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PubMed1985

Effect of resolution improvement on required count density in ECT imaging: a computer simulation.

The effects of changes in spatial resolution and total number of counts on image quality were investigated for positron and single photon emission computed tomography (ECT) systems. A variety of high contrast phantoms were generated in a computer simulation and count density and spatial resolution were varied independently over a wide range. As system spatial resolution is improved, significantly fewer counts are needed to give images of comparable visual quality. Using 100% object contrast, it was found that the number of counts could be reduced by a factor of four for a 2 mm improvement in spatial resolution over a wide range of parameters. This is due to the fact that image contrast increases rapidly with spatial resolution improvements in high contrast objects such as those used in this simulation and typically encountered in brain and cardiac ECT studies.

Computers↗

PubMed2005

Impact of reservoir potentials on the analyte behavior in microchip electrophoresis: computer simulation and experimental validation for DNA fragments.

Fundamental understanding of the impact of reservoir potentials on the analyte behavior on the microfluidic chips is an important issue in microchip electrophoresis (MCE) for suitable injection and separation of analytes, since the applied potentials may significantly affect the shape of sample plug, sample leakage from the injection channel to the separation channel, injected sample amount, and separation efficiency. This study addressed this issue for the case of a conventional cross-geometry microchip with four reservoirs using computer simulations, the results of which were verified by the analysis of DNA fragments. For the microchip with a definite structure and migration distance, the injected sample amount was shown to be the vital parameter for improving the limit of detection and resolution. During injection, the shape of the sample plug could be adjusted by varying the reservoir potentials. It was demonstrated that a "magnified injection" (applying high voltage on the three reservoirs to the sample reservoir) is useful to enhance the detection sensitivity depending on the analyte composition, although such injection was previously avoided because of introducing too large amounts of the analyte in comparison with two established modes, floating and pinched injection. Optimal magnified injection was proved to improve the sensitivity for about 4 times over that of pinched injection for the analysis of DNA step ladders using microchip gel electrophoresis (MCGE). Sample leakage of DNA fragments could be suppressed by applying a high positive voltage on injection channel during separation, but the voltage degraded the injected amount and resolution.

Computer Simulation↗

PubMed1989

Computer simulations of globular protein folding and tertiary structure.

In summary, although a large number of disparate techniques have been applied to predict the tertiary structure of globular proteins from their amino acid sequence, the solution is not yet at hand. Methodologies for predicting the conformation of constrained, small protein fragments appear to be successful. As the size of the system increases, the level of detail of the treatment decreases; approaches that employ very detailed potentials appear to be limited to about 30-40 residues. Although this is a major advance, methods that reduce the effective number of degrees of freedom are clearly required. Lattice representations coupled to highly efficient Monte Carlo procedures appear to be one such approach. Thus, although a number of theoretical advances in the computer simulation of globular protein structure have been made, much work remains to be done before the globular protein folding problem is solved.

Computer Simulation↗

PubMed2001

Probing the general base catalysis in the first step of BamHI action by computer simulations.

BamHI is a type II restriction endonuclease that catalyzes the scission of the phoshodiester bond in the GAGTCC cognate sequence in the presence of two divalent metal ions. The first step of the reaction is the preparation of water for nucleophilic attack by Glu-113, which has been proposed to abstract the proton from the attacking water molecule. Alternatively, the 3'-phosphate group to the susceptible phosphodiester bond has been suggested to play a role as the general base. The two hypotheses have been tested by computer simulations using the semiempirical protein dipoles Langevin dipoles (PDLD/S) method. Deprotonation of water by Glu-113 has been found to be less favorable by 5.7 kcal/mol than metal-catalyzed deprotonation with a concomitant proton transfer to bulk solvent. The preparation of the nucleophile by the 3'-phosphate group is less favorable by 12.3 kcal/mol. These results suggest that both the general base and the substrate-assisted mechanisms in the first step of BamHI action are less likely than the metal-catalyzed reaction. The metal ions in the active site of BamHI make the largest contributions to the reduction of the free energy of hydroxide ion formation. On the basis of these findings we propose that the first step of endonuclease catalysis does not require a general base; rather, the essential attacking nucleophile in BamHI catalytic action is stabilized by the metal ions.

Catalysis↗

PubMed1994

The 'shortmer' approach to nucleic acid sequence analysis. I: Computer simulation of sequencing projects to find economical primer sets.

In principle it is most economical to sequence large DNA fragments consecutively ('primer walking'), provided there is an immediate supply of sequencing primers. To solve the problem of primer supply we previously suggested generating a bank of short oligonucleotide primers ('shortmers'). In every sequencing reaction shortmers would have to be selected from this bank that are suitable to hybridize adjacently on the sequencing template. After their ligation the shortmers would form a long, and hence more specific, primer in the subsequent sequencing reaction. In the present study a computer simulation of large sequencing projects revealed a reduced set of approximately 12,000 selected octanucleotides (out of all 65,536) retaining maximum priming flexibility and minimum redundant information on the simulated sequence analyses. Establishing routine protocols for nucleic acid sequencing following the shortmer approach will abolish the tightest bottleneck of the consecutive sequencing route (primer supply) and hence may render this general scheme more attractive than the shotgun sequencing scheme. A twofold (or more) speed-up of genome sequencing projects by the shortmer approach may be assumed.

Algorithms↗

PubMed1978

Burst generation by electrically coupled network in the snail helisoma: analysis using computer simulation.

The effectiveness of electrical coupling between neurons as a mechanism for mediating single and repetitive bursts is investigated here using computer simulation. The cyberchron network in the snail Helisoma generates repetitive bursts controlling the animal's feeding behavior and served as the basic model for the simulation studies described in this paper. The action potential properties of individual neurons were modeled by the Rall equations describing generalized action potentials. Several properties of electrical coupling and its role in burst generation were demonstrated, including: (1) A neuron in an electrically coupled network can generate action potentials at a higher frequency than an isolated neuron with similar membrane properties due to the loading through the electrical junctions. However, the ability of electrically coupled neurons to generate high-frequency bursts of action potentials requires a concomitantly greater amount of driving current to overcome the junctional loading. (2) Temporal and spatial summation of synaptic input onto a neuron is maintained at its most effective level because the postsynaptic current is integrated across the long postsynaptic membrane time constant. (3) Initial simulations concentrated on a pair of electrically coupled neurons which were below threshold. Stimulation of one of the two neurons with a short pulse resulted in a reverberation or regenerative excitation between the two neurons. The reverberation terminated after a number of action potentials dependent on the specific model parameters. Similar results were obtained with a network containing a greater number (20) of model neurons if approximately one-half of the neurons were stimulated simultaneously. However, none of the cases studied produced more than a single discrete burst. (4) Simulations were also conducted on 20-neuron networks containing two subpopulations of model neurons differing in their values of coupling resistance and excitability. Some networks of this type required stimulation of only one cell to make the two subpopulations of model neurons reverberate with one another. Such simulations suggest the possibility that 'preferred' input pathways involving a small number of neurons would be capable of 'turning on' the activity of the entire network.

Animals↗

PubMed2005

The evolutionary forces maintaining a wild polymorphism of Littorina saxatilis: model selection by computer simulations.

Two rocky shore ecotypes of Littorina saxatilis from north-west Spain live at different shore levels and habitats and have developed an incomplete reproductive isolation through size assortative mating. The system is regarded as an example of sympatric ecological speciation. Several experiments have indicated that different evolutionary forces (migration, assortative mating and habitat-dependent selection) play a role in maintaining the polymorphism. However, an assessment of the combined contributions of these forces supporting the observed pattern in the wild is absent. A model selection procedure using computer simulations was used to investigate the contribution of the different evolutionary forces towards the maintenance of the polymorphism. The agreement between alternative models and experimental estimates for a number of parameters was quantified by a least square method. The results of the analysis show that the fittest evolutionary model for the observed polymorphism is characterized by a high gene flow, intermediate-high reproductive isolation between ecotypes, and a moderate to strong selection against the nonresident ecotypes on each shore level. In addition, a substantial number of additive loci contributing to the selected trait and a narrow hybrid definition with respect to the phenotype are scenarios that better explain the polymorphism, whereas the ecotype fitnesses at the mid-shore, the level of phenotypic plasticity, and environmental effects are not key parameters.

Animals↗

PubMed1997

Computer simulation of cerebral blood flow in moyamoya and the results of surgical therapies.

Moyamoya is the disease which involves the terminal portions of the internal carotid or origins of the middle or anterior cerebral arteries. The posterior communicating arteries are also involved, but not the vertebrals or the basilar artery. The disease occurs more commonly in females than males and it has two age peaks at less than 10 and 40 years. Over the years many treatment options or procedures have been advocated for this disease either with direct bypasses or indirect revascularization procedures or both in combination. Whether one procedure is better than another is a matter of question and still to be determined. Along with it, there are various diagnostic and research work have been done for the etiology and the management of this disease. We have tried to implement a computer model of cerebral blood flow in order to assess and predict the flow in this disease process. At this time to know and predict the effectivity of certain types of offered treatment of Moyamoya disease is only to evaluate patients clinically with long term follow ups and at some interval after surgery with angiography or blood flow determinations. This study tries to focus on the use of computerized model of predicting cerebral blood flow which tries to assess the cerebral flow and decide which treatment option would be the best for a particular patient. After various computer simulations the blood flow following each treatment option is detected and the situation which offers the best treatment in a particular case is offered to the patient. To confirm the use of utility of this computer model a larger population of patients with Moyamoya disease need to be evaluated.

Adult↗

PubMed1981

Computer simulation of the dynamics of cell populations.

A modified version of the program of Valleron and Friendel is presented for the computer simulation of growing populations of cells. The method effects a sizable reduction of the storage requirement and allows one to follow the growth and division of cell clones for a large number of generations. Moreover, it is particularly useful to simulate specific biological events assumed to occur in the cell under various hypotheses and to compare them. Examples of this are also given.

Animals↗

PubMed1991

Reconstruction of hippocampal granule cell electrophysiology by computer simulation.

A model of the hippocampal granule cells was created that closely approximated most of the measured intracellular responses from a neuron under a variety of stimulus conditions. This model suggests that: (1) A simple, four-conductance model can account for most of the intracellular behavior of these neurons. (2) The repolarization mechanism in granule cells may be different from that in squid axons. A weak potassium conductance may be present in hippocampal granule neurons, which simultaneously give rise to a small, passive depolarizing afterpotential. (3) The strength duration properties may assist in identifying the electronic and sodium channel properties with short stimulus pulse widths. (4) Repetitive firing responses are highly dependent on the cell's recent history of activation and the regulation of the slow potassium conductance and calcium dynamics. (5) The anodic break response is probably not a property of typical granule cells. Through thorough and precise comparison of experimental and model responses, computer simulations can help assembling channel information into verifiable models that accurately reproduce intracellular data.

Action Potentials↗

PubMed2004

Feasibility of diffusion-NMR surface-to-volume measurements tested by calculations and computer simulations.

It has been demonstrated previously that the surface-to-volume ratio S/V can be determined from the derivative of the time-dependent diffusion coefficient D(t), in the limit t --> 0. Several questions arise concerning the practicality of determining S/V by NMR. In particular, how large are the errors generated by (1) working outside the t --> 0 limit and (2) measuring D outside the b --> 0 limit, both for narrow and full-width gradient pulses? Here b is gamma2G2delta2Delta for narrow pulses and gamma2G2t3/12 for broad pulses. These questions are addressed by random-walk computer simulations and numerical calculations in geometries relevant to small-airways of lung. The results demonstrate that one can work well outside the t --> 0 and b --> 0 limits, provided 10-20% accuracy in the measured S/V is sufficient. Emphasis is placed on the useful range of times t for which NMR determinations of lung S/V are feasible.

Algorithms↗

PubMed1997

A minimal model for calcium signal generated by tyrosine kinase and G protein linked receptors; a stochastic computer simulation with CALSIM.

A software was designed to simulate the calcium signal following hormone or growth factor stimulation in epithelial cells. The software written in C runs on a PC under Windows environment. It is based on a Markov process where the dynamic of the system is characterised by phenomenological transition probabilities. Moreover a minimal model is proposed to analyse the role of plasma channels and IP3 receptors, together with the opposite action of the CaATPase pumps, in the cytosolic and endoplasmic reticulum (ER) calcium signal control. The simulation is applied on the calcium response following stimulation by carbacol (protein G coupled receptors) or epidermal growth factor (tyrosine kinase type receptors) in A431 epithelial cells. The experimental calcium signals can be grouped in three classes; a spike and a return to the basal level (signal A), a spike and a decrease to a plateau level (signal B) or a slow increase to a plateau (signal C). Epidermal growth factor induces signal A and B while carbacol gives signal B and C. When a 'pseudo' steady state is reached oscillations occur. Computer simulations show that signal A can result from the activation of IP3 receptors while signal C would result from the activation of the plasma channels; signal B appears as the additive contribution of both channels, while oscillations are compatible with a calcium induced calcium release mechanism. Simulations suggest that the calcium dynamic in the ER is a mirror of cytosolic calcium but that a simple way to produce similar calcium elevation in these two compartments is to activate plasma channels. Implications of such a mechanism is discussed.

Adenocarcinoma↗

PubMed1997

Conformational analysis of potent sweet taste ligands by nuclear magnetic resonance, computer simulations and X-ray diffraction studies.

Four potent sweet-tasting molecules, N-(3,3-dimethylbutyl)-L-aspartyl-L-phenylalanine methylester 1 (7000 times more potent than sucrose), N-(3,3-dimethylbutyl)-L-aspartyl-D-valine (S)-alpha-ethylbenzylamide 2 (3000 time more potent than sucrose), L-aspartyl-D-valine (R)-alpha-methoxymethylbenzylamide 3 (1350 times more potent than sucrose and L-aspartyl-(1R,2S,4S)-1-methyl-2-hydroxy-4-phenylhexylamide 4 (2500 times more potent than sucrose) were studied by 1H NMR and computer simulations. These flexible molecules adopt multiple conformations in solution. The "L-shaped" structure, which we believe to be responsible for sweet taste is accessible to all four compounds in solution. Extended conformations with the AH and B-containing moieties in the +y-axis and the hydrophobic group X pointing in the y-axis have also been observed for all four sweeteners. For compounds 1 and 3, the solid-state conformations were determined by X-ray diffraction studies. These results demonstrate that compounds 1 and 3 adopt an "L-shaped" structure even in the crystalline state. The extraordinary potency of the N-alkylated compound 1 compared with the unsubstituted Asp-Phe-OMe may be explained by the effect of a second hydrophobic binding domain in addition to interactions arising from the "L-shaped" structure.

Computer Simulation↗

PubMed2006

Compartmental models of mammalian motoneurons of types S, FR and FF and their computer simulation.

Mathematical models of motoneurons (MNs) of types S, FR and FF were developed based on cat MN data. Each of the three models has an initial segment, a soma and a dendritic tree. The initial segment and the soma include models of several types of ionic currents, including a calcium-dependent slow potassium current. The dendritic tree is modeled as a series association of several electrically passive cylinders. Afterhyperpolarization parameters, current to frequency relation and the responses to input current steps, ramps and sinusoids were used for model validation. The effects of sinusoidally varying synaptic inputs at different levels of the dendritic tree were studied by computer simulation. The corresponding frequency response functions resulted of lowpass type with cutoff frequencies from 10 to 40 Hz, for synapses occurring more distally or more proximally, respectively. The nonlinear effects caused by two sinusoidally varying synaptic conductances (at 7 and 11 Hz), acting at different dendritic segments, were quantified by spectral analysis of the current reaching the soma. The simulations pointed to two main nonlinear effects: (i) harmonics of the two input frequencies (e.g., 14 Hz) and (ii) intermodulation terms (e.g., 4 Hz). When the two synaptic inputs occurred on more distal dendritic compartments the nonlinear effects were more pronounced.

Animals↗

PubMed1994

In vivo/in vitro correlation of intravitreal delivery of drugs with the help of computer simulation.

The elimination of dexamethasone sodium m-sulfobenzoate, DMSB, following intravitreal injection, was measured in rabbit vitreous body under in vivo and in vitro conditions. The rate of elimination in vivo was appreciably greater than that in vitro, indicating that the in vivo data include not only the elimination due to metabolism/degradation in the vitreous humor, but also the elimination through the surrounding tissues such as the posterior aqueous humor, the retina/choroid/sclera membrane, and the lens. A general mathematical model based on Fick's second law of diffusion was developed for describing the pharmacokinetics of the intravitreal injection of DMSB. The model parameters were independently determined from a set of in vitro experiments. The in vivo data of elimination of DMSB following intravitreal injection agreed with the profiles calculated from the mathematical model, together with the model parameters determined from the in vitro experiments. The present in vivo/in vitro correlation, with the help of computer simulation, can be used for optimizing the therapeutic systems of intravitreal drug delivery.

Animals↗

PubMed1997

Using computer simulated results of a bulk drug substance assay to determine acceptance criteria for method validation.

PURPOSE: To determine the statistical variability expected for a well designed HPLC assay of a bulk drug substance (BDS). The results are used to develop appropriate acceptance criteria for a method validation protocol as well as to evaluate the level of uncertainty expected for assay results using a variety of sampling/injection schemes. METHODS: Computer simulation was used to generate a large quantity of data and the variability of the mock results was evaluated. Error propagation was also calculated, whenever possible, to confirm results obtained from the simulations. RESULTS: Protocol acceptance criteria were developed that were consistent with the expected variability for data resulting from the execution of the validation protocol. In certain cases simulations provided the only avenue of obtaining results that could not otherwise be readily determined. CONCLUSIONS: Computer modeling can be used to obtain suitable acceptance criteria for validation results which are consistent with method variability. This is particularly significant in the case of linearity where it has been difficult to develop acceptance criteria based on anything other than analyst intuition and experience. Assay simulations clearly demonstrated that the variability expected for a typical BDS assay is large relative to the average specification range and therefore little insight about relative purity can be gained comparing individual passing assay results.

Chromatography, High Pressure Liquid↗

PubMed1987

How many genes to start with? A computer simulation about the origin of life.

A geneticist's view on the origin of life would focus on individual nucleic acid molecules rather than on their concentrations, on stochastics rather than on differential equations. The 'package model' envisages primordial compartments that contain ensembles of primordial genes. These are replicated independently from each other. During package fission they are distributed to two daughter packages. Packages with a complete ensemble of genes can continue to propagate. However, mutations as well as the stochastic nature of replication and package fission occasionally cause arising packages to miss genes from the ensemble, thus resulting in the death of those packages. A computer simulation, considering the complementarity of RNA as well as abortive termination of replication, yielded results that are similar to those of a preliminary simulation irrespective of these parameters: the results suggest that life could not have started with more than 3 genes, or else the primordial replicase would have to achieve at least a reduction of the replicational error rate by a factor of 13 and a reduction of undue chain termination by a factor of 10 to 25.

Computer Simulation↗

PubMed2006

Physiological control of blood pumps using intrinsic pump parameters: a computer simulation study.

Implantable flow and pressure sensors, used to control rotary blood pumps, are unreliable in the long term. It is, therefore, desirable to develop a physiological control system that depends only on readily available measurements of the intrinsic pump parameters, such as measurements of the pump current, voltage, and speed (in revolutions per minute). A previously proposed DeltaP control method of ventricular assist devices (VADs) requires the implantation of two pressure sensors to measure the pressure difference between the left ventricle and aorta. In this article, we propose a model-based method for estimating DeltaP, which eliminates the need for implantable pressure sensors. The developed estimator consists of the extended Kalman filter in conjunction with the Golay-Savitzky filter. The performance of the combined estimator-VAD controller system was evaluated in computer simulations for a broad range of physical activities and varying cardiac conditions. The results show that there was no appreciable performance degradation of the estimator-controller system compared to the case when DeltaP is measured directly. The proposed approach effectively utilizes a VAD as both a pump and a differential pressure sensor, thus eliminating the need for dedicated implantable pressure and flow sensors. The simulation results show that different pump designs may not be equally effective at playing a dual role of a flow actuator and DeltaP sensor.

Computer Simulation↗