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At least 1,027 records · Page 57Linked to original sources
PubMed2005

A computational model of the functional role of the ventral-striatal D2 receptor in the expression of previously acquired behaviors.

The functional role of dopamine has attracted a great deal of interest ever since it was empirically discovered that dopamine-blocking drugs could be used to treat psychosis. Specifically, the D2 receptor and its expression in the ventral striatum have emerged as pivotal in our understanding of the complex role of the neuromodulator in schizophrenia, reward, and motivation. Our departure from the ubiquitous temporal difference (TD) model of dopamine neuron firing allows us to account for a range of experimental evidence suggesting that ventral striatal dopamine D2 receptor manipulation selectively modulates motivated behavior for distal versus proximal outcomes. Whether an internal model or the TD approach (or a mixture) is better suited to a comprehensive exposition of tonic and phasic dopamine will have important implications for our understanding of reward, motivation, schizophrenia, and impulsivity. We also use the model to help unite some of the leading cognitive hypotheses of dopamine function under a computational umbrella. We have used the model ourselves to stimulate and focus new rounds of experimental research.

Animals↗
PubMedDate not supplied

A fully computational model for predicting percutaneous drug absorption.

The prediction of transdermal absorption for arbitrary penetrant structures has several important applications in the pharmaceutical industry. We propose a new data-driven, predictive model for skin permeability coefficients k(p) based on an ensemble model using k-nearest-neighbor models and ridge regression. The model was trained and validated with a newly assembled data set containing experimental data and structures for 110 compounds. On the basis of three purely computational descriptors (molecular weight, calculated octanol/water partition coefficient, and solvation free energy), we have developed a model allowing for the reliable, purely computational prediction of skin permeability coefficients. The model is both accurate and robust, as we showed in an extensive validation (correlation coefficient for leave-one-out cross validation: Q = 0.948, mean standard error: 0.2 for log k(p)).

Animals↗
PubMed2006

Cochlear pharmacokinetics with local inner ear drug delivery using a three-dimensional finite-element computer model.

HYPOTHESIS: Cochlear fluid pharmacokinetics can be better represented by three-dimensional (3D) finite-element simulations of drug dispersal. BACKGROUND: Local drug deliveries to the round window membrane are increasingly being used to treat inner ear disorders. Crucial to the development of safe therapies is knowledge of drug distribution in the inner ear with different delivery methods. Computer simulations allow application protocols and drug delivery systems to be evaluated, and may permit animal studies to be extrapolated to the larger cochlea of the human. METHODS: A finite-element 3D model of the cochlea was constructed based on geometric dimensions of the guinea pig cochlea. Drug propagation along and between compartments was described by passive diffusion. To demonstrate the potential value of the model, methylprednisolone distribution in the cochlea was calculated for two clinically relevant application protocols using pharmacokinetic parameters derived from a prior one-dimensional (1D) model. In addition, a simplified geometry was used to compare results from 3D with 1D simulations. RESULTS: For the simplified geometry, calculated concentration profiles with distance were in excellent agreement between the 1D and the 3D models. Different drug delivery strategies produce very different concentration time courses, peak concentrations and basal-apical concentration gradients of drug. In addition, 3D computations demonstrate the existence of substantial gradients across the scalae in the basal turn. CONCLUSION: The 3D model clearly shows the presence of drug gradients across the basal scalae of guinea pigs, demonstrating the necessity of a 3D approach to predict drug movements across and between scalae with larger cross-sectional areas, such as the human, with accuracy. This is the first model to incorporate the volume of the spiral ligament and to calculate diffusion through this structure. Further development of the 3D model will have to incorporate a more accurate geometry of the entire inner ear and incorporate more of the specific processes that contribute to drug removal from the inner ear fluids. Appropriate computer models may assist in both drug and drug delivery system design and can thus accelerate the development of a rationale-based local drug delivery to the inner ear and its successful establishment in clinical practice.

Animals↗
PubMed1991

Computer modelling of the NAD binding site of ADP-ribosylating toxins: active-site structure and mechanism of NAD binding.

Five ADP-ribosylating bacterial toxins, pertussis toxin, cholera toxin, diphtheria toxin, Escherichia LT toxin and Pseudomonas exotoxin A, show significant homology in selected segments of their sequence. Site-directed mutagenesis and chemical modification of residues within these regions cause loss of catalytic activity and of NAD binding. On the basis of these results and of molecular modelling based on the three-dimensional structure of exotoxin A, the geometry of an NAD binding site common to all the toxins is deduced and described in the paper. For diphtheria toxin, sequence similarity with exotoxin A is such that its preliminary structure can be computed by molecular modelling, whereas for the other toxins similarity appears to be restricted to the NAD binding site. Moreover, an analysis of molecular fitting of the NAD molecule into its binding cavity suggests a new model for the conformation of the bound NAD that better accounts for all available experimental information.

ADP Ribose Transferases↗
PubMed2000

A mechanistic account of the mirror effect for word frequency: a computational model of remember-know judgments in a continuous recognition paradigm.

A theoretical account of the mirror effect for word frequency and of dissociations in the pattern of responding Remember vs. Know (R vs. K) for low- and high-frequency words was tested both empirically and computationally by comparing predicted with observed data theory in 3 experiments. The SAC (Source of Activation Confusion) theory of memory makes the novel prediction of more K responses for high- than for low-frequency words, for both old and new items. Two experiments used a continuous presentation and judgment paradigm that presented words up to 10 times. The computer simulation closely modeled the pattern of results, fitting new Know and Remember patterns of responding at each level of experimental presentation and for both levels of word frequency for each participant. Experiment 3 required list discrimination after each R response (Group 1) or after an R or K response (Group 2). List accuracy was better following R responses. All experiments were modeled using the same parameter values.

Adult↗
PubMed2001

Dissecting the superoxide dismutase-ascorbate-glutathione-pathway in chloroplasts by metabolic modeling. Computer simulations as a step towards flux analysis.

The present study introduces metabolic modeling as a new tool to analyze the network of redox reactions composing the superoxide dismutase-ascorbate (Asc)-glutathione (GSH) cycle. Based on previously determined concentrations of antioxidants and defense enzymes in chloroplasts, kinetic properties of antioxidative enzymes, and nonenzymatic rate constants of antioxidants with reactive oxygen, models were constructed to simulate oxidative stress and calculate changes in concentrations and fluxes of oxidants and antioxidants. Simulated oxidative stress in chloroplasts did not result in a significant accumulation of O2*- and H2O2 when the supply with reductant was sufficient. Model results suggest that the coupling between Asc- and GSH-related redox systems was weak because monodehydroascorbate radical reductase prevented dehydroascorbate (DHA) formation efficiently. DHA reductase activity was dispensable. Glutathione reductase was mainly required for the recycling of GSH oxidized in nonenzymatic reactions. In the absence of monodehydroascorbate radical reductase and DHA reductase, glutathione reductase and GSH were capable to maintain the Asc pool more than 99% reduced. This suggests that measured DHA/Asc ratios do not reflect a redox balance related to the Asc-GSH-cycle. Decreases in Asc peroxidase resulted in marked H2O2 accumulation without significant effects on the redox balance of Asc/DHA or GSH/GSSG. Simulated loss of SOD resulted in higher H2O2 production rates, thereby affecting all subsequent steps of the Asc-GSH-cycle. In conclusion, modeling approaches contribute to the theoretical understanding of the functioning of antioxidant systems by pointing out questions that need to be validated and provide additional information that is useful to develop breeding strategies for higher stress resistance in plants.

Ascorbic Acid↗
PubMed1983

Computer modelling of ENT out-patients.

The behaviour of queues in ENT out-patients has been simulated by a computer program. This allowed various appointment systems to be studied and improved to allow a smooth flow of patients through the clinic, in such a way that the idle time of the clinic staff is reduced without increasing patient waiting times.

Appointments and Schedules↗
PubMed2004

Physical and computer modelling of blood flow in a systemic-to-pulmonary shunt.

UNLABELLED: The aim of this work was the application of computer and physical in vitro simulation methods for estimating surgery procedure hemodynamics. The modified Blalock-Taussig (mB-T) palliative surgical procedure is performed to increase the pulmonary blood flow in children with congenital heart defects. Such a systemic-to-pulmonary shunt yields substantial modification in the blood flow within the large blood vessels. The objective of the present study was to investigate basic characteristics of the flow, flow pattern and pressure-flow efficiency, before and after opening of the mB-T graft. METHODS: The model was based on the vessel geometry obtained from the Visible Human Project and included the arch of aorta, the three arteries branching from the arch, the pulmonary trunck, and the left and right pulmonary arteries. The graft was added between the left subclavian artery and the left pulmonary artery. The glass model of the vessels was produced and investigated in a physical model of the cardiovascular system with an artificial ventricular device as the blood pump. Flow rate and hydrostatic pressure were measured at the inlet to and outlets from the glass model and in a few points within the system. Laser flow visualization was also performed. Computer simulations were done using the boundary conditions from the physical model. RESULTS: The opening of the mB-T graft changed flow distribution in all branches (including inflow). A complex flow pattern with large eddies and channelling of the flow in the vicinity of the graft and within it was observed in flow visualization and in computer simulations. Because of that complexity the local measurements of hydrostatic pressure at the vessel wall could not predict the average flow rate. The reversed flow in the graft was observed during the systole. CONCLUSIONS: The complex flow pattern developed in the physical model of the mB-T graft. The channelling of the flow and the formation of large eddies may yield high shear stress and modify blood properties. The rigid wall model can describe only some flow characteristics observed in vivo. Computer simulation is a very fast and accurate method which permits earlier qualification of cardiac surgeons on how to change cardiac vascular blood flow after operations.

Arteriovenous Shunt, Surgical↗
PubMed2005

Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway.

The MAPK (mitogen-activated protein kinase) pathway is one of the most important and intensively studied signalling pathways. It is at the heart of a molecular-signalling network that governs the growth, proliferation, differentiation and survival of many, if not all, cell types. It is de-regulated in various diseases, ranging from cancer to immunological, inflammatory and degenerative syndromes, and thus represents an important drug target. Over recent years, the computational or mathematical modelling of biological systems has become increasingly valuable, and there is now a wide variety of mathematical models of the MAPK pathway which have led to some novel insights and predictions as to how this system functions. In the present review we give an overview of the processes involved in modelling a biological system using the popular approach of ordinary differential equations. Focusing on the MAPK pathway, we introduce the features and functions of the pathway itself before comparing the available models and describing what new biological insights they have led to.

Animals↗
PubMed2005

Bio-computational model of object-recognition: quantum Hebbian processing with neurally shaped Gabor wavelets.

Theoretical and simulational evidence, as well as experimental indications, are accumulating that quantum associative memory and imaging are possible. We compare these data with biological evidence, since we find them to a significant extent compatible. This paper presents a computationally implementable integrative model of appearance-based viewpoint-invariant recognition of objects. The neuro-quantum hybrid model incorporates neural processing up to V1 and quantum associative processing in V1, achieving together an object-recognition result in V2 and ITC. Results of our simulation of the central quantum-like parts of the bio-model, receiving neurally pre-processed inputs, are presented. This part contains our original simulated storage by multiple quantum interference of image-encoding Gabor wavelets done in a Hebbian way, especially using the Griniasty et al. pose-sequence learning rule.

Humans↗
PubMed2000

Studies on the structure-function relationship of the HNK-1 associated glucuronyltransferase, GlcAT-P, by computer modeling and site-directed mutagenesis.

All members of a glucuronyltransferase (GlcAT) gene family cloned to date contain four conserved regions (modules I-IV), which are widely located in the catalytic domain. In order to understand the biological significance of these modules, we investigated the structure-function relationship of GlcAT-P by means of the combination of site-directed mutagenesis and computer aided three-dimensional modeling. The wild-type and mutant GlcAT-Ps were expressed in Escherichia coli as glutathione-S-transferase (GST)-fused soluble proteins. Most of the mutants in which a polar amino acid within the modules was replaced with alanine lost their transferase activity almost completely, while all of the mutants in which the replacement was outside these modules retained the original catalytic activity. A three-dimensional (3-D) model of GlcAT-P was constructed by computer simulation with the three-dimensional structure of adenylate kinase (1AKE) as a template. This model predicted that the large catalytic domain of GlcAT-P forms a globular shape with a Rossmann-fold motif consisting of five alpha-helix and beta-sheet repeats. The putative catalytic pocket consisting mainly of modules I-III is surrounded by a cluster of polar amino acids, which are essential for the transferase activity and also for the binding to the acceptor substrate (essential amino acids), asialo-orosomucoid. There is the second cluster of essential amino acids almost on the opposite surface of the molecule, in which an aspartic acid repeat (DDD) is located. The biological significance of the second cluster is currently not clear but it may be associated with the interaction of the enzyme with modulation molecules, manganese and membrane phospholipids.

Amino Acid Sequence↗
PubMed2003

Computational model for neural representation of multiple disparities.

It has been known that the visual system can detect more than one disparity and/or motion direction at the same region in the image. These multiple (or transparent) surfaces can be perceived when, for example, we are looking scenes through a glass. However, many conventional models cannot deal with these multiple surfaces. The present paper investigates the neural encoding and decoding of multiple disparities with the binocular energy model, which is known as a biologically plausible model. Based on the analysis of the response of the energy model to multiple disparities, the present paper proposes a stereo model that can detect disparities of two overlapping surfaces.

Algorithms↗
PubMed2004

The effect of incorporating vessel compliance in a computational model of blood flow in a total cavopulmonary connection (TCPC) with caval centerline offset.

BACKGROUND: The total cavopulmonary connection (TCPC), a palliative correction for congenital defects of the right heart, is based on the corrective technique developed by Fontan and Baudet. Research into the TCPC has primarily focused on reducing power loss through the connection as a means to improve patient longevity and quality of life. The goal of our study is to investigate the efficacy of including a caval offset on the hemodynamics and, ultimately, power loss of a connection. As well, we will quantify the effect of vessel wall compliance on these factors and, in addition, the distribution of hepatic blood to the lungs. METHODS: We employed a computational fluid dynamic model of blood flow in the TCPC that includes both the non-Newtonian shear thinning characteristics of blood and the nonlinear compliance of vessel tissue. RESULTS: Power loss in the rigid-walled simulations decayed exponentially as caval offset increased. The compliant-walled results, however, showed that after an initial substantial decrease in power loss for offsets up to half the caval diameter, power loss increased slightly again. We also found only minimal mixing in both simulations of all offset models. CONCLUSIONS: The increase in power loss beyond an offset of half the caval diameter was due to an increase in the kinetic contribution. Reduced caval flow mixing, on the other hand, was due to the formation of a pressure head in the offset region which acts as a barrier to flow.

Blood Flow Velocity↗
PubMed1994

Coiled-coil stutter and link segments in keratin and other intermediate filament molecules: a computer modeling study.

Structural discontinuities have previously been identified in four regions of the coiled-coil rod domain structure present in intermediate filament (IF) protein molecules. These include a point at which a phase shift occurs in the heptad periodicity characteristic of the sequence of polar and apolar residues in alpha-helical coiled-coils, and three links that lack a heptad substructure. We have studied these regions by computer-based molecular modeling and comparative sequence analysis and conclude that the phasing discontinuity can be accommodated without significant distortion of the overall double-helical chain conformation; the L2 link has a similar conformation in all different types of IF molecules, a favorable conformation being one in which the two strands wrap tightly around each other; the L12 links vary in length between different IF types but contain important sequence similarities suggestive of a partial beta structure; the L1 links show larger variations in length, a lower degree of similarity, and probably diverse structures. Variations in the overall charges of the different links suggest that ionic interactions may play a significant role in filament assembly. The results also have general significance for other alpha-fibrous proteins in which either the characteristic heptad phasing undergoes a discontinuity or where a short non-coiled-coil sequence occurs within a coiled-coil rod domain structure.

Amino Acid Sequence↗
PubMed2004

Computer modelling of mixed metal fluorides for optical applications.

This paper describes a new computational method for predicting the optical behaviour of doped inorganic materials. There is considerable interest in using inorganic materials in photonic devices, and in many cases, the optical properties of these materials depend on doping by ions such as those from the rare earth series. Among the inorganic materials of interest are the mixed metal fluorides (e.g. BaLiF(3), BaY(2)F(8), YLiF(4), LiCaAlF(6), LiSrAlF(6)), doped with trivalent rare earth ions. The paper describes the use of Mott-Littleton calculations to determine the optimum location for dopant ions, followed by crystal field calculations which make direct use of the output of the Mott-Littleton calculations to calculate the optical properties of the dopant ion taking into account its symmetry and the positions of the surrounding ions, including any vacancies or interstitial ions present by virtue of charge compensation. It is then possible to predict whether a given dopant ion at a particular site in a material will have favourable optical properties.

Journal Article↗