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PubMed1995

A computer simulation of pulmonary perfusion in three dimensions.

Pulmonary perfusion is spatially correlated with neighboring regions of lung having similar magnitudes of flow and distant pieces exhibiting negative correlation. Although local correlation has been noted in a wide variety of natural processes, negative correlation has not and it may be unique to organ blood flow. We investigate the regional perfusion predicted by a three-dimensional branching vascular model to determine whether such a model can create negative correlation of perfusion. The distribution of flows is modeled by a dichotomously branching tree in which the fraction of flow from parent to daughter branches is gamma and 1-gamma at each bifurcation. The flow asymmetry parameter (gamma) is randomly chosen for each bifurcation from a normal distribution with a mean of 0.5 with an SD of sigma. The branches branch along one of three orthogonal directions to assure a space-filling structure. This model produces flow distributions similar to those observed in experimental animals, with perfusion being positively correlated locally and negatively correlated at distance. The model is refined by incorporating an effect of gravity, which redirects a fraction (delta), of the flow against gravity to the companion daughter branch in the gravitational direction. A flow bias in the "dorsal" direction is also introduced to account for differences in supine-prone perfusion gradients. In its final form, this three-dimensional branching model accounts for previously observed 1) spatial correlation of regional perfusion with negative correlation over distance, 2) isogravitational perfusion heterogeneity, 3) differences in supine and prone perfusion gradients, 4) positive correlation of flows between supine and prone postures, 5) relatively small contributions of gravity to perfusion heterogeneity, and 6) fractal distributions of flow. This three-dimensional branching vascular model relates the function and structure of the pulmonary vascular tree, offering an explanation for both heterogeneous and spatially correlated regional flows.

Animals↗

PubMed1988

Computer simulation of management strategies for Psorophora columbiae in the rice agroecosystem.

Various control strategies were evaluated using a previously-described and validated (Focks et al. 1988a, 1988b) simulation model (PcSim) of the population dynamics of Psorophora columbiae breeding in the rice agroecosystem. As expected from field experience, focally-applied ground or aerial ULV aerosols of insecticides were seen to provide local control of peak populations. Similar control was predicted for larvicides when also used in and around urban and suburban areas. Both of these measures were predicted by simulation to provide only short term control of adults as a result of immigration of adults from surrounding, untreated provide only short term control of adults as a result of immigration of adults from surrounding, untreated areas. Evaluations of the effectiveness of diapause egg control or the elimination of early spring broods to provide lasting, season-long suppression were not encouraging if only conventional methods such as insecticides or tillage were used. This was primarily because the ability of Ps. columbiae to recolonize treated areas during the course of a breeding season would require the treatment of prohibitively large, parish- (i.e., county-) sized areas. Evaluations of host management (either removal or residual insecticide treatment of cattle) in and around urban and suburban areas were more encouraging. This technique, by providing continuing pressure on populations, has the potential to offset the impact of immigration and thereby afford long-term suppression in local areas. Finally, evaluations of the impact of modifications to irrigation practices indicated that this approach warrants consideration as a supplemental control technique. These results suggest that field evaluations of model predictions would be useful. They emphasize the need to better understand the movement and spatial distribution of Ps. columbiae. These factors would bear directly on the cost and therefore, the practicality of several of the long-term suppression strategies evaluated as they determine the size of the treatment area surrounding population centers needed to offset the impact of immigration from surrounding, untreated areas.

Agriculture↗

PubMedDate not supplied

Parallel computing simulation of fluid flow in the unsaturated zone of Yucca Mountain, Nevada.

This paper presents the application of parallel computing techniques to large-scale modeling of fluid flow in the unsaturated zone (UZ) at Yucca Mountain, Nevada. In this study, parallel computing techniques, as implemented into the TOUGH2 code, are applied in large-scale numerical simulations on a distributed-memory parallel computer. The modeling study has been conducted using an over-1-million-cell three-dimensional numerical model, which incorporates a wide variety of field data for the highly heterogeneous fractured formation at Yucca Mountain. The objective of this study is to analyze the impact of various surface infiltration scenarios (under current and possible future climates) on flow through the UZ system, using various hydrogeological conceptual models with refined grids. The results indicate that the 1-million-cell models produce better resolution results and reveal some flow patterns that cannot be obtained using coarse-grid modeling models.

Environmental Monitoring↗

PubMed1995

Conformation and interactions of bombolitin I analogues with SDS micelles and phospholipid vesicles: CD, fluorescence, two-dimensional NMR and computer simulations.

Bombolitins are five structurally related heptadecapeptides acting at the membrane level able to lyse erythrocytes and liposomes and to enhance the activity of phospholipase A2 (PLA2). In the presence of SDS or phospholipid vesicles bombolitins are able to form amphiphilic alpha-helical structures and this property seems to be the major determinant of bioactivity. In order to test the model of interaction between bombolitin I and membranes, an analogue was synthesized in which all the lysines were replaced by arginines: Ile-Arg-Ile-Thr-Thr-Met-Leu-Ala-Arg-Ile-Gly-Arg-Val-Leu-Ala-His-Val-NH2 ([Arg2,9,12, Ile10]bombolitin I). The design of this sequence allowed the synthesis of a second analogue through a specific postsynthetic dansylation at the epsilon-amino group of a lysine residue replacing the original leucine residue at position 7. The first analogue was fully characterized by CD and two-dimensional nmr in the presence of SDS or phospholipid vesicles. The peptide folds into an amphiphilic alpha-helical conformation with the helical segment spanning the central part of the sequence from Ile3 to His16. This behavior is identical to that observed for the native sequence. The replacement of lysine residues by arginine has no detectable effect on the conformational preference of the peptide chain. By CD and fluorescence spectroscopy measurements, the fluorophore-containing analogue [Arg2,9,12, Lys7 (epsilon-dansyl)] bombolitin I also folded into the alpha-helical conformation in the presence of SDS micelles or phospholipid vesicles. In particular, the dansyl fluorophore, which is located approximately in the middle of the apolar surface of the amphiphilic helix, is clearly buried in a hydrophobic environment when the peptide is bound to phospholipid vesicles. These findings support the hypothesis that the peptide helices are oriented parallel to the vesicle surface.

Amino Acid Sequence↗

PubMed1987

Anomalous structure and properties of poly (dA).poly(dT). Computer simulation of the polynucleotide structure with the spine of hydration in the minor groove.

The results of the search for low-energy conformations of poly(dA).poly(dT) and of the poly(dA).poly(dT) "complex" with the spine of hydration similar to that found by Dickerson and co-workers (Kopka, M.L., Fratini, A.V., Drew, H.R. and Dickerson, R.E. (1983) J. Mol. Biol. 163, 129-146) in the minor groove of the CGCGAATTCGCG crystals are described. It is shown that the existence of such a spine in the minor groove of poly(dA).poly(dT) is energetically favourable. Moreover, the spine of hydration makes the polynucleotide conformation similar to the poly(dA).poly(dT) structure in fibers and to the conformation of the central part of CGCGAATTCGCG in crystals; it also acquires features characteristic of the structure of poly(dA).poly(dT) and DNA oligo(dA)-tracts in solution. It is shown that the existence of the TpA step in conformations characteristic of the poly(dA).poly(dT) complex with the spine of hydration is energetically unfavourable (in contrast to the ApT step) and therefore this step should result in destabilization of the spine of hydration in the DNA minor groove. Thus, it appears that the spine of hydration as described by Dickerson and co-workers is unlikely to exist in the poly d(A-T).poly d(A-T) structure. The data obtained permit us to interpret a large body of experimental facts concerning the unusual structure and properties of poly(dA).poly(dT) and oligo(dA)-tracts in DNA both in fibers and in solution. The results provide evidence of the existence of the minor groove spine of hydration both in fibers and in solution on A/T tracts of DNA which do not contain the TpA step. The spine plays an active role in the formation of the anomalous conformation of these tracts.

Base Sequence↗

PubMed2006

Computer simulation study of molecular recognition in model DNA microarrays.

DNA microarrays have been widely adopted by the scientific community for a variety of applications. To improve the performance of microarrays there is a need for a fundamental understanding of the interplay between the various factors that affect microarray sensitivity and specificity. We use lattice Monte Carlo simulations to study the thermodynamics and kinetics of hybridization of single-stranded target genes in solution with complementary probe DNA molecules immobilized on a microarray surface. The target molecules in our system contain 48 segments and the probes tethered on a hard surface contain 8-24 segments. The segments on the probe and target are distinct and each segment represents a sequence of nucleotides ( approximately 11 nucleotides). Each probe segment interacts exclusively with its unique complementary target segment with a single hybridization energy; all other interactions are zero. We examine how the probe length, temperature, or hybridization energy, and the stretch along the target that the probe segments complement, affect the extent of hybridization. For systems containing single probe and single target molecules, we observe that as the probe length increases, the probability of binding all probe segments to the target decreases, implying that the specificity decreases. We observe that probes 12-16 segments ( approximately 132-176 nucleotides) long gave the highest specificity and sensitivity. This agrees with the experimental results obtained by another research group, who found an optimal probe length of 150 nucleotides. As the hybridization energy increases, the longer probes are able to bind all their segments to the target, thus improving their specificity. The hybridization kinetics reveals that the segments at the ends of the probe are most likely to start the hybridization. The segments toward the center of the probe remain bound to the target for a longer time than the segments at the ends of the probe.

Computer Simulation↗

PubMed2002

Redrawing organ distribution boundaries: results of a computer-simulated analysis for liver transplantation.

For several years, the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) Liver and Intestinal Transplantation Committee has been examining effects of changes and proposed changes to the liver allocation system. The Institute of Medicine recently recommended that the size of liver distribution units be increased to improve the organ distribution system. Methods to achieve this and the potential impact on patients and transplant centers of such a change are evaluated in this study. In hypothetical scenarios, we combined geographically contiguous organ procurement organizations (OPOs) in seven different configurations to increase the size of liver distribution units to cover populations greater than 9 million persons. Using the UNOS Liver Allocation Model (ULAM), we examined the effect of 17 different organ allocation sequences in these proposed realignments and compared them with those predicted by ULAM for the current liver distribution system by using the following primary outcome variables: number of primary liver transplantations performed, total number of deaths, and total number of life-years saved. Every proposed new liver distribution unit plan resulted in fewer primary transplantations. Many policies increased the total number of deaths and reduced total life-years saved compared with the current system. Most of the proposed plans reduced interregional variation compared with the current plan, but no one plan consistently reduced variation for all outcome variables, and all reductions in variations were relatively small. All new liver distribution unit plans led to significant shifts in the number of transplantations performed in individual OPOs compared with the current system. The ULAM predicts that changing liver distribution units to larger geographic areas has little positive impact on overall results of liver transplantation in the United States compared with the current plan. Enlarging liver distribution units likely will result in significant shifts in organs across current OPO boundaries, which will have a significant impact on the activity of many transplant centers.

Computer Simulation↗

PubMed1994

Computer simulation of the lactational transfer of tetrachloroethylene in rats using a physiologically based model.

A physiologically based pharmacokinetic (PBPK) model describing transfer of inhaled tetrachloroethylene (PCE) into breast milk with the consequent exposure of the nursing pups was developed and validated in lactating rats. The PBPK model was based on partition coefficients (PCs), which were determined by the equilibration of tissues with known concentrations of PCE vapor. The blood/air and milk/blood PCs for the dam were 33.5 and 12.0, the liver/blood and fat/blood PCs for the dam were 1.9 and 42.4, and the slowly perfused tissues/blood and rapidly perfused tissues/blood PCs for the dam were 0.9 and 1.7, respectively. The blood/air PC for the pup was 24.3, and the solid tissues/blood PC for the pup was 4.5. Metabolic constants were determined by a gas uptake method. The pseudo-maximal velocity of PCE metabolism in the dam was low, 0.03 mg/kg/hr, and the apparent Michaelis-Menten constant was 0.3 mg/liter. The lactating Sprague-Dawley females were exposed to PCE vapor for 2 hr with concentrations ranging from 20 to 1000 ppm PCE. The dams were returned to the pups after exposure and the pups received PCE via breast milk while they nursed. PCE concentrations in the air, blood, milk, and tissues were determined by gas chromatography and compared to PBPK model predictions. Nursing resulted in a peak pup blood PCE concentration of 0.9 mg/liter and a peak pup solid tissue PCE concentration of 8 mg/kg. The PBPK lactation model adequately described the distribution of inhaled PCE in maternal blood and milk, as well as in the nursed pup's gastrointestinal tract, blood, and solid tissues. It is concluded that the predictions based on PBPK modeling for disposition of PCE in lactating rats and their pups were in good agreement with the experimental data.

Administration, Inhalation↗

PubMed1999

Role of active site residues in the glycosylase step of T4 endonuclease V. Computer simulation studies on ionization states.

T4 Endonuclease V (EndoV) is a base excision repair enzyme that removes thymine dimers (TD) from damaged DNA. To elucidate the role of the active site residues in catalysis, their pK(a)'s were evaluated using the semimicroscopic version of the protein dipoles-Langevin dipoles method (PDLD/S). Contributions of different effects to the pK(a) such as charge-charge interactions, conformational rearrangement, protein relaxation, and DNA binding were analyzed in detail. Charging of the active site residues was found to be less favorable in the complex than in the free enzyme. The pK(a) of the N-terminus decreased from 8.01 in the free enzyme to 6.52 in the complex, while the pK(a) of Glu-23 increased from 1. 52 to 7.82, which indicates that the key residues are neutral in the reactant state of the glycosylase step. These pK(a)'s are in agreement with the optimal pH range of the reaction and support the N-terminus acting as a nucleophile. The Glu-23 in its protonated form is hydrogen bonded to O4' of the sugar of 5' TD and can play a role in increasing the positive charge of C1' and, hence, accelerating the nucleophilic substitution. Furthermore, the neutral Glu-23 is a likely candidate to protonate O4' to induce ring opening required to complete the glycosylase step of EndoV. The positively charged Arg-22 and Arg-26 provide an electrostatically favorable environment for the leaving base. To distinguish between S(N)1 and S(N)2 mechanisms of the glycosylase step the energetics of protonating O2 of 5' TD was calculated. The enzyme was found to stabilize the neutral thymine by approximately 3.6 kcal/mol, whereas it destabilizes the protonated thymine by approximately 6.6 kcal/mol with respect to an aqueous environment. Consequently, the formation of a protonated thymine intermediate is unlikely, indicating an S(N)2 reaction mechanism for the glycosylase step.

Bacteriophage T4↗

PubMed1995

Computer simulation of local blood flow and vessel mechanics in a compliant carotid artery bifurcation model.

To investigate the effect of the distensible artery wall on the local flow field and to determine the mechanical stresses in the artery wall, a numerical model for the blood flow in the human carotid artery bifurcation has been developed. The wall displacement and stress analysis use geometrically non-linear shell theory where incrementally linearly elastic wall behavior is assumed. The flow analysis applies the time-dependent, three-dimensional, incompressible Navier-Stokes equations for non-Newtonian inelastic fluids. In an iteratively coupled approach the equations of the fluid motion and the transient shell equations are numerically solved using the finite element method. The study shows the occurring characteristics in carotid artery bifurcation flow, such as strongly skewed axial velocity in the carotid sinus with high velocity gradients at the internal divider wall and with flow separation at the outer common-internal carotid wall and at the bifurcation side wall. Flow separation results in locally low oscillating wall shear stress. Further strong secondary motion in the sinus is found. The comparison of the results for a rigid and a distensible wall model demonstrates quantitative influence of the vessel wall motion. With respect to the quantities of main interest, it can be seen, that flow separation and recirculation slightly decrease in the sinus and somewhat increase in the bifurcation side region, and the wall shear stress magnitude decreases by 25% in the distensible model. The global structure of the flow and stress patterns remains unchanged. The deformation analysis shows that the tangential displacements are generally lower by one order of magnitude than the normal directed displacements. The maximum deformation is about 16% of the vessel radius and occurs at the side wall region of the intersection of the two branches. The analysis of the maximum principal stresses at the inner vessel surface shows a complicated stress field with locally high gradients and indicates a stress concentration factor of 6.3 in the apex region.

Algorithms↗

PubMed2006

Insights into the effect of combustion-generated carbon nanoparticles on biological membranes: a computer simulation study.

Classical molecular dynamics simulations of atomistic models of combustion-generated carbon nanoparticles and lipid bilayers have been performed to explore their possible structural, dynamical, and thermodynamic effects on biological membranes. The DREIDING generic force field is used for the carbonaceous nanoparticles of different morphologies, as produced from combustion sources, and the united atom model was employed for the dimyristoylphosphatidylcholine (DMPC) bilayer. It is observed that particle shape and structure have significant effects on solvation, mobility, adsorption, and permeation behavior of the particles. While combustion-generated carbon nanoparticles with an aspect ratio close to unity prefer to stay near the membrane center, precursors with other shapes mostly reside within the hydrocarbon tail region of the membrane. Carbon nanoparticles are not trapped in a local region even inside the membranes but move freely with a speed depending on their molecular weight. The adsorption of the particles on the surface of the biological membrane is comparable to thermal fluctuations because the weak segregation effect by water molecules is the main driving force to the adsorption behavior. The bigger the precursors are, the stronger they are bound to the membrane surface. The presence of combustion-generated nanoparticles inside the membrane perturbs local lipid density by pushing the neighboring lipid molecules away from the nanoparticles. This, coupled with thermal fluctuations, can induce an instantaneous membrane pore to allow water protrusion. From the umbrella sampling method, the potential of mean force for the permeation of carbona nanoparticles into the bilayer was also obtained. Surprisingly, elongated particles have a free energy barrier an order of magnitude smaller compared with more round ones. In addition, the round carbon nanoparticles showed strong hysteresis due to the local trapping of water molecules. Although the carbon soot precursors studied in this work are not the well-known carbon nanoparticles such as fullerenes or carbon nanotubes, the qualitative features of this study may be applicable to them as well.

Carbon↗

PubMed2005

Computer simulation of macroion layering in a wedge film.

The layering of macroions confined to a wedge slit formed by two uncharged hard walls is studied using a canonical Monte Carlo method combined with a simulation cell that contains both wedge-shaped slit and bath regions. The macroion solution is modeled within a one-component fluid approach that in an effective way incorporates the double layer repulsion due to simple electrolyte ions as well as the discrete nature of an aqueous solvent. The layer formation under a wedge confinement is analyzed by carrying out separate simulation runs for a set of consecutive wedge segments designed to represent a single wedge slit. As the wedge thickness progressively increases, the sequence of regions along the wedge film with distinct features of macroion layering has been established. This sequence comprises (i) a wedge region of the thickness smaller than the macroion diameter that is free of macroions; (ii) a region with a one-dimensional macroion chain along the wedge corner at a wedge thickness of a one macroion diameter; (iii) a region comprising a low-ordered macroion monolayer that extends until the wedge thickness slightly above two macroion diameters; (iv) a region comprising a pair of well-defined two-dimensional configurations of macroions segregated on each of the wedge walls; and (v) a free-of-macroions wedge region between two surface monolayers that now originates from an electrostatic repulsion imposed by the surface macroions, which is followed by (vi) a well-defined macroion monolayer film between two surface monolayers, a less defined bilayer film, a three-layer film, and so on up to the bulk solution. Once formed, the macroion surface monolayers persist for all remaining wedge thicknesses up to the bulk, forming in such a way effective charged wedge boundaries. Such a formation of the macroion surface monolayers on the uncharged confining walls is related to the haloing mechanism for regulating the stability in colloidal suspensions [Tohver et al. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 8951] and is discussed as well. Finally, the estimated boundary of the free of macroion region between surface monolayers correlates well with the location of the boundary of the so-called "vacuum" phase that has been observed experimentally in an aqueous suspension of charged polystyrene spheres bounded by electrostatically repulsive glass walls [Pieransky et al. Phys. Rev. Lett. 1983, 50, 900].

Adsorption↗

PubMed1993

A computer simulation of free-volume distributions and related structural properties in a model lipid bilayer.

A novel combined approach of molecular dynamics (MD) and Monte Carlo simulations is developed to calculate various free-volume distributions as a function of position in a lipid bilayer membrane at 323 K. The model bilayer consists of 2 x 100 chain molecules with each chain molecule having 15 carbon segments and one head group and subject to forces restricting bond stretching, bending, and torsional motions. At a surface density of 30 A2/chain molecule, the probability density of finding effective free volume available to spherical permeants displays a distribution with two exponential components. Both pre-exponential factors, p1 and p2, remain roughly constant in the highly ordered chain region with average values of 0.012 and 0.00039 A-3, respectively, and increase to 0.049 and 0.0067 A-3 at the mid-plane. The first characteristic cavity size V1 is only weakly dependent on position in the bilayer interior with an average value of 3.4 A3, while the second characteristic cavity size V2 varies more dramatically from a plateau value of 12.9 A3 in the highly ordered chain region to 9.0 A3 in the center of the bilayer. The mean cavity shape is described in terms of a probability distribution for the angle at which the test permeant is in contact with one of and does not overlap with anyone of the chain segments in the bilayer. The results show that (a) free volume is elongated in the highly ordered chain region with its long axis normal to the bilayer interface approaching spherical symmetry in the center of the bilayer and (b) small free volume is more elongated than large free volume. The order and conformational structures relevant to the free-volume distributions are also examined. It is found that both overall and internal motions have comparable contributions to local disorder and couple strongly with each other, and the occurrence of kink defects has higher probability than predicted from an independent-transition model.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed2005

Computer simulation studies of microcrystalline cellulose Ibeta.

Molecular mechanics (MM) simulations have been used to model two small crystals of cellulose Ibeta surrounded by water. These small crystals contained six different extended surfaces: (110), (11 0), two types of (100), and two types of (010). Significant changes took place in the crystal structures. In both crystals there was an expansion of the unit cell, and a change in the gamma angle to almost orthogonal. Both microcrystals developed a right-hand twist of about 1.5 degrees per cellobiose unit, similar to the twisting of beta-sheets in proteins. In addition, in every other layer, made up of the unit cell center chains, a tilt of the sugar rings of 14.8 degrees developed relative to the crystal plane as a result of a transition of the primary alcohol groups in these layers away from the starting TG conformation to GG. In this conformation, these groups made interlayer hydrogen bonds to the origin chains above and below. No change in the primary alcohol conformations or hydrogen-bonding patterns in the origin chain layers was observed. Strong localization of the adjacent water was found for molecules in the first hydration layer of the surfaces, due to both hydrogen bonding to the hydroxyl groups of the sugar molecules and also due to hydrophobic hydration of the extensive regions of nonpolar surface resulting from the axial aliphatic hydrogen atoms of the 'tops' of the glucose monomers. Significant structuring of the water was found to extend far out into the solution. It is hypothesized that the structured layers of water might present a barrier to the approach of cellulase enzymes toward the cellulose surfaces in enzyme-catalyzed hydrolysis, and might inhibit the escape of soluble products, contributing to the slow rates of hydrolysis observed experimentally. Since the water structuring is different for the different surfaces, this might result in slower hydrolysis rates for some surfaces compared to others.

Carbohydrate Conformation↗

PubMed1992

Computer simulation of carbachol-driven rhythmic population oscillations in the CA3 region of the in vitro rat hippocampus.

1. We used simulations of the in vitro CA3 region of the hippocampus to analyse the 5 Hz population oscillations recorded experimentally in carbachol. 2. A simulation model of the in vitro CA3 region was constructed with 1000 pyramidal neurones and 200 inhibitory neurones (100 producing fast inhibitory postsynaptic potentials (IPSPs) and 100 producing slow IPSPs of delayed onset). Each neurone contained nineteen soma-dendritic compartments. Pyramidal neurones contained six voltage- and/or calcium-dependent ionic currents, whose kinetics were consistent with voltage-clamp data. The connectivity and waveform of unitary synaptic events for excitatory and fast inhibitory synapses were consistent with dual intracellular recordings. This network was shown to generate previously described network oscillations, including synchronized bursts recorded in the presence of GABAA blockers, and synchronized synaptic potentials observed during partial blockade of GABAA inhibition. 3. The model generated 5 Hz oscillations as recorded in carbachol under the following conditions: (a) excitatory synaptic conductance was within a limited range; (b) there was blockade of fast and slow IPSPs (consistent with the experimental lack of effect of bicuculline and phaclofen on carbachol oscillations and the known depression of IPSPs by acetylcholine); (c) the after hyperpolarization (AHP) conductance was reduced (consistent with the known pharmacology of carbachol); (d) the apical dendrites of the pyramidal cells were depolarized, as suggested by the carbachol-induced depolarization of pyramidal neurones. Each oscillation was associated in pyramidal cells with a burst of action potentials riding on a depolarizing wave. The N-methyl-D-aspartate (NMDA) type of excitatory synapse was not necessary for the oscillations to occur. 4. Progressive reduction of excitatory synaptic strength led to an oscillation of the same frequency, with bursts riding on smaller EPSPs (consistent with the experiment). Further reduction of excitatory synaptic strength abolished the population oscillation by uncoupling the neurones. When excitatory synaptic conductance was too large, population oscillations were attenuated as the cells switched from a bursting mode to a repetitively firing mode. 5. Increasing the AHP conductance prolonged the interburst interval as expected. Inclusion of slow IPSPs exerted a similar effect. 6. When fast IPSPs were included, an oscillation with different characteristics emerged: a 10 Hz oscillation that was gated by compound GABAA IPSPs. On any oscillatory wave, few pyramidal neurones fired, and the firing of individual neurones was irregular.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Reconstruction of hippocampal CA1 pyramidal cell electrophysiology by computer simulation.

1. We have developed a 16-compartment model that reproduces most of the features of the CA1 pyramidal cell electrophysiology observed experimentally. The model was constructed using seven active ionic conductances: gNa, gCa, gDR, gCT, gA, gM, and gAHP whose kinetics have been, inferred, in most cases, from the available voltage-clamp data obtained from these cells. We focussed the simulation on the initial and late accommodation, the slow depolarization potential and the spike broadening during repetitive firing, because their mechanisms are not well understood. 2. Current-clamp records were reproduced by iterative adjustments to the ionic maximum conductances, scaling and/or "reshaping" of the gates' time constant within the experimental voltage-clamp data, and shifting the position of the steady-state gate opening. The final properties of the ionic channels were not significantly different from the voltage-clamp experiments. 3. The resulting model reproduces all four after-potentials that have been recorded to follow activation of the cell. The fast, medium, and slow after-hyperpolarization potentials (AHPs) were, respectively, generated by ICT, IM, and IAHP. Furthermore, the model suggests that the mechanisms underlying the depolarization after potential (DAP) is mostly due to passive recharging of the soma by the dendrites. 4. The model also reproduces most of the firing features experimentally observed during injection of long current pulses. Model responses showed a small initial decrease in the firing frequency during a slow underlying depolarization potential, followed by a more significant frequency decrease. Moreover, a gradual broadening of the action potential and loss of the fast AHP were also observed during the initial high-frequency firing, followed, as the firing frequency decreased, by a gradual recovery of the spikes' original width and fast AHP amplitude increase. 5. A large reduction of the K repolarizing current was required to reproduce the spike broadening and reduction of the fast AHP experimentally observed in CA1 cells during repetitive firing responses. The incorporation of a transient Ca- and voltage-dependent K current (ICT) into the model successfully reproduced these experimental observations. In contrast, we were unable to reproduce this phenomenon when a large persistent Ca- and voltage-dependent K current (generally named IC) was included in the model. These results suggest that there is a strong contribution to action-potential repolarization and fast AHP by a transient Ca- and voltage-dependent K current (ICT). 6. The two accommodation steps were induced by a progressively enlargement of two K currents IM (initial) and IAHP (late).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1996

Computer simulation of factors involved in the down-regulation of hormonal effects.

Down-regulation of hormonal effects is in the presented simulation related to the number of functional receptors and quantity of available hormonal stimulation. The former is in the model substituted with the quantity of stimulation able to produce a full down-regulation (Hs100) of target cells. The halftime (t1/2) of the hormonal effect recovery means the interval before the second hormonal stimulation can elicit half of the initial hormonal effect. Recovered hormonal effects are calculated after periods of two, three, four and five t1/2. The interval among hormonal stimulations varied from 1/2 to 5/2 of t1/2. Shorter than t1/2 intervals showed profound down-regulation even at weak hormonal stimulations (> 20% of Hs100). Stable levels of hormonal effects after frequent hormonal stimulations are found only in cases of very weak stimulations (< 10% of Hs100). Intervals equalling t1/2 among weak stimulations (< 20% Hs100) produced stable hormonal effects. Further prolongation among repeated stimulations improved stability of hormonal effects and even strong stimulations (> 60% of Hs100) were followed with only temporary profound down-regulation. Hormone-binding receptors unable to activate target cells are in the model described as defective. Probability for the target cell to be stimulated is in the model defined as P. Relative quantity of hormonal stimulation per target cell needed to achieve certain P is calculated for cells bearing different proportions of defective receptors. Activation following weak hormone stimulations is highly probable (> 90%) for cells bearing less than 30% of defective receptors. With the proportion of defective receptors over 60%, the activation probability after weak hormone stimulations is reduced (< 66%). Down-regulation can be considered as a modulator of hormonal effects. In prediabetic patients, intense stimulation of pancreatic insulin secretion by frequent or increased ingestion of carbohydrates might lead to sustained hyperinsulinemia. A substantial portion of the target tissue would become down-regulated with increased number of defective insulin receptors. Poor glucose utilization in the down-regulated tissue with resultant hyperglycemia would further stimulate insulin secretion until failure. Reduced tissue transportability of large hormone molecules, such as hGH, or proinsulin, can make their effects more pronounced in the perivascular space. Circulating hormone binding proteins or the basal membrane thickening in small vessels can further decrease the hormonal effects on more remote cells. Physical activity in IDDM patients increases insulin effect. Possible explanation is that increased muscle perfusion is making more insulin available to the less down-regulated skeletal muscle cells.

Computer Simulation↗

PubMed1996

Computer simulation of cerebrovascular circulation: assessment of intracranial hemodynamics during induction of anesthesia.

OBJECTIVE: The purpose of this project was to develop a computer model of cerebrovascular hemodynamics interacting with a pharmacokinetic drug model to examine the effects of various stimuli on cerebral blood flow and intracranial pressure during anesthesia. METHODS: The mathematical model of intracranial hemodynamics is a seven-compartment, constant-volume system. A series of resistance relate blood and cerebrospinal fluid fluxes to pressure gradients between compartments. Arterial, venous, and tissue compliance are also included. Autoregulation is modeled by transmural pressure-dependent, arterial-arteriolar resistance. The effect of a drug (thiopental) on cerebrovascular circulation was simulated by a variable arteriolar-capillary resistance. Thiopental concentration was predicted by a three-compartment, pharmacokinetic model. The effect site compartment was included to account for a disequilibrium between drug plasma and biophase concentrations. The model was validated by comparing simulation results with available experimental observations. The simulation program is written in VisSim dynamic simulation language for an IBM-compatible PC. RESULTS: The model developed was used to calculate the cerebral blood flow and intracranial pressure changes that occur during the induction phase of general anesthesia. Responses to laryngoscopy and intubation were predicted for simulated patients with elevated intracranial pressure and non-autoregulated cerebral circulation. Simulation shows that the induction dose of thiopental reduces intracranial pressure up to 15%. The duration of this effect is limited to less than 3 minutes by rapid redistribution of thiopental and cerebral autoregulation. Subsequent laryngoscopy causes acute intracranial hypertension, exceeding the initial intracranial pressure. Further simulation predicts that this untoward effect can be minimized by an additional dose of thiopental administered immediately prior to intubation. CONCLUSION: The presented simulation allows comparison of various drug administration schedules to control intracranial pressure and preserve cerebral blood flow during induction of anesthesia. The model developed can be extended to analyze more complex intraoperative events by adding new submodels.

Anesthesia, General↗