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At least 685 records · Page 38Linked to original sources
PubMed1997

Computer simulation of clonal growth cancer models. I. Parameter estimation using an iterative absolute bisection algorithm.

Quantitative models of the relationship between exposure to chemical carcinogens and carcinogenic response are useful for hypothesis evaluation and risk assessment. The degree to which such models accurately depict the underlying biology is often a function of the need for mathematical tractability. When closed-form expressions are used, the need for tractability may significantly limit their complexity. This problem can be minimized by using numerical computer simulation methods to solve the model, thereby allowing more complex and realistic descriptions of the biology to be used. Unfortunately, formal methods of parameter estimation for numerical models are not as well developed as they are for analytical models. In this report, we develop a formal parameter estimation routine and apply it to a numerical clonal growth simulation (CGS) model of the growth of preneoplastic lesions consisting of initiated cells. An iterative bisection algorithm was used to estimate parameters from time-course data on the number of initiated cells and the number of clones of these cells. The algorithm successfully estimated parameter values to give a best fit to the observed dataset and was robust vis-à-vis starting values of the parameters. Furthermore, the number of data points to which the model was fit, the number of stochastic repetitions and other variables were examined with respect to their effects on the parameter estimates. This algorithm facilitates the application of CGS models for hypothesis evaluation and risk assessment by ensuring uniformity and reproducibility of parameter estimates.

Algorithms↗
PubMed1990

A thermodynamic model of hemoglobin suitable for physiological applications.

We propose a quantitative model of the thermodynamics of hemoglobin in contact with its five major ligands (O2, CO2, Cl-, 2,3-bisphosphoglycerate, and H+). Our model incorporates the two-state formalism of J. Monod, J. Wyman, and J.P. Changeux (J. Mol. Biol. 12: 88-118, 1965) for treatment of quanternary transitions and also the mean field formalism of K. Linderstrom-Lang (C. R. Trav. Lab. Carlsberg Ser. Chim. 15: 1-30, 1924) for treatment of electrostatic interactions. On the basis of this approach, we develop an algorithm for the efficient computation of observable quantities, such as the occupancy of various ligand binding sites, and an objective statistical procedure for determining both maximum likelihood values and confidence limits of all the intrinsic thermodynamic parameters of hemoglobin. Finally, we show that the predictions of our theory are in good agreement with independent experimental observations.

Carbon Dioxide↗
PubMed1995

Influence of eye position on activity in monkey superior colliculus.

1. Most recording studies on the role of the monkey superior colliculus (SC) in eye movement generation have so far indicated that the code of the recruited population of cells is a fixed vector command representing the desired saccadic eye displacement vector, irrespective of the position of the eyes in the orbit. Experimental evidence from microstimulation, lesions, and neuroanatomy, however, suggests that the SC may have access to an eye position signal. 2. In this paper we have tested the hypothesis that SC activity is influenced by eye position, by recording from presaccadic burst neurons while monkeys made rapid eye movements in the light covering a large part of the oculomotor range. 3. In four alert rhesus monkeys, we obtained sufficient data from 57 SC single units. The activity of a substantial part of these cells (30/57) appeared to be significantly influenced by eye position. Although the tuning properties of these cells for saccade amplitude and direction remained invariant for changes in eye position, the peak firing rate of these units was systematically influenced by the position of the eyes in the head. 4. We have characterized this eye position dependence of a neuron's activity by a qualitative, model-independent, as well as by a quantitative model description (gain field), which takes into account both the tuning properties of the cell for eye displacement vectors and the dependence of eye position. 5. Although a majority of gain fields had their eye position sensitivity vector roughly aligned with the optimal saccade vector direction (colinear gain field, 17/30), a substantial part of the gain fields had their eye position sensitivity vectors in quite different directions, approximately homogeneously distributed with respect to the cell's ON direction. 6. We conclude that the SC has access to a signal related to the position of the eyes in the orbit. Several hypotheses on the possible functional role of this signal, in relation to the neural code of the motor map, are discussed.

Animals↗
PubMed2005

Influence of auditory modeling on learning a swimming skill.

Auditory modeling has been an effective method of learning a new skill in laboratory settings; however, research examining the effectiveness of auditory modeling in a real world task is limited. Thus, the purpose of this study was to examine the effectiveness of auditory modeling on the learning of a swimming skill, specifically the butterfly stroke. Participants were 37 male college students enrolled in two swimming classes. The classes were randomly assigned as the control group, i.e., the standard swimming curriculum for the butterfly stroke including demonstration, verbal instructions, and practice, and the auditory modeling group, i.e., standard swimming curriculum for the butterfly stroke plus auditory modeling. Quantitative and qualitative analyses indicate that auditory modeling is an effective method for enhancing the learning of this real world motor skill.

Adult↗
PubMed1999

Prevention of adhesions to polypropylene mesh in a rabbit model.

The purpose of this study was to develop a quantitative model for evaluating adhesion formation and to determine whether Seprafilm (HAL-F) bioresorbable membrane (Genzyme Corp., Cambridge, MA) is effective in preventing adhesions to polypropylene mesh (PPM). PPM has been shown to be an effective material for the repair of abdominal wall defects. One disadvantage of PPM is its tendency to form dense adhesions when in contact with abdominal viscera. HAL-F, a sodium hyaluronate/carboxymethylcellulose absorbable membrane, has been shown to prevent adhesion formation after midline closures. Its efficacy in preventing adhesions to PPM has not been examined previously. A 5 x 7-cm anterior abdominal wall defect was created in 24 New Zealand White rabbits. This defect was then repaired with PPM. In the experimental group, a 5 x 7-cm piece of HAL-F was placed between the mesh and the abdominal viscera. At 30 days, the animals were killed and adhesions were categorized and quantified using digital image analysis of inked specimens. The strength of mesh incorporation into surrounding tissues was also examined using an Instron tensiometer. The formation of adhesions between the viscera and mesh repair was significantly reduced by the use of HAL-F. The surface area involved for bowel adhesions was reduced 94 per cent (P = 0.00132). The strength of incorporation was not adversely affected. HAL-F is highly effective in preventing adhesions to PPM, without adversely effecting the strength of mesh incorporation.

Abdominal Muscles↗
PubMed2000

Mixed model analysis of quantitative trait loci.

We develop a mixed model approach of quantitative trait locus (QTL) mapping for a hybrid population derived from the crosses of two or more distinguished outbred populations. Under the mixed model, we treat the mean allelic value of each source population as the fixed effect and the allelic deviations from the mean as random effects so that we can partition the total genetic variance into between- and within-population variances. Statistical inference of the QTL parameters is obtained by using the Bayesian method implemented by Markov chain Monte Carlo (MCMC). This unified QTL mapping algorithm treats the fixed and random model approaches as special cases of the general mixed model methodology. Utility and flexibility of the method are demonstrated by using a set of simulated data.

Algorithms↗
PubMed1991

How membrane chain-melting phase-transition temperature is affected by the lipid chain asymmetry and degree of unsaturation: an effective chain-length model.

Hydrocarbon effects on the lipid chain-melting phase-transition temperature are analyzed. The membrane fluidization temperature is shown to increase with the effective chain length, which is proportional to the thickness of the well-packed hydrocarbon region. The latter, as a rule, increases with the length of the longest ordered and aligned segment on each chain. This conclusion is independent of the cause for the reduced chain packing in membrane interior: chain unsaturation (which effectively decouples the two hydrocarbon segments disjoined by a double bond) or chain asymmetry (which causes the terminal hydrocarbon segments to lose close contact) both affect the bilayer chain-melting phase-transition temperature comparably on the effective chain-length scale. Thermodynamic consequences of the trans unsaturation are approximately 50% smaller than the effects of the double bonds in the cis conformation, owing to the smaller membrane perturbation by the former double bonds. A simple quantitative model is introduced for the analysis of the phospholipid chain-melting phase behavior. This new model permits quantitative predictions of the chain-melting transition temperature solely on the basis of the known lipid chemical composition. It also explains lipid sensitivity to the hydrocarbon type and attachment. The model agreement with the experimental data is usually better than to within 99% and thus comparable to experimental scatter, even when only a few or no adjustable parameters are used. The membrane fluidization temperature is calculated for a number of potentially interesting, also as yet unexplored, phospholipids, and the biological significance of the effective chain-length concept is discussed.

Hydrocarbons↗
PubMed2006

The time-profile of cell growth in fission yeast: model selection criteria favoring bilinear models over exponential ones.

BACKGROUND: There is considerable controversy concerning the exact growth profile of size parameters during the cell cycle. Linear, exponential and bilinear models are commonly considered, and the same model may not apply for all species. Selection of the most adequate model to describe a given data-set requires the use of quantitative model selection criteria, such as the partial (sequential) F-test, the Akaike information criterion and the Schwarz Bayesian information criterion, which are suitable for comparing differently parameterized models in terms of the quality and robustness of the fit but have not yet been used in cell growth-profile studies. RESULTS: Length increase data from representative individual fission yeast (Schizosaccharomyces pombe) cells measured on time-lapse films have been reanalyzed using these model selection criteria. To fit the data, an extended version of a recently introduced linearized biexponential (LinBiExp) model was developed, which makes possible a smooth, continuously differentiable transition between two linear segments and, hence, allows fully parametrized bilinear fittings. Despite relatively small differences, essentially all the quantitative selection criteria considered here indicated that the bilinear model was somewhat more adequate than the exponential model for fitting these fission yeast data. CONCLUSION: A general quantitative framework was introduced to judge the adequacy of bilinear versus exponential models in the description of growth time-profiles. For single cell growth, because of the relatively limited data-range, the statistical evidence is not strong enough to favor one model clearly over the other and to settle the bilinear versus exponential dispute. Nevertheless, for the present individual cell growth data for fission yeast, the bilinear model seems more adequate according to all metrics, especially in the case of wee1Delta cells.

Biophysics↗
PubMed2002

Analysis of genetic effects of major genes and polygenes on quantitative traits. II. Genetic models for seed traits of crops.

Genetic models for quantitative seed traits with effects of several major genes and polygenes, as well as their GE interaction, were proposed. Mixed linear model approaches were suggested for analyzing the genetic models. Monte Carlo simulations were conducted to evaluate unbiasedness and efficiency for estimating fixed effects and variance components of the embryo and the endosperm models, including effects of a major gene from an unbalanced modified diallel mating design with nine parents, respectively. Simulation results showed that estimates of generalized least squares (GLS) were unbiased and efficient, while those of ordinary least squares (OLS) were almost as good as GLS. Minimum norm quadratic unbiased estimation (MINQUE) could obtain unbiased estimates of the variance components. It was also suggested that precision of MINQUE estimation would be improved with augmentation of experimental size. Data from a modified diallel design in upland cotton ( Gossypium hirsutum L.) were used as a worked example to illustrate the parameter estimation.

Journal Article↗
PubMed1995

Quantitative binding site model generation: compass applied to multiple chemotypes targeting the 5-HT1A receptor.

We present enhancements to the Compass algorithm that automatically deduce interchemotype relationships and generate predictive quantitative models of receptor binding based solely on structure-activity data. We applied the technique to a series of compounds assayed for 5-HT1A binding. A model was constructed from 20 compounds of two chemotypes and used to predict the affinities and bioactive conformation of 35 new compounds, most of which had new underlying scaffolds and/or functional groups. The model's mean error of prediction was 0.5 log units (essentially the assay resolution), even on quite divergent series. The predictions are supported by an interpretable hypothesis for the binding determinants of the receptor and the geometric relationships of the chemotypes.

Algorithms↗
PubMed1999

Investigation of BOLD signal dependence on cerebral blood flow and oxygen consumption: the deoxyhemoglobin dilution model.

The relationship between blood oxygenation level-dependent (BOLD) MRI signals, cerebral blood flow (CBF), and oxygen consumption (CMR(O2)) in the physiological steady state was investigated. A quantitative model, based on flow-dependent dilution of metabolically generated deoxyhemoglobin, was validated by measuring BOLD signals and relative CBF simultaneously in the primary visual cortex (V1) of human subjects (N = 12) during graded hypercapnia at different levels of visual stimulation. BOLD and CBF responses to specific conditions were averaged across subjects and plotted as points in the BOLD-CBF plane, tracing out lines of constant CMR(O2). The quantitative deoxyhemoglobin dilution model could be fit to these measured iso-CMR(O2) contours without significant (P </= 0.05) residual error and yielded MRI-based CMR(O2) measurements that were in agreement with PET results for equivalent stimuli. BOLD and CBF data acquired during graded visual stimulation were then substituted into the model with constant parameters varied over plausible ranges. Relative changes in CBF and CMR(O2) appeared to be coupled in an approximate ratio of approximately 2:1 for all realistic parameter settings. Magn Reson Med 42:849-863, 1999.

Brain Mapping↗
PubMed2002

How and why does the immunological synapse form? Physical chemistry meets cell biology.

During T lymphocyte (T cell) recognition of an antigen, a highly organized and specific pattern of membrane proteins forms in the junction between the T cell and the antigen-presenting cell (APC). This specialized cell-cell junction is called the immunological synapse. It is several micrometers large and forms over many minutes. A plethora of experiments are being performed to study the mechanisms that underlie synapse formation and the way in which information transfer occurs across the synapse. The wealth of experimental data that is beginning to emerge must be understood within a mechanistic framework if it is to prove useful in developing modalities to control the immune response. Quantitative models can complement experiments in the quest for such a mechanistic understanding by suggesting experimentally testable hypotheses. Here, a quantitative synapse assembly model is described. The model uses concepts developed in physical chemistry and cell biology and is able to predict the spatiotemporal evolution of cell shape and receptor protein patterns observed during synapse formation. Attention is directed to how the juxtaposition of model predictions and experimental data has led to intriguing hypotheses regarding the role of null and self peptides during synapse assembly, as well as correlations between T cell effector functions and the robustness of synapse assembly. We remark on some ways in which synergistic experiments and modeling studies can improve current models, and we take steps toward a better understanding of information transfer across the T cell-APC junction.

Antigen Presentation↗
PubMed1994

A contextual model of concurrent-chains choice.

An extension of the generalized matching law incorporating context effects on terminal-link sensitivity is proposed as a quantitative model of behavior under concurrent chains. The contextual choice model makes many of the same qualitative predictions as the delay-reduction hypothesis, and assumes that the crucial contextual variable in concurrent chains is the ratio of average times spent, per reinforcement, in the terminal and initial links; this ratio controls differential effectiveness of terminal-link stimuli as conditioned reinforcers. Ninety-two concurrent-chains data sets from 19 published studies were fitted to the model. Averaged across all studies, the model accounted for 90% of the variance in pigeons' relative initial-link responding. The model therefore demonstrates that a matching law analysis of concurrent chains-the assumption that relative initial-link responding equals relative terminal-link value-remains quantitatively viable. Because the model reduces to the generalized matching law when terminal-link duration is zero, it provides a quantitative integration of concurrent schedules and concurrent chains.

Journal Article↗
PubMed2004

A new topological descriptors based model for predicting intestinal epithelial transport of drugs in Caco-2 cell culture.

PURPOSE: Quantitative Structure-Permeability Relationships (QSPerR) of the intestinal permeability across the (Caco-2) cells monolayer could be obtained by the application of new molecular descriptors. METHOD: A novel topologic-molecular approach to computer molecular design ( TOMOCOMD-CARDD ) has been used to estimate the intestinal-epithelial transport of drug in Caco-2 cell culture. RESULTS: The Permeability Coefficients in Caco-2 cells (P) for 33 structurally diverse drugs were well described using quadratic indices of the molecular pseudograph's atom adjacency matrix as molecular descriptors. A quantitative model that discriminates the high-absorption compounds from those with moderate-poor absorption was obtained for the training data set, showing a global classification of 87.87%. In addition, two QSPerR models, through a multiple linear regression, were obtained to predict the P [apical to basolateral (AP-->BL) and basolateral to apical (BL-->AP)]. A leave- n -out and leave- one -out cross-validation procedure revealed that the discriminant and regression models respectively, had a good predictability. Furthermore, others 18 drugs were selected as a test set in order to assess the predictive power of the models and the accuracy of the final prediction was similar to achieve for the data set. Besides, the use of both regression models, in a combinative way, is possible to predict the Permeability Directional Ratio (PDR, BL-->AP/AP-->BL) value. The found models were used in virtual screening of drug intestinal permeability and a relationship between calculated P and percentage of human intestinal absorption for several compounds was established. Furthermore, this approximation permits us to obtain a good explanation of the experiment based on the molecular structural features. CONCLUSIONS: These results suggest that the proposed method is able to predict the P values and it proved to be a good tool for studying the oral absorption of drug candidates during the drug development process.

Biological Transport↗
PubMed1992

An experimental design strategy for quantitating complex pharmacokinetic models: enterohepatic circulation with time-varying gallbladder emptying as an example.

A four-step strategy is proposed for determining appropriate experimental designs for investigating the pharmacokinetics of drugs characterized by complex compartmental models and this strategy has been applied to the pharmacokinetics of enterohepatic circulation (EHC). The four steps are (1) to establish an appropriate pharmacokinetic model, (2) to complete an identifiability analysis for the model to determine the route(s) of administration and sampling compartment(s) that are theoretically adequate for the quantitation of model parameters, (3) to carry out nonlinear least-squares fitting for the proposed number and timing of simulated error-free data points, and (4) to complete nonlinear least-squares fits of the model to data obtained by adding random error to the simulated data in step 3. The four-compartment model chosen for EHC of unchanged drug contained central, peripheral, gallbladder, and intestinal compartments and an intermittent gallbladder emptying rate constant. Identifiability analysis demonstrated that three alternative experimental designs for route(s) of administration and sampling compartment(s) are adequate for quantitating all model parameters, when the gallbladder emptying rate constant as a function of time is known (using controlled emptying from an engineered gallbladder in an animal model or quantitation in humans or animals using imaging techniques). Parameter estimates from fitting error-free data matched closely with the known values for all three experimental designs, indicating an adequate number and appropriate timing of data points. Results from fitting simulated data containing +/- 10% random error indicated unacceptable coefficients of variation and a nonrandom pattern in residual plots for one of the experimental designs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Modeling cognitive control in task-switching.

This article describes a quantitative model, which suggests what the underlying mechanisms of cognitive control in a particular task-switching paradigm are, with relevance to task-switching performance in general. It is suggested that participants dynamically control response accuracy by selective attention, in the particular paradigm being used, by controlling stimulus representation. They are less efficient in dynamically controlling response representation. The model fits reasonably well the pattern of reaction time results concerning task switching, congruency, cue-target interval and response-repetition in a mixed task condition, as well as the differences between mixed task and pure task conditions.

Adult↗
PubMed1989

Model for population distributions of lymphocyte-target cell conjugates.

A quantitative model for the population distributions of the different types of conjugates formed between cytotoxic T lymphocytes and target cells has been developed. The comparison of the theoretical predictions with data of the literature reveals that the transit populations among the different types of conjugates depends on the lymphocyte-to-target ratio, R, and two constants, k and k1. These constants (where k greater than k1) govern, respectively, the transit populations among conjugates of the type LTi (LTn----LTn-1----...LT), and among LjT conjugates (LT----L2T----...----LmT). We have found that high ratios are necessary to obtain conjugates where multiple T lymphocytes are bound to one target cell, and that under these conditions the predominant conjugate, LjT, varies according to j = 1 + k1R. Conversely, for low values of R the predominant population is of the type LTi, where i also shows a linear dependence on R. Our model explains also why the conjugate LT is normally the predominant population under the experimental conditions reported in the literature. A discussion of the influence exerted by the population distributions of lymphocyte-target cell conjugates on the kinetic of the lytic process for these kinds of effector-target systems has also been made.

Immunity, Cellular↗
PubMed2002

A polymer model for large-scale chromatin organization in lower eukaryotes.

A quantitative model of large-scale chromatin organization was applied to nuclei of fission yeast Schizosaccharomyces pombe (meiotic prophase and G2 phase), budding yeast Saccharomyces cerevisiae (young and senescent cells), Drosophila (embryonic cycles 10 and 14, and polytene tissues) and Caenorhabditis elegans (G1 phase). The model is based on the coil-like behavior of chromosomal fibers and the tight packing of discrete chromatin domains in a nucleus. Intrachromosomal domains are formed by chromatin anchoring to nuclear structures (e.g., the nuclear envelope). The observed sizes for confinement of chromatin diffusional motion are similar to the estimated sizes of corresponding domains. The model correctly predicts chromosome configurations (linear, Rabl, loop) and chromosome associations (homologous pairing, centromere and telomere clusters) on the basis of the geometrical constraints imposed by nuclear size and shape. Agreement between the model predictions and literature observations supports the notion that the average linear density of the 30-nm chromatin fiber is approximately 4 nucleosomes per 10 nm contour length.

Animals↗