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PubMed2000

Computational model of the fluid dynamics in systemic-to-pulmonary shunts.

A systemic-to-pulmonary shunt is a connection created between the systemic and pulmonary arterial circulations in order to improve pulmonary perfusion in children with congenital heart diseases. Knowledge of the relationship between pressure and flow in this new, surgically created, cardiovascular district may be helpful in the clinical management of these patients, whose survival is critically dependent on the blood flow distribution between the pulmonary and systemic circulations. In this study a group of three-dimensional computational models of the shunt have been investigated under steady-state and pulsatile conditions by means of a finite element analysis. The model is used to quantify the effects of shunt diameter (D), curvature, angle, and pulsatility on the pressure-flow (DeltaP-Q) relationship of the shunt. Size of the shunt is the main regulator of pressure-flow relationship. Innominate arterial diameter and angles of insertion have less influence. Curvature of the shunt results in lower pressure drops. Inertial effects can be neglected. The following simplified formulae are derived: DeltaP=(0. 097Q+0.521Q(2))/D(4) and DeltaP=(0.096Q+0.393Q(2))/D(4) for the different shunt geometries investigated (straight and curved shunts, respectively).

Blood Circulation↗
PubMed1997

Stimulus generalization of fear responses: effects of auditory cortex lesions in a computational model and in rats.

The conditioning of fear responses to a simple acoustic stimulus (pure tone) paired with footshock can be mediated by the transmission of auditory information to the lateral nucleus of the amygdala from either the auditory thalamus or the auditory cortex. We examined the processing capacity of the thalamo-amygdala pathway by making lesions of the auditory cortex and testing the extent to which conditioned fear responses generalized to tones other than the one paired with footshock. Two studies were performed, one in an anatomically constrained computational model of the fear conditioning network and the other in rats. Stimulus generalization was unaffected in both. These findings support the validity of the model as an approach to studying the neural basis of conditioned fear learning, and in addition suggest that the thalamo-amygdala pathway, possibly by the use of population coding, is capable of performing at least crude stimulus discriminations.

Acoustic Stimulation↗
PubMed1988

Three computer models for the calculation of prevalence of peptic ulcer disease during long-term treatment.

At present the effects of maintenance treatment for peptic ulcer disease are usually calculated by using 'life-table' analyses. Whilst these accurately demonstrate the speed with which an initial relapse occurs they make no allowance for the fact that, in clinical practice, a relapse often responds to a further course of full-dose treatment and the patient then returns to maintenance therapy. A further compounding factor is that, in any long-term study, patients will be lost to follow-up for a variety of reasons not all related to failure of the treatment. In this paper we describe the use of 'prevalence rates' to better reflect the outcome of peptic ulcer management. Three 'computer models', which have been developed to address the problems of patients leaving the study for any reason during such a long time-period, are also described, as are the underlying assumptions made. Using the results from a long-term study of continuous treatment with cimetidine, the 'prevalence rates' of ulcer disease over 6 years were calculated. Observed relapse rates appeared to fall with time (from 2.7% for duodenal ulcer (DU) and 2.5% for gastric ulcer (GU) to 1% and 2% respectively). However, on applying the models to the data, prevalence rates tended to rise slowly with time for the first 3 years in each of the models tested. At 6 years, two of the models suggested that the prevalence rate for DU would be about 8%; this is not very different to the reported recurrence rate after surgical treatment by truncal vagotomy and pyloroplasty. It is concluded that 'prevalence rates' should be used to assess long-term medical treatments for ulcer disease. Similar methods could also be used to examine the medical treatment of any other disease where multiple relapses, capable of responding to re-treatment, occur. The use of models proved beneficial in compensating for patients lost during the study.

Computer Simulation↗
PubMed1982

A hybrid computer model of stochastic activity of the neurone.

The authors describe a hybrid computer neurone model intended for the investigation of stochastic transformations effected by neurones in correlation to some of their physiological parameters. The model is designed so as to give the best possible characterization of the internal dynamics of a neurone with minimum limiting conditions. It allows the generation of suitable input stochastic processes or operates with input processes obtained experimentally in the living neurone and it carries out basic statistical tests of the output stochastic process.

Computers, Hybrid↗
PubMed1999

High-resolution NMR and computer modeling studies of the cannabimimetic aminoalkylindole prototype WIN-55212-2.

Aminoalkylindoles (AAIs), although structurally dissimilar from the classical cannabinoids (CCs), are known to be capable of binding to cannabinoid receptors and of evoking cannabimimetic responses. However, their mode of binding remains unknown. In this communication, we have carried out further studies on the AAI prototype (R)-[2, 3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1, 4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN-55212-2, 1) by the combined use of high-resolution 2D NMR and computer modeling. Our results suggest that the minimum energy conformations of the molecule 1 have distinct pharmacophoric features: (i) The naphthyl ring is oriented off the plane of the benzoxazine ring by approximately 59 degrees with the carbonyl C=O group pointing toward the C2-CH(3) group. (ii) At the C10-position the axial morpholinomethyl conformation is preferred over the equatorial in order to relieve a steric interaction with the C2-methyl group. The preferred conformer as defined by the three key pharmacophores, naphthyl, morpholino, and 3-keto groups, shows that the morpholinyl ring of the molecule 1 deviates from the plane of the benzoxazine ring by about 32 degrees and orients in the left molecular quadrant. This model supports the hypothesis that a certain deviation of the morpholino group from the plane of the indole ring in compound 1 is essential for cannabimimetic activity. We postulate that such an alignment by the respective pharmacophores allows them to interact optimally with the receptor. The results should help us to better understand the pharmacophoric requirements of the AAIs and serve as a basis for future SAR studies and drug design.

Benzoxazines↗
PubMed2006

A computational model of fractionated conflict-control mechanisms in task-switching.

A feature of human cognition is the ability to monitor and adjust one's own behavior under changing circumstances. A dynamic balance between controlled and rapid responding is needed to adapt to a fluctuating environment. We suggest that cognitive control may include, among other things, two distinct processes. Incongruent stimuli may drive top-down facilitation of task-relevant responses to bias performance toward exploitation vs. exploration. Task or response switches may generally slow responses to bias toward accuracy vs. speed and exploration vs. exploitation. Behavioral results from a task switching study demonstrate these two distinct processes as revealed by higher-order sequential effects. A computational model implements the two conflict-control mechanisms, which allow it to capture many complex and novel sequential effects. Lesion studies with the model demonstrate that the model is unable to capture these effects without the conflict-control loops and show how each monitoring component modulates cognitive control. The results suggest numerous testable predictions regarding the neural substrates of cognitive control.

Adult↗
PubMed1996

Asp-49 is not an absolute prerequisite for the enzymic activity of low-M(r) phospholipases A2: purification, characterization and computer modelling of an enzymically active Ser-49 phospholipase A2, ecarpholin S, from the venom of Echis carinatus sochureki (saw-scaled viper).

Several studies have shown that Asp-49 is the residue that controls calcium binding in, and so plays a critical role in the calcium-mediated activation of, low-M(r) group I-III phospholipases A2 (PLA2s). The present paper provides experimental evidence that Asp-49 is not an absolute prerequisite for the enzymic activity of PLA2s, and that proteins with amino acid(s) other than Asp at position 49 can exhibit significant phospholipase activity. The purification, complete amino acid sequence and characterization of ecarpholin S, a PLA2 from Echis carinatus sochureki (saw-scaled viper) venom, is described. This single-chain, 122-amino-acid, basic (pI 7.9) protein is a group II PLA2. Although Asp-49 is replaced by Ser and Tyr-28 by Phe (both of these positions being involved in the Ca(2+)-binding site of PLA2s), the lipolysis of soybean phosphatidylcholine and egg yolk in the presence of 10 mM CaCl2 was 1.5 times and 2.9 times greater respectively with ecarpholin S than with recombinant human group II PLA2. The Ca(2+)-dependencies of the enzymic activities of ecarpholin S and rPLA2 were found to be similar. Ecarpholin S added to washed platelets induced aggregation; the presence of Ca2+ was a prerequisite for this platelet-aggregating effect. Computer modelling of the Ca(2+)-binding site of Ser-49 PLA2 compared with the Asp-49 and Lys-49 forms, for which crystallographic data exist, shows that the Ca(2+)-binding site is sterically blocked by Lys-49 but not by Ser-49; in the latter, the Ser hydroxy group may replace the Asp carboxylate in stabilization of Ca2+ binding. Sequence comparisons of ecarpholin S and other low-M(r) PLA2s predicts the presence of a Ser-49 group in the protein family of low-M(r) PLA2s that is distinct from the Asp-49 and Lys-49 groups.

Amino Acid Sequence↗
PubMed2005

Experimental generation and computational modeling of intracellular pH gradients in cardiac myocytes.

It is often assumed that pH(i) is spatially uniform within cells. A double-barreled microperfusion system was used to apply solutions of weak acid (acetic acid, CO(2)) or base (ammonia) to localized regions of an isolated ventricular myocyte (guinea pig). A stable, longitudinal pH(i) gradient (up to 1 pH(i) unit) was observed (using confocal imaging of SNARF-1 fluorescence). Changing the fractional exposure of the cell to weak acid/base altered the gradient, as did changing the concentration and type of weak acid/base applied. A diffusion-reaction computational model accurately simulated this behavior of pH(i). The model assumes that H(i)(+) movement occurs via diffusive shuttling on mobile buffers, with little free H(+) diffusion. The average diffusion constant for mobile buffer was estimated as 33 x 10(-7) cm(2)/s, consistent with an apparent H(i)(+) diffusion coefficient, D(H)(app), of 14.4 x 10(-7) cm(2)/s (at pH(i) 7.07), a value two orders of magnitude lower than for H(+) ions in water but similar to that estimated recently from local acid injection via a cell-attached glass micropipette. We conclude that, because H(i)(+) mobility is so low, an extracellular concentration gradient of permeant weak acid readily induces pH(i) nonuniformity. Similar concentration gradients for weak acid (e.g., CO(2)) occur across border zones during regional myocardial ischemia, raising the possibility of steep pH(i) gradients within the heart under some pathophysiological conditions.

Acetates↗
PubMed1991

Delineation of rat kidney alpha 2A- and alpha 2B-adrenoceptors with [3H]RX821002 radioligand binding: computer modelling reveals that guanfacine is an alpha 2A-selective compound.

We developed a method for the simultaneous determination of drug affinity constants for rat alpha 2A- and alpha 2B-adrenoceptor subtypes by using [3H]RX821002 radioligand binding in the kidney. Three competition curves were obtained for each drug: one for the test compound in the absence of ARC 239 (a drug found to have 108-fold higher affinity for alpha 2B- than for alpha 2A-adrenoceptors), one in the presence of ARC 239, and one for ARC 239. It is possible to determine the Kds of a tested drug for both alpha 2A- and alpha 2B-adrenoceptors by simultaneous computer modelling because of the increased constraint in the calculations given by the inclusion of ARC 239 into the assay. Using this approach, we found guanfacine and oxymetazoline to be highly alpha 2A-selective. The most alpha 2B-selective were ARC 239, prazosin and corynanthine. A number of other drugs, for example UK-14,304, rilmenidine and clonidine, were non-selective or showed minor selectivity for alpha 2A- or alpha 2B-adrenoceptors. Moreover, using Monte Carlo simulations, we showed that the three-curve method gives more accurate estimates of drug binding constants for assays when two receptor sites are present than methods analysing only one competition curve.

Animals↗
PubMed1982

Transient kinetics of electron transfer reactions of flavodoxin: ionic strength dependence of semiquinone oxidation by cytochrome c, ferricyanide, and ferric ethylenediaminetetraacetic acid and computer modeling of reaction complexes.

Electron transfer reactions between Clostridum pasteurianum flavodoxin semiquinone and various oxidants [horse heart cytochrome c, ferricyanide, and ferric ethylenediaminetetraacetic [horse heart cytochrome c, ferricyanide, and ferric ethylenediaminetetraacetic acid (EDTA)] have been studied as a function of ionic strength by using stopped-flow spectrophotometry. The cytochrome c reaction is complicated by the existence of two cytochrome species which react at different rates and whose relative concentrations are ionic strength dependent. Only the faster of these two reactions is considered here. At low ionic strength, complex formation between cytochrome c and flavodoxin is indicated by a leveling off of the pseudo-first-order rate constant at high cytochrome c concentration. This is not observed for either ferricyanide or ferric EDTA. For cytochrome c, the rate and association constants for complex formation were found to increase with decreasing ionic strength, consistent with negative charges on flavodoxin interacting with the positively charged cytochrome electron transfer site. Both ferricyanide and ferric EDTA are negatively charged oxidants, and the rate data respond to ionic strength changes as would be predicted for reactants of the same charge sign. These results demonstrate that electrostatic interactions involving negatively charged groups are important in orienting flavodoxin with respect to oxidants during electron transfer. We have also carried out computer modeling studies of putative complexes of flavodoxin with cytochrome c and ferricyanide, which relate their structural properties to both the observed kinetic behavior and some more general features of physiological electron transfer processes. The results of this study are consistent with the ionic strength behavior described above.

Clostridium↗
PubMed1992

The structures of bacteriorhodopsin with different retinal-Schiff base orientations--computer modeling and energy minimization studies.

Bacteriorhodopsin has been the subject of intense study in order to understand its photochemical function. The recent atomic model proposed by Henderson and coworkers based on electron cryo-microscopic studies has helped in understanding many of the structural and functional aspects of bacteriorhodopsin. However, the accuracy of the positions of the side chains is not very high since the model is based on low-resolution data. In this study, we have minimized the energy of this structure of bacteriorhodopsin and analyzed various types of interactions such as--intrahelical and interhelical hydrogen bonds and retinal environment. In order to understand the photochemical action, it is necessary to obtain information on the structures adopted at the intermediate states. In this direction, we have generated some intermediate structures taking into account certain experimental data, by computer modeling studies. Various isomers of retinal with 13-cis and/or 15-cis conformations and all possible staggered orientations of Lys-216 side chain were generated. The resultant structures were examined for the distance between Lys-216-schiff base nitrogen and the carboxylate oxygen atoms of Asp-96--a residue which is known to reprotonate the schiff base at later stages of photocycle. Some of the structures were selected on the basis of suitable retinal orientation and the stability of these structures were tested by energy minimization studies. Further, the minimized structures are analyzed for the hydrogen bond interactions and retinal environment and the results are compared with those of the minimized rest state structure. The importance of functional groups in stabilizing the structure of bacteriorhodopsin and in participating dynamically during the photocycle have been discussed.

Bacteriorhodopsins↗
PubMed1990

Nosocomial infections: validation of surveillance and computer modeling to identify patients at risk.

To estimate the accuracy of routine hospital-wide surveillance for nosocomial infection, the authors performed a validation study at the University of Iowa Hospitals and Clinics, a 900-bed tertiary care institution, by daily concurrent surveys of all patients' charts. The study extended over a 10-month period from January to October 1987. The sensitivity and specificity of the reported data were 80.7% (95% confidence interval (CI) 72.2-89.2) and 97.5% (95% CI 96.4-98.5), respectively. The predictive values of positive or negative reports of an infection were 75.3% (95% CI 66.3-84.2) and 98.1% (95% CI 97.3-99.1), respectively. In a separate analysis, the data entry system was reviewed for eight descriptive variables among all patients with infections (n = 443) identified over a 2-month period. The data entry was found to be 94-99% accurate. To improve the efficiency of current surveillance, the authors used data gathered during the study to develop a computer model for the identification of patients with a high probability of having a nosocomial infection. The use of stepwise logistic regression identified five variables which independently predicted infection: age of the patient (years), days of antibiotics, days of hospitalization, and the number of days on which urine and/or wound cultures were obtained. Optimal sensitivity and specificity (81.6% and 72.5%, respectively) were found when the model examined patients with an 8% or higher a priori probability of infection; this figure corresponded to a review of 33% of the patients' charts. Increasing the a priori probability would progressively increase specificity and reduce both sensitivity and the number of charts needed for review. If it is prospectively validated, the model may provide a more efficient mechanism by which to conduct hospital-wide surveillance.

Age Factors↗
PubMed1995

A computational model for signal processing by the dorsal cochlear nucleus. I. Responses to pure tones.

Much information is available on the anatomical organization and neurophysiological properties of the major cell types in the dorsal cochlear nucleus (DCN). The complicated response properties of individual cells and units in the DCN indicate that substantial information processing already occurs at the level of the DCN. A large number of connectional hypotheses have been put forward to explain various aspects of the response characteristics of DCN cells, but many of the consequences of these hypotheses have not been investigated quantitatively. In this paper, we investigate these hypotheses by constructing and testing mathematical and computational models and compare our results to those of previous modeling studies. The simplest versions of our models include auditory nerve (AN) fibers, type II cells (inhibitory interneurons) and type IV cells (fusiform and giant cells). The model response maps, i.e., the pattern of output of model type IV cells, generated by the simplest model have some but not all the features of the experimental response maps of type IV neurons. In particular, the excitatory region which occurs at best frequency is not isolated and the excitatory region at low frequencies and high amplitude is narrower than observed. Since experimental evidence exists that some of the connections between these cell types are divergent or convergent across adjacent isofrequency sheets, the effect of such convergence and divergence was then investigated. Response maps so obtained reproduce many of the qualitative features of the experimental maps. Enlargement of the model by including inhibitory interneurons (e.g., stellate cells) that receive convergent input from AN fibers and which inhibit type II cells results in the generation of response maps that, with some variations in connectional patterns and physiological properties of neurons, match most of the essential features seen in the large variety of experimental maps obtained from the cat DCN.

Animals↗
PubMed2001

Computer modeling of fecal coliform contamination of an urban estuarine system.

This study is focused on the investigation of the sources, distribution and fate of fecal coliform populations in the North Fork of the New River that flows through the City of Fort Lauderdale, Florida, USA. The dynamics of this brackish river are driven by weak tides, regulated freshwater discharges, overland runoff, storm water drainage from sewers, and groundwater exchange. Extensive field studies failed to document any alleged source(s) of contamination, including birds, domesticated and undomesticated mammals, humans, septic tank leakage, urban runoff, non-point discharges from agricultural lands, waste disposal from live-aboard vessels and/or in situ re-growth of fecal coliform. In order to facilitate field sampling, and support the data analyses efforts, computer simulations were applied to assess the likelihood of the various possible pollution scenarios. The physically based computer model used is the WASP (Water Quality Analysis Simulation Program Modeling System) of the US Environmental Protection Agency. In addition, the Neural Network MATLAB Toolbox was utilized for data analysis. WASP was able to accurately simulate the water hydrodynamics and coliform concentrations within the North Fork, while the neural network assisted in identifying correlations between fecal coliform and the various parameters involved. The numerical results supported the conclusion that fecal coliform were introduced by the animal populations along the riverbanks and by storm water washout of the adjacent drainage basins and the banks. The problem is exaggerated due to the low flashing capacity of the river.

Agriculture↗
PubMed2003

A computational model of cuneothalamic projection neurons.

The dorsal column nuclei, cuneatus and gracilis, play a fundamental role in the processing and integration of somesthetic ascending information. Intracellular and patch-clamp recordings obtained in cat in vivo have shown that cuneothalamic projection neurons present two modes of activity: oscillatory and tonic (Canedo et al 1998 Neuroscience 84 603-17). The former is the basis of generating, in sleep and anaesthetized states, slow, delta and spindle rhythms under the control of the cerebral cortex (Mariño et al 2000 Neuroscience 95 657-73). The latter is needed, during wakefulness, to process somesthetic information in real time. To study this behaviour we have developed the first realistic computational model of the cuneothalamic projection neurons. The modelling was guided by experimental recordings, which suggest the existence of hyperpolarization-activated inward currents, transient low- and high-threshold calcium currents, and calcium-activated potassium currents. The neuronal responses were simulated during (1) sleep, (2) transition from sleep to wakefulness and (3) wakefulness under both excitatory and inhibitory synaptic input. In wakefulness the model predicts a set of synaptically driven firing modes that could be associated with information processing strategies in the middle cuneate nucleus.

Action Potentials↗
PubMed2005

Construction and 3-D computer modeling of connector arrays with tetragonal to decagonal transition induced by pRNA of phi29 DNA-packaging motor.

The bottom-up assembly of patterned arrays is an exciting and important area in current nanotechnology. Arrays can be engineered to serve as components in chips for a virtually inexhaustible list of applications ranging from disease diagnosis to ultrahigh-density data storage. In attempting to achieve this goal, a number of methods to facilitate array design and production have been developed. Cloning and expression of the gene coding for the connector of the bacterial virus phi29 DNA-packaging motor, overproduction of the gene products, and the in vitro construction of large-scale carpet-like arrays composed of connector are described in this report. The stability of the arrays under various conditions, including varied pH, temperature and ionic strength, was tested. The addition of packaging RNA (pRNA) into the array caused a dramatic shift in array structure, and resulted in the conversion of tetragonal arrays into larger decagonal structures comprised of both protein and RNA. RNase digestion confirmed that the conformational shift was caused by pRNA, and that RNA was present in the decagons. As has been demonstrated in biomotors, conformational shift of motor components can generate force for motor motion. The conformational shift reported here can be utilized as a potential force-generating mechanism for the construction of nanomachines. Three-dimensional computer models of the constructed arrays were also produced using a variety of connector building blocks with or without the N- or C-terminal sequence, which is absent from the current published crystal structures. Both the connector array and the decagon are ideal candidates to be used as templates to build patterned suprastructures in nanotechnology.

Bacillus Phages↗
PubMed2005

[Pressure stress in glaucoma--assessment through classical techniques and computational modelling].

UNLABELLED: Even if glaucoma remains a major eye illness with unknown etiology, the importance of vascular factors associated with mechanical factors contributing to the pathogenesis and development of glaucomatous optic neuropathy has been emphasized. the objective of the study consists in elaboration of a biomechanical model of the human eye correlated with clinical and ultrasonography evaluations aiming to early identification of changes induced by pressure stress in open angle glaucoma (OAG) at retrobulbar arteries and optic nerve head level. METHOD AND MATERIAL: The present study included a lot formed by 97 patients without glaucoma, aged 20-75 years (lot 1) and a lot formed by 71 patients with open angle glaucoma, aged 45-80 years (lot 2). We used usual methods in ophthalmological examinations and diagnosis (bottom ocular fundus examinations eye examinations, visual - field examinations, measurements of PIO), ultrasonography methods (CDI, pulsed Doppler, spectral Doppler and power-angio), computational modelling methods for ocular structures. RESULTS AND CONCLUSIONS: In open angle glaucoma color Doppler imaging shows changes in retrobulbar hemodynamic for most of the studied cases, ultrasonography techniques being considered as an important tool for the diagnosis and progression control in glaucomatous damage. Limitations of ultrasonography techniques consist of early identification of these alterations and can be improved by the elaboration of a biomechanical model of the human eye that will permit an abstraction and generalisation of the hemodynamic aspects with the aim of simulation of changes induced by high intraocular pressure on retrobulbar arteries level, the possibility of viewing these changes in their dynamics (on lower pressure values than 30 mmHg).

Adult↗
PubMed1997

Use of 3-D computer modelling and kinetic studies to analyse grapefruit pyrophosphate-dependent phosphofructokinase.

The glycolytic reaction of grapefruit PPi-dependent phosphofructokinase (PFP) depends on the presence of Fru-2,6-P2 (Ka = 6.7 nM). This molecule was further demonstrated in grapefruit juice sac cells. Citrate, alpha-ketoglutarate and isocitrate competitively inhibited the binding of Fru-2,6-P2 to PFP. The affinity for Fru-6-P (Km = 159 microM) and PPi (Km = 33 microM) were not affected by the addition of these molecules. In the gluconeogenic reaction, the presence of Fru-2,6-P2 did not affect the Km of Fru-1,6-P2 (61 microM) in contrast to orange fruit PFP. These results led to the building of a computer model of PFP, based on the known structure of Bacillus stearothermophilus ATP-dependent phosphofructokinase (ATP-PFK). The results show that catalysis of Fru-6-P in the alpha chain is most unlikely, due to amino-acid substitutions and that Fru-2,6-P2 can bind between the alpha and beta subunits.

Adenosine Diphosphate↗