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PubMed2000

How does GAP catalyze the GTPase reaction of Ras? A computer simulation study.

The formation of a complex between p21(ras) and GAP accelerates the GTPase reaction of p21(ras) and terminates the signal for cell proliferation. The understanding of this rate acceleration is important for the elucidation of the role of Ras mutants in tumor formation. In principle there are two main options for the origin of the effect of GAP. One is a direct electrostatic interaction between the residues of GAP and the transition state of the Ras-GAP complex and the other is a GAP-induced shift of the structure of Ras to a configuration that increases the stabilization of the transition state. This work examines the relative importance of these options by computer simulations of the catalytic effect of Ras. The simulations use the empirical valence bond (EVB) method to study the GTPase reaction along the alternative associative and dissociative paths. This approach reproduces the trend in the overall experimentally observed catalytic effect of GAP: the calculated effect is 7 +/- 3 kcal/mol as compared to the observed effect of approximately 6.6 kcal/mol. Furthermore, the calculated effect of mutating Arg789 to a nonpolar residue is 3-4 kcal/mol as compared to the observed effect of 4.5 kcal/mol for the Arg789Ala mutation. It is concluded, in agreement with previous proposals, that the effect of Arg789 is associated with its direct interaction with the transition state charge distribution. However, calculations that use the coordinates of Ras from the Ras-GAP complex (referred to here as Ras') reproduce a significant catalytic effect relative to the Ras coordinates. This indicates that part of the effect of GAP involves a stabilization of a catalytic configuration of Ras. This configuration increases the positive electrostatic potential on the beta-phosphate (relative to the corresponding situation in the free Ras). In other words, GAP stabilizes the GDP bound configuration of Ras relative to that of the GTP-bound conformation. The elusive oncogenic effect of mutating Gln61 is also explored. The calculated effect of such mutations in the Ras-GAP complex are found to be small, while the observed effect is very large (8.7 kcal/mol). Since the Ras is locked in its Ras-GAP configuration in our simulations, we conclude that the oncogenic effect of mutation of Gln61 is indirect and is associated most probably with the structural changes of Ras upon forming the Ras-GAP complex. In view of these and the results for the Ras' we conclude that GAP activates Ras by both direct electrostatic stabilization of the transition state and an indirect allosteric effect that stabilizes the GDP-bound form. The present study also explored the feasibility of the associative and dissociative mechanism in the GTPase reaction of Ras. It is concluded that the reaction is most likely to involve an associative mechanism.

Computer Simulation↗

PubMed1983

Babesia bovis: computer simulation of the relationship between the tick vector, parasite, and bovine host.

Components contributing to the survival of Babesia bovis in its tick vector (Boophilus microplus) and bovine host were identified and their relationship simulated with an interactive BASIC computer program. Estimates for major independent variables (host-finding success, feeding success, filial infection rate, recovery rate) were derived from published laboratory and field data. Values for dependent variables (tick burden, inoculation rate, tick and bovine infection rates) were calculated during successive tick generations until equilibrium conditions were reached. The simulation was used to predict the effects of alternate disease control strategies. Babesiosis outbreaks were associated with simulated daily infestations of approximately two to eight engorged ticks. Below this range, B. bovis parasites disappeared, while above it all cattle were infected during the period of calfhood resistance (through 9 months of age). The babesial inoculation rate was most unstable over the above range due to instability in tick populations and tick infection rates. The risk of babesiosis outbreaks among older, less resistant cattle was also greatest over this range. The optimum daily infestation was eight to nine engorged ticks. This level would maintain herd immunity to babesiosis without causing significant physiologic stress to the bovine host. The difficulty in maintaining ecological and immunological stability at low infestation rates discourages "strategic dipping" as a means of maintaining herd immunity to babesiosis. Introduction of tick-resistant cattle provided a more effective means of reducing the risk of babesiosis outbreaks. The economic implications of computer-simulated babesiosis control alternatives should be analyzed. The validity of simulation parameters should be confirmed by field studies on the relationship between tick burdens and the babesial inoculation rate. These studies would be greatly facilitated by development of an assay system for the detection of babesiae in field-collected ticks.

Aging↗

PubMed1993

Mathematical description and computer simulation of retinal cometlike afterimages: a modified neural equation with stability analysis.

A mathematical model for the spatiotemporal description of a well-known psychophysical phenomenon, the cometlike afterimage effect (CLAIE), is presented. The CLAIE occurs when a bright circular light spot moves slowly in the peripheral human retina. Under these conditions, the leading edge of the dot looks circular, but the trailing edge becomes elongated like a comet's tail whose length increases with speed and luminance, and the illusion is more prominent for photopic backgrounds. This cometlike motion smear is described on the basis of the temporal responsiveness and adaptation of rods. The model is an extension of an existing neural model of M. N. Oğuztöreli et al., with an additional term that allows prolonged saturation and long decay time following exposure to intense stimuli, and these effects are held responsible for the cometlike smear. The model predicts the response of photoreceptors through a nonlinear ordinary integrodifferential equation, which includes known biophysical terms for response dynamics, adaptation, saturation, and kinetics of intermediate components of the phototransduction process. The introduction of a saturation coefficient into the neural equation makes it possible to distinguish the different saturation thresholds of the rod-and-cone system. Numerical determination of the stationary solutions and complete linear stability analysis of the improved neural equation are given for a neuron of second order, and some computational results are presented for phase flows around different singular points in the phase field. A computer simulation based on the improved neural equation is presented for modeling the development and features of the CLAIE as a function of the speed and luminance of the stimulus and the background intensity. The computational results agree well with the psychophysical findings relating to the CLAIE.

Afterimage↗

PubMed2001

Computer-simulation studies on roles of potassium currents in neurotransmission of the auditory nerve.

Our previous work showed that action potentials (APs) fired in spiral ganglion (SG) neurons broaden gradually as a result of cumulative inactivation of the potassium current (I(K)), or with the application of a tinnitus-inducing drug (quinine). These results led us to speculate that AP width could affect neurotransmission of the auditory nerve under both normal and pathological conditions. This study used both experimental and theoretical approaches to test this hypothesis. We first measured the effect of AP broadening on Ca2+ entry into SG neurons. The effect of pre-synaptic AP broadening on post-synaptic responses was then assessed using computer-simulations. Results showed that wider presynaptic APs augmented responses of all types of postsynaptic glutamatergic receptors mainly by amplifying responses of postsynaptic receptors whose locations were not well aligned with the presynaptic release sites. A cumulative inactivation of I(K) in SG neurons significantly enhanced the responses of kainate receptors at all spike rates, while the augmentations for the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and N-methyl-D-aspartic acid receptors were most prominent below 100 spikes/s. These modeling results suggest that, in addition to the AP firing rate and timing, the width of APs could affect the neurotransmission of the auditory nerve under both normal and pathological conditions.

Action Potentials↗

PubMed1980

Computer simulation of Gumboro disease outbreak. IV. Epizootics obtained by mode G-4 with flock size, age and immunity changed.

For the computer simulation of Gumboro disease outbreak by Model G-4 a program was written in FORTRAN. Of over twenty parameters involved in the model, the following three were used as input variables: (1) age of chickens at housing a1 (= 1 and 21); (2) size of flock at housing, N(a1) (= 100 and 1,000); and (3) geometric mean of the level of parentally conferred immunity at hatching, G(1) (= 0, 2, 8, and 32). The outputs were the graphic images demonstrating the chronological changes in a flock of innate resistance, parentally conferred immunity, and their sum, and the epizootic patterns composed of numbers of chickens at subclinical stage, clinically diseased, recovered, condemned, etc. at each age. As a result, stronger epizootics were produced at a lower level of parentally conferred immunity, and a higher age and a larger size of flocks. It was suggested that the subclinical stage might not be understood as an inapparent infection, and that a further postulate on the infection might be necessary to be introduced into this model to increase the practical utility, as well as the theoretical soundness, of this series of studies.

Age Factors↗

PubMed1996

Age-at-interview bias in anticipation studies: computer simulations and an example with panic disorder.

The phenomenon of anticipation has received considerable interest recently, especially among researchers investigating the genetics of psychiatric disorders. Anticipation can involve an earlier age at onset, greater severity, and/or a higher number of affected individuals in successive generations within a family. There is some controversy concerning detection of age-at-onset anticipation, due to problems of sampling bias, which may account for the phenomenon by preferentially sampling either lateronset parents or earlier-onset children. One source of bias that has not been explicitly investigated is differential age at interview between parent and child, such that parents have passed through more of the risk period than their offspring. We conducted a computer simulation study of affected parent-child pairs to determine whether, for realistic age-at-onset and age-at-interview distributions, this source of bias is a serious one. Our results show that the timing of diagnostic assessment can strongly affect the ascertainment of parent-child pairs, to produce a severely biased sample exhibiting apparent anticipation. Under realistic assumptions, an investigator may face a greatly increased risk of false positives (i.e. detecting anticipation when none exists). For example, a nominal 5% significance level may correspond to true p values as high as 50% or even approaching 100%. We conclude with an application to existing data on panic disorder.

Adult↗

PubMed1995

BULLET: a computer simulation of shotgun DNA sequencing.

BULLET is a computer program that simulates shotgun sequencing of DNA. The program has been used to simulate the sequencing of DNA fragments from 2 to 30 kb. To obtain 80% single or double-stranded sequence, a doubling of the DNA fragment size necessitates twice the number of sequencing reactions. However, a similar linear relationship does not apply to the determination of 100% single or double-stranded sequence. Data from BULLET were used to derive simple linear formulae that estimate the number of sequencing reactions necessary to partially sequence a fragment of DNA irrespective of size. When 80% of the double-stranded sequence has been determined, approximately 98% of single-stranded sequence will be known. This is a reasonable point to change to a more directed strategy of DNA sequencing.

Algorithms↗

PubMed1989

Use of a computer simulation to evaluate a seminar on child abuse.

A computerized patient simulation was used to evaluate the effectiveness of a seminar on child abuse in changing students' behavior in assessing the problem and developing a treatment plan. The CAMPS system (DACIS Software) was selected because it allows students freedom to follow any pathway in selecting over 500 items of history, physical examination, laboratory, and treatments. In interacting with this simulation, students demonstrated how they integrate their knowledge into a clinical setting. The three-hour seminar covered the topics of physical and sexual abuse, patient neglect, and utilization of community resources for treatment. The control (n = 43) and experimental (n = 38) groups, enrolled in an introductory course in pediatrics, were given references to read about child abuse as part of the core curriculum, but they may or may not have had exposure to patients in their clinical work. Only the experimental group attended the seminar. As part of the course evaluation program, both groups interacted with eight computer simulations, two of which involved cases of child abuse. In the classic case of child abuse, the control and experimental groups had similar results. In the more difficult diagnostic problem (shaken baby), the groups differed significantly in total score, cost of the evaluation, and percentage of correct diagnosis.

Child↗

PubMedDate not supplied

Computer simulation of sensorless fuzzy control of a rotary blood pump to assure normal physiology.

Rotary blood pumps have been considered effective permanently implantable devices. However, control of such pumps is quite complicated. Sensorless control of pump flow is required because no invasive flow or pressure sensors are wanted. Whereas insufficient pump output can cause underperfusion and should be avoided, overpumping may cause ventricular collapse and must be prevented. An intelligent physiologic control algorithm is highly desirable to reach optimal pump output based on physiologic requirements. We present an intelligent physiologic control mechanism for the blood pump allowing it to achieve normal physiology. Sensorless control of pump flow is gained by analysis of the electric motor current and speed. The required pump output flow is chosen based on heart rate, and an intelligent fuzzy logic based control mechanism is developed to adjust the motor input so that the pump output can reach required flow while also preventing the occurrence of ventricular suction or cannular collapse. Computer simulation was carried out, and the results indicate that the proposed algorithms can achieve required pump flow to obtain normal physiology, whereas overpumping can be prevented to provide safe operation.

Algorithms↗

PubMed1987

Nonuniformity of nucleotide substitution rates in molecular evolution: computer simulation and analysis of 5S ribosomal RNA sequences.

The effects of temporal (among different branches of a phylogeny) and spatial (among different nucleotide sites within a gene) nonuniformities of nucleotide substitution rates on the construction of phylogenetic trees from nucleotide sequences are addressed. Spatial nonuniformity may be estimated by using Shannon's (1948) entropy formula to measure the Relative Nucleotide Variability (RNV) at each nucleotide site in an aligned set of sequences; this is demonstrated by a comparative analysis of 5S rRNAs. New methods of constructing phylogenetic trees are proposed that augment the Unweighted Pair-Group Using Arithmetic Averages (UPGMA) algorithm by estimating and compensating for both spatial and temporal nonuniformity in substitution rates. These methods are evaluated by computer simulations of 5S rRNA evolution that include both kinds of nonuniformities. It was found that the proposed Reference Ratio Method improved both the ability to reconstruct the correct topology of a tree and also the estimation of branch lengths as compared to UPGMA. A previous method (Farris et al. 1970; Klotz et al. 1979; Li 1981) was found to be less successful in reconstructing topologies when there is high probability of multiple mutations at some sites. Phylogenetic analyses of 5S rRNA sequences support the endosymbiotic origins of both chloroplasts and mitochondria, even though the latter exhibit an accelerated rate of nucleotide substitution. Phylogenetic trees also reveal an adaptive radiation within the eubacteria and another within the eukaryotes for the origins of most major phyla within each group during the Precambrian era.

Animals↗

PubMed1997

Use of computer simulation to evaluate a putative cluster of genetic or teratologic outcomes: adjustment for "multiple hypotheses" and application to a reported excess of Down's syndrome.

The identification of an apparent excess of a genetic outcome in a particular area and/or a particular time often provokes considerable public alarm about the presence of an environmental mutagen. It is often difficult to determine in any particular case whether the observation, whatever its nominal statistical significance, is due to chance concatenation of events or to an environmental factor. Statistical evaluation is made more difficult by the profuse number of possible hypotheses that could have triggered concern about an excess. This renders it difficult to calculate the actual probability of the observation (or one more extreme). By attempting to identify similar types of outcomes that could have provoked an apparent excess and then undertaking computer simulations assuming random deviations from a constant rate, one may attempt to adjust for the problem of multiple hypotheses. We apply this approach to a reported excess of Down's syndrome in Norway in 1985-1986 in younger mothers, and conclude that there is a high probability that it arose by chance.

Adolescent↗

PubMed1983

Computer simulation of the cardiac conduction system.

A discrete computer model simulating the operation of the cardiac impulse transmission apparatus and the electropotential changes of the heart musculature has been developed on a NORD-100 minicomputer. The model is written in NORD-FORTRAN and allows description of practically all basic pathologies of the transmission apparatus. A simulated ECG curve is produced in each case. The current version of the model is especially suited for studies of heart rhythms. Pacemaker descriptions (of most important pacemaker types) have been introduced into the model and the computer computations make it possible to assess the effects of different pacemaker modes under different pathological situations. The principles on which the model is based is described and the paper shows concisely several examples in the form of simulated ECG records.

Arrhythmias, Cardiac↗

PubMed1994

A computer simulation accounting for dissimilar electrophoretic behavior between two similarly curved DNA fragments due to a difference in arc-length.

Arc-shaped bent DNA fragments of the same predicted planar curvature but differing in length by 20% were compared in regard to their mobilities in 3 to 10% polyacrylamide. The longer (155 bp) fragment is retarded far more severely than the shorter (124 bp) fragment. The effect of gel concentration in promoting the retardation is far more pronounced for the 155 bp than for the 124 bp fragment. Moreover, a temperature change from 25 degrees C to 4 degrees C does not substantially affect the gel concentration dependent mobility of the 124 bp fragment while it increases the retardation of the 155 bp fragment greatly. The strong increase in retardation brought about by a mere 20% increase in the length of the arc was accounted for by a simple computer simulation of gel electrophoresis which considered the rate of passage of arc-shaped objects through a two-dimensional array of disc-shaped obstacles. Since the simulation relies exclusively on geometric factors, its success in predicting the behavior of the 124 and 155 bp DNA fragments suggests that geometric factors are largely responsible for their electrophoretic properties. The simulation can account for the strong temperature effect on the retardation of a model of the 155 bp DNA in polyacrylamide gels by showing that a decreased degree of random motion has a profound effect on the modeled 155 bp particle, but not on the modeled 124 bp DNA.

Computer Simulation↗

PubMed1981

Computer simulation and experimental analysis of unipolar epicardial potentials in relation to the direction of propagation of the excitation.

A theoretical model for computer simulation has been introduced to predict the unipolar epicardial potentials corresponding to the different angles of propagation of the excitation wavefront. The simulated waveforms were compared with those observed in the animal experiments. In these experiments three unipolar epicardial potentials and one intramural potential were recorded using a thumbtack electrode with and without bipolar epicardial pacing. The direction of the propagation of the excitation was determined from the arrival time of the recorded waveforms. There was a close correspondence between the observed and the simulated waveforms. Furthermore, it was attempted to establish a quantitative relationship between the unipolar potential waveshape and the angle of propagation theta of the excitation. The difference between the positive and the negative peak normalized by the peak-to-peak height was used to define the change in the waveshape. A distinct relation was found to exist between the normalized difference R and the angle theta for the simulated potentials. There was a good correlation (r = 0.96 for n = 85) between angle theta 1 calculated from the arrival times and theta 2 determined from R, which suggest that the angle theta can be estimated from the unipolar epicardial potentials alone, without using any intramural electrode.

Action Potentials↗

PubMed1993

Use of pharmacologic data and computer simulations to design an efficacy trial of intravesical mitomycin C therapy for superficial bladder cancer.

Treatment of superficial bladder cancers by intravesical mitomycin C (MMC) chemotherapy gives a varying and incomplete response. Our recent pharmacokinetics and pharmacodynamics studies have shown that treatment effectiveness is limited by drug degradation in acidic urine and by drug dilution due to residual urine volume and urine production. A model was developed to predict drug exposure in tumors in the bladder wall and to correlate drug exposure with antitumor effect. The model is based on the known pharmacokinetic data in patients treated with intravesical chemotherapy, drug-penetration data in the bladder wall of patients undergoing radical cystectomy, and pharmacodynamic data on patients' bladder-tumor chemosensitivity. Computer simulations based on the model were generated. The simulations predicted that changes in treatment parameters would affect the therapeutic outcome in the following rank order: dose > residual volume > urine production > dosing volume > urine pH > dwell time. Tissue exposure could be enhanced by increased dose, complete bladder emptying, reduced fluid intake, use of the minimal dosing volume, and alkalinization of the urine to a neutral pH. Increasing the dwell time from 2 to 4 h gave an insignificant improvement and posed a compliance problem. The selected optimized regimen of a 40-mg dose, no residual volume, 0.62-ml/min urine production, a 20-ml dosing volume, and alkaline urine pH yielded a calculated 8.5-fold increase in tissue exposure over that achieved by the standard regimen, which consisted of a 20-mg dose, 32-ml residual volume, 1.5-ml/min urine production, a 20-ml dosing volume, and acidic urine pH. On the basis of previously established pharmacodynamic data, we hypothesize that the increase in tissue exposure in the optimized treatment would result in a 20% improvement over the standard therapy along with an increase in the recurrence-free rate from 56% to 76% of patients. A phase III efficacy trial comparing the optimized and standard regimens is proposed.

Administration, Intravesical↗

PubMed1999

Computer Simulation of the Aggregation and Sintering Restructuring of Fractal-like Clusters Containing Limited Numbers of Primary Particles.

A random particle computer simulation (in three dimensions) was conducted to investigate the structure and aggregation characteristics of small clusters (containing limited numbers of primary particles per cluster). Though an individual cluster of small size does not satisfy the power law, it was found that these aggregated clusters are fractal-like and comply with the fractal power law form in a statistical sense. This statistically averaged fractal dimension decreases as the clusters become smaller. A cluster-restructuring model is further developed to simulate the topological evolution of dendritic structured materials due to sintering at high temperatures. Results indicate that the cluster fractal dimension increases as sintering proceeds for small clusters, in contrast to results for large clusters wherein the topology is retained and the fractal dimension remains constant. A relationship of the fractal dimension change with the normalized surface area of dendrites for different-sized clusters is established. Copyright 1999 Academic Press.

Journal Article↗

PubMed2004

Critical role of flow-modified permittivity in electrorheology: model and computer simulation.

We propose a model that takes into account the effect of flow-modified permittivity (FMP) on electrorheology (ER). Our computer simulation shows that for Mason numbers less than 0.1, ER effects are mainly attributable to the deformation of chain structures, in agreement with earlier theoretical and simulation work. At larger Mason numbers, where chain structures have been destroyed by shear flows, we show that an FMP-induced misalignment between the particle dipole moments and the applied electric field plays a crucial role in producing ER effects. We also identify conditions under which negative ER effects are seen at large Mason numbers.

Journal Article↗

PubMed1986

Comparison of four single-point phenytoin dosage prediction techniques using computer-simulated pharmacokinetic values.

The predictive abilities of the following four single-point phenytoin dosage adjustment methods were compared using computer-simulated data: the Bayesian feedback method of Vozeh et al. (B), a linearized version of the Bayesian method (LB), the population-clearance method of Graves et al. (G), and the Rambeck nomogram (R). A series of 512 "subjects" with normally distributed values for volume of distribution, weight, and the Michaelis-Menten variables Vmax and Km were simulated. The steady-state serum concentration (SSSC) resulting from the administration of a standard dose of phenytoin sodium (5 mg/kg/day) was calculated, and "subjects" with SSSCs less than or equal to 12 mg/L or greater than or equal to 17 mg/L were entered in the study. If the concentration was greater than 50 mg/L or the standard dosage exceeded Vmax, the dosage was reduced empirically by 25%. Normally distributed random errors were introduced into the SSSC values to simulate actual patient data. The pharmacokinetic values, dosages, and SSSCs were used for predicting the dosage required to attain an SSSC of 14.9 mg/L. In the unstratified population, the mean error and mean-squared error were lowest for methods G and B, followed by methods LB and R. Methods B and LB gave the highest percentages of satisfactory dosage predictions based on the resultant SSSC value. The performance of all methods was superior at initial SSSCs greater than 8 mg/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗