[Computer modelling of the behavior of nerve fiber membranes under rhythmic stimulation].
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Biological Transport, Active↗
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Capnography and the Bain circuit I: A computer model.
The Mapleson D anesthesia breathing system has no valves and allows rebreathing of carbon dioxide. Its coaxial version is known as the Bain system. The interpretation of capnograms obtained during its use requires an understanding of the interrelationships of patient and system variables. Toward that end, a systematic description of mechanical ventilation with the Bain circuit was undertaken based on the physical laws of gas transport. The mathematical formulation of the model contains the relations between pressure, flow, and volume in the tube, alveolar space, and ventilator. The flows, calculated from these relations, are used to determine the CO2 concentrations in the different parts of the model. Two sets of data are used--patient and system. The patient data, used to solve the equations numerically, are lung-thorax compliance, CO2 inflow into alveolar space (CO2 production), functional residual capacity, dead space volume, airway resistance, and respiratory quotient. The ventilation system data comprise the dimensions and volumes of the Bain circuit, ventilator, connectors, and tubes; spill valve pressure; resistances to flow in the individual tube parts; ventilator settings; and fresh-gas flow rates. After incorporation of a volunteer's respiratory variables into the model, capnograms obtained from the model compared well with those obtained from the volunteer. The structure of the model is such that it permits easy introduction or changes of patient and system variables to obtain individual results or model specific circumstances. This flexibility makes it a useful tool for understanding the properties of the Bain circuit under a variety of clinical circumstances. The results may be displayed in a number of different ways.
Anesthesia, General↗
How batrachotoxin modifies the sodium channel permeation pathway: computer modeling and site-directed mutagenesis.
A structural model of the rNav1.4 Na+ channel with batrachotoxin (BTX) bound within the inner cavity suggested that the BTX pyrrole moiety is located between a lysine residue at the DEKA selectivity filter (Lys1237) and an adjacent phenylalanine residue (Phe1236). We tested this pyrrole-binding model by site-directed mutagenesis of Phe1236 at D3/P-loop with 11 amino acids. Mutants F1236D and F1236E expressed poorly, whereas nine other mutants either expressed robust Na+ currents, like the wild-type (F1236Y/Q/K), or somewhat reduced current (F1236G/A/C/N/W/R). Gating properties were altered modestly in most mutant channels, with F1236G displaying the greatest shift in activation and steady-state fast inactivation (-10.1 and -7.5 mV, respectively). Mutants F1236K and F1236R were severely resistant to BTX after 1000 repetitive pulses (+50 mV/20 ms at 2 Hz), whereas seven other mutants were sensitive but with reduced magnitudes compared with the wild type. It is noteworthy that rNav1.4-F1236K mutant Na+ channels remained highly sensitive to block by the local anesthetic bupivacaine, unlike several other BTX-resistant mutant channels. Our data thus support a model in which BTX, when bound within the inner cavity, interacts with the D3/P-loop directly. Such a direct interaction provides clues on how BTX alters the Na+ channel selectivity and conductance.
Amino Acid Sequence↗
Computer modelling of the cerebrospinal fluid flow dynamics of aqueduct stenosis.
As the craniospinal space is a pressure loaded system it is difficult to conceptualize and understand the flow dynamics through the ventricular system. Aqueduct stenosis compromises flow, increasing the pressure required to move cerebrospinal fluid (CSF) through the ventricles. Under normal circumstances, less than one pascal (1 Pa) of pressure is required to move a physiological flow of CSF through the aqueduct. This is too small to measure using clinical pressure transducers. A computational fluid dynamics (CFD) program, CFX, has been used to model two forms of aqueduct stenosis: simple narrowing and forking of the aqueduct. This study shows that with mild stenoses, the increase in pressure required to drive flow becomes significant (86-125 Pa), which may result in an increased transmantle pressure difference but not necessarily an increased intraventricular pressure. Severe stenoses will result in both. Wall shear stresses increase concomitantly and may contribute to local damage of the aqueduct wall and further gliosis with narrowing.
Cerebrospinal Fluid↗
Computer modelling of the binding of non-selective ligands to biological receptors.
The application of common linearization methods (log-probit analysis or Hill plot transformation) to the evaluation of receptor binding experiments leads to serious errors, if the ligands used possess insufficient receptor selectivity. The use of simultaneous non-linear curve-fitting procedures in this case is recommended and illustrated.
Binding Sites↗
A computational model of action selection in the basal ganglia. II. Analysis and simulation of behaviour.
In a companion paper a new functional architecture was proposed for the basal ganglia based on the premise that these brain structures play a central role in behavioural action selection. The current paper quantitatively describes the properties of the model using analysis and simulation. The decomposition of the basal ganglia into selection and control pathways is supported in several ways. First, several elegant features are exposed--capacity scaling, enhanced selectivity and synergistic dopamine modulation--which might be expected to exist in a well designed action selection mechanism. The discovery of these features also lends support to the computational premise of selection that underpins our model. Second, good matches between model globus pallidus external segment output and globus pallidus internal segment and substantia nigra reticulata area output, and neurophysiological data, have been found which are indicative of common architectural features in the model and biological basal ganglia. Third, the behaviour of the model as a signal selection mechanism has parallels with some kinds of action selection observed in animals under various levels of dopaminergic modulation.
Animals↗
Computational model of obsessive-compulsive disorder: examination of etiologic hypothesis and treatment strategies.
Research has shown that obsessive compulsive disorder (OCD) is related to structural and functional abnormalities in the brain, and several authors have organized these findings into theories of OCD neuropsychiatric dysfunction. In this paper, these theories were used to develop a neural network model of OCD. OCD symptoms were hypothesized to result from a hyperactive orbitofrontal-striato-thalamic-orbitofrontal neural loop. The network was constructed and trained with a backpropagation algorithm, and it was then used to assess etiologic theories of OCD (e.g., basal ganglia dysfunction, inadequate dopaminergic inhibitory influence on basal ganglia and excessive input from the limbic system). The network was also observed in analogues of the treatment of OCD with serotonergic medications and behavior therapy. Results show that a) the network behaved both normally and abnormally, depending on what combinations of perceptual, motivational, and neurochemical inputs were presented to it; b) several etiologic mechanisms produced changes in the networks' behaviors similar to patients' subjective experiences of OCD symptoms; and c) different treatment strategies, both those modeled as pharmacologic and behavioral therapies, produced reductions in simulated OCD symptoms.
Algorithms↗
A QuickBasic computer model of spermatogenesis.
A program in QuickBasic has been written for the purpose of simulating spermatogenesis in any animal in order to more fully understand the dynamics of sperm production. Two basic informations are needed to run the program: controlling factors (CF-s) and the stem cell population size. These can be interactively manipulated for theoretical evaluations or be implemented from actual animal data for assessment of valid sperm yield.
Algorithms↗
Computer modeling of the neurotoxin binding site of acetylcholine receptor spanning residues 185 through 196.
A model of the complex between the acetylcholine receptor and the snake neurotoxin, cobratoxin, was built by molecular model building and energy optimization techniques. The experimentally identified functionally important residues of cobratoxin and the dodecapeptide corresponding to the residues 185-196 of acetylcholine receptor alpha subunit were used to build the model. Both cis and trans conformers of cyclic L-cystine portion of the dodecapeptide were examined. Binding residues independently identified on cobratoxin are shown to interact with the dodecapeptide AChR model.
Amino Acid Sequence↗
Computational models to predict blood-brain barrier permeation and CNS activity.
The blood-brain permeation of a structurally diverse set of 281 compounds was modeled using linear regression and a multivariate genetic partial least squares (G/PLS) approach. Key structural features affecting the logarithm of blood-brain partitioning (logBB) were captured through statistically significant quantitative structure-activity relationship (QSAR) models. These relationships reveal the importance of logP, polar surface area, and a variety of electrotopological indices for accurate predictions of logBB. The best models reveal an excellent correlation (r > 0.9) for a training set of 58 compounds. Likewise, the comparison of the average logBB values obtained from an ensemble of QSAR models with experimental values also verifies the statistical quality of the models (r > 0.9). The models provide good agreement (r approximately 0.7) between the predicted logBB values for 34 molecules in the external validation set and the experimental values. To further validate the models for use during the drug discovery process, a prediction set of 181 drugs with reported CNS penetration data was used. A >70% success rate is obtained by using any of the QSAR models in the qualitative prediction for CNS permeable (active) drugs. A lower success rate (approximately 60%) was obtained for the best model for CNS impermeable (inactive) drugs. Combining the predictions obtained from all the models (consensus) did not significantly improve the discrimination of CNS active and CNS inactive molecules. Finally, using the therapeutic classification as a guiding tool, the CNS penetration capability of over 2000 compounds in the Synthline database was estimated. The results were very similar to the smaller set of 181 compounds.
Blood-Brain Barrier↗
Diagnosis of paced electrocardiograms by inverse computer modeling of pacemaker actions.
The explanation and interpretation of ECGs recorded from paced patients may be very difficult because of pacemaker specification, programmed parameters, and idiosyncrasy and also because of hidden interactions between the device and its environment. Moreover, the recent development of very sophisticated pacemakers makes the heart-pacemaker interaction (HPI) difficult to understand even when the recorded ECG is accompanied by an event marker. A computer system providing an automatic analysis of the HPI based on ECG data has been developed and implemented on an IBM PC AT computer. The system evaluates all possible combinations of HPI events and establishes whether they correspond to the pacemaker. The system inputs interactively the description of the pacemaker mode and programming, and the description of the analyzed ECG in the form of timing of "definite" and "possible" sensing events and generator pulses. The computer performs the analysis and establishes whether the device operates correctly within its permitted error. The system has been tested by evaluating different examples of paced ECGs. The presented examples confirm the ability of the system and show the potential for its future clinical use. Future development of the system and the provision of computer support for the understanding of the HPI of complex DDDR pacemakers are discussed.
Algorithms↗
Enhanced semantic priming in schizophrenia: a computer model based on excessive pruning of local connections in association cortex.
BACKGROUND: Many studies have found that people with schizophrenia exhibit abnormally high levels of semantic priming. Post-mortem and neuroimaging studies of schizophrenia suggest a reduction of neuritic processes (dendrites and synapses). AIMS: To demonstrate that reductions in neuritic processes can produce excessive priming in patients with schizophrenia. METHOD: Associative memory was simulated using a computer-based neural network system consisting of two interactive neural groups, one coding for individual memories and the other for the category to which each memory belonged. RESULTS: Variation of a single parameter determining the density of local connections within the two neuronal groups gave a close approximation to levels of memory access and semantic priming previously reported in normal subjects and in patients with schizophrenia. CONCLUSIONS: This study suggests that schizophrenia arises from excessive pruning of local connections in association cortex. Its findings shed light on the mechanisms underlying cognitive priming more generally, and how it might emerge developmentally.
Adolescent↗
A digital computer model for glucose-insulin dynamics.
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Blood Glucose↗
Myasthenia gravis: analog computer model.
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Adolescent↗
Computational models of hair cell bundle mechanics: III. 3-D utricular bundles.
Six utricular hair bundles from a red-eared turtle are modeled using 3-D finite element analysis. The mechanical model includes shear deformable stereocilia, realignment of all forces during force load increments, and tip and lateral link inter-stereocilia connections. Results show that there are two distinct bundle types that can be separated by mechanical bundle stiffness. The more compliant group has fewer total stereocilia and short stereocilia relative to kinocilium height; these cells are located in the medial and lateral extrastriola. The stiff group are located in the striola. They have more stereocilia and long stereocilia relative to kinocilia heights. Tip link tensions show parallel behavior in peripheral columns of the bundle and serial behavior in central columns when the tip link modulus is near or above that of collagen (1x10(9) N/m(2)). This analysis shows that lumped parameter models of single stereocilia columns can show some aspects of bundle mechanics; however, a distributed, 3-D model is needed to explore overall bundle behavior.
Animals↗
Computer modeling of electrostatic steering and orientational effects in antibody-antigen association.
Brownian dynamics simulations are performed to investigate the role of long-range electrostatic forces in the association of the monoclonal antibody HyHEL-5 with hen egg lysozyme. The electrostatic field of the antibody is obtained from a solution of the nonlinear Poisson-Boltzmann using the x-ray crystal coordinates of this protein. The lysozyme is represented as an asymmetric dumbell consisting of two spheres of unequal size, an arrangement that allows for the modeling of the orientational requirements for docking. Calculations are done with the wild-type antibody and several point mutants at different ionic strengths. Changes in the charge distribution of the lysozyme are also considered. Results are compared with experiment and a simpler model in which the lysozyme is approximately by a single charged sphere.
Animals↗
Computer modeling of ventricular rhythm during atrial fibrillation and ventricular pacing.
We propose a unified atrial fibrillation (AF)-ventricular pacing (VP) (AF-VP) model to demonstrate the effects of VP on the ventricular rhythm during atrial fibrillation AF. In this model, the AV junction (AVJ) is treated as a lumped structure characterized by refractoriness and automaticity. Bombarded by random AF impulses, the AVJ can also be invaded by the VP-induced retrograde wave. The model includes bidirectional conduction delays in the AVJ and ventricle. Both refractory period and conduction delay of the AVJ are dependent upon its recovery time. The electrotonic modulation by blocked impulses is also considered in the model. Our simulations show that, with proper parameter settings, the present model can account for most principal statistical properties of the RR intervals during AF. We further demonstrate that the AV conduction property and the ventricular rate in AF depend on both AF rate and the degree of electrotonic modulation in the AVJ. Finally, we show that multilevel interactions between AF and VP can generate various patterns of ventricular rhythm that are consistent with previous experimental observations.
Action Potentials↗
Some hemodynamic problems studied by means of a circulatory analog computer model.
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Blood Circulation↗