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At least 865 records · Page 48Linked to original sources

PubMed2002

A 3D structure model of integrin alpha 4 beta 1 complex: I. Construction of a homology model of beta 1 and ligand binding analysis.

It is well established that integrin alpha 4 beta 1 binds to the vascular cell adhesion molecule (VCAM) and fibronectin and plays an important role in signal transduction. Blocking the binding of VCAM to alpha 4 beta 1 is thought to be a way of controlling a number of disease processes. To better understand how various inhibitors might block the interaction of VCAM and fibronectin with alpha 4 beta 1, we began constructing a structure model for the integrin alpha 4 beta 1 complex. As the first step, we have built a homology model of the beta 1 subunit based on the I domain of the integrin CD11B subunit. The model, including a bound Mg(2+) ion, was optimized through a specially designed relaxation scheme involving restrained minimization and dynamics steps. The native ligand VCAM and two highly active small molecules (TBC772 and TBC3486) shown to inhibit binding of CS-1 and VCAM to alpha 4 beta 1 were docked into the active site of the refined model. Results from the binding analysis fit well with a pharmacophore model that was independently derived from active analog studies. A critical examination of residues in the binding site and analysis of docked ligands that are both potent and selective led to the proposal of a mechanism for beta 1/beta 7 ligand binding selectivity.

Amino Acid Sequence↗

PubMed1976

Models for depolymerizing enzymes: criteria for discrimination of models.

Several models for the action of alpha amylase have been proposed to account for the nonrandom distribution of oligosaccharides in the amylase digests of polysaccharides. The preferred-attack model attempts to account for the nonrandom distribution by assuming that the probability for bond cleavage depends upon the position of the bond in the chain. The repetitive, or multiple-attack, model suggests that the nonrandom distribution of oligosaccharides arises because an amylase can form a cage-like complex with a substrate and attack it several times during a single encounter. The multiple-enzyme or dual-site model suggests that the nonrandom yield of oligosaccharides arises from the combined action of exo- and endo-enzymes. The effects of pH, inhibitors, and substrate chain-length on enzyme action have been studied in several laboratories to determine which of the three action-patterns best describes the action of alpha amylase. The influence of these variables on product distributions or enzyme action-patterns are mathematically modeled in the Appendix. The experimental data on porcine-pancreatic alpha amylase are discussed in the light of the derivations.

Amylases↗

PubMed2005

Modeling a multivariable reactor and on-line model predictive control.

A nonlinear first principle model is developed for a laboratory-scaled multivariable chemical reactor rig in this paper and the on-line model predictive control (MPC) is implemented to the rig. The reactor has three variables-temperature, pH, and dissolved oxygen with nonlinear dynamics-and is therefore used as a pilot system for the biochemical industry. A nonlinear discrete-time model is derived for each of the three output variables and their model parameters are estimated from the real data using an adaptive optimization method. The developed model is used in a nonlinear MPC scheme. An accurate multistep-ahead prediction is obtained for MPC, where the extended Kalman filter is used to estimate system unknown states. The on-line control is implemented and a satisfactory tracking performance is achieved. The MPC is compared with three decentralized PID controllers and the advantage of the nonlinear MPC over the PID is clearly shown.

Algorithms↗

PubMed1998

Computational blood flow modelling: errors associated with reconstructing finite element models from magnetic resonance images.

Construction of computational blood flow models from magnetic resonance (MR) scans of real arteries is a powerful tool for studying arterial hemodynamics. In this report we experimentally determine a lower bound for errors associated with such an approach, and present techniques for minimizing such errors. A known, simple three-dimensional geometry (cylindrical tube) was imaged using a commercial MR scanner, and the resulting images were used to construct finite element flow models. Computed wall-shear stresses were compared to known values and peak errors of 40-60% were found. These errors can be attributed to limited spatial resolution, image segmentation and model construction. A simple smoothing technique markedly reduced these peak errors. We conclude that smoothing is required in the construction of arterial models from in vivo MR images. If used appropriately, such images can be used to construct acceptably accurate computational models of realistic arterial geometries.

Blood Circulation↗

PubMed1999

Modelling MRI enhancing lesion counts in multiple sclerosis using a negative binomial model: implications for clinical trials.

In multiple sclerosis (MS) the number of new enhancing lesions seen on monthly magnetic resonance imaging (MRI) scans is the most widely used response variable in MRI-monitored studies of experimental treatments. However, no statistical model has been proposed to describe the distribution of the number of such lesions across MS patients. This article briefly summarizes the statistical models for counted data. The negative binomial (NB) model is proposed to fit the number of new enhancing lesions counted in a set of 56 untreated MS patients followed for 9 months. It is shown that the large variability present in this data set is better addressed by the NB model (residual deviance=66.6, 54 degrees of freedom) than by the Poisson model (residual deviance=1830.1, 55 degrees of freedom). Applications of the parametrization of lesion counts are discussed, and an example related to computer simulations for the sample size estimation is presented.

Adolescent↗

PubMed1990

The theory of sliding filament models for muscle contraction. III. Dynamics of the five-state model.

The five-state model derived in the last paper is shown to provide a unified description of most dynamical behaviour of striated muscle, with a set of rate constants in accord with in-vitro values. It predicts several observed phenomena beyond the scope of older models. Rapid binding of M.ADP.Pi to actin generates a high-frequency tail in the Nyquist plot for AC stiffness, which is only weakly dependent on contraction velocity. Known effects of changes in Ca2+ level are predicted if Ca2+ activates only the phosphate-release step, e.g. in the relaxed-state there is substantial stiffness at high frequencies and weak stiffness at low frequencies. Under partial activation the tension drops with increasing extension speed, and Nyquist plots suggest that the reverse phosphate step should be unaffected by Ca2+. Lowering the phosphate level increases tension and also the first two loop amplitudes of the Nyquist plot. The model also yields an improved tension-velocity characteristic, acceptable length-step response, and simulates Brenner & Eisenberg's "stop and stretch" experiment which is shown to be closely related to isometric activation. Oscillatory length response to small tension steps is shown to be a general feature of any model whose AC stiffness can be fitted by a three-term Kawai formula. The model must be enlarged to include the rigor-state, and to describe the effects of variations in ATP and ADP levels correctly.

Adenosine Diphosphate↗

PubMed1996

A mathematical model for the spatio-temporal dynamics of intrinsic pathway of blood coagulation. I. The model description.

We developed and analyzed the mathematical model of the intrinsic pathway based on the current biochemical data on the kinetics of blood coagulation individual stages. The model includes eight differential equations describing the spatio-temporal dynamics of activation of factors XI, IX, X, II, I, VIII, V, and protein C. The assembly of tenase and prothrombinase complexes is considered as a function of calcium concentration. The spatial dynamics of coagulation was analyzed for the one-dimensional case. We examined the formation of active factors, their spreading, and growth of the clot from the site of injury in the direction perpendicular to the vessel wall, into the blood thickness. We assumed that the site of injury (in the model one boundary of the space segment under examination) becomes a source of the continuous influx of factor XIa. In the first part, we described the model, selected the parameters, etc. In the second part, we compared the model with experimental data obtained in the homogeneous system and analyzed the spatial dynamics of the clot growth.

Blood Coagulation↗

PubMed2003

The macrosphere model: evaluation of a new stroke model for permanent middle cerebral artery occlusion in rats.

BACKGROUND AND PURPOSE: The suture middle cerebral artery occlusion (MCAO) model is widely used for the simulation of focal cerebral ischemia in rats. This technique causes hypothalamic injury resulting in hyperthermia, which can worsen outcome and obscure neuroprotective effects. Herein, we introduce a new MCAO model that avoids these disadvantages. METHODS: Permanent MCAO was performed by intraarterial embolization using six TiO(2) macrospheres (0.3-0.4 mm in diameter) or by the suture occlusion technique. Body temperature was monitored, functional and histologic outcome was assessed after 24 h. Additional 16 rats were subjected to macrosphere or suture MCAO. Lesion progression was evaluated using magnetic resonance imaging (MRI). RESULTS: The animals subjected to suture MCAO developed hyperthermia (>39 degrees C), while the temperature remained normal in the macrosphere MCAO group. Infarct size, functional outcome and model failure rate were not significantly different between the groups. Lesion size on MRI increased within the first 90 min and remained unchanged thereafter in both groups. CONCLUSIONS: The macrosphere MCAO model provides reproducible focal cerebral ischemia, similar to the established suture technique, but avoids hypothalamic damage and hyperthermia. This model, therefore, may be more appropriate for the preclinical evaluation of neuroprotective therapies and can also be used for stroke studies under difficult conditions, e.g., in awake animals or inside the MRI scanner.

Animals↗

PubMed2000

Evaluation of the free ion activity model of metal-organism interaction: extension of the conceptual model.

The present study integrates the concepts of the free ion activity model (FIAM) into biological receptor theory (BRT; i.e. pharmacodynamic principles) to obtain a more rigorous conceptual model; one that more precisely quantifies the interaction of chemical species at biological receptor sites. The developed model, which is viewed as an extended FIAM, explains the conditions under which the FIAM will be effective in explaining biological response (BR). It establishes that BR is directly proportional to the activity of the free metal ion in the linear regions of concentration-response curves only. Additionally, it indicates that [X-cell], the activity of free surface sites on the cell membrane, does not need to be constant in the region of BR, as assumed by the original FIAM. The extended FIAM was tested by re-examining concentration-response data from the literature on aquatic organisms exposed to several ecotoxicologically-relevant trace metals. These data, which would be considered exceptions to the original FIAM, were found to be consistent with the extended FIAM. Due to its more rigorous conceptual basis, the extended FIAM is capable of modelling concentration-response experiments from a wider range of water chemistry conditions (i.e. varying pH, hardness and dissolved organic matter) than the original model and, as such, potentially provides a more useful tool for evaluating metal-organism interactions. This study proposes, for the first time, a quantitative method of uncoupling the biological effects of a metal hydroxide (1:1) complex from that of amelioration of the free metal ion (M(z+)) by H(+). Since the activities of H(+) and metal-hydroxide cannot be independently varied, it has been previously very difficult to evaluate whether metal-hydroxide species contribute to eliciting a BR. Furthermore, the extended FIAM can directly derive fundamental information from concentration-response curves, such as the binding constants of H(+) or the hardness cations (Ca(2+) and/or Mg(2+)) to the cell membrane surface of aquatic organisms.

Algorithms↗

PubMed2000

Evaluation of a model of the cochlear neural membrane. II: comparison of model and physiological measures of membrane properties measured in response to intrameatal electrical stimulation.

This study examines existing equation sets describing neural membrane ionic currents, such as the Hodgkin-Huxley (1952) equations, used to define the membrane currents in a numerical model of the auditory neuron and determines their adequacy for modeling the summation and refraction properties of auditory neurons in response to electrical stimulation. Specifically, the summation and refraction time constants of each equation set are compared to physiological measures of these time constants. Since previous studies have shown the cell body and peripheral process of the auditory neuron may influence the measurement of neural time constants, the physiological time constants used for comparison are those which were recorded using intrameatal electrical stimulation. The intrameatal electrode should stimulate the neuron in an area where the axon has a uniform geometry. Accordingly, the neural model used to duplicate this experiment was also of uniform geometry. Of the membrane equation sets evaluated, none was clearly superior for modeling both the refraction and summation properties of the auditory neuron, though some equation sets were capable of accurately modeling either the refraction or the summation properties, provided operating temperatures were adjusted to provide appropriate kinetics.

Animals↗

PubMed1996

The role of the periodontal ligament in bone modeling: the initial development of a time-dependent finite element model.

Current remodeling theories, as applied to long bones, suggest that such processes are controlled by mechanical strains either within or on the bone surface. In this study, the stresses and strains within the periodontal ligament and surrounding bone, consequent to orthodontic loading of a tooth, were investigated by application of the finite element method. Previously, various authors have applied two and three dimensional instantaneous (essentially static) models to analyze the problems. The study reported in this article describes an initial time-dependent (continuous/dynamic) finite element model for tooth movement that uses newly developed software, the results being cross-referenced against historical data. These early results, from a two-dimensional mathematical model of a loaded canine tooth, suggest that the remodeling process may be controlled by the periodontal ligament rather than the bone. In the finite element model, bone was found to experience a low strain of 1 x 10(-5), whereas the periodontal ligament experienced a strain of 0.1 when the "tooth model" is loaded. Only this latter figure is above the threshold usually reported to be necessary to initiate the remodeling process. Further developments in this rapidly advancing area of biomechanical research should facilitate a greater increase in our knowledge of tissue stress and strain after loading.

Bone Remodeling↗

PubMed1998

Modeling NMR chemical shifts: a comparison of charge models for solid state effects on 15N chemical shift tensors.

This paper presents results from applying different point charge models to take into account intermolecular interactions to model the solid state effects on the 15N NMR chemical shifts tensors. The DFT approach with the BLYP gradient corrected exchange correlation functional has been used because it can include electron correlation effects at a reasonable cost and is able to reproduce 15N NMR chemical shifts with reasonable accuracy. The results obtained with the point charge models are compared with the experimental data and with results obtained using the cluster model, which includes explicitly neighboring molecular fragments. The results show that the point charge models can take into account solid state effects at a cost much lower than the cluster methods.

Magnetic Resonance Spectroscopy↗

PubMed2002

Development of quantitative structure-property relationship models for pseudoternary microemulsions formulated with nonionic surfactants and cosurfactants: application of data mining and molecular modeling.

Data mining, computer-aided molecular modeling, descriptor calculation and multiple linear regression techniques were utilized to produce statistically significant and predictive models for O/W and W/O microemulsions. The literature was scanned over the last 20 years, subsequently, 68 phase diagrams from eight different references were collected. Molecular modeling techniques were then applied on the components of the microemulsion systems to generate plausible 3-D structures. Subsequently, various physicochemical descriptors were calculated based on the resulting 3-D structures. The generated descriptors were correlated with microemulsion existence areas utilizing multiple linear regression analysis (MLR). The generated models were statistically cross-validated and were found to be of significant predictive power. Furthermore, the resulting models allowed better understanding of the process of microemulsion formation.

Drug Compounding↗

PubMed1996

Modelling ECG signals with hidden Markov models.

In this paper, we have studied the use of continuous probability density function hidden Markov models for the ECG signal analysis problem. Our previous work has focused on syntactic pattern recognition methods in signal processing. Hidden Markov model is basically a non-deterministic probabilistic finite state machine, which can be constructed inductively. It has been widely used in speech recognition and DNA modelling. We have found that hidden Markov models are very suitable for ECG recognition and analysis problems and that they are able to model accurately segmented ECG signals.

Artificial Intelligence↗

PubMed2002

Representation primitives, process models and patient data in computer-interpretable clinical practice guidelines: a literature review of guideline representation models.

Representation of clinical practice guidelines in a computer-interpretable format is a critical issue for guideline development, implementation, and evaluation. We studied 11 types of guideline representation models that can be used to encode guidelines in computer-interpretable formats. We have consistently found in all reviewed models that primitives for representation of actions and decisions are necessary components of a guideline representation model. Patient states and execution states are important concepts that closely relate to each other. Scheduling constraints on representation primitives can be modeled as sequences, concurrences, alternatives, and loops in a guideline's application process. Nesting of guidelines provides multiple views to a guideline with different granularities. Integration of guidelines with electronic medical records can be facilitated by the introduction of a formal model for patient data. Data collection, decision, patient state, and intervention constitute four basic types of primitives in a guideline's logic flow. Decisions clarify our understanding on a patient's clinical state, while interventions lead to the change from one patient state to another.

Artificial Intelligence↗

PubMed2002

Extension of the biotic ligand model of acute toxicity to a physiologically-based model of the survival time of rainbow trout (Oncorhynchus mykiss) exposed to silver.

Chemical speciation controls the bioavailability and toxicity of metals in aquatic systems and regulatory agencies are recognizing this as they develop updated water quality criteria (WQC) for metals. The factors that affect bioavailability may be quantitatively evaluated with the biotic ligand model (BLM). Within the context of the BLM framework, the 'biotic ligand' is the site where metal binding results in the manifestation of a toxic effect. While the BLM does account for the speciation and complexation of dissolved metal in solution, and competition among the free metal ion and other cations for binding sites at the biotic ligand, it does not explicitly consider either the physiological effects of metals on aquatic organisms, or the direct effect of water chemistry parameters such as pH, Ca(2+)and Na(+) on the physiological state of the organism. Here, a physiologically-based model of survival time is described. In addition to incorporating the effects of water chemistry on metal availability to the organism, via the BLM, it also considers the interaction of water chemistry on the physiological condition of the organism, independent of its effect on metal availability. At the same time it explicitly considers the degree of interaction of these factors with the organism and how this affects the rate at which cumulative damage occurs. An example application of the model to toxicity data for rainbow trout exposed to silver is presented to illustrate how this framework may be used to predict survival time for alternative exposure durations. The sodium balance model (SBM) that is described herein, a specific application of a more generic ion balance model (IBM) framework, adds a new physiological dimension to the previously developed BLM. As such it also necessarily adds another layer of complexity to this already useful predictive framework. While the demonstrated capability of the SBM to predict effects in relation to exposure duration is a useful feature of this mechanistically-based framework, it is envisioned that, with suitable refinements, it may also have utility in other areas of toxicological and regulatory interest. Such areas include the analysis of time variable exposure conditions, residual after-effects of exposure to metals, acclimation, chronic toxicity and species and genus sensitivity. Each of these is of potential utility to longer-term ongoing efforts to develop and refine WQC for metals.

Animals↗

PubMed1997

Structure and assembly of the catalytic region of human complement protease C1r: a three-dimensional model based on chemical cross-linking and homology modeling.

C1r is the modular serine protease responsible for autocatalytic activation of C1, the first component of the complement classical pathway. Its catalytic region is a noncovalent homodimer of two gamma-B monomers, each comprising two contiguous complement control protein (CCP) modules, IV and V [also known as short consensus repeats (SCRs)], a 15-residue intermediary segment, and the serine protease B domain. With a view to gain insight into domain-domain interactions within this region, fragment C1r (gamma-B)2, obtained by autolytic proteolysis of the active protease, was cross-linked with the water-soluble reagent 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide. Cross-linked species gamma-B intra and gamma-B inter, containing intra- and intermonomer cross-links, respectively, were isolated and then fragmented by CNBr cleavage and trypsin digestion. N-Terminal sequence and mass spectrometry analyses of the resulting cross-linked peptides allowed us to identify one intramonomer cross-link between Lys426 of module V and the C-terminal Asp688 of the serine protease B domain and one intermonomer cross-link between the N-terminal Gly280 of fragment gamma and Glu493 of the B domain. Three-dimensional homology modeling of the CCP modules IV and V and of the B domain was also performed. The complementary information provided by chemical cross-linking and homology modeling studies was used to construct a three-dimensional model of the gamma-B monomer, in which module V interacts with the serine protease on the side opposite to both the active site and the Arg446-Ile447 activation site. Also, a tentative three-dimensional model of the (gamma-B)2 dimer was built, indicating a loose "head to tail" association of the monomers, with the active sites facing opposite directions toward the outside of the dimer. The latter model is compared with available low-resolution structural data, and its functional implications are discussed in terms of the conformational changes occurring during C1r activation.

Amino Acid Sequence↗

PubMedDate not supplied

A predictive aggregate transport model for microfiltration of combined macromolecular solutions and poly-disperse suspensions: testing model with transgenic goat milk.

To meet the technical challenge of recovering human IgG fusion protein from transgenic whole goat milk at reasonable cost with high purity and yield, a predictive aggregate transport model for microfiltration has been developed (Baruah and Belfort, 2003). Here, to test the model's predictability of permeate flux and mass transport, a comprehensive series of experiments with varying wall shear rate, feed temperature, feed concentration, and module design are presented. A very good fit was obtained between the model predictions and measurements for a wide variety of experimental conditions. For microfiltration module design comparison, a linear hollow fiber module (representing current commercial technologies) gave lower permeation flux and higher yield than a helical hollow fiber module (representing the latest self-cleaning methodology). These results are easily explained with the model that is now being used to define operating conditions for maximizing performance. The procedure described by the model is generalizable and can be used to obtain optimal filtration performance for applications other than milk.

Animals↗