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At least 289 records · Page 16Linked to original sources
PubMed1997

A molecular modeling analysis of the binding interactions between the okadaic acid class of natural product inhibitors and the Ser-Thr phosphatases, PP1 and PP2A.

We have proposed computer-generated models of the catalytic subunits of the serine-threonine protein phosphatases PP1 and PP2A complexed with their endogenous substrate phospho-DARPP-32, and several known naturally occurring inhibitors. This study is part of an overall effort to elucidate the signal transduction pathways in which PP1 and PP2A may play an important role.

Amino Acid Sequence↗
PubMed1995

[Use of voxel-oriented femur models for stress analysis. Generation, calculation and validation of CT-based FEM models].

A means of interfacing computed tomography with the finite element method for the analysis of stress distribution in human femurs is described. With the aid of data transfer and image processing programs, three-dimensional voxel models of four macerated and a fresh-frozen cadaveric femur were generated from CT data sets. The underlying basic principle is direct generation of model elements from one or more adjacent CT-voxels, which are characterised by their coordinates and local absorption coefficients. A new algorithm was used for smoothing the edges of the model. All the models were analysed with respect to their stress distribution under different load situations, and the results were compared with the data of a parallel study utilizing the strain-gauge technique. Using the method of linear regression, a high correlation (coefficient of determination r2: 0.80-0.91) was found between the calculated and experimentally measured principal stresses at the surface of the bones.

Biomechanical Phenomena↗
PubMed1998

Dynamics of membrane excitability determine interspike interval variability: a link between spike generation mechanisms and cortical spike train statistics.

We propose a biophysical mechanism for the high interspike interval variability observed in cortical spike trains. The key lies in the nonlinear dynamics of cortical spike generation, which are consistent with type I membranes where saddle-node dynamics underlie excitability (Rinzel & Ermentrout, 1989). We present a canonical model for type I membranes, the theta-neuron. The theta-neuron is a phase model whose dynamics reflect salient features of type I membranes. This model generates spike trains with coefficient of variation (CV) above 0.6 when brought to firing by noisy inputs. This happens because the timing of spikes for a type I excitable cell is exquisitely sensitive to the amplitude of the suprathreshold stimulus pulses. A noisy input current, giving random amplitude "kicks" to the cell, evokes highly irregular firing across a wide range of firing rates; an intrinsically oscillating cell gives regular spike trains. We corroborate the results with simulations of the Morris-Lecar (M-L) neural model with random synaptic inputs: type I M-L yields high CVs. When this model is modified to have type II dynamics (periodicity arises via a Hopf bifurcation), however, it gives regular spike trains (CV below 0.3). Our results suggest that the high CV values such as those observed in cortical spike trains are an intrinsic characteristic of type I membranes driven to firing by "random" inputs. In contrast, neural oscillators or neurons exhibiting type II excitability should produce regular spike trains.

Algorithms↗
PubMed1976

Simulation studies of self-associating systems; discrimination between specific and isodesmic associations.

The possibilities of discriminating between definite and indefinite (isodesmic) modes of self-association are explored by fitting the different models to stimulated data, using non-linear least-squares curve-fitting to determine the fitting parameters for real and impostor models. It was found that over an extensive range of values for the equilibrium constant of a non-ideal isodesmic generating model, only a non-ideal monomer-dimer-tetramer-octamer was a successful impostor model. Some criteria for rejecting inappropriate models are discussed.

Binding Sites↗
PubMed1997

Improving the quality of the NCQA (National Committee for Quality Assurance) Annual Member Health Care Survey Version 1.0.

The National Committee for Quality Assurance (NCQA) developed a standardized survey instrument in 1995 designed to measure enrollee satisfaction with the care and services received from health plans across the United States. After the survey was administered for a large number of health plans and thousands of responses were received, some areas for survey improvement have emerged. The objective of this research was to evaluate the NCQA Annual Member Health Care Survey Version 1.0 (the standard form) relative to an alternate survey form created in cooperation with the HMO Group, Maritz Marketing Research, Inc., and Healthcare Research Systems, Ltd. The alternate form of the NCQA survey was constructed to test several theories of measurement improvement via rewording of items, reordering of items, deletion of items, and addition of items. The most important findings of the research project are reported herein. Ten geographically dispersed member health maintenance organizations (HMOs) of The HMO Group took part in the project. A split-half design was used to test the standard and alternate survey forms concurrently. Surveys were administered by using the NCQA-recommended mail methodology of survey and cover letter, reminder card, and second survey. Assuming a 50% response rate, a target of 400 responses (200 for each survey form) per HMO was planned. The window for responding was allowed to remain open 4 weeks beyond the mailing of the second survey to achieve the desired response rate. A total of 4,056 responses were collected (2,022 for the standard form and 2,034 for the alternate form). It was found that the addition of "No Experience" and "No Opinion" response options to the majority of satisfaction items reduced the random error associated with informed responses and produced statistically significant higher correlations with the global satisfaction items relative to the standard form items. Only four of the eight Short Form 12 summary scales, General Health, Reported Health Transition, Mental Health, and Social Functioning, were useful for adjusting data (covariation). The entire set of comorbidities (chronic disease checklist) could be eliminated without losing significant data adjustment capability. The multiple linear regression models generated by using the global satisfaction items on the alternate form had higher adjusted R2 values than the standard-form models. The alternate-form item Overall Value correlated highly with cost items and general satisfaction item, making it a useful global satisfaction variable for predictive modeling.

Health Care Surveys↗
PubMed1993

The steady expiratory pressure-flow relation in a model pulmonary bifurcation.

Experiments were conducted over a range of Reynolds numbers from 50 to 8000 to study the pressure-flow relationship for a single bifurcation in a multi-generation model during steady expiratory flow. Using the energy equation, the measured static pressure drop was decomposed into separate components due to fluid acceleration and viscous energy dissipation. The frictional pressure drop was found to closely approximate that for an equivalent length of curved tube with the same curvature ratio as in the model bifurcation. The sensitivity of these results to changes in airway cross-sectional shape, non-planar configuration, and flow regime (laminar-turbulent) was investigated. In separate experiments using dye visualization and hot-wire anemometry, a transition to turbulent flow was observed at Reynolds numbers between 1000 and 1500. Transition had very little effect on the pressure-flow relation.

Acceleration↗
PubMed1992

Simulation of Doppler ultrasound signals for a laminar, pulsatile, nonuniform flow.

A simulation for Doppler ultrasound quadrature signals from pulsatile, nonuniform flow is presented. It is an extension of an earlier simulation presented by Jones and Giddens (1990a) which was valid for laminar, uniform, steady flow and which included the stochastic characteristics introduced by scattering particles which enter and leave the sample volume at random times. Fourier transform and autoregressive spectral analysis techniques are used to compare the simulated signals to Doppler signals collected from an in vitro flow setup. Power spectra, Doppler frequency estimates and standard deviations of these estimates serve as standards of comparison. Results show that the simulation model generates realistic quadrature signals. The study improves the understanding of the physics of the Doppler process and shows that it can be modeled for complex flow conditions. The input parameters of the simulation are the Doppler instrument parameters and flow characteristics. This allows the simulation to be used for transducer design as well as in the study of the applicability of signal analysis techniques to Doppler ultrasound.

Blood Flow Velocity↗
PubMed1995

Transbilayer pores formed by beta-barrels: molecular modeling of pore structures and properties.

Transmembrane beta-barrels, first observed in bacterial porins, are possible models for a number of membrane channels. Restrained molecular dynamics simulations based on idealized C alpha beta templates have been used to generate models of such beta-barrels. Model beta-barrels have been analyzed in terms of their conformational, energetic, and pore properties. Model beta-barrels formed by N = 4, 8, 12 and 16 anti-parallel Ala10 strands have been developed. For each N, beta-barrels with shear numbers S = N to 2N have been modeled. In all beta-barrel models the constituent beta-strands adopt a pronounced right-handed twist. Interstrand interactions are of approximately equal stability for all models with N > or = 8, whereas such interactions are weaker for the N = 4 beta-barrels. In N = 4 beta-barrels the pore is too narrow (minimum radius approximately 0.6 A) to allow ion permeation. For N > or = 8, the pore radius depends on both N and S; for a given value of N an increase in S from N to 2N is predicted to result in an approximately threefold increase in pore conductance. Calculated maximal conductances for the beta-barrel models are compared with experimental values for porins and for K+ channels.

Alanine↗
PubMed1991

Functional interactions in the brain: use of correlations between regional metabolic rates.

Correlation coefficients between pairs of regional metabolic rates have been used to study patterns of functional associations among brain regions in humans and animals. An overview is provided concerning the additional information about brain functioning this type of analysis yields. A computer simulation model is presented for the purpose of giving a partial validation for correlational analysis. The model generates a set of simulated metabolic data upon which correlational analysis is performed. Because the underlying pattern of functional couplings in the model is known, these simulations demonstrate that the correlation coefficient between normalized metabolic rates is proportional to the strength of the functional coupling constant and that correlational analysis yields information on regional involvement in neural systems not evident in the pattern of absolute metabolic values.

Adult↗
PubMed1997

A neural model of multimodal adaptive saccadic eye movement control by superior colliculus.

How does the saccadic movement system select a target when visual, auditory, and planned movement commands differ? How do retinal, head-centered, and motor error coordinates interact during the selection process? Recent data on superior colliculus (SC) reveal a spreading wave of activation across buildup cells the peak activity of which covaries with the current gaze error. In contrast, the locus of peak activity remains constant at burst cells, whereas their activity level decays with residual gaze error. A neural model answers these questions and simulates burst and buildup responses in visual, overlap, memory, and gap tasks. The model also simulates data on multimodal enhancement and suppression of activity in the deeper SC layers and suggests a functional role for NMDA receptors in this region. In particular, the model suggests how auditory and planned saccadic target positions become aligned and compete with visually reactive target positions to select a movement command. For this to occur, a transformation between auditory and planned head-centered representations and a retinotopic target representation is learned. Burst cells in the model generate teaching signals to the spreading wave layer. Spreading waves are produced by corollary discharges that render planned and visually reactive targets dimensionally consistent and enable them to compete for attention to generate a movement command in motor error coordinates. The attentional selection process also helps to stabilize the map-learning process. The model functionally interprets cells in the superior colliculus, frontal eye field, parietal cortex, mesencephalic reticular formation, paramedian pontine reticular formation, and substantia nigra pars reticulata.

Animals↗
PubMed1989

Ecological modelling in an evolutionary context.

I argue that one of the strong features in disciplines like molecular biology and cosmology is the extent ot which they use a powerful theoretical framework to generate and test quantitative predictions. Studies of biological evolution can exploit a similar advantage by integrating our current understanding of physiological and sociobiological processes to generate models of much greater sophistication than has commonly been the practice hitherto. I illustrate this with a number of examples drawn from the evolutionary biology of human and nonhuman primates.

Animals↗
PubMed1988

Three-dimensional reconstruction of myocardial contrast perfusion from biplane cineangiograms by means of linear programming techniques.

The assessment of coronary flow reserve from the instantaneous distribution of the contrast agent within the coronary vessels and myocardial muscle at the control state and at maximal flow has been limited by the superimposition of myocardial regions of interest in the two-dimensional images. To overcome these limitations, we are in the process of developing a three-dimensional (3D) reconstruction technique to compute the contrast distribution in cross sections of the myocardial muscle from two orthogonal cineangiograms. To limit the number of feasible solutions in the 3D-reconstruction space, the 3D-geometry of the endo- and epicardial boundaries of the myocardium must be determined. For the geometric reconstruction of the epicardium, the centerlines of the left coronary arterial tree are manually or automatically traced in the biplane views. Next, the bifurcations are detected automatically and matched in these two views, allowing a 3D-representation of the coronary tree. Finally, the circumference of the left ventricular myocardium in a selected cross section can be computed from the intersection points of this cross section with the 3D coronary tree using B-splines. For the geometric reconstruction of the left ventricular cavity, we envision to apply the elliptical approximation technique using the LV boundaries defined in the two orthogonal views, or by applying more complex 3D-reconstruction techniques including densitometry. The actual 3D-reconstruction of the contrast distribution in the myocardium is based on a linear programming technique (Transportation model) using cost coefficient matrices. Such a cost coefficient matrix must contain a maximum amount of a priori information, provided by a computer generated model and updated with actual data from the angiographic views. We have only begun to solve this complex problem. However, based on our first experimental results we expect that the linear programming approach with advanced cost coefficient matrices and computed model will lead to acceptable solutions in the 3D-reconstruction of the myocardial contrast distribution from biplane cineangiograms.

Cineangiography↗
PubMedDate not supplied

Lumped model of terminal aortic impedance in the dog.

The aim of this study was the formulation of a minimal lumped model of the aortic impedance as seen in the abdominal aorta just downstream of the origin of renal arteries. At this location simultaneous measurements of pressure and flow were taken in four anesthetized and open-chest dogs (weight, 30.9 +/- 5.8 kg) under basal, vasodilated (sodium nitroprusside) and vasoconstricted (methoxamine) conditions. Using these measurements we identified and compared three lumped models, A, B, and C, with decreasing complexity from A to C. The frequency response of these models was given the general form of peripheral resistance, Rp, multiplied by the ratio between (a) two zeros and two poles (model A); (b) two zeros and one pole (model B); and (c) one zero and one pole (model C). Rp was calculated as the ratio of mean pressure to mean flow. The other model parameters (time constants, damping factors, and natural frequencies) were estimated by minimizing the sum of squared differences between experimental and model generated pulsatile flows. After parameter estimation, the F-test was applied to compare the goodness of data fit obtained from the three models. Results of this test and the analysis of parameter estimation errors indicated that model B was preferable with respect to models A and C. The analysis of general model performance was followed by a consideration of alternative specific model structures that are physically realizable. With the aid of a determined model structure we evaluated the overall compliance of terminal aortic circulation under a variety of vascular states induced by injection of vasoactive agents.

Animals↗
PubMed1990

Routes to chaos in a model of a bursting neuron.

Chaotic regimens have been observed experimentally in neurons as well as in deterministic neuronal models. The R15 bursting cell in the abdominal ganglion of Aplysia has been the subject of extensive mathematical modeling. Previously, the model of Plant and Kim has been shown to exhibit both bursting and beating modes of electrical activity. In this report, we demonstrate (a) that a chaotic regime exists between the bursting and beating modes of the model, and (b) that the model approaches chaos from both modes by a period doubling cascade. The bifurcation parameter employed is the external stimulus current. In addition to the period doubling observed in the model-generated trajectories, a period three "window" was observed, power spectra that demonstrate the approaches to chaos were generated, and the Lyaponov exponents and the fractal dimension of the chaotic attractors were calculated. Chaotic regimes have been observed in several similar models, which suggests that they are a general characteristic of cells that exhibit both bursting and beating modes.

Animals↗
PubMed1988

Estimation of intramyocardial pressure and coronary blood flow distribution.

To characterize the intramyocardial pressure (IMP) and coronary blood flow distribution in a stenosed coronary circulation, we compared four analog circuits for modeling coronary impedance. The resistor (R)-diode (D) model simulates vascular collapse, and the capacitor (C) simulates compliance effect. Identification of the best model and magnitudes of the endocardial and epicardial IMPs (IMPendo and IMPepi) was done retrospectively using data from studies in 28 anesthetized swine. Performance evaluation was based on comparison of model predicted vs. observed coronary distal pressure (DP) waveforms and endocardial-to-epicardial (endo-epi) flow ratios as determined by radiolabeled microspheres. The R-D-C model gave the best performance at IMPendo = 1.1 times left ventricular pressure (LVP), and IMPepi = 0.1.LVP + 15 mmHg; with good fit to DP (r = 0.98, slope of regression line = 1.0) and estimates of endo-epi flow ratio (r = 0.78, slope = 1.01, P less than 0.02, SEE = 0.21, n = 139). The R-D model gave comparable results even though capacitance was omitted. Although R-C and R models predicted distal coronary pressure well, they failed to predict endo-epi flow ratios (r less than 0.50). The R-D-C and R-D models were applied in seven prospective studies. Both models generated reasonable estimates of endo-epi flow distribution (r = 0.78, n = 50). Thus the R-D-C or R-D models of the stenosed coronary circulation can be used to provide reliable estimates of transmural blood flow distribution.

Animals↗
PubMed1991

A tissue pressure model for palpatory perception of the cranial rhythmic impulse.

A tissue pressure model was developed to provide a possible physiologic basis for the manifestation of the cranial rhythmic impulse (CRI). The model assumes that the sensation described as the CRI is related to activation of slowly adapting cutaneous mechanoreceptors by tissue pressures of both the examiner and the subject, and that the sources of change in these tissue pressures are the combined respiratory and cardiovascular rhythms of both examiner and subject. The model generates rhythmic impulses with patterns similar to those reported for the CRI. Also, a significant correlation was found between frequencies calculated from the model and published values for CRI obtained by palpation. These comparisons suggest that the CRI may arise in soft tissues and represents a complex interaction of at least four different physiologic rhythms.

Humans↗
PubMed1986

Genetics of Darwinian fitness. III. A generalized approach to age structured selection and life history.

Most models in life history assume that maximization of lambda holds. Demographic genetic theory supports this assumption provided (i) the fecundity of each mating is determined solely by the age and genotype of the female, (ii) the two sexes experience the exact same selection intensities, and (iii) the two sexes are equal in their age specific schedules of survival and fecundity. But these assumptions will often not hold in nature: thus a more general means of analysis closely integrated with a broader genetic treatment is attempted here. First, operators are derived to map sex specific non-overlapping generation models into the more general case in which generations can overlap. Application of such operators then suggests a broader representation of age structured selection in which evolution acts according to a single composite Wrightian topography whose gradient is a weighted mean taken over selective gradients in all of the age classes. Application of this view is straightforward, showing, for example, that (i) the evolutionary maximization of lambda, which is the basis of present optimization theories for life history, is extremely fragile with biological deviation from mathematical assumptions used in its derivation, (ii) the cost of meiosis argument is shown not to conflict with traditional life history theory, although its correct application will depend critically and subtly upon how genic effects on fertility are measured, and (iii) correct weightings for age specific selection converge to those of Hamilton (1966) and Schaffer (1974) only when sex specific differences in fertility and survival are nonexistent or when selection occurs only in the demographically dominant sex. For life history problems beyond assumptions underlying tradition approaches the composite adaptive topography seems to provide a suitable alternate means for analysis.

Adaptation, Physiological↗
PubMed1996

Noninvasive visualization of blood flow in the choriocapillaris of the rat.

PURPOSE: The rat has been used to generate models of various eye diseases. However, methods to study the choriocapillaris noninvasively have been inadequate in this species. Laser-targeted angiography was applied to generate local, repetitive angiograms of the choriocapillaris in the rat and to assess the similarity between the choriocapillaris of the rat and that of the subhuman primate. METHODS: Carboxyfluorescein was encapsulated in heat-sensitive liposomes and injected intravenously in rats. The liposome contents were then released locally in the choroid by the application of a short, noncoagulating heat pulse provided by an argon laser. Videoangiograms of the downstream spread of the bolus of dye were generated with excitation illumination provided by another output from the argon laser. RESULTS: Laser-targeted angiography demonstrated that the bolus of dye perfused the choriocapillaris. Clusters of choriocapillaris lobules were observed and appeared similar to those described in the primate. Dynamic filling and emptying patterns also were similar to those of the primate. Lobules were filled by a central arteriole and drained by a venous annulus. CONCLUSIONS: This study demonstrates the feasibility of noninvasively studying the choriocapillaris of the living rat using the technique of laser-targeted angiography. It demonstrates as well the similarity between the rat and the primate choriocapillaris, thus indicating that the rat is an acceptable and convenient model for the study of physiological and pathologic changes in the choroidal vasculature.

Animals↗