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PubMed2004

A computational model of spatio-temporal dynamics in depth filling-in.

We present a computational model based on the heat conduction equation, which can well explain human performance of depth interpolation. The model assumes that the depth information is locally represented and spatial integration is made by iterative processing of mutual interaction of neighbors. It reconstructs a dynamically transforming surface which is in good agreement with the results of psychophysical experiments on depth perception of untextured (uniform-colored) surface moving in depth. The model can also explain a temporal-frequency property of human percept. We conclude that the local ambiguity, which is quite common in everyday visual scenes, is solved by an interpolation mechanism based on iterative local interaction of locally represented visual information.

Depth Perception↗
PubMed2001

Computational models of antibody-based tumor imaging and treatment protocols.

We present improved computational models for investigating monoclonal antibody-based protocols for diagnostic imaging and therapy of solid tumors. Our earlier models used a boundary condition (Dirichlet) that specified concentrations of diffusing molecular species at the interface between a prevascular tumor nodule and surrounding normal tissue. Here we introduce a concentration-dependent flux boundary condition with finite rates of diffusion in the normal tissue. We then study the effects of this new condition on the tumor's temporal uptake and spatial distribution of radiolabeled targeting agents. We compare these results to ones obtained with the Dirichlet boundary condition and also conduct parameter sensitivity analyses. Introducing finite diffusivity for any molecular species in normal tissue retards its delivery to and removal from the tumor nodule. Effects are protocol- and dose regimen-dependent: generally, however, mean radionuclide concentration and tumor-to-blood ratio declined, whereas relative exposure and mean residence time increased. Finite diffusivity exacerbates the negative effects of antigen internalization. Also, the sensitivity analyses show that mean concentration and tumor-to-blood ratio are quite sensitive to transcapillary permeability and lymphatic efflux values, yet relatively insensitive to precise values of diffusion coefficients. Our analysis underscores that knowledge of antigen internalization rates and doses required to saturate antigen in the tumor will be important for exploiting antibody-based imaging and treatment approaches.

Antibodies, Monoclonal↗
PubMed2003

Computational models of oral and craniofacial development, growth, and repair.

This paper illustrates how biological and clinical problems stimulate research in biomedical informatics and how such research contributes to their solution. The computational models described use techniques from Logic Programming, Machine Learning, Computer Vision, and Biomathematics. They address problems in the development, growth, and repair of oral and craniofacial tissues arising in cell biology, clinical genetics, and dentistry. At the micro-level, the dynamic interaction of cells in the oral epithelium is modeled. At the macro-level, models are constructed of either the craniofacial shape of an individual or the craniofacial shape differences within and between healthy and congenitally abnormal populations. In between, in terms of scale, there are models of normal dentition and the use of computerized expert knowledge to guide the design of dental prostheses used to restore function in partially edentulous patients.

Adult↗
PubMed1994

A computer model of amplitude-modulation sensitivity of single units in the inferior colliculus.

A computer model is presented of a neural circuit that replicates amplitude-modulation (AM) sensitivity of cells in the central nucleus of the inferior colliculus (ICC). The ICC cell is modeled as a point neuron whose input consists of spike trains from a number of simulated ventral cochlear nucleus (VCN) chopper cells. Input to the VCN chopper cells is provided by simulated spike trains from a model of the auditory periphery [Hewitt et al., J. Acoust. Soc. Am. 91, 2096-2109 (1992)]. The performance of the model at the output of the auditory nerve, the cochlear nucleus and ICC simulations in response to amplitude-modulated stimuli is described. The results are presented in terms of both temporal and rate modulation transfer functions (MTFs) and compared with data from physiological studies in the literature. Qualitative matches were obtained to the following main empirical findings: (a) Auditory nerve temporal-MTFs are low pass, (b) VCN chopper temporal-MTFs are low pass at low signal levels and bandpass at moderate and high signal levels, (c) ICC unit temporal-MTFs are low pass at low signal levels and broadly tuned bandpass at moderate and high signal levels, and (d) ICC unit rate-MTFs are sharply tuned bandpass at low and moderate signal levels and flat at high levels. VCN and ICC units preferentially sensitive to different rates of modulation are presented. The model supports the hypothesis that cells in the ICC decode temporal information into a rate code [Langner and Schreiner, J. Neurophysiol. 60, 1799-1822 (1988)], and provides a candidate wiring diagram of how this may be achieved.

Animals↗
PubMed2004

Computational model of dynein-dependent self-organization of microtubule asters.

Polar arrays of microtubules play many important roles in the cell. Normally, such arrays are organized by a centrosome anchoring the minus ends of the microtubules, while the plus ends extend to the cell periphery. However, ensembles of molecular motors and microtubules also demonstrate the ability to self-organize into polar arrays. We use quantitative modeling to analyze the self-organization of microtubule asters and the aggregation of motor-driven pigment granules in fragments of fish melanophore cells. The model is based on the observation that microtubules are immobile and treadmilling, and on the experimental evidence that cytoplasmic dynein motors associated with granules have the ability to nucleate MTs and attenuate their minus-end dynamics. The model explains the observed sequence of events as follows. Initially, pigment granules driven by cytoplasmic dynein motors aggregate to local clusters of microtubule minus ends. The pigment aggregates then nucleate microtubules with plus ends growing toward the fragment boundary, while the minus ends stay transiently in the aggregates. Microtubules emerging from one aggregate compete with any aggregates they encounter leading to the gradual formation of a single aggregate. Simultaneously, a positive feedback mechanism drives the formation of a single MT aster--a single loose aggregate leads to focused MT nucleation and hence a tighter aggregate which stabilizes MT minus ends more effectively leading to aster formation. We translate the model assumptions based on experimental measurements into mathematical equations. The model analysis and computer simulations successfully reproduce the observed pathways of pigment aggregation and microtubule aster self-organization. We test the model predictions by observing the self-organization in fragments of various sizes and in bi-lobed fragments. The model provides stringent constraints on rates and concentrations describing microtubule and motor dynamics, and sheds light on the role of polymer dynamics and polymer-motor interactions in cytoskeletal organization.

Animals↗
PubMed1991

A comparison of three computer models for prediction of dose in acute amitriptyline overdose.

The pharmacokinetics of amitriptyline in overdose have been reported not to fit conventional compartmental models. In this study, the dose-concentration-time relationships of amitriptyline in overdose were modeled with discriminant analysis, with an evolutionary heuristic search program, and with a decision-tree model based on the entropy of uncertainty of classification. The computer models all used the same data from dogs administered treatment (80 mg/kg), toxic (250 mg/kg), or fatal (500 mg/kg) doses directly into the surgically isolated duodenum. All the models achieved a high degree of success (77 to 93%) in assigning records to the high-, low-, or middle-dose groups. Two of the models gave a probability of the assignment. Results of this analysis suggest that blood amitriptyline and nortriptyline concentrations are most useful in estimating dose in acute amitriptyline overdose.

Amitriptyline↗
PubMed1995

A new computer model for estimating the impact of vaccination protocols and its application to the study of Chlamydia trachomatis genital infections.

We describe a new computer model for studying the impact of vaccination protocols on the prevalence of disease. This state transition model uses two parameters, the forward rate and the cure rate, that are derived from epidemiological data to compute the percentage of individuals infected in the population. The cure rate is the percentage of individuals that are cured within one time step (which in this study is one year) and the forward rate is used to calculate the number of new infections due to transmission. The forward rate and the cure rate are incorporated into an update function that has the property that if the vaccination efficacy is 0%, or no vaccination is applied, then the percentage of individuals infected stays constant. We present computer simulations of this model designed to assess the influence of two variables on the prevalence of Chlamydia trachomatis infection in a study population. More specifically, we determined the effect of vaccines with efficacies ranging from 50% to 100% and we analysed the impact on the population for vaccines efficacious for periods of 10, 20 and 40 years. The results of the computer simulation show that even the least efficacious vaccination programme rapidly decreases the prevalence of C. trachomatis infection in the population. On the other hand, a vaccine that is efficacious for a period of only 1 year had minimal impact on the prevalence of the disease in the total population.

Adolescent↗
PubMed1992

Computer modelling of bioprosthetic heart valves.

The underlying assumptions and principles of a computer-based model for tissue heart valves are described. The model is used to relate observations of leaflet morphology to the requirements of proper valve function. Stress is the fundamental mechanical factor that limits the longevity of bioprosthetic heart valves--the higher the stress levels in the leaflets, the shorter will be the time over which the leaflets can maintain satisfactory structural integrity. Direct measurement of stress is impractical with real heart valves, but the calculation of stress and the study of its interdependence on other key parameters of tissue valve design is a good alternative. The methodology of computer modelling of heart valves is discussed and the technique is illustrated with some examples. Models of pericardial valves, the aortic allograft and porcine bioprostheses are compared.

Bioprosthesis↗
PubMed2000

A computational model of information processing in the frontal cortex and basal ganglia.

Performance on the Wisconsin Card Sort Test (WCST) of patients with schizophrenia, Parkinson's disease (PD), and Huntington's disease (HD) was simulated by a neural network model constructed on principles derived from neuroanatomic loops from the frontal cortex through the basal ganglia and thalamus. The model provided a computational rationale for the empirical pattern of perseverative errors associated with frontal cortex dysfunction and random errors associated with striatal dysfunction. The model displayed perseverative errors in performance when the gain parameter of the activation function in units representing frontal cortex neurons was reduced as an analog of reduced dopamine release. Random errors occurred when the gain parameter of the activation function in units representing striatal neurons was reduced, or when the activation level was itself reduced as an analog of a striatal lesion. The model demonstrated that the perseveration of schizophrenic, Huntington's, and demented Parkinsonian patients may be principally due to ineffective inhibition of previously learned contextual rules in the frontal cortex, while the random errors of Parkinson's and Huntington's patients are more likely to be due to unsystematic errors of matching in the striatum. The model also made specific, empirically falsifiable predictions that can be used to explore the utility of these putative mechanisms of information processing in the frontal cortex and basal ganglia.

Basal Ganglia↗
PubMed1990

A computer model of re-entry in cardiac tissue.

This paper describes the use of a computer model to investigate the nature of impulse propagation and the mechanisms of electrical instability which precipitate ventricular arrhythmias. The model provides the opportunity for a systematic analysis of the conditions of cardiac conduction under controlled conditions. From the simulation studies performed it is found that the most critical parameter which influences re-entry circuit formation is the ratio of exited to refractory duration.

Arrhythmias, Cardiac↗
PubMed1999

Computational modeling of an early evolutionary stage of the nervous system.

The object of this work is to create a computational model that examines the early evolution of the nervous system in relation to adaptive behavior. The main questions are: how did the nervous system and the most primitive forms of intelligence came into being, how a system can be organized during evolution that is able to ensure the adaptive behavior of a being, what are the basic rules of construction that are sufficient to create a workable nervous system without specifying the details of the construction. The biological bases of the model are the phyla Cnidaria and Porifera as they stand at the beginning of the genesis of nervous organization. We found in our model that in a network of homogenous epithelial-like cells, which is considered the starting point of the genesis of the nervous system, the changes that have positive influence on the behavior are those that make the spreading of the electric potential more efficient. It can cause the increase of the effectiveness of the behavior by itself without creating new specific cell-types. There are some alternatives to increasing the effectiveness of spreading of stimuli, for example increasing the value of biophysical parameters of the cells, or increasing the density of nerve cells and the number of synapses. If during the evolution a sort of cell comes into being that is able to conduct electrical stimuli--even in a rudimentary way--it can increase the adaptivity of behavior by itself without the need for specific information of how to organize the construction of this system.

Adaptation, Physiological↗
PubMedDate not supplied

[Computer modeling of the uniarticular motion of a limb based on the principle of equilibrium point].

A computer model of controlling the uniarticular motion of a limb is described. The model is based on the principle of equilibrium point, which is realized via the central parameterization of the stretch reflex. The ranges of parameter changes providing steady-state control are specified. Three main operating regimes of the model. (without feedback, with feedback with respect to position without rate control, and with feedback with respect to rate) are distinguished. A comparison of model experiments with natural motions is made in order to estimate the adequacy and universality of the principle underlying the control of arbitrary motions.

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↗
PubMed1992

A finite-difference computer model of solute diffusion in bacterial films with simultaneous metabolism and chemical reaction.

This finite-difference computer model is designed to simulate complex diffusion/reaction events in bacterial films. It is modular, each module mirroring closely a particular physical, chemical or biochemical factor. It is capable of handling > 20 diffusing/reacting species, but can be easily expanded or simplified to match particular systems. It was originally designed for modelling the events in dental plaque leading to tooth decay, but should find application in other fields. It allows for ion-exchange interactions with, for example, fixed charges on bacterial surfaces, which can act as pH and cation buffer sites. pH-dependent utilization of substrate is modelled implicitly, combining Michaelis-Menten kinetics with diffusion in a single iterative procedure. Advantages are given for computing diffusion of all other species explicitly using single-species diffusion coefficients, with charge-coupling by means of the algorithm Q-COUPLE. Activity corrections and enzyme pH-dependence are included. Chemical equilibria and mineral deposition/dissolution are computed iteratively node by node. The program is tested against some problems having analytical solutions, and an example is given of its application to demineralization of teeth as a result of bacterial action in dental plaque.

Algorithms↗
PubMedDate not supplied

[Computer modeling of the three-dimensional structure of full-length cytochrome B5].

The computer-aided reconstruction of 3D structure of full-length cytochrome b5 was done. Software Sybyl 6.4 from Tripos running on workstation Silicon Graphics Indigo2 (R4400, XZ) was used. The reconstruction was carried out by computer modelling of membrane part of cytochrom b5 with subsequent linking with known structure of water-soluble b5 part (fragment 5-91 of amino acid residues-file 3B5C in the protein data bank, PDB). The obtained structure of full-length cytochrome b5 was refined in the mixture of polar and nonpolar solvents by molecular dynamics simulation and deterministic minimization. Molecular dynamics simulation was performed in periodic box of binary system of solvents with a step of 1 fs during 550 ps at constant number of particles, pressure and temperature. The balance of system was achieved after 400 ps. With period in 5 ps the potential energy was minimized without molecular dynamics interruption. As a result 100 conformations of full-length cytochrome b5 were obtained. Distribution of potential energy was from -2.7 x 10(4) to -4.2 x 10(4) kcal/mol. Conformation of cytochrome b5 with minimal value of potential energy was accepted as the final. Analysis of lipophilic surface of obtained model have shown that membrane bounded part is more hydrophobic and forms a loop structure. This model corresponds to some known experimental data about cytochrome b5 structure.

Amino Acid Sequence↗
PubMed2006

Computational model of in vivo human energy metabolism during semistarvation and refeeding.

Changes in body weight and composition are the result of complex interactions among metabolic fluxes contributing to macronutrient balances. To better understand these interactions, a mathematical model was constructed that used the measured dietary macronutrient intake during semistarvation and refeeding as model inputs and computed whole body energy expenditure, de novo lipogenesis, and gluconeogenesis as well as turnover and oxidation of carbohydrate, fat, and protein. Published in vivo human data provided the basis for the model components that were integrated by fitting a few unknown parameters to the classic Minnesota human starvation experiment. The model simulated the measured body weight and fat mass changes during semistarvation and refeeding and predicted the unmeasured metabolic fluxes underlying the body composition changes. The resting metabolic rate matched the experimental measurements and required a model of adaptive thermogenesis. Refeeding caused an elevation of de novo lipogenesis that, along with increased fat intake, resulted in a rapid repletion and overshoot of body fat. By continuing the computer simulation with the prestarvation diet and physical activity, the original body weight and composition were eventually restored, but body fat mass was predicted to take more than one additional year to return to within 5% of its original value. The model was validated by simulating a recently published short-term caloric restriction experiment without changing the model parameters. The predicted changes in body weight, fat mass, resting metabolic rate, and nitrogen balance matched the experimental measurements, thereby providing support for the validity of the model.

Adipose Tissue↗
PubMed1994

A computational model with ionic conductances for the fusiform cell of the dorsal cochlear nucleus.

A computational model of a fusiform cell of the dorsal cochlear nucleus was developed. The results of model simulations are compared with the results of in vitro experimental observations obtained by other investigators. The structure of the present model is similar to that of Hodgkin-Huxley [J. Physiol. 117, 500-544 (1952)]. The model incorporates five nonlinear voltage-dependent conductances (three potassium and two sodium types) and their associated equilibrium-potential batteries, a leakage conductance, the membrane capacitance, and a current source. Model responses were obtained under both current- and voltage-clamp conditions. When a hyper- and depolarizing current sequence was applied [Manis, J. Neurosci. 10, 2338-2351 (1990)], the cell model was able to reproduce builduplike and pauserlike discharge patterns closely resembling Manis' observations. A transient "A"-type potassium conductance in the model played a major role in generating this phenomenon. The model predicts that blocking the "A" conductance should convert a builduplike or pauserlike pattern into a sustained regular pattern. A persistent sodium conductance in the model played the main role in reproducing: Spontaneous regular discharge; a discharge after a long latency under a long small (+0.025 nA) current; and nonlinear voltage-current characteristics with positive currents. Usefulness of the model can be seen as follows: (1) Several sets of experimental observations can be integrated into a common framework; (2) possible roles of different ionic conductances postulated to be present in the cell can be inferred by observing the model behavior with the conductances intact or blocked; and (3) time courses of ionic currents and conductance values obtained from the model under current- and voltage-clamp conditions can serve as predictions to be tested in future experimental studies.

Cochlea↗
PubMedDate not supplied

Comparison of consensus scoring strategies for evaluating computational models of protein-ligand complexes.

Here, the comparisons of performance of nine consensus scoring strategies, in which multiple scoring functions were used simultaneously to evaluate candidate structures for a protein-ligand complex, in combination with nine scoring functions (FlexX score, GOLD score, PMF score, DOCK score, ChemScore, DrugScore, PLP, ScreenScore, and X-Score), were carried out. The systematic naming of consensus scoring strategies was also proposed. Our results demonstrate that choosing the most appropriate type of consensus score is essential for model selection in computational docking; although the vote-by-number strategy was an effective selection method, the number-by-number and rank-by-number strategies were more appropriate when computational tractability was taken into account. By incorporating these consensus scores into the FlexX program, reasonable complex models can be obtained more efficiently than those selected by independent FlexX scores. These strategies might also improve the scoring of other docking programs, and more-effective structure-based drug design should result from these improvements.

Computer Simulation↗