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PubMed1999

A three-dimensional model for arterial tree representation, generated by constrained constructive optimization.

The computational method of constrained constructive optimization (CCO) has been generalized in two important respects: (1) arterial model trees are now grown within a convex, three-dimensional piece of tissue and (2) terminal flow variability has been incorporated into the model to account for the heterogeneity of blood flow observed in real vascular beds. Although no direct information from topographic anatomy enters the model, computer-generated CCO trees closely resemble corrosion casts of real arterial trees, both on a visual basis and with regard to morphometric parameters. Terminal flow variability was found to induce transitions in the connective structure early in the trees' development. The present generalization of CCO offers--for the first time--the possibility to generate optimized arterial model trees in three dimensions, representing a realistic geometrical substrate for hemodynamic simulation studies. With the implementation of terminal flow variability the model is ready to simulate processes such as the adaptation of arterial diameters to changes in blood flow rate or the formation of different patterns of angiogenesis induced by changing needs of blood supply.

Algorithms↗
PubMed2001

Criteria for the evaluation of studies in transgenic models.

The generation, evaluation, and presentation of data from the ILSI Alternatives to Carcinogenicity Testing (ACT) program was standardized to ensure that the results of studies performed in multiple laboratories could be reliably compared. To this end, standardized experimental protocols, tissue collection procedures, histopathology nomenclature, diagnoses, and terminology were employed by study participants. In the experimental phase, this approach provided important cross-model consistency. To ensure comparability in the data evaluation phase of the project, interpretive criteria were defined to allow the characterization of study outcome as positive, negative, or equivocal in regards to carcinogenic response. These criteria helped to provide consistency across models because separate Assay Working Groups were established to evaluate the results of each model. To organize and compile the data from the ILSI ACT program, a database has been developed and data entered in standardized format to facilitate cross- and intramodel comparisons. In summary, the early development of standardized test protocols, evaluation procedures, and interpretive criteria has resulted in a data set in which users can have a high level of assurance that results in the database reflect consistently applied experimental and interpretive guidelines.

Academies and Institutes↗
PubMed1992

A crystallographic molecular lattice builder applied to model lipid bilayers.

It is often desirable for noncrystallographers to generate graphical models of three-dimensional crystal structures based on published coordinates of the atoms that make up the crystallographic unit cells. This type of visualization is particularly important for small-molecule crystals, such as lipid crystals, where one may be interested in investigating interactions between the individual molecules in addition to their conformations. BILAYER BUILDER is a program that generates a portion of the entire crystal structure from the coordinates of the molecules in a single unit cell. It gives users of small desktop computers, such as the Apple Macintosh, the capability to generate and examine model crystal structures with a molecular graphics display program. BILAYER BUILDER stores the crystal coordinates in a Brookhaven Protein Data Bank file format for possible use in a variety of applications on many different computers. Initially, it was written for use with lipid crystals and bilayers but may be used for building an assortment of molecular crystals.

Computer Graphics↗
PubMed1982

The double dipole model of theta rhythm generation: simulation of laminar field potential profiles in dorsal hippocampus of the rat.

A set of compartmental models of CA1 pyramidal, granular and polymorph cells of the dorsal hippocampus have been used to simulate membrane potentials generated by synaptic activation at various levels along these cells. From the membrane potential distributions the field potentials in dorsal CA1 and the dorsal blade of the dentate area have been simulated using a model based on volume conduction theory. Field potential profiles similar to laminar profiles, found experimentally in the dorsal hippocampus during theta rhythm, could only be simulated by assuming (almost) simultaneous synaptic excitation of the 3 cell types at given sites. The results lead to 2 alternative models for the simultaneous excitation of CA1 pyramidal cells and dentate granular cells during theta rhythm. Other electrophysiological evidence favours the model in which the two neuronal populations are activated distally near the fissure.

Animals↗
PubMed2006

Using the constrained DFT approach in generating diabatic surfaces and off diagonal empirical valence bond terms for modeling reactions in condensed phases.

The empirical valence bond (EVB) model provides an extremely powerful way for modeling and analyzing chemical reactions in solutions and proteins. However, this model is based on the unverified assumption that the off diagonal elements of the EVB Hamiltonian do not change significantly upon transfer of the reacting system from one phase to another. This ad hoc assumption has been rationalized by its consistency with empirically observed linear free energy relationships, as well as by other qualitative considerations. Nevertheless, this assumption has not been rigorously established. The present work explores the validity of the above EVB key assumption by a rigorous numerical approach. This is done by exploiting the ability of the frozen density functional theory (FDFT) and the constrained density functional theory (CDFT) models to generate convenient diabatic states for QM/MM treatments, and thus to examine the relationship between the diabatic and adiabatic surfaces, as well as the corresponding effective off diagonal elements. It is found that, at least for the test case of S(N)()2 reactions, the off diagonal element does not change significantly upon moving from the gas phase to solutions and thus the EVB assumption is valid and extremely useful.

Algorithms↗
PubMed1995

Generation and characterization of a delta F508 cystic fibrosis mouse model.

We have generated mice carrying the most common mutation in cystic fibrosis (CF), delta F508, within the cystic fibrosis (Cftr) gene. Mutant animals show pathological and electrophysiological changes consistent with a CF phenotype. delta F508-/- mice die from peritonitis and show deficiencies in cAMP-activated electrogenic Cl- transport. These mice produce delta F508 transcripts and show the temperature-dependent trafficking defect first described for the human delta F508 CFTR protein. A functional CFTR Cl- channel not demonstrated by null CF mice or present at 37 degrees C was detected following incubation of epithelial cells at 27 degrees C. Thus, these mice are an accurate delta F508 model and will be valuable for testing drugs aimed at overcoming the delta F508 trafficking defect.

Animals↗
PubMed2000

Line source representation for laser-generated ultrasound in aluminum

Modeling the ultrasound generated by a laser source is critical for using noncontact laser-generated ultrasonic systems for the characterization of material properties. In this work, a laser line source was modeled and verified experimentally by measuring the ultrasonic shear wave signal generated in aluminum with a broadband laser generation/electromagnetic acoustic transducer (EMAT)-detection system. Results of calculations and experiments show that the amplitude directivity of a laser line source is identical to that of a point source in the plane perpendicular to the line axis while the temporal dependence differs.

Journal Article↗
PubMed1990

A theoretical model for stress-generated fluid flow in the canaliculi-lacunae network in bone tissue.

A mathematical model was developed to study stress-induced fluid flow in the canaliculi-lacunae system in an osteon. The effect of canaliculi diameters on the magnitude and depth of penetration of squeeze flow through the canaliculi system was investigated. An optimal canaliculus diameter (which would maximize the fluid velocity through the canaliculi) was determined. For canaliculi diameters of 0.2 micron, squeeze flow can nourish four to five concentric layers of osteocytes in an osteon. It is possible that such stress-induced flow may be important in bone remodeling, and that lack of such flow may be one cause for producing osteoporosis due to immobilization.

Bone Matrix↗
PubMed1998

Genetic alterations in the development of mammary and prostate cancer in the C3(1)/Tag transgenic mouse model.

We have generated a transgenic mouse model in which female mice develop ductal mammary adenocarcinomas and male mice develop prostatic adenocarcinomas by using a transgene containing the hormone-responsive rat prostatic steroid binding protein 5' flanking region C3(1) fused to the simian virus 40 (SV40) large T antigen. We have identified some genetic alterations during mammary and prostate tumor progression: (i) p53 is functionally inactivated during mammary cancer development without p53 mutations; (ii) Alterations in apoptosis during mammary tumor progression are p53 and bcl-2 independent; (iii) Ha-ras mutations occur early in the development of prostate cancer. This unique animal model offers the opportunity to study multistep tumorigenesis in these organs.

Adenocarcinoma↗
PubMed2005

Computational modeling of a dynamic knee simulator for reproduction of knee loading.

As a first step towards reproducing desired three-dimensional joint loading and motion on a dynamic knee simulator, the goal of this study was to develop and verify a three-dimensional computational model that generated control profiles for the simulator using desired knee loading and motion as model inputs. The developed model was verified by predicting tibio-femoral loading on an instrumented analog knee for given actuator forces and the ability to generate simulator control profiles was demonstrated using a three-dimensional walking profile. The model predicted axial tibia loading for a sagittal-plane dual-limb squat within 1% of measured peak loading. Adding out-of-sagittal-plane forces decreased the accuracy of load prediction. The model generated control profiles to the simulator that produced axial tibia loading within 16% of desired for walking. Discrepancies in predicted and measured quadriceps forces influenced the accuracy of the generated control profiles. Future work will replace the analog knee in both the model and machine with a prosthetic knee.

Biomimetics↗
PubMed1995

Reassurance seeking, stress generation, and depressive symptoms: an integrative model.

The purpose of this study was to examine a mechanism through which interpersonal vulnerability factors may be linked with depressive symptoms by integrating a stress-generation model with an interpersonal theory of depression. The proposed conceptual framework was tested with 267 college students in a prospective structural equation model with 3 assessments over a 5-week period. Results supported all hypotheses. Initial depressive symptoms and initial reassurance seeking style were positively associated, and initial depressive symptoms were positively related to the occurrence of subsequent minor social stressors. Finally, a reassurance-seeking style was positively related to outcome depressive symptoms indirectly through minor social stressors. As predicted, stress generation operated as a mediating mechanism linking an initial reassurance-seeking style to subsequent depressive symptoms.

Adaptation, Psychological↗
PubMed1993

Model of chemically excitable membranes generating autonomous chaotic oscillations.

A simple mathematical model of the chemically excitable membranes leading to autonomous chaotic oscillations is presented. The model assumes two kinds of autocatalytic ion channels, one is for cations and the other is for anions. Self-consistency between the ion distributions and the electric potentials is taken into account by including the counter ions explicitly. Cations and anions pass through their own channels with their permeabilities changing nonlinearly with the densities of ions at the surfaces of the membrane. Cation and anion transport systems then form two subsystems that oscillate and interact with each other through the membrane potential. When the coupling strength between the two ion systems and adsorption rate of ions to channels are varied, various types of chaotic oscillations are generated autonomously, i.e., without a stimulating periodic force. Experimental evidence to the present model is discussed. It is suggested that endogenous chaos in biological systems may appear from the electric coupling among different kinds of ion transport systems.

Catalysis↗
PubMed2003

Constraints-based models: regulation of gene expression reduces the steady-state solution space.

Constraints-based models have been effectively used to analyse, interpret, and predict the function of reconstructed genome-scale metabolic models. The first generation of these models used "hard" non-adjustable constraints associated with network connectivity, irreversibility of metabolic reactions, and maximal flux capacities. These constraints restrict the allowable behaviors of a network to a convex mathematical solution space whose edges are extreme pathways that can be used to characterize the optimal performance of a network under a stated performance criterion. The development of a second generation of constraints-based models by incorporating constraints associated with regulation of gene expression was described in a companion paper published in this journal, using flux-balance analysis to generate time courses of growth and by-product secretion using a skeleton representation of core metabolism. The imposition of these additional restrictions prevents the use of a subset of the extreme pathways that are derived from the "hard" constraints, thus reducing the solution space and restricting allowable network functions. Here, we examine the reduction of the solution space due to regulatory constraints using extreme pathway analysis. The imposition of environmental conditions and regulatory mechanisms sharply reduces the number of active extreme pathways. This approach is demonstrated for the skeleton system mentioned above, which has 80 extreme pathways. As regulatory constraints are applied to the system, the number of feasible extreme pathways is reduced to between 26 and 2 extreme pathways, a reduction of between 67.5 and 97.5%. The method developed here provides a way to interpret how regulatory mechanisms are used to constrain network functions and produce a small range of physiologically meaningful behaviors from all allowable network functions.

Animals↗
PubMed1995

Experimentally derived model for the locomotor pattern generator in the Xenopus embryo.

1. Simulations of Xenopus embryo spinal neurons were endowed with Hodgkin-Huxley-style models of voltage-dependent Na+, Ca2+, slow K+ and fast K+ currents together with a Na(+)-dependent K+ current. The parameters describing the activation, inactivation and relaxation of these currents were derived from previous voltage-clamp studies of Xenopus embryo spinal neurons. Each of the currents was present at realistic densities. 2. The model neurons fired repetitively in response to current injection. The Ca2+ current was essential for repetitive firing in response to current injection. The fast K+ current appeared mainly to control spike width, whereas the slow K+ current exerted a powerful influence on the reptitive firing properties of the neurons without markedly affecting spike width. 3. The properties of the model neurons could be made more consistent with those previously reported for Xenopus embryo neurons during intracellular recordings in vivo, if the shunting effect of the sharp microelectrode was incorporated into the model. 4. The model neurons were then used to create a simplified version of the spinal network that controls swimming in the frog embryo. This model network could generate the motor pattern for swimming: the activity between the left and right sides alternated with a cycle period that varied from 50 to 120 ms. This is very similar to the range of cycle periods observed in the real embryo. The shunting effect of the microelectrode was once again taken into account. 5. Reductions of the K+ currents perturbed the motor pattern and gave three forms of aberrant motor activity very similar to those previously seen during the application of K+ channel blockers to the real embryo. The ability to generate the correct motor pattern for swimming in the model depended on the balance between the K+ currents and the inward Na+ and Ca2+ currents rather than their absolute values. 6. The model network could generate a motor pattern for swimming over a very wide range of excitatory (2-10 nS) and inhibitory (2-400 nS) synaptic strengths. Rough estimates of the physiological synaptic strengths in the real circuit (around 20-60 nS for inhibition and 2-5 nS for excitation) fall within the range of synaptic strengths that gave simulation of the swimming motor pattern in the model. 7. The cycle period of the motor activity in the model shortened either as the excitatory synapses were strengthened or as the inhibitory synapses were weakened. 8. The prediction that the strength of the mid-cycle inhibition determines cycle period has been tested by using low levels of strychnine to reduce glycinergic reciprocal inhibition in a graded manner in the real embryo. As the inhibition was reduced, the cycle period of fictive swimming in the embryo shortened by amounts very close to those predicted by the model. 9. This new experimentally derived model can replicate many of the known features of fictive swimming in the real embryo and may be of value as an analytical tool in attempting to understand how the spinal circuitry of the Xenopus embryo and related amphibian embryos control a variety of motor behaviours.

Animals↗
PubMed2003

Prediction of the effect of mobile-phase salt type on protein retention and selectivity in anion exchange systems.

This study examines the effect of different salt types on protein retention and selectivity in anion exchange systems. Particularly, linear retention data for various proteins were obtained on two structurally different anion exchange stationary-phase materials in the presence of three salts with different counterions. The data indicated that the effects are, for the most part, nonspecific, although various specific effects could also be observed. Quantitative structure retention relationship (QSRR) models based on support vector machine feature selection and regression models were developed using the experimental chromatographic data in conjunction with various molecular descriptors computed from protein crystal structure geometries. Star plots for each descriptor used in the final model were generated to aid in interpretation. The resulting QSRR models were predictive, with cross-validated r2 values of 0.9445, 0.9676, and 0.8897 for Source 15Q and 0.9561, 0.9876, and 0.9760 for Q Sepharose resins in the presence of three different salts. The predictive power of these models was validated using a set of test proteins that were not used in the generation of these models. Interpretation of the models revealed that particular trends for proteins and salts could be captured using QSRR techniques.

Algorithms↗
PubMed2006

Unravelling the regulatory structure of biochemical networks using stimulus response experiments and large-scale model selection.

To unravel the complex in vivo regulatory interdependences of biochemical networks, experiments with the living organism are absolutely necessary. Stimulus response experiments (SREs) have become increasingly popular in recent years. The response of metabolite concentrations from all major parts of the central metabolism is monitored over time by modem analytical methods, producing several thousand data points. SREs are applied to determine enzyme kinetic parameters and to find unknown enzyme regulatory mechanisms. Owing to the complex regulatory structure of metabolic networks and the amount of measured data, the evaluation of an SRE has to be extensively supported by modelling. If the enzyme regulatory mechanisms are part of the investigation, a large number of models with different enzyme kinetics have to be tested for their ability to reproduce the observed behaviour. In this contribution, a systematic model-building process for data-driven exploratory modelling is introduced with the aim of discovering essential features of the biological system. The process is based on data pre-processing, correlation-based hypothesis generation, automatic model family generation, large-scale model selection and statistical analysis of the best-fitting models followed by an extraction of common features. It is illustrated by the example of the aromatic amino acid synthesis pathway in Escherichia coli.

Adaptation, Physiological↗
PubMed2006

Approximate model for surface-plasmon generation at slit apertures.

We present a semianalytical model that quantitatively predicts the scattering of light by a single subwavelength slit in a thick metal screen. In contrast to previous theoretical works related to the transmission properties of the slit, the analysis emphasizes the generation of surface plasmons at the slit apertures. The model relies on a two-stage scattering mechanism, a purely geometric diffraction problem in the immediate vicinity of the slit aperture followed by the launching of a bounded surface-plasmon wave on the flat interfaces surrounding the aperture. By comparison with a full electromagnetic treatment, the model is shown to provide accurate formulas for the plasmonic generation strength coefficients, even for metals with a low conductivity. Limitations are outlined for large slit widths (>lambda) or oblique incidence (>30 degrees ) when the slit is illuminated by a plane wave.

Journal Article↗
PubMed2006

A note on generation times in epidemic models.

The time between the infection of a primary case and one of its secondary cases is called a generation time. The distribution (and mean) of the generation times is derived for a rather general class of epidemic models. The relation to assumptions on distributions of latency times and infectious times or more generally on random time varying infectiousness, is investigated. Serial times, defined as the times between occurrence of observable events in the progress of an infectious disease (e.g., the onset of clinical symptoms), are also considered.

Algorithms↗