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At least 1,369 records · Page 76Linked to original sources
PubMed2005

Computational model of device-induced thrombosis and thromboembolism.

A numerical model of thrombosis/thromboembolism (T/TE) is presented that predicts the progression of thrombus growth and thromboembolization in low-shear devices (hemodialyzers, oxygenators, etc.). Coupled convection-diffusion-reaction equations were solved to predict velocities, platelet agonist (ADP, thromboxane A2, and thrombin) concentrations, agonist-induced and shear-induced platelet activation, and platelet transport and adhesion to biomaterial surfaces and adherent platelets (hence, thrombus growth). Single-platelet and thrombus embolization were predicted from shear forces and surface adhesion strengths. Values for the platelet-biomaterial reaction constant and the platelet adhesion strength were measured in specific experiments, but all other parameter values were obtained from published sources. The model generated solutions for sequential time steps, while adjusting velocity patterns to accommodate growing surface thrombi. Heparinized human blood was perfused (0.75 ml/min) through 580 microm-ID polyethylene flow cells with flow contractions (280 microm-ID). Thrombus initiation, growth, and embolization were observed with videomicroscopy, while embolization was confirmed by light scattering, and platelet adhesion was determined by scanning electron microscopy. Numerical predictions and experimental observations were similar in indicating: 1) the same three thrombotic locations in the flow cell and the relative order of thrombus development in those locations, 2) equal thrombus growth rates on polyethylene and silicon rubber (in spite of differing overall T/TE), and 3) similar effects of flow rate (1.5 ml/min versus 0.75 ml/min) on platelet adhesion and thrombosis patterns.

Blood Flow Velocity↗
PubMed1984

Computer modeling identifies glucokinase as glucose sensor of pancreatic beta-cells.

Previous work from this laboratory indicates that glucokinase serves as the glucose sensor of pancreatic islets. Here we show by nonlinear computer optimization that the kinetic properties of glucokinase (together with hexokinase, known to be present in islets) account for the observed glycolytic rates in islets as a function of glucose level. Alternative enzymes that have been suggested to perform the same function as glucokinase, N-acetyl-D-glucosamine kinase and glucose-6-phosphatase, are shown to have incompatible properties, including a poor fit, different curve shapes, and unreasonable parameter values resulting from optimization. Their activities in islets are shown to be too low to account for observed glucose usage rates. This work endorses our previous proposal that glucokinase acts as the glucose sensor in pancreatic islet cells.

Blood Glucose↗
PubMed1989

Cellular uncoupling can unmask dispersion of action potential duration in ventricular myocardium. A computer modeling study.

Although slow conduction is a requirement for the preparation of sustained reentry, it alone is not sufficient for the initiation of reentry. Additionally, unidirectional block and recovery of excitability distal to the site of block must occur. Thus, a comprehensive description of the electrophysiological determinants of reentry must explain both slow conduction and unidirectional block. Although there is a growing body of research exploring the influence of axial resistivity and anisotropy on slow conduction, somewhat less is known about the relation of axial resistivity to spatial dispersion of action potential duration, a condition favorable to the development of unidirectional block. We hypothesized that when cells are well coupled, local differences in intrinsic action potential duration are not evident and that, as axial resistivity increases, local variation in action potential duration becomes manifest. We tested this hypothesis in a numerical model of electrical propagation in a grid of resistively coupled ionic current sources simulating a sheet of ventricular myocardium. Spatial dispersion of intrinsic action potential duration was simulated by varying the magnitude of the fully activated slow inward conductance in Beeler-Reuter membrane ionic kinetics. By then altering coupling resistance, we showed that dispersion of manifest action potential duration is masked in the setting of normal low-resistance cellular coupling and unmasked by increased axial resistance. When nonuniform anisotropy was simulated, dramatic pacing-site-dependent changes in both the pattern of activation and dispersion of action potential duration were noted. These findings may be important in understanding the mechanism of reentrant tachycardia initiation in the border zone of chronic, healed myocardial infarctions where evidence suggests that abnormal cellular coupling is the predominant electrophysiological derangement. In this study, we have shown, using a detailed ionic current-based model of cardiac electrical propagation, that changes in axial resistivity can modulate how spatial dispersion of intrinsic action potential duration is manifest.

Action Potentials↗
PubMedDate not supplied

[Study of effect of water on the interaction of DNA and actinocin derivatives with various aminoalkyl chain length by infrared spectrophotometry and computer modeling].

A comparative study of the effect of water on the interaction of DNA with actinocin derivatives having different numbers of methylene groups in side chains was performed by IR spectroscopy. It was found that, as relative humidity increases, water molecules simultaneously bind to hydrate-active sites of DNA and ligands. The absorption band at v = 1137 cm-1, caused by oscillations of the C-O and P-O groups of atoms in the DNA-ligand complex having two methylene groups, is due to the interactions between the cationic groups of the ligand and the sugar-phosphate backbone of DNA, which may be one of the reasons for the high stability of this complex. Using computer simulation of interaction of DNA fragments and actinocin derivatives in water environment, molecular models of the formation of their complexes for two ways of binding were constructed.

Computer Simulation↗
PubMed2004

Computational modeling of the catalytic reaction in triosephosphate isomerase.

We present a comprehensive analysis of the catalytic cycle of the enzyme triosephosphate isomerase (TIM), including both the reactive chemistry and the catalytic loop and side-chain motions. Combining accurate mixed quantum mechanics/molecular mechanics (QM/MM) and protein structure prediction methods, we have modeled both the structural and chemical aspects of the reversible isomerization of dihydroxyacetone phosphate (DHAP) to d-glyceraldehyde 3-phosphate (GAP), for which there is a wealth of experimental data. The conjunction of this novel computational approach with the use of the recent near-atomic resolution TIM-DHAP Michaelis complex PDB structure, 1NEY.pdb, has enabled us to obtain robust qualitative and, where available, quantitative agreement with a wide range of experimental data. Among the principal conclusions that we are able to draw are the importance of the monoanionic (as opposed to dianioic) form of the substrate phosphate group in the catalytic cycle, detailed positioning and energetics of the key catalytic residues in the active-site, the flexible nature of Glu165, which favors its direct involvement in the formation of the enediol intermediate, energetics of the open and closed form of the catalytic loop region in the presence and absence of substrate, and quantitative reproduction of various experimentally measured reaction rates, typically to within approximately 1 kcal/mol. Our results are consistent with the available experimental data, and provide an initial picture as to why loop opening when GAP is the product has a higher barrier than when DHAP is the product.

Algorithms↗
PubMed1994

Simultaneity in the Ternus configuration: psychophysical data and a computer model.

The Ternus configuration is an apparent motion display which is typically described as being bistable; subjects usually describe seeing either element motion or group motion, depending upon temporal properties of the display. The results of an experiment are reported in which subjects are also permitted to report seeing four stationary display elements (simultaneity). It was found that simultaneity was produced when both frame durations and interstimulus intervals (ISIs) were brief. A weaker than expected effect of stimulus onset asynchrony (SOA) was revealed because this third type of judgment was obtained. Furthermore, statistical analyses indicated that SOA was not by itself the best predictor of judgment type. The interaction between duration and ISI was also an important predictor. This suggested that a complete account of the Ternus configuration requires two mechanisms: a visible persistence mechanism, governed by an SOA law, and a motion correspondence mechanism, governed by an ISI law. These two mechanisms were added to Dawson's (1991) [Psychological Review, 98, 569-603] autoassociative network for motion correspondence processing. The resulting model could generate each of the three interpretations of the Ternus configuration at appropriate combinations of frame duration and ISI.

Association↗
PubMed2007

A computational model for motor pattern switching between taste-induced ingestion and rejection oromotor behaviors.

The mechanism of switching activity patterns in a central pattern generator is fundamental to the generation of diverse motor behaviors. Based on what is known about a brainstem substrate mediating the oral components of ingestion and rejection, we use computational techniques to construct a hypothetical multifunctional network that switches between the motor outputs of ingestion (licking) and rejection (gaping). The network was constructed using single-compartment conductance-based models for individual neurons based on Hodgkin-Huxley formalism. Using a fast-slow reduction and geometric analysis we describe a mechanism for pattern switching between licks and gapes. The model supports the hypothesis that a single configuration of network connections can produce both activity patterns. It further predicts that prolonged inhibition of some network neurons could lead to a switch in network activity from licks to gapes.

Animals↗
PubMed1998

Striatal mechanisms in Parkinson's disease: new insights from computer modeling.

We review data and hypotheses concerning the functional anatomy of the striatum and the role of its corticostriatal and nigrostriatal afferents in Parkinson's disease (PD). Starting from molecular mechanisms of glutamatergic and dopaminergic actions in the striatum we have developed a compartmental model of striatal principal neurons that displays a significant degree of biological realism. Simulations of a network of striatal projection neurons under conditions likely to be found in healthy subjects as well as untreated and therapeutic situations of advanced PD provide clues concerning the dynamics of neuronal interactions and their possible effects on downstream motor structures in the generation of positive and negative motor symptoms. We present tentative biological explanations of the symptoms of rigidity and akinesia in PD leading to predictions concerning the origin of abnormal movements and the beneficial effects of dopaminergic treatment. Although these attempts are not yet sufficient to account for the complexity of clinical symptoms found in PD they can guide further empirical research and foster fruitful interactions between experimentalists, theoreticians, and clinicians in unraveling the functional anatomy of the basal ganglia.

Computer Simulation↗
PubMed1981

A computer model of the evolution of specific maximum lifespan.

To answer the question of why organisms have evolved finite and specific maximum lifespans, I have built and experimentally studied a discrete-event simulation model of the evolution of lifespan. Through natural selection, the model evolves an apparent plateau in maximum lifespan, the height of which is a decreasing function of both the intensity of niche fluctuations and specific fecundity. Evolved lifespan is therefore finite (small and essentially constant over accessible time intervals) and specific. Experiments demonstrate that the plateau is not due to group selection. Instead, it occurs because the rate of increase of maximum lifespan by natural selection - in an environment presenting a finite probability that death will occur prior to reaching the genetically specified maximum - is a decreasing function of maximum lifespan itself and asymptotically approaches zero. This supports in part a class of existing hypotheses that finite lifespan is due to an equilibrium between weak selection, as in the model, and various lifespan-decreasing processes, which however were not simulated in the present experiments. Although the model shows that such counter processes are not strictly necessary for the evolution of finite and specific maximum lifespan, my interpretation of the model's correspondence to organic evolution does imply a counter process, a bias in random genetic drift toward shorter lifespan, that is more general than those previously hypothesized.

Biological Evolution↗
PubMed1985

Intrathoracic and abdominal pressure variations as an efficient method for cardiopulmonary resuscitation: studies in dogs compared with computer model results.

Intrathoracic pressure variations are currently proposed as the main flow-generation mechanisms in standard and modified cardiopulmonary resuscitation (CPR) techniques. A method of changing pressure within the thorax and abdomen without any degree of heart compression was developed and tested in dogs. Intrathoracic and abdominal pressure waves were induced by cyclic inflation and deflation of the lungs and of perithoracic and periabdominal balloons. Various modes of CPR, depending on the rate of cycling, the use of a periabdominal balloon inflation, and a delay between the abdominal and thoracic pressure waves, were studied during ventricular fibrillation. During artificial systole (high intrathoracic pressure phase), the pressure which developed in the right ventricle (96.7 +/- 20.5 mmHg) was higher than the pressure in the aorta (89.3 +/- 20.5 mmHg, p less than 0.001). In artificial diastole (low intrathoracic pressure phase), the right ventricular pressure (11.7 +/- 2.6 mmHg) was lower than the aortic pressure (17.5 +/- 3.3 mmHg, p less than 0.001). The average flow in the carotid artery was 21.7 +/- 7.8 ml . min-1, which was 18 +/- 6% of the baseline carotid flow before CPR. Three different factors were found to improve the efficiency of CPR: periabdominal balloon inflation simultaneous with the intrathoracic pressure waves; increased frequency of the pressure waves from 60 to 100 cycles per minute; and inflation of the periabdominal balloon 50 to 100 ms before the thoracic balloon. Blood-gas and acid-base balance analysis during CPR revealed well-oxygenated arterial blood with a marked respiratory alkalosis and a slowly developing metabolic acidosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Abdomen↗
PubMed2004

Computational modelling of final covers for uranium mill tailings impoundments.

To properly design a final cover for uranium mill tailings impoundments the designer must attempt to find an effective geotechnical solution which addresses the radiological and non-radiological potential impact and prevents geochemical processes from occurring within the tailings. This paper presents a computer-based method for evaluating the performance of engineered final covers for the remediation of uranium mill tailings impoundments. Three hypothetical final covers were taken from scientific literature to investigate the proposed method: (i) a compacted clay liner (CCL); (ii) a composite liner (CL) and (iii) a capillary barrier (CB). The processes investigated: (i) the saturated hydraulic flux; (ii) the unsaturated hydraulic flux (exclusively for the capillary barrier) and (iii) the radon exhalation to the atmosphere. The computer programs utilised for the analyses are: (i) Hydrologic Evaluation of Landfill Performance (HELP); (ii) SEEP/W and (iii) RADON. The site considered for the development of the research presented herein was the uranium mill tailings impoundment located at the Brazilian city of Poços de Caldas, in the Minas Gerais State.

Computer Simulation↗
PubMed1993

Convergence of auditory nerve fibers onto bushy cells in the ventral cochlear nucleus: implications of a computational model.

1. Convergence of auditory nerve (AN) fibers onto bushy cells of the ventral cochlear nucleus (VCN) was investigated with a model that describes the electrical membrane properties of these cells. The model consists of a single compartment, representing the soma, and includes three voltage-sensitive ion channels (fast sodium, delayed-rectifier-like potassium, and low-threshold potassium). These three channels have characteristics derived from voltage clamp data of VCN bushy cells. The model also contains a leakage channel, membrane capacitance, and synaptic inputs. The model accurately reproduces the membrane rectification seen in current clamp studies of bushy cells, as well as their unique current clamp responses. 2. In this study, the number and synaptic strength of excitatory AN inputs to the model were varied to investigate the relationship between input convergence parameters and response characteristics. From 1 to 20 excitatory synaptic inputs were applied through channels in parallel with the voltage-gated channels. Each synapse was driven by an independent AN spike train; spike arrivals produced brief (approximately 0.5 ms) conductance increases. The number (NS) and conductance (AE) of these inputs were systematically varied. The input spike trains were generated as a renewal point process that accurately models characteristics of AN fibers (refractoriness, adaptation, onset latency, irregularity of discharge, and phase locking). Adaptation characteristics of both high and low spontaneous rate (SR) AN fibers were simulated. 3. As NS and AE vary over the ranges 1-20 and 3-80 nS, respectively, the full range of response types seen in VCN bushy cells are produced by the model, with AN inputs typical of high-SR AN fibers. These include primarylike (PL), primarylike-with-notch (Pri-N), and onset-L (On-L). In addition, Onset responses, whose association with bushy cells in uncertain, and "dip" responses, which are not seen in the VCN, are produced. Dip responses occur with large NS and/or AE, and are due to depolarization block. When the AN inputs have the adaptation characteristics of low-SR AN fibers, PL--but not Pri-N or On-L responses--are produced. This suggests that neurons showing Pri-N and On-L responses must receive high-SR AN inputs. 4. The regularity of discharge of the model is compared with that of VCN bushy cells, using a measure derived from the mean and standard deviation of interspike intervals. Regularity is an important constraint on the model because the regularity of VCN bushy cells is the same as that of their AN inputs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Interactions of glutamate and dopamine in a computational model of the striatum.

A network model of simplified striatal principal neurons with mutual inhibition was used to investigate possible interactions between cortical glutamatergic and nigral dopaminergic afferents in the neostriatum. Glutamatergic and dopaminergic inputs were represented by an excitatory synaptic conductance and a slow membrane potassium conductance, respectively. Neuronal activity in the model was characterized by episodes of increased action potential firing rates of variable duration and frequency. Autocorrelation histograms constructed from the action potential activity of striatal model neurons showed that reducing peak excitatory conductance had the effect of increasing interspike intervals. On the other hand, the maximum value of the dopamine-sensitive potassium conductance was inversely related to the duration of firing episodes and the maximal firing rates. A smaller potassium conductance restored normal firing rates in the most active neurons at the expense of a larger proportion of neurons showing reduced activity. Thus, a homogeneous network with mutual inhibition can produce equally complex dynamics as have been proposed to occur in a striatal network with two neuron populations that are oppositely regulated by dopamine. Even without mutual inhibition it appears that increased dopamine concentrations could partially compensate for the effects of reduced glutamatergic input in individual neurons.

Action Potentials↗