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PubMed1978

Patterns of output firing generated by a many-input neuronal model for different model parameters and patterns of synaptic drive.

A relatively simple neuronal model with a large number of 'synaptic' inputs is described. The model has been extensively studied in order to investigate the influence which patterns of presynaptic firing may have upon the pattern of output firing. The model has been studied in two versions. In one the threshold remained constant, while in the other the threshold was increased following an output firing. This increase in threshold decayed with time and was analogous to the after-hyperpolarization of a real neurone. The effect on the frequency of output firing of changes in the threshold and of the overall input rate were studied in detail. The pattern of output firing was studied for two patterns of input firing. In one, each presynaptic input fired steadily, each at a different rate; in the other, the input firings were randomly distributed in time, being generated by a Poisson process. It was found that, for a given total input rate, the pattern of output firing was markedly more regular when the input processes were regular, even though the mean rate of output firing was not appreciably different for the two different distributions of input firings. It is shown that, with suitable parameters for the model, it is possible to mimic very closely the discharge of tonically discharging motoneurones under different experimental conditions. This suggests that the more general properties of the model may have considerable relevance to the way in which real neurones integrate their synaptic input.

Action Potentials↗

PubMed1993

A computer heart model incorporating anisotropic propagation. I. Model construction and simulation of normal activation.

Present-day computer models of the entire heart, capable of simulating the activation isochrones and subsequently the body surface potentials, focus on considerations of myocardial anisotropy. Myocardial anisotropy enters into play at two levels, first by affecting the spatial pattern of activation owing to faster propagation along cardiac fibers and second by altering the equivalent dipole sources used to calculate the surface potentials. The construction of a new and detailed model of the human heart is described, based on 132 transverse sections obtained following a computed tomography scan of a frozen human heart whose chambers were inflated with pressurized air. The entire heart anatomy was reconstructed as a three-dimensional array of approximately 250,000 points spaced 1 mm apart. Conduction in the thin-walled atria was assumed isotropic from the sinus node region to the atrioventricular node, where it was subject to a 50 ms delay. A two-tier representation of the specialized conduction system was used, with the initial segments of the left and right bundles represented by a system of cables that feeds to the second tier, which is a sheet of conduction tissue representing the distal Purkinje system. Approximately 1,120 "Purkinje-myocardium" junctions present at the terminations of the cables and sprinkled uniformly over the sheet, transmit the excitation to the ventricles. A stylized representation of myocardial fiber rotation was incorporated into the ventricles and the local fiber direction at each model point used to compute the velocity of propagation to its nearest neighbors. Accordingly, the activation times of the entire ventricular myocardium could be determined using the 1,120 or so Purkinje-myocardium junctions as start points. While myocardial anisotropy was considered in the ventricular propagation process, it was ignored in the computation of the equivalent dipole sources. Nevertheless, the computed electrocardiogram, vectorcardiogram, and body surface potential maps obtained with the new heart model properly positioned inside an inhomogeneous torso model were all within normal limits.

Anisotropy↗

PubMed1991

Three-dimensional model of Escherichia coli ribosomal 5 S RNA as deduced from structure probing in solution and computer modeling.

The conformation of Escherichia coli 5 S rRNA was investigated using chemical and enzymatic probes. The four bases were monitored at one of their Watson-Crick positions with dimethylsulfate (at C(N-3) and A(N-1], with a carbodiimide derivative (at G(N-1) and U(N-3] and with kethoxal (at G(N-1, N-2]. Position N-7 of purine was probed with diethylpyrocarbonate (at A(N-7] and dimethylsulfate (at G(N-7]. Double-stranded or stacked regions were tested with RNase V1 and unpaired guanine residues with RNase T1. We also used lead(II) that has a preferential affinity for interhelical and loop regions and a high sensitivity for flexible regions. Particular care was taken to use uniform conditions of salt, magnesium, pH and temperature for the different enzymatic chemical probes. Derived from these experimental data, a three dimensional model of the 5 S rRNA was built using computer modeling which integrates stereochemical constraints and phylogenetic data. The three domains of 5 S rRNA secondary structure fold into a Y-shaped structure that does not accommodate long-range tertiary interactions between domains. The three domains have distinct structural and dynamic features as revealed by the chemical reactivity and the lead(II)-induced hydrolysis: domain 2 (loop B/helix III/loop C) displays a rather weak structure and possesses dynamic properties while domain 3 (helix V/region E/helix IV/loop D) adopts a highly structured and overall helical conformation. Conserved nucleotides are not crucial for the tertiary folding but maintain an intrinsic structure in the loop regions, especially via non-canonical pairing (A.G, G.U, G.G, A.C, C.C), which can close the loops in a highly specific fashion. In particular, nucleotides in the large external loop C fold into an organized conformation leading to the formation of a five-membered loop motif. Finally, nucleotides at the hinge region of the Y-shape are involved in a precise array of hydrogen bonds based on a triple interaction between U14, G69 and G107 stabilizing the quasi-colinearity of helices II and V. The proposed tertiary model is consistent with the localization of the ribosomal protein binding sites and possesses strong analogy with the model proposed for Xenopus laevis 5 S rRNA, indicating that the Y-shape model can be generalized to all 5 S rRNAs.

Base Sequence↗

PubMed1990

A discrete, stochastic model for microbial filter feeding: a model for feeding of ciliated protists on spatially uniform, nondepletable suspensions.

Suspension-feeding ciliates, either bacteriovorous or planktonic, are adapted to feed on particulate food matter of size much smaller than their own size. These microorganisms collect their prey by generating water currents that draw prey toward their capture surfaces. Under such conditions food particles are treated in bulk, and captures of individual food particles from a suspension by individual single-celled organisms are discrete events that occur at random intervals of time. Each such event is followed by a sequence of additional events that also occur at random intervals of time. This sequence culminates in the incorporation of the digestible portion of the food particle into the cell's cytoplasm and the expulsion of the indigestible portion from the cell. In theory, the rate of the overall ingestion-digestion process can be limited by the passage of particles through any stage of this sequence of events. In this paper, we assume that only the initial events in the sequence, those that occur in the oral region of the cell, limit the rate of the ingestion-digestion process, and we develop a discrete, stochastic model of filter feeding based on that assumption. We use the model to show how advanced instrumentation, such as flow cytometry, can be used to measure parameters of the model and also to answer a number of important questions about the mechanism of filter feeding. We show also how the model can be applied to nonhomogeneous cell populations for which parameters of the model are distributed.

Animals↗

PubMed1990

Physiologically based pharmacokinetic modeling of the lactating rat and nursing pup: a multiroute exposure model for trichloroethylene and its metabolite, trichloroacetic acid.

A physiologically based pharmacokinetic (PB-PK) model was developed to describe trichloroethylene (TCE) kinetics in the lactating rat and nursing pup. The lactating dam was exposed to TCE either by inhalation or by ingestion in drinking water. The nursing pup's exposure to TCE was by ingestion of maternal milk containing TCE. The kinetics of trichloroacetic acid (TCA), a metabolite of TCE, were described in the lactating dam and developing pup by a hybrid one-compartment model. The lactating dam's exposure to TCA was from metabolism of TCE to TCA. The pup's exposure to TCA was from metabolism of TCE ingested in suckled milk and from direct ingestion of TCA in maternal milk. For the PB-PK model, partition coefficients (PCs) were determined by vial equilibration, and metabolic constants for TCE oxidation, by gas uptake methods. The blood/air and the fat/blood PCs for the dam were 13.1 and 34.2, and for the pup, 10.6 and 42.3, respectively. The milk/blood PC for the dam was 7.1. In lactating rats and rat pups (19-21 days old) the maximum velocities of oxidative metabolism were 9.26 +/- 0.073 and 12.94 +/- 0.107 mg/kg/hr. The plasma elimination rate constant (K = 0.063 +/- 0.004 hr-1) and apparent volume of distribution (Vd = 0.568 liter/kg) for TCA in the lactating dam were estimated from both intravenous dosing studies and an inhalation study with TCE. For the pup, K (0.014 +/- hr-1) and Vd (0.511 liter/kg) were estimated from a single 4-hr inhalation exposure with TCE. The dose-rate-dependent stoichiometric yield of TCA from oxidative metabolism of TCE in the lactating rat is 0.17 for a low-concentration inhalation exposure (27 ppm TCE) and 0.27 for an exposure above metabolic saturation (about 600 ppm TCE). For the pup, the stoichiometric yield of TCA is 0.12. With changing physiological values during lactation for compartmental volumes, blood flows, and milk yields obtained from the published literature and kinetic parameters and PCs determined by experimentation, a PB-PK model was constructed to predict maternal and pup concentrations of TCE and TCA. To test the fidelity of the PB-PK lactation model, a multiday inhalation exposure study was conducted from Days 3 to 14 of lactation and a drinking water study, from Days 3 to 21 of lactation. The inhalation exposure was 4 hr/day, 5 days/week, at 610 ppm. The TCE concentration in the drinking water was 333 micrograms/ml. Prediction compared favorably with limited data obtained at restricted time points during the period of lactation.

Animals↗

PubMed1992

Mechanisms for gene conversion and homologous recombination: the double-strand break repair model and the successive half crossing-over model.

Two mechanisms for gene conversion and homologous recombination were discussed. (1) The double-strand break repair model. A double-strand break is expanded to a gap, which is then repaired by copying a homologous sequence. The gene conversion is often accompanied by crossing-over of the flanking sequences. We obtained evidence for this model in Red pathway of bacteriophage lambda and RecE pathway of E. coli. (2) The successive half crossing-over model. Half crossing-over leaves one recombinant duplex and one or two end(s) out of two parental duplexes. The resulting ends are, in turn, recombinogenic. Successive rounds of the half crossing-over mechanism explains why apparent plasmid gene conversion in RecF pathway of E. coli is not accompanied by crossing-over. This model can explain chromosomal gene conversion if we assume that the donor is first replicated. Gene conversion during mating-type switching in yeast, antigenic variation in unicellular microorganisms, and chromosomal gene conversion in mammalian somatic cells are explained by this model. Distinguishing between these two mechanisms is important in understanding recombination in yeast and mammalian cells and also in its application to gene targeting.

Animals↗

PubMed1993

A Macintosh BASIC program for fitting linear additive models to data by weighted least squares methods, with automatic elimination of redundant parameters from the model.

A BASIC program for fitting linear additive models to data with weighted or unweighted least squares methods and matrix procedures is described. Written and compiled to run on Macintosh II type machines (68020/68030/68040) with coprocessor (68881/68882), the program fits the model supplied by the user as an X or design matrix and provides the option of making the model's parameters orthogonal. Predicted values plus regression and residual terms are calculated. For the weighted fit, the significance of the residual term is evaluated and redundant parameters sequentially and automatically removed until a minimum adequate model is achieved. An appropriate design matrix allows weighted fitting of models for multiway analyses of variance (e.g. factorial, nested and split plot), simple or multiple linear or curvilinear regression, combinations of these in covariance analyses, and genetic analyses (including diallel cross analyses). Sums of squares for individual parameters and orthogonal comparisons can be calculated by the program.

Least-Squares Analysis↗

PubMedDate not supplied

Head to head dimer model; an alternative model for the strand exchange reaction by RecA protein of Escherichia coli.

The RecA protein of E coli promotes a strand exchange reaction in vitro which appears to be similar to homologous genetic recombination in vivo. A model for the mechanism of strand transfer reaction by RecA protein has been proposed by Howard-Flanders et al based on the assumption that the RecA monomer has two distinctive DNA binding sites both of which can bind to ssDNA as well as dsDNA. Here, I propose an alternative model based on the assumption that RecA monomer has a single domain for binding to a polynucleotide chain with a unique polarity. In addition, the model is based on a few mechanical assumptions that, in the presence of ATP, two RecA molecules form a head to head dimer as the basic binding unit to DNA, and that the binding of RecA protein to a polynucleotide chain induces a structural change of RecA protein that causes a higher state of affinity for another RecA molecule that is expressed as cooperativy. The model explains many of the biochemical capabilities of RecA protein including the polar polymerization of RecA protein on single stranded DNA and polar strand transfer of DNA by the protein as well as the formation of a joint DNA molecule in a paranemic configuration. The model also presents the energetics in the strand transfer reaction.

Adenosine Triphosphate↗

PubMed2005

Modelling the fate of sulphur-35 in crops. 2. Development and validation of the CROPS-35 model.

Gas-cooled nuclear power plants in the UK release sulphur-35 during their routine operation, which can be readily assimilated by vegetation. It is therefore necessary to be able to model the uptake of such releases in order to quantify any potential contamination of the food chain. A model is described which predicts the concentration of (35)S in crop components following an aerial gaseous release. Following deposition the allocation to crop components is determined by an export function from a labile pool, the leaves, to those components growing most actively post exposure. The growth rates are determined by crop growth data, which is also used to determine the concentration. The loss of activity is controlled by radioactive decay only. The paper describes the calibration and the validation of the model. To improve the model, further experimental work is required particularly on the export kinetics of (35)S. It may be possible to adapt such a modelling approach to the prediction of crop content for gaseous releases of (3)H and (14)C from nuclear facilities.

Calibration↗

PubMed2024

Evaluating the impact of modeling choices on the performance of integrated genetic and clinical models.

PURPOSE: The value of genetic information for improving the performance of clinical risk prediction models has yielded variable conclusions. Many methodological decisions have the potential to contribute to differential results. We performed multiple modeling experiments integrating clinical and demographic data from electronic health records with genetic data to understand which decisions may affect performance. METHODS: Clinical data in the form of structured diagnostic codes, medications, procedural codes, and demographics were extracted from 2 large independent health systems, and polygenic risk scores (PRS) were generated across all patients of European ancestry with genetic data in the corresponding biobanks. Crohn's disease was studied based on its substantial genetic component, established electronic health records-based definition, and sufficient prevalence for training and testing. We investigated the impact of choices regarding the PRS integration method, training sample, model complexity, and performance metrics. RESULTS: Overall, our results showed that including PRS resulted in higher performance, but this gain was only robust in situations with limited clinical information. We found consistent performance increases from more compute-intensive models, such as random forest, but the impact of other decisions varied by site. CONCLUSION: This work highlights the importance of considering methodological decision points in interpreting the impact of PRS on prediction performance in clinical models.

Humans↗

PubMed2004

Computational models of hair cell bundle mechanics: II. Simplified bundle models.

Simplified versions of hair cell bundles are mechanically modeled. The influence of various geometric and material combinations on bundle stiffness, link tensions and deformation shape are examined. Three models are analyzed within this paper: two stereocilia connected by one link, two stereocilia connected by a biologically realistic set of links, and a column of stereocilia connected by realistic links. Stereocilia are modeled using a distributed parameter model [J. Biomech. Eng. 122, 44]. Some fundamental rules for linking bundles emerge from these tests: (1) Links must have a threshold stiffness value for the bundle to deform as a whole. Beyond this value, the stereocilia are perfectly linked and variations in link stiffness do not significantly effect the bundle stiffness or link tension. (2) Decreasing the relative heights of successive stereocilia may increase link tension while decreasing bundle stiffness. (3) When lateral links exist, the top most lateral links carry the majority of tension. Lower links in single column model appear mechanically insignificant. (4) Extending the length of the bundle in a column does not increase the stiffness once the column reaches a certain length.

Animals↗

PubMed2006

Modeling the growth of Listeria monocytogenes based on a time to detect model in culture media and frankfurters.

In the current study, temperature dependent growth of Listeria monocytogenes strain H7776, with an initial inoculum level of approximately 0.1 CFU/mL or g, was modeled based on "time to detect" (TTD) using the Arrhenius equation. The activation energies (E(a)) obtained from specific growth rate and lag phase duration in tryptic soy broth (TSB) and frankfurters were compared. At 4 degrees C, the TTD for L. monocytogenes was 217 h in TSB and 48 h in portions of frankfurters. The TTD decreased as temperature increased from 4 to 36 degrees C in both culture media and frankfurters, and this relationship was modeled using the Arrhenius equation. Based on this model, the E(a) values for the TTD in TSB and frankfurters averaged 22.7 and 18.7 kcal/mol, respectively, and were not significantly different (p<0.05). Linear regression was performed on the exponential part of the growth curve to evaluate specific growth rate constants at each temperature using the Monod model. The E(a) values were also calculated based on the specific growth rate and the lag phase of L. monocytogenes in TSB and frankfurters incubated in the same range of temperatures. The average E(a) values for the specific growth rates and the lag phase durations in TSB cultures were 19 and 21 kcal/mol, respectively. In frankfurters, the average E(a) values were slightly greater for both specific growth rate and lag phase duration (29 and 35 kcal/mol, respectively), but these values were not significantly different from the E(a) calculated for the TTD in each medium. These results indicate that the TTD concept can be used to develop and validate safety-based shelf life models.

Colony Count, Microbial↗

PubMed2004

Molecular modeling of sigma 1 receptor ligands: a model of binding conformational and electrostatic considerations.

We have performed molecular modeling studies on several sigma 1 specific ligands, including PD144418, spipethiane, haloperidol, pentazocine, and others to develop a pharmacophore for sigma 1 receptor-ligand binding, under the assumption that all the compounds interact at the same receptor binding site. The modeling studies have investigated the conformational and electrostatic properties of the ligands. Superposition of active molecules gave the coordinates of the hypothetical 5-point sigma 1 pharmacophore, as follows: R1 (0.85, 7.26, 0.30); R2 (5.47, 2.40, -1.51); R3 (-2.57, 4.82, -7.10); N (-0.71, 3.29, -6.40); carbon centroid (3.16, 4.83, -0.60), where R1, R2 were constructed onto the aromatic ring of each compound to represent hydrophobic interactions with the receptor; and R3 represents a hydrogen bond between the nitrogen atom and the receptor. Additional analyses were used to describe secondary binding sites to electronegative groups such as oxygen or sulfur atom. Those coordinates are (2.34, 5.08, -4.18). The model was verified by fitting other sigma 1 receptor ligands. This model may be used to search conformational databases for other possibly active ligands. In conjunction with rational drug design techniques the model may be useful in design and synthesis of novel sigma 1 ligands of high selectivity and potency. Calculations were performed using Sybyl 6.5.

Binding Sites↗

PubMed2004

Generalized image models and their application as statistical models of images.

A generalized image model (GIM) is presented. Images are represented as sets of four-dimensional (4D) sites combining position and intensity information, as well as their associated uncertainty and joint variation. This model seamlessly allows for the representation of both images and statistical models (such as those used for classification of normal/abnormal anatomy and for inter-patient registration), as well as other representations such as landmarks or meshes. A GIM-based registration method aimed at the construction and application of statistical models of images is proposed. A procedure based on the iterative closest point (ICP) algorithm is modified to deal with features other than position and to integrate statistical information. Furthermore, we modify the ICP framework by using a Kalman filter to efficiently compute the transformation. The initialization and update of the statistical model are also described. Preliminary results show the feasibility of the approach and its potentialities.

Algorithms↗

PubMed2004

Modelling liver tissue properties using a non-linear visco-elastic model for surgery simulation.

In this work, we introduce an extension of the linear elastic tensor-mass method allowing fast computation of non-linear and visco-elastic mechanical forces and deformations for the simulation of biological soft tissue. We aim at developing a simulation tool for the planning of cryogenic surgical treatment of liver cancer. Percutaneous surgery simulation requires accurate modelling of the mechanical behaviour of soft tissue, and previous experimental characterizations have shown that linear elasticity is only a coarse approximation of the real properties of biological tissues. We first show that our model can simulate different types of non-linear and visco-elastic mechanical behaviours at speeds which are compatible with real-time applications. Then an experimental setup is presented which was used to characterize the mechanical properties of deer liver tissue under perforation by a biopsy needle. Experimental results demonstrate that a linear model is not suitable for simulating this application, while the proposed model succeeds in accurately modelling the axial load measured on the needle.

Animals↗

PubMed2006

Dynamic causal modeling: a generative model of slice timing in fMRI.

Dynamic causal modeling (DCM) of functional magnetic resonance imaging (fMRI) data allows one to make inferences about the architecture of distributed networks in the brain, in terms of effective connectivity. fMRI data are usually acquired using echo planar imaging (EPI). EPI sequences typically acquire slices at different times over a few seconds. DCM, in its original inception, was not informed about these slice timings and assumed that all slices were acquired simultaneously. It has been shown that DCM can cope with slice timing differences of up to 1 s. However, many fMRI studies employ a repetition time (TR) of 3 to 5 s, which precludes a straightforward DCM of these data. We show that this limitation can be overcome easily by including slice timing in the DCM. Using synthetic data we show that the extended DCM furnishes veridical posterior means, even if there are large slice-timing differences. Model comparisons show that, in general, the extended DCM out-performs the original model. We contrast the modeling of slice timing, in the context of DCM, with the less effective approach of 'slice-timing correction', prior to modeling. We apply our procedure to real data and show that slice timings are important parameters. We conclude that, generally, one should use DCM with slice timing.

Humans↗

PubMed2005

Evaluation of a year-long dispersion modelling of PM10 using the mesoscale model TAPM for Christchurch, New Zealand.

This paper examines the utility of The Air Pollution Model (TAPM; version 2) in simulating meteorology and dispersion of PM(10) for 1999 over the coastal city of Christchurch, New Zealand. Christchurch usually experiences severe degradation in air quality during austral winter. The formation of a nocturnal inversion layer and the emissions of particulate matter (PM(10)) mainly from solid fuel home heating appliances lead to severe smog episodes on an average of 30 nights during winter. The complex local topography surrounding the city in combination with influences from the urban areas can produce complicated boundary layer winds during quiescent weather. Simulated PM(10) data are used for construction of annual exposure maps for the urban areas in order to assess the health impact of air pollutants due to chronic exposure (presented in an accompanying paper). Meteorology and PM(10) dispersion results are statistically compared with the only permanent air pollution monitoring station available in order to evaluate the model's performance. Statistical measures such as the Index of Agreement (IOA) between modelled and measured data indicate that the model performs well. IOA is greater than 0.6 for meteorological variables, and various calculated skill scores place confidence in the model's performance. However, TAPM has a tendency to overestimate surface wind speed over urban areas during stagnant nocturnal conditions, resulting in quick flushing of pollutants.

Air Pollutants↗

PubMed2005

SOMO (SOlution MOdeler) differences between X-Ray- and NMR-derived bead models suggest a role for side chain flexibility in protein hydrodynamics.

Reduced numbers of frictional/scattering centers are essential for tractable hydrodynamic and small-angle scattering data modeling. We present a method for generating medium-resolution models from the atomic coordinates of proteins, basically by using two nonoverlapping spheres of differing radii per residue. The computed rigid-body hydrodynamic parameters of BPTI, RNase A, and lysozyme models were compared with a large database of critically assessed experimental values. Overall, very good results were obtained, but significant discrepancies between X-ray- and NMR-derived models were found. Interestingly, they could be accounted for by properly considering the extent to which highly mobile surface side chains differently affect translational/rotational properties. Models of larger structures, such as fibrinogen fragment D and citrate synthase, also produced consistent results. Foremost among this method's potential applications is the overall conformation and dynamics of modular/multidomain proteins and of supramolecular complexes. The possibility of merging data from high- and low-resolution structures greatly expands its scope.

Algorithms↗