte and an immobilized ligand on or near a surface are described numerically by an iterative computer model. The model is applied to a microflow chamber which is used for surface plasmon resonance measurements. It calculates diffusion perpendicular to the surface, flow parallel to the surface, and the interaction between any number of soluble and immobilized species. If the reaction between analyte and ligand is fast, binding and dissociation are influenced by the transport of the analyte to or away from the surface. In this case the measurement yields apparent association and dissociation rate constants which are not identical with the reaction rate of analyte and ligand. The transition between mass transport-controlled processes and reaction-controlled processes is described and attention is drawn to possible misinterpretations of experimental binding and dissociation curves. The measurement of rate constants higher than allowed by the conventional technique can be performed by elution of the analyte with a second analyte of low molecular weight.

Antibodies↗
PubMed1999

Influence of internal dynamics on accuracy of protein NMR structures: derivation of realistic model distance data from a long molecular dynamics trajectory.

In order to study the effect of internal dynamics on the accuracy of NMR structures in detail, we generated NOE distance data from a long molecular dynamics trajectory of BPTI. Cross-relaxation rates were calculated from the trajectory by analysis of the appropriate proton-proton vector autocorrelation functions. A criterion for the convergence of correlation functions was developed, and the analysis was restricted to those correlation functions that had converged within the simulation time. Effective distances were determined from the calculated cross-relaxation rates. Internal dynamics affected the derived distances in a realistic way, since they were subject both to radial averaging (which increases the cross-relaxation rate) and angular averaging (which decreases the cross-relaxation rate). The comparison of the effective distances with average distance between the protons during the trajectory showed that for most the effects of angular and distance averaging essentially cancel out. For these distances, the effective distance derived from an NOE is therefore a very good estimate of the average distance, or the distance in the average structure. However, for about 10% of the distances, the effective distance was more than 10% larger than the average distance, while for about 5%, it was more than 10% smaller, in some cases by more than 2 A. Little correlation is observed between the effects on cross-relaxation rates to different protons of the same residue. The results of this analysis have implications for the way structures are calculated from NOE distance data. For many distances, the assumption of a rigid structure is valid, and large error bounds would result in the loss of too much information content. On the other hand, the error bounds very often employed are not wide enough for some of the effects seen in our study.

Animals↗
PubMed1997

A general approach to error estimation and optimized experiment design, applied to multislice imaging of T1 in human brain at 4.1 T.

In this report, a procedure to optimize inversion-recovery times, in order to minimize the uncertainty in the measured T1 from 2-point multislice images of the human brain at 4.1 T, is discussed. The 2-point, 40-slice measurement employed inversion-recovery delays chosen based on the minimization of noise-based uncertainties. For comparison of the measured T1 values and uncertainties, 10-point, 3-slice measurements were also acquired. The measured T1 values using the 2-point method were 814, 1361, and 3386 ms for white matter, gray matter, and cerebral spinal fluid, respectively, in agreement with the respective T1 values of 817, 1329, and 3320 ms obtained using the 10-point measurement. The 2-point, 40-slice method was used to determine the T1 in the cortical gray matter, cerebellar gray matter, caudate nucleus, cerebral peduncle, globus pallidus, colliculus, lenticular nucleus, base of the pons, substantia nigra, thalamus, white matter, corpus callosum, and internal capsule.

Artifacts↗
PubMed1995

Tests for distributed, nonfocal brain activations.

Most approaches to detecting changes in functional brain images assume that activations are focal or very localized. However, the brain's response to cognitive of sensorimotor challenge may be spatially or anatomically distributed. In this paper we consider the usefulness of a test based on the mean sum of squares of statistical parametric maps. The performance of this test is evaluated using simulated and real data and is compared to the gamma 2 test, a test of the size of the activated region, and a focal activation test based on the intensity of local maxima. We demonstrate that the mean sum of squares test is more sensitive to nonfocal signals and propose that it could be used to complement approaches that are more sensitive to focal activations.

Arousal↗
PubMed1996

Endophrenology: new statistical techniques for studies of brain form. Life on the hyphen in neuro-informatics.

The interweaving here of statistics, image analysis, and neuroscience is a fine example of how neuro-informatics is more than the concentration of its constituent disciplines. Each of the component tools of the morphometric synthesis--the deformation model, Procrustes shape coordinates, the thin-plate spline--gains greatly in power in the context of the others, and enhances, too, great recent strides in the instrumentation leading to the raw image data itself (MR scanner physics, multiple stains, new contrast agents). The modern morphometric tool kit seems better matched to the description of gross brain variation than we had any reason to expect. Now the new tools can be exploited to produce remarkably sharper new findings. At the same time, the demands of neuro-informatics will press the toolmakers to provide equivalently powerful new techniques in areas presently less developed, such as cortical form or correlations of images with parametric experimental designs or with clinical histories.

Animals↗
PubMed2001

Qualitative and quantitative evaluation of six algorithms for correcting intensity nonuniformity effects.

The desire to correct intensity nonuniformity in magnetic resonance images has led to the proliferation of nonuniformity-correction (NUC) algorithms with different theoretical underpinnings. In order to provide end users with a rational basis for selecting a given algorithm for a specific neuroscientific application, we evaluated the performance of six NUC algorithms. We used simulated and real MRI data volumes, including six repeat scans of the same subject, in order to rank the accuracy, precision, and stability of the nonuniformity corrections. We also compared algorithms using data volumes from different subjects and different (1.5T and 3.0T) MRI scanners in order to relate differences in algorithmic performance to intersubject variability and/or differences in scanner performance. In phantom studies, the correlation of the extracted with the applied nonuniformity was highest in the transaxial (left-to-right) direction and lowest in the axial (top-to-bottom) direction. Two of the six algorithms demonstrated a high degree of stability, as measured by the iterative application of the algorithm to its corrected output. While none of the algorithms performed ideally under all circumstances, locally adaptive methods generally outperformed nonadaptive methods.

Algorithms↗
PubMed2001

"Voxel-based morphometry" should not be used with imperfectly registered images.

John Ashburner and Karl Friston (2000) introduced a standardized method of "voxel-based morphometry" (VBM) for comparisons of local concentrations of gray matter between two groups of subjects. Segmented images of gray matter from grossly normalized high-resolution images are smoothed and their group differences analyzed by the now-conventional voxelwise Worsley approach to Gaussian random fields of differences. This comment concerns an unfortunate interaction between the algorithm's spatial normalization and voxelwise comparison steps, whereby several obvious quantitative confounds are injected at the core of the inference engine the authors put forward. Specifically, the statistics of the resulting voxelwise comparisons are uninformative about group differences wherever the spatial normalization algorithm has failed to register on any robustly appearing image gradient. The method of Ashburner and Friston is defensible only far from all image gradients.

Artifacts↗
PubMed2001

Nonadditive two-way ANOVA for event-related fMRI data analysis.

A significant recent development in functional magnetic resonance imaging (fMRI) is the introduction of event-related fMRI, also known as time-resolved fMRI. Because the exact shape of the MR response in an event-related fMRI experiment is often not known, traditional methods developed for block design experiments, such as t test and correlation analysis, are not well-suited for extracting activated pixels from the event-related data. In this work, a statistical technique based on nonadditive two-way analysis of variance is developed for use in event-related studies. Theoretical and experimental work were carried out for establishing a statistical threshold to determine pixel activation. Experimental studies were performed to demonstrate the utility of this approach.

Adult↗
PubMed2001

An optimization approach to signal extraction from noisy multivariate data.

We consider a problem of blind signal extraction from noisy multivariate data, in which each datum represents a system's response, observed under a particular experimental condition. Our prototype example is multipixel functional images of brain activity in response to a set of prescribed experimental stimuli. We present a novel multivariate analysis technique, which identifies the different activity patterns (signals) that are attributable to specific experimental conditions, without a priori knowledge about the signal or the noise characteristics. The extracted signals, which we term the generalized indicator functions, are optimal in the sense that they maximize a weighted difference between the signal variance and the noise variance. With an appropriate choice of the weighting parameter, the method returns a set of images whose signal-to-noise ratios satisfy some user-defined level of significance. We demonstrate the performance of our method in optical intrinsic signal imaging of cat cortical area 17. We find that the method performs effectively and robustly in all tested data, which include both real experimental data and numerically simulated data. The method of generalized indicator functions is related to canonical variate analysis, a multivariate analysis technique that directly solves for the maxima of the signal-to-noise ratio, but important theoretical and practical differences exist, which can make our method more appropriate in certain situations.

Animals↗
PubMed2002

Detection versus estimation in event-related fMRI: choosing the optimal stimulus timing.

With the advent of event-related paradigms in functional MRI, there has been interest in finding the optimal stimulus timing, especially when the interstimulus interval is varied during the imaging run. Previous works have proposed stimulus timings to optimize either the estimation of the impulse response function (IRF) or the detection of signal changes. The purpose of this paper is to clarify that estimation and detection are fundamentally different goals and to determine the optimal stimulus timing and distribution with respect to both the accuracy of estimating the IRF and the power of detection assuming a particular hemodynamic model. Simulated stimulus distributions are varied systematically, from traditional blocked designs to rapidly varying event related designs. These simulations indicate that estimation of the hemodynamic impulse response function is optimized when stimuli are frequently alternated between task and control states, with shorter interstimulus intervals and stimulus durations, whereas the detection of activated areas is optimized by blocked designs. The stimulus timing for a given experiment should therefore be generated with the required detectability and estimation accuracy.

Cerebral Cortex↗
PubMed1992

Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs.

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction of a stochastic model and analysis of published data, that compounds which are readily diffusible and partitioned into hepatocytes may undergo axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell membranes provide little resistance and which are highly extracted, thereby creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compound under conditions of altered hepatic blood flow and protein binding. For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe the steady-state kinetics of lipophilic drugs such as lidocaine, meperidine, and propranolol may be finally resolved. The effects of axial tissue diffusion and vascular dispersion on hepatic availability of drugs are compared. Vascular dispersion is of major importance to the availability of poorly diffusible compounds, whereas axial tissue diffusion becomes increasingly dominant for highly diffusive and partitioned substances.

Computer Simulation↗
PubMed1995

Computer-algebra calculations and measurements on AB spin systems for double-spin-echo sequences.

The time evolution of the density operator of an AB spin system during a double-spin-echo pulse sequence is evaluated analytically by a computer-algebra system. The computer-algebra system allows one to generate the extensive formulas describing the density operator and yields an expression for the integral of the spectral signals. The simulation of spectra for arbitrary sequence timings can be easily performed by this new tool without risking errors that might occur in conventional calculations. The computer-algebra method can be extended straightforward to other pulse angles and types of sequences. The double-spin-echo pulse sequence is used in the point-resolved spectroscopy (PRESS) method which is often applied for volume selective examinations in vivo. For verification of the results generated by the computer-algebra system, 1H spectra from a half-liter spherical sample with an aqueous solution that was 0.1 M in sodium citrate and 0.1 M in sodium acetate were recorded after 90 degrees-180 degrees-180 degrees double-spin-echo pulse sequences on a 1.5-T whole-body unit. The measured behavior of the citrate AB spin system corresponds very well with the theoretical predictions. Thus, the theory provides the basis for optimization of sequence timings for double-spin-echo measurements with high signal gain from AB systems as, for example, citrate. In addition, the theoretically predicted signal modulations could be fitted to the experimental data, providing the transverse relaxation time of the AB-coupled protons.

Computer Simulation↗
PubMed1988

Combining transmural left ventricular mechanics and energetics to predict oxygen demand.

This study relates to our earlier study which predicts the transmural distribution as well as the global left ventricular (LV) function and oxygen demand, based on the LV structure, geometry and sarcomere function. Here, we test the predicted global oxygen demand against experimental data in anesthetized, open chest dogs under changing working conditions. The experimental oxygen demand was calculated from the arterio-venous difference in oxygen content times the measured coronary flow. LV load was manipulated by a combination of a pressurized chamber connected to the femoral artery, phenylephrine infusion and an adjustable arteriovenous shunt. The heart was paced in two present heart rates. The study demonstrates that the global predictions, based on the local distributed oxygen demand model, are comparable to those obtained by other methods of global metabolic predictions. However, unlike other global methods, the distributed model gives spatial information and predicts an endo/epi ratio of oxygen demand ranging between 1.05 to 1.14, depending on the loading conditions, which is comparable to available experimental data. For the experimental conditions studied here (stroke volume, heart rate, aortic pressure), the theoretical analysis shows that only the end diastolic volume is significantly correlated to the endo/epi ratio of the transmural oxygen demand.

Animals↗
PubMed1997

Distributed large-scale simulation of magnetic resonance imaging.

The concept and the implementation of a parallelized and spin-based simulator for magnetic resonance (MR) imaging is presented. The dynamics of magnetization are modeled using the Bloch equation covering arbitrary radiofrequency (RF) pulses, gradients, main-field inhomogeneity, and relaxation. A temporal decomposition of a given sequence is introduced, leading to basic sequence elements called atoms. A concept of spatial sampling of the object by spins is proposed, in the course of which Shannon's sampling theorem must be respected. In biomedical MR imaging, spins can be modeled as noninteracting entities, permitting an efficient parallelization of the simulation. The simulator ParSpin was implemented on a heterogeneous, interconnected cluster of workstations based on existing message passing libraries. The communication overhead has been kept moderately small. The aggregate computing performance of many processors enables the research into very complex problems (e.g., three-dimensional or steady-state MR experiments requiring up to 10(6) spins). Additionally, ParSpin allows a comprehensive visualization for educational purposes.

Computer Simulation↗