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At least 1,711 records · Page 95Linked to original sources
PubMed2003

Computational modelling of the open-state Kv 1.5 ion channel block by bupivacaine.

Binding of R(+)-bupivacaine to open-state homology models of the mammalian K(v)1.5 membrane ion channel is studied using automated docking and molecular dynamics (MD) methods. Homology models of K(v)1.5 are built using the 3D structures of the KcsA and MthK channels as a template. The packing of transmembrane (TM) alpha-helices in the KcsA structure corresponds to a closed channel state. Opening of the channel may be reached by a conformational transition yielding a bent structure of the internal S6 helices. Our first model of the K(v) open state involves a PVP-type of bending hinge in the internal helices, while the second model corresponds to a Gly-type of bending hinge as found in the MthK channel. Ligand binding to these models is probed using the common local anaesthetic bupivacaine, where blocker binding from the intracellular side of the channel is considered. Conformational properties and partial atomic charges of bupivacaine are determined from quantum mechanical HF/6-31G* calculations with inclusion of solvent effects. The automated docking and MD calculations for the PVP-bend model predict that bupivacaine could bind either in the central cavity or in the PVP region of the channel pore. Linear interaction energy (LIE) estimates of the binding free energies for bupivacaine predict strongest binding to the PVP region. Surprisingly, no binding is predicted for the Gly-bend model. These results are discussed in light of electrophysiological data which show that the K(v)1.5 channel is unable to close when bupivacaine is bound.

Amino Acid Sequence↗
PubMed2004

Evaluation of the enantiomeric selectivity in the chiral ligand-exchange chromatography of amino acids by a computational model.

The chromatographic resolution of enantiomeric amino acids is accomplished on a reversed phase column using aqueous mobile phase containing the chiral reagent N,N-dimethyl-S-phenylalanine-Cu(II). The separation is a result of the whole interaction between the diastereomeric complex surface and the mixed stationary phase realized by the dynamic coating of the RP-18 carbon chains layer. The elution order seems to be related to the different water coordination capability on copper ion in the formation of the mixed ternary complexes.

Amino Acids↗
PubMed2005

Effects of an impedance threshold valve upon hemodynamics in Standard CPR: studies in a refined computational model.

UNLABELLED: An impedance threshold valve (ITV) is a new airway adjunct for resuscitation that permits generation of a small vacuum in the chest during the recoil phase of chest compression. OBJECTIVES: To explore in detail the expected magnitude and the hemodynamic mechanisms of circulatory augmentation by an ITV in Standard CPR. METHOD: A 14-compartment mathematical model of the human cardiopulmonary system--upgraded to include applied chest compression force, elastic recoil of the chest wall, anatomic details of the heart and lungs, and the biomechanics of mediastinal compression--is exercised to explore the conditions required for circulatory augmentation by an ITV during various modes of CPR. RESULTS: The ITV augments systemic perfusion pressure by about 5 mmHg compared to any particular baseline perfusion pressure without the ITV. When baseline perfusion is low, owing to either diminished chest compression force, the existence of a thoracic pump mechanism of blood flow, or the presence of an effective compression threshold, then the relative improvement produced by an ITV is significant. With an ITV the heart expands into soft pericardiac tissue, which makes the heart easier to compress. CONCLUSIONS: An ITV can augment perfusion during CPR. The observed effectiveness of ITVs in the laboratory and in the clinic suggests a thoracic pump mechanism for Standard CPR, and perhaps also an effective compression threshold that must be exceeded to generate blood flow by external chest compression.

Cardiopulmonary Resuscitation↗
PubMed2004

A computational model for the electrostatic sequestration of PI(4,5)P2 by membrane-adsorbed basic peptides.

The multivalent acidic phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) plays a key role in many biological processes. Recent studies show that unstructured clusters of basic residues from a number of peripheral proteins can laterally sequester PI(4,5)P2 in membranes. Specifically, experiments suggest that the basic effector domain of the myristoylated alanine-rich C kinase substrate (MARCKS), or a peptide corresponding to this domain, MARCKS(151-175), sequesters several PI(4,5)P2 and that this sequestration is due to nonspecific electrostatic interactions. Here, we use the finite difference Poisson-Boltzmann method to test this hypothesis by calculating the electrostatic free energy of lateral sequestration of PI(4,5)P2 by membrane-adsorbed basic peptides: Lys-7, Lys-13, and FA-MARCKS(151-175), a peptide based on MARCKS(151-175). In agreement with experiments, we find that the electrostatic free energy becomes more favorable when: 1), Lys-13 and FA-MARCKS(151-175) sequester several PI(4,5)P2; 2), the linear charge density of the basic peptide increases; 3), the mol percent monovalent acidic lipid in the membrane decreases; and 4), the ionic strength of the solution decreases. In addition, the electrostatic sequestration free energy is in excess of the entropic penalty associated with localizing PI(4,5)P2. Our calculations, thus, provide a structural and quantitative description of the observed interaction of PI(4,5)P2 with membrane-adsorbed basic sequences.

Algorithms↗
PubMed2000

Syntactic structure assembly in human parsing: a computational model based on competitive inhibition and a lexicalist grammar.

We present the design, implementation and simulation results of a psycholinguistic model of human syntactic processing that meets major empirical criteria. The parser operates in conjunction with a lexicalist grammar and is driven by syntactic information associated with heads of phrases. The dynamics of the model are based on competition by lateral inhibition ('competitive inhibition'). Input words activate lexical frames (i.e. elementary trees anchored to input words) in the mental lexicon, and a network of candidate 'unification links' is set up between frame nodes. These links represent tentative attachments that are graded rather than all-or-none. Candidate links that, due to grammatical or 'treehood' constraints, are incompatible, compete for inclusion in the final syntactic tree by sending each other inhibitory signals that reduce the competitor's attachment strength. The outcome of these local and simultaneous competitions is controlled by dynamic parameters, in particular by the Entry Activation and the Activation Decay rate of syntactic nodes, and by the Strength and Strength Build-up rate of Unification links. In case of a successful parse, a single syntactic tree is returned that covers the whole input string and consists of lexical frames connected by winning Unification links. Simulations are reported of a significant range of psycholinguistic parsing phenomena in both normal and aphasic speakers of English: (i) various effects of linguistic complexity (single versus double, center versus right-hand self-embeddings of relative clauses; the difference between relative clauses with subject and object extraction; the contrast between a complement clause embedded within a relative clause versus a relative clause embedded within a complement clause); (ii) effects of local and global ambiguity, and of word-class and syntactic ambiguity (including recency and length effects); (iii) certain difficulty-of-reanalysis effects (contrasts between local ambiguities that are easy to resolve versus ones that lead to serious garden-path effects); (iv) effects of agrammatism on parsing performance, in particular the performance of various groups of aphasic patients on several sentence types.

Humans↗
PubMed1998

Computational model of oscillatory airflow in a bronchial bifurcation.

Airflow distribution in the bronchial tree is an important factor that controls gas mixing in the lungs, especially, in diseased lungs or during high frequency ventilation. A nonlinear analog model has been developed to investigate the dependency of airflow distribution in asymmetric bronchial bifurcations on structural and physiological parameters. The system parameters (electrical analogs) are time-dependent and were extracted from laboratory studies of airway models and physiological measurements. The model was used to study flow distribution in peripheral pathways of normal and pathological airways during different modes of quiet breathing as well as high frequency ventilation. Model simulations revealed that (i) increasing of ventilation frequency or stroke volume increases the time and percentage of pendelluft in each cycle, (ii) diameter asymmetry between parallel pathways is more dominant than length asymmetry and enhances the degree of asynchronous ventilation to peripheral pathways, and (iii) asymmetry in the compliance of peripheral airways and lung parenchyma greatly increases the degree of asynchronous ventilation.

Airway Resistance↗
PubMed1997

Perceived location of bars and edges in one-dimensional images: computational models and human vision.

Observers used a cursor to mark the location and polarity of all the bar and edge features seen in compound (f + 3f) gratings of moderate frequency and contrast. They almost always reported six bars and six edges per cycle of the fundamental frequency (f = 0.4 c/deg, contrast 32%), for all phases of the third harmonic (3f = 1.2 c/deg, contrast 10.7%). This general pattern of features was predicted by the positions of peaks and troughs in the outputs of even and odd filters applied to the stimulus waveform, but not by peaks of "local energy" since there were only two energy peaks per cycle. We considered a family of filters whose amplitude spectrum has slope p on a log-log plot. The best-fitting filter slope was determined for bars (even filter) and edges (odd filter) in conjunction with a classification rule in which all peaks and troughs in the response profile are counted as features. If bars were seen at luminance peaks, and edges seen at gradient peaks (zero-crossings in the second derivative) we should have found p = 0 for bars and p = 1 for edges. In fact, for both bars and edges the best-fitting slope was about p = 0.5. For edges, this is consistent with the use of a smoothed (Gaussian) derivative operator. The filters form a quadrature pair, as in the energy model, but features are not constrained to lie at energy peaks. A compressive transducer preceding the filters improved the goodness-of-fit for predicted edge locations, but did not affect the estimate of filter slopes, nor the goodness-of-fit for bar locations. In an experiment with single blurred edges we confirmed that the perceived location of edges is shifted towards the darker side of the edge in direct proportion to the contrast of the edge. This was well predicted by adding a compressive transducer to the filter model.

Contrast Sensitivity↗
PubMed1997

The detection of structure in glass patterns: psychophysics and computational models.

Experiments are reported which examine the judgement of the mean orientation of textures composed either of short lines or dipoles (Glass patterns). The effects of element length, density, and orientation variation are described. Psychophysical data are compared with predictions from four schemes for extracting features from Glass patterns: token matching, isotropic filtering, oriented filtering, and "adaptive" filtering (selection of local peak output from multiply oriented filters). Glass patterns are spatially broadband but only contain orientation structure at a narrow range of scales making them suitable for examining how filter size is selected for texture processing. A criterion for scale selection is proposed: that local variation of feature orientation should be minimized. Simulations indicate that neither models using isotropic filtering nor token matching achieve human levels of performance on certain tasks. Adaptive filtering, operating at a scale selected using the criterion described, provides good agreement with the psychophysical data reported and is a practical scheme for deriving features using oriented filters.

Humans↗
PubMed1997

A computational model of the response of honey bee antennal lobe circuitry to odor mixtures: overshadowing, blocking and unblocking can arise from lateral inhibition.

Recent studies of learning about elements of odorant mixtures in honey bees identified several types of interactions between mixture components, such as overshadowing and blocking. The latter phenomenon in particular indicates at least a limited ability of subjects to identify the most salient element of a binary mixture. Here we show that the circuitry in the antennal lobes, the first neuropil in which synaptic interaction affects sensory processing, could give rise to both effects given the incorporation of modifiable synapses onto inhibitory circuitry. The neural model of the antennal lobe that we present incorporates identified cell types and includes a biologically realistic modulatory neuron with which modifiable Hebb-like synaptic interactions take place. A learning rule that incorporates modifiable connections from output (projection) neurons onto the modulatory neuron is sufficient to account for behavioral results on generalization and overshadowing. A second type of excitatory connection from the modulatory neuron onto local inhibitory interneurons is necessary to reproduce behavioral results from blocking and unblocking. We suggest that the neural representations of odor mixtures in the antennal lobe can be modified by previous exposure to one of the mixture components. These results provide testable hypotheses that will guide future behavioral and physiological analyses.

Algorithms↗
PubMedDate not supplied

Age vs Alzheimer's: a computational model of changes in representation.

Previous research has demonstrated that the language of older adults leads to denser representations in a high dimensional model of memory than does the language of younger adults (Conley & Burgess, in press), and thus that density in the model (HAL or the hyperspace analogue to language) may constitute a useful metric in comparing memory for younger and older adults. This paper extends the previous research by examining the role of density in semantic representations that emerged from the language generated by adults with Alzheimer' s and comparing the results with age-matched normal controls. We found that, just as older adults have denser representations in semantic space than do younger adults, adults with Alzheimer's have still denser representations than normal older adults. These results support the hypothesis that greater density, normally associated in the model with good semantic depth, may in fact reach a "saturation point" and affect retrieval in older adults and especially adults with Alzheimer's.

Age Factors↗
PubMed2003

Computational modeling of cerebral diffusion-application to stroke imaging.

Water diffusion within the structure of a brain extracellular space is analyzed numerically for various diffusion parameters of brain tissue namely extracellular space porosity and tortuosity. An algorithm for predicting diffusion pattern of water molecules within human brain considering the mechanics of water diffusion within porous media is developed. The extracellular space is modeled as a homogeneous porous medium with uniform porosity and permeability. Discretization of the fluid flow, heat transfer and mass transport equations is achieved using a finite element scheme based on the Galerkin method of weighted residuals. Concentration maps are developed in this study for various clinical conditions. The effect of the space porosity and the turtousity on the heat and mass transport within the extracellular space are found to be significant. The results presented in this work play an important role in producing more effective imaging techniques for brain injury based on the apparent diffusion coefficient.

Algorithms↗
PubMed2000

Anxiety-like behavior in rats: a computational model.

This work describes a neural network model of the rat exploratory behavior in the elevated plus-maze, a test used to study anxiety. It involves three parameters: drive to explore; drive to avoid aversive stimuli; and spontaneous locomotor activity. Each network unit corresponds to a specific location in the maze and the connections, only between closest neighbors, represent the possible adjacent places to which a virtual rat can navigate. Competitive learning is used to generate a sequence of network states that correspond to the virtual rat successive locations in the maze. To evaluate the generality of the model it was also tested for two modifications of the elevated plus-maze: one with totally closed arms and the other with totally open arms. The results are compared with data obtained with rats. The simulations are consistent with experimental evidence and may provide an efficient way of describing the anxiety-like rat behavior in the elevated plus-maze. This could be useful for researching the emotional parameters involved in this anxiety animal model.

Animals↗