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PubMed2003

A computational model for the identification of biochemical pathways in the krebs cycle.

We have applied an algorithmic methodology which provably decomposes any complex network into a complete family of principal subcircuits to study the minimal circuits that describe the Krebs cycle. Every operational behavior that the network is capable of exhibiting can be represented by some combination of these principal subcircuits and this computational decomposition is linearly efficient. We have developed a computational model that can be applied to biochemical reaction systems which accurately renders pathways of such reactions via directed hypergraphs (Petri nets). We have applied the model to the citric acid cycle (Krebs cycle). The Krebs cycle, which oxidizes the acetyl group of acetyl CoA to CO(2) and reduces NAD and FAD to NADH and FADH(2), is a complex interacting set of nine subreaction networks. The Krebs cycle was selected because of its familiarity to the biological community and because it exhibits enough complexity to be interesting in order to introduce this novel analytic approach. This study validates the algorithmic methodology for the identification of significant biochemical signaling subcircuits, based solely upon the mathematical model and not upon prior biological knowledge. The utility of the algebraic-combinatorial model for identifying the complete set of biochemical subcircuits as a data set is demonstrated for this important metabolic process.

Algorithms↗

PubMed2005

A computational model for color naming and describing color composition of images.

The extraction of high-level color descriptors is an increasingly important problem, as these descriptions often provide links to image content. When combined with image segmentation, color naming can be used to select objects by color, describe the appearance of the image, and generate semantic annotations. This paper presents a computational model for color categorization and naming and extraction of color composition. In this paper, we start from the National Bureau of Standards' recommendation for color names, and through subjective experiments, we develop our color vocabulary and syntax. To assign a color name from the vocabulary to an arbitrary input color, we then design a perceptually based color-naming metric. The proposed algorithm follows relevant neurophysiological findings and studies on human color categorization. Finally, we extend the algorithm and develop a scheme for extracting the color composition of a complex image. According to our results, the proposed method identifies known color regions in different color spaces accurately, the color names assigned to randomly selected colors agree with human judgments, and the description of the color composition of complex scenes is consistent with human observations.

Algorithms↗

PubMed1975

A computer model and a mechanical model of the circulation and their use in the evaluation of indices of myocardial blood flow.

Computer and mechanical models of the circulation have been made to study isotopic techniques of determining indices of myocardial blood flow. Parameters in the program and dimensions in the mechanical model have been scaled to represent the human circulation. Single rapid injections of 131I labelled human serum albumen were given into the venous line of the mechanical model and records obtained from collimated scintillation detectors positioned over the heart, lung and brain. Similar injections and recordings were simulated in the computer model. Two indices of myocardial flow have been studied. The first, described by Mena et al. is the ratio of the half time of the downslope of the left ventricular curve to the half time of the downslope of the brain curve. This index distinguished myocardial flows of 0,5% and 10% of total cardiac output but was also affected by changes in cerebral flow. A new index is proposed in which the half time of the left ventricular curve downslope is related to the half time of the downslope of the lung curve. This index can distinguish myocardial flows of 0,5% and 10% total flow but is not affected by changes in cerebral flow.

Blood Circulation↗

PubMed2002

Computer model creates a 'virtual world' for forecasting costs, outcomes.

New model creates a 'virtual world' for forecasting costs and outcomes. While predictive modeling programs are garnering most of the attention these days in the health care forecasting arena, pioneers at Kaiser Permanente have created quite a buzz with a new computer model which may be able to promise even richer information that can be tailored to specific populations. See how the model, dubbed "Archimedes," is already beginning to tackle many of the complex questions regarding chronic disease management.

Chronic Disease↗

PubMed2006

Computer modeling of secondary fiber development and growth: I. Nonprimate lenses.

PURPOSE: The purpose of this study was to use qualitative and quantitative structural data from nonprimate lenses with branched (Y and line) sutures to generate computer models (animations) of secondary fiber development and suture formation. METHODS: A minimum of 12-18 adult lenses/species (mice, cows, frogs, and rabbits) were used in this study. Lenses were analyzed by light (LM), transmission (TEM), and scanning electron microscopy (SEM). Fiber width, thickness, and length were ascertained from micrographs and by using formulations to calculate distances between degrees of latitude and longitude on asymmetrical oblate spheroids. This information was then used to create scale computer assisted drawings (CADs) of fibers at different stages of their development. The CADs were then placed on a timeline and animated to produce dynamic representations of secondary fiber development and growth. RESULTS: Animating secondary fiber development and suture formation with the inclusion of quantifiable differences in fiber dimensions at progressive stages of their differentiation revealed the following: first, there is the presumption that fibers migrate, rotate, and elongate until they reach their sutural destinations is not likely to be correct. When developing fibers reach approximately 60-65% of their eventual total length, their migration and rotation is complete. The remaining fiber elongation (the production of end segments) occurs without either concomitant cellular migration or rotation. Second, it is presumed that suture branches originate peripherally and are then constructed sequentially until all of the branches come to confluence at the poles is also not likely to be correct. While suture branches do originate peripherally, if the rate of elongation is constant in the anterior and posterior directions (intrafiber elongation speed) and between developing fibers within a forming growth shell (interfiber elongation speed), then only a part of their construction proceeds sequentially toward the poles. A second suture branch origin will be established at the poles resulting in a short distal portion of suture branches being formed sequentially in the reverse direction. Suture formation will conclude when a long proximal and a short distal portion of branches come to confluence within unequal anterior and posterior polar cap regions. This segmented suture formation scheme will be more pronounced in line suture lenses than in Y suture lenses. Third, because lenses with branched sutures have growth shells consisting of fibers of unequal length, fiber maturation is likely to be initiated in these lenses before a growth shell as well as suture formation is completed and would proceed in distinct patterns over a period of time. This is in marked contrast to avian lens fiber maturation which does not begin until growth shell and suture (branchless umbilical) formation is completed and then occurs rapidly and essentially simultaneously across the entire growth shell. CONCLUSIONS: Animations of secondary fiber development and suture formation based on quantitative analysis of electron micrographs reveals important novel aspects of these processes that have not been apparent from the results of previous mechanistic studies. The more complex schemes of fiber differentiation and suture formation presented herein are consistent with the notion that lens function (dynamic focusing) is interdependent on lens structure and physiology. The animations confirm that while all vertebrate lenses have a similar structure, differences in the level of their structural complexity established early in development and maintained throughout life can account for the varying amount of optical quality known to exist between species.

Animals↗

PubMed2006

A computational model to link psychophysics and cortical cell activation patterns in human texture processing.

The human visual system uses texture information to automatically, or pre-attentively, segregate parts of the visual scene. We investigate the neural substrate underlying human texture processing using a computational model that consists of a hierarchy of bi-directionally linked model areas. The model builds upon two key hypotheses, namely that (i) texture segregation is based on boundary detection--rather than clustering of homogeneous items--and (ii) texture boundaries are detected mainly on the basis of a large scenic context that is analyzed by higher cortical areas within the ventral visual pathway, such as area V4. Here, we focus on the interpretation of key results from psychophysical studies on human texture segmentation. In psychophysical studies, texture patterns were varied along several feature dimensions to systematically characterize human performance. We use simulations to demonstrate that the activation patterns of our model directly correlate with the psychophysical results. This allows us to identify the putative neural mechanisms and cortical key areas which underlie human behavior. In particular, we investigate (i) the effects of varying texture density on target saliency, and the impact of (ii) element alignment and (iii) orientation noise on the detectability of a pop-out bar. As a result, we demonstrate that the dependency of target saliency on texture density is linked to a putative receptive field organization of orientation-selective neurons in V4. The effect of texture element alignment is related to grouping mechanisms in early visual areas. Finally, the modulation of cell activity by feedback activation from higher model areas, interacting with mechanisms of intra-areal center-surround competition, is shown to result in the specific suppression of noise-related cell activities and to improve the overall model capabilities in texture segmentation. In particular, feedback interaction is crucial to raise the model performance to the level of human observers.

Action Potentials↗

PubMed1991

X-ray and computer modeling studies on gellan-related polymers: molecular structures of welan, S-657, and rhamsan.

The primary structures of the four bacterial polysaccharides gellan, welan, S-657, and rhamsan are the same with respect to their backbones, but have different side-chains. This difference has a profound influence on their behavior in aqueous media. Solutions of gellan gum form stable aqueous gels under appropriate ionic conditions. By contrast, welan, S-657, and rhamsan do not gel but give very viscous solutions over a wide range of thermal, pH, and salt conditions. X-Ray fiber diffraction analysis and computer modeling of these branched polysaccharides demonstrate that they all have the same half-staggered, double-helical conformations as in the unbranched gellan, suggesting, therefore, that the side chains are responsible for diminishing gelling behavior. Depending on the size and location, the side chains shield the carboxylate groups to varying degrees; this shielding is substantial in welan and S-657, but less in rhamsan. In all cases, side-chain-main-chain interactions within the double helix prevent the carboxylate-mediated aggregation of double helices that is necessary for the gelation.

Carbohydrate Conformation↗

PubMed1984

NMR and computer modeling studies of the conformations of glutathione derivatives at the active site of glyoxalase I.

The conformations of four derivatives of glutathione bound at the active site of the metalloenzyme glyoxalase I have been determined by NMR measurements and by computer model building using a distance geometry approach. Paramagnetic effects of Mn2+-glyoxalase I on the longitudinal relaxation rates of the carbon-bound protons of the substrate analog S-(acetonyl)-glutathione at three frequencies, the hydrophobic competitive inhibitor S-(propyl)glutathione at four frequencies, and the charged competitive inhibitor S-(carboxymethyl)glutathione at a single frequency were used to calculate Mn2+ to proton distances in each complex. These and previously determined distances from Mn2+ to the protons and 13C-enriched carbon atoms of the product S-(D-lactoyl)glutathione were used in a distance geometry program to compute the conformations of each enzyme-bound derivative which best fit the measured distances and other known constraints such as bond lengths, van der Waals radii, planar and trans-peptide bonds, and thioester linkages. The distance geometry program also provided a measure of the uniqueness of the conformations consistent with the experimental data. Extended Y-shaped conformations were detected for each of the bound glutathione derivatives, similar to the x-ray structure and the theoretically calculated conformation of glutathione itself, suggesting this to be a low energy form. Acceptable conformations of each enzyme-bound derivative fell into two classes with the metal either above or below the mean plane through the glutathione compound. The conformational uncertainty within each class was relatively small, ranging from deviations of 0.9-1.9 A in the average positions of each of the atoms. A small but significant difference in the conformation of the substrate analog as compared to the product was detected in the position of the reaction center carbon directly bonded to the glutathione sulfur atom. Unlike the second-sphere metal complexes formed by the bound substrate analog, the product, or the hydrophobic competitive inhibitor, the charged competitive inhibitor S-(carboxymethyl)glutathione binds farther from the metal, in the third coordination sphere.

Binding Sites↗

PubMed2001

Computational modeling predicts the structure and dynamics of chromatin fiber.

BACKGROUND: The compact form of the chromatin fiber is a critical regulator of fundamental processes such as transcription and replication. These reactions can occur only when the fiber is unraveled and the DNA strands contained within are exposed to interact with nuclear proteins. While progress on identifying the biochemical mechanisms that control localized folding and hence govern access to genetic information continues, the internal structure of the chromatin fiber, let alone the structural pathways for folding and unfolding, remain unknown. RESULTS: To offer structural insights into how this nucleoprotein complex might be organized, we present a macroscopic computer model describing the mechanics of the chromatin fiber on the polymer level. We treat the core particles as electrostatically charged disks linked via charged elastic DNA segments and surrounded by a microionic hydrodynamic solution. Each nucleosome unit is represented by several hundred charges optimized so that the effective Debye-Hückel electrostatic field matches the field predicted by the nonlinear Poisson-Boltzmann equation. On the basis of Brownian dynamics simulations, we show that oligonucleosomes condense and unfold in a salt-dependent manner analogous to the chromatin fiber. CONCLUSIONS: Our predicted chromatin model shows good agreement with experimental diffusion coefficients and small-angle X-ray scattering data. A fiber of width 30 nm, organized in a compact helical zigzag pattern with about 4 nucleosomes per 10 nm, naturally emerges from a repeating nucleosome folding motif. This fiber has a cross-sectional radius of gyration of R(c) = 8.66 nm, in close agreement with corresponding values for rat thymus and chicken erythrocyte chromatin (8.82 and 8.5 nm, respectively).

Algorithms↗

PubMed1989

Mechanism of Wenckebach periods: hypothesis based on computer modeling experiments.

Wenckebach periodicity is characterized by progressive lengthening of conduction intervals and by progressive shortening of the intervals between conducted excitations. Although different hypotheses have been suggested to explain the mechanisms of Wenckebach periods, no serious proposition explaining both components of the phenomenon has yet been reported. A computer model simulating detailed mechanisms of excitation transmission and electrotonic interactions between neighboring cardiac cells has been employed to investigate the conduction properties of a one-dimensional cable composed of simulated cells. When introducing gradual prolongation of the recovery phase for the elements in the center of the cable and when incorporating physiologically realistic shapes of premature action potential curves into the simulation experiments, the model was able to reproduce all aspects of Wenckebach periodicity. Systematic evaluation with simulation experiments showed that a shorter duration of premature action potentials (i.e., of action potentials resulting from excitation of a cell before it has been fully repolarized) produced shortening of intervals between conducted excitations during a Wenckebach period.

Action Potentials↗

PubMed2006

Establishment and maintenance of planar epithelial cell polarity by asymmetric cadherin bridges: a computer model.

Animal scales, hairs, feathers, and cilia are oriented due to cell polarization in the epithelial plane. Genes involved have been identified, but the signal and mechanism remain unknown. In Drosophila wing polarization, the action of a gradient of Frizzled activity is widely assumed; and cell-cell signalling by cadherins such as Flamingo surely plays a major role. We present a computer model where reading the Frizzled gradient occurs through biased, feedback-reinforced formation of Flamingo-based asymmetric intercellular complexes. Through these complexes neighboring cells are able to compare their Frizzled activity levels. Our computations are highly noise-resistant and reproduce both wild-type and all known mutant wing phenotypes; other phenotypes are predicted. The model puts stringent limits on a Frizzled activation signal, which should exhibit unusual properties: (1) the extracellular Frizzled signalling gradient should be counterdirectional--decreasing from proximal (P) to distal (D), whereas during polarization, the intracellular Frizzled gradient builds up from P to D; (2) the external gradient should be relatively weak and short-lived, lest it prevent inversion of intracellular Frizzled. These features, largely independent of model details, may provide useful clues for future experimental efforts.

Animals↗

PubMed2005

Complex pattern formation of marine gradient bacteria explained by a simple computer model.

We report on the formation of conspicuous patterns by the sulfide-oxidizing bacterium Thiovulum majus and a recently described vibrioid bacterium. These microaerophilic bacteria form mucus veils on top of sulfidic marine sediment exhibiting regular spaced bacterial patterns (honeycombs, interwoven bands, or inverse honeycombs). A simple qualitative computer model, based on chemotaxis towards oxygen and the ability of the bacteria to induce water advection when attached, can explain the formation of the observed patterns. Our study shows that complex bacterial patterns in nature can be explained in terms of chemotaxis and resource optimisation without involvement of cell-cell signalling or social behavior amongst bacteria.

Bacterial Physiological Phenomena↗

PubMed1991

Computer modelling studies on the mechanism of action of ribonuclease T1.

The mechanism of action of ribonuclease (RNase) T1 is still a matter of considerable debate as the results of x-ray, 2-D nmr and site-directed mutagenesis studies disagree regarding the role of the catalytically important residues. Hence computer modelling studies were carried out by energy minimisation of the complexes of RNase T1 and some of its mutants (His40Ala, His40Lys, and Glu58Ala) with the substrate guanyl cytosine (GpC), and of native RNase T1 with the reaction intermediate guanosine 2',3'-cyclic phosphate (G greater than p). The puckering of the guanosine ribose moiety in the minimum energy conformer of the RNase T1-GpC (substrate) complex was found to be O4'-endo and not C3'-endo as in the RNase T1-3'-guanylic acid (inhibitor/product) complex. A possible scheme for the mechanism of action of RNase T1 has been proposed on the basis of the arrangement of the catalytically important amino acid residues His40, Glu58, Arg77, and His92 around the guanosine ribose and the phosphate moiety in the RNase T1-GpC and RNase T1-G greater than p complexes. In this scheme, Glu58 serves as the general base group and His92 as the general acid group in the transphosphorylation step. His40 may be essential for stabilising the negatively charged phosphate moiety in the enzyme-transition state complex.

Amino Acids↗

PubMed1991

Studies on DNA-cleaving agents: computer modeling analysis of the mechanism of activation and cleavage of dynemicin-oligonucleotide complexes.

Dynemicin A is a recently identified antitumor antibiotic. Upon activation, dynemicin is reported to cause double-stranded cleavage of DNA, putatively through the intermediacy of a diradical. Computer modeling of this activation and cleavage process is described herein as part of an effort to establish a structural hypothesis for this mechanistic sequence and for the design of simple analogues. Intercalation complexes of duplex dodecamers [d(CGCGAATTCGCG)]2 and [d(GC)6]2 with both enantiomers of dynemicin and of all related mechanistic intermediates are evaluated. Examination of these structures shows that cycloaromatization of dynemicin to a diradical intermediate results in the rotation of the diradical-forming subunit with respect to the intercalation plane that is of an opposite sense for the two dynemicin enantiomers. In addition, the activation of the (2S) enantiomer of dynemicin occurs by a less restricted approach trajectory than the corresponding (2R) enantiomer. In all complexes, the 5'-3' strand is at least 1 A closer than the 3'-5' strand to the diyl intermediate. As a result, complexes are produced in which the diyl moiety is aligned along [(2S)] or across [(2R)] the minor groove, leading to different predictions for the selectivity of radical-initiated, oxidative lesion of DNA. Molecular dynamics simulations are found to support these predictions, including the 3-base-pair offset cleavage reported for dynemicin.

Anthraquinones↗

PubMed2005

A computational model of mitochondrial AZT metabolism.

The mechanisms of the mitochondrial toxicity of AZT (azidothymidine; zidovudine) are not clear. The two main contenders are the incorporation of phosphorylated AZT into the mtDNA (mitochondrial DNA) and the competitive inhibition of natural deoxynucleotide metabolism. We have built a computational model of AZT metabolism in mitochondria in order to better understand these toxicity mechanisms. The model includes the transport of non-phosphorylated and phosphorylated forms of AZT into mitochondria, phosphorylation, and incorporation into mtDNA. The model also includes the mitochondrial metabolism of the natural deoxynucleotides. We define three simulated cell types, i.e. rapidly dividing, slowly dividing and postmitotic cells. Our standard simulation indicates that incorporation of AZT into mtDNA is highest in rapidly dividing cells because of the higher mitochondrial AZTTP (3'-azidothymidine-5'-triphosphate)/dTTP ratio in this cell type. However, under these standard conditions the rate of incorporation into mtDNA is too low to be a major cause of toxicity. These simulations relied on the assumption that phosphorylated AZT is transported with the same kinetics as phosphorylated thymidine. In simulations with mitochondria set to have a limited ability to transport phosphorylated AZT, AZTTP accumulates to toxic levels in the mitochondria of postmitotic cells, while low levels are maintained in mitochondria from rapidly dividing cells. This result is more consistent with the tissue toxicities observed in patients. Our model also predicts that inhibition by AZT of mitochondrial deoxycytidine phosphorylation by thymidine kinase 2 may contribute to the mitochondrial toxicity, since in simulations using a typical peak plasma AZT level the mtDNA replication rate is decreased by 30% in postmitotic cell simulations.

Animals↗

PubMed2000

A computer model of normal conduction in the human atria.

Although considerable progress has been made in understanding the process of wavefront propagation and arrhythmogenesis in human atria, technical concerns and issues of patient safety have limited experimental investigations. The present work describes a finite volume-based computer model of human atrial activation and current flow to complement these studies. Unlike previous representations, the model is three-dimensional, incorporating both the left and right atria and the major muscle bundles of the atria, including the crista terminalis, pectinate muscles, limbus of the fossa ovalis, and Bachmann's bundle. The bundles are represented as anisotropic structures with fiber directions aligned with the bundle axes. Conductivities are assigned to the model to give realistic local conduction velocities within the bundles and bulk tissue. Results from simulations demonstrate the role of the bundles in a normal sinus rhythm and also reveal the patterns of activation in the septum, where experimental mapping has been extremely challenging. To validate the model, the simulated normal activation sequence and conduction velocities at various locations are compared with experimental observations and data. The model is also used to investigate paced activation, and a mechanism of the relative lengthening of left versus right stimulation is presented. Owing to both the realistic geometry and the bundle structures, the model can be used for further analysis of the normal activation sequence and to examine abnormal conduction, including flutter. The full text of this article is available at http://www.circresaha.org.

Atrial Function↗

PubMed1994

Computer modeling of adsorption on an activated charcoal surface.

The molecular modeling program SYBYL was used to simulate the adsorption of various barbiturates by an activated charcoal surface. The compounds barbituric acid (BA), barbital (B), phenobarbital (PB), mephobarbital (M), and primidone (Pr) were modeled, and their structures were energetically minimized. These structures agreed with literature reports for the conformations of these molecules in dimethyl sulfoxide-d6, methanol-d4, and chloroform-d. The activated charcoal surface was modeled using graphitic crystallites which had either no oxygen-containing functional group, a C-OH functional group, or a C = O functional group. The presence of the C-O (presumably C-OH) and C = O functional states on activated charcoal surfaces had been previously determined by X-ray photoelectron spectroscopy. It was assumed that the crystallite was locally flat. Upon docking, conformational changes were observed for barbital, phenobarbital, mephobarbital, and primidone. Estimates for the heat of adsorption ranged from -62.3 kJ/mol for barbituric acid to -91.1 kJ/mol for mephobarbital on the hydroxylated surface. Allowance for the heat of desorption of the required number of water molecules from the surface, also determined by SYBYL, gave heat of displacement values of -19.4 kJ/mol for barbituric acid and -32.6 kJ/mol for mephobarbital. These values compared well to the heat of displacement values obtained by isoperibol calorimetry, which were -20.3 kJ/mol for barbituric acid and -31.6 kJ/mol for mephobarbital. Previous laboratory studies had demonstrated the greater importance of the C-O functional state for barbiturate adsorption compared to the C = O functional state. The computer-modeled system predicted the same result.

Adsorption↗

PubMed1989

A computer-model analysis of the influence of the upper airway on passive flow-volume loops in infants.

The present study was undertaken to determine the effects of upper airway resistance (Rua) and elastance (Eua) on the mechanical parameters calculated from the expiratory limb of the passive flow-volume curve in normal infants, using a computer model. The model included separate compartments for the respiratory system, upper airway, and measurement equipment. Inclusion of Rua in the model decreased the slope of the expiratory limb of the flow-volume loop, and the resistance calculated from the flow-volume loop accurately reflected the total resistance of the model. Inclusion of Eua in the model caused a decrease in the end-inspiratory (driving) pressure and a corresponding decrease in the peak expiratory flow but did not alter the slope of the linear portion of the expiratory limb of the flow-volume loop. Resistance calculated from the loop underestimated true model resistance by 14.5%. However, further small fluctuations in Eua did not cause significant variability in the value of resistance calculated. Total elastance was accurately calculated whether or not Rua and Eua were included in the model. The results of this analysis demonstrate that, while Eua causes the true resistance to be underestimated, fluctuations in Eua are not likely to be an important source of variability in the mechanical parameters calculated from the passive flow-volume loop; however, any changes in Rua will be reflected in the value of resistance calculated and therefore are likely to cause substantial variability in the calculated resistance.

Airway Resistance↗