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PubMed2004

Integration of computer modeling and initial studies of site-directed mutagenesis to improve cellulase activity on Cel9A from Thermobifida fusca.

Cellulases are a complex group of enzymes that are fundamental for the degradation of amorphous and crystalline cellulose in lignocellulosic material. Unfortunately, cellulases have a low catalytic efficiency on their substrates when compared to similar enzymes such as amylases, which has led to a strong interest in improving their activities. Thermobifida fusca secretes six cellulose degrading enzymes: two exo- and three endocellulases and an endo/exocellulase Cel9A (formerly called E4). Cel9A shows unique properties because of its endo- and exocellulase characteristics, strong activity on crystalline cellulose, and good synergistic properties. Therefore, it is an excellent target for mutagenesis techniques to improve crystalline cellulose degradation. In this article, we describe research conducted to improve Cel9A catalytic efficiency using a rational design and computer modeling. A computer model of Cel9A was created using the program CHARMM plus its PDB structure and a cellohexose molecule attached to the catalytic site as a starting model. Initially molecular graphics and energy minimization were used to extend the cellulose chain to 18 glucose residues spanning the catalytic domain and cellulose-binding domain (CBD). The interaction between this cellulose chain and conserved CBD residues was determined in the model, and mutations likely to improve the binding properties of the CBD were selected. Site-directed mutations were carried out using the pET vector pET26b, Escherichia coli DH5-alpha, and the QuickChange mutagenesis method. E. coli BL21-DE3 was used for protein production and expression. The purified proteins were assayed for enzymatic activity on filter paper, swollen cellulose, bacterial microcrystalline cellulose, and carboxymethylcellulose (CMC). Mutation of the conserved residue F476 to Y476 gave a 40% improved activity in assays with soluble and amorphous cellulose such as CMC and swollen cellulose.

Actinomycetales↗

PubMed2000

An evaluation of a computational model of lexical access: comment on Dell et al. (1997).

The computational model of lexical access proposed by G. S. Dell, M. F. Schwartz, N. Martin, E. M. Saffran, and D. A. Gagnon (1997) is evaluated. They argued that fits of their model to naming data obtained from normal and brain-damaged patients support assumptions regarding interactivity in the lexicon, global damage in aphasia, and continuity between normal and aphasic naming behavior. Additional analysis reveals that the model fits the empirical data poorly and that the claims Dell et al. made on the basis of the model's performance would not follow even if the model were accurate. Although use of a novel automatic regression procedure improved the model's fit, it cannot account for 5 of Dell et al.'s 21 patients (24%), and its limitations were found to be inherent in its design. It is argued that claims such as those made by Dell et al. can only be addressed by considering evidence from multiple related tasks and by comparing multiple computational models.

Aphasia↗

PubMed2000

Three-dimensional computational model of left heart diastolic function with fluid-structure interaction.

Aided by advancements in computer speed and modeling techniques, computational modeling of cardiac function has continued to develop over the past twenty years. The goal of the current study was to develop a computational model that provides blood-tissue interaction under physiologic flow conditions, and apply it to a thin-walled model of the left heart. To accomplish this goal, the Immersed Boundary Method was used to study the interaction of the tissue and blood in response to fluid forces and changes in tissue pathophysiology. The fluid mass and momentum conservation equations were solved using Patankar's Semi-Implicit Method for Pressure Linked Equations (SIMPLE). A left heart model was developed to examine diastolic function, and consisted of the left ventricle, left atrium, and pulmonary flow. The input functions for the model included the pulmonary driving pressure and time-dependent relationship for changes in chamber tissue properties during the simulation. The results obtained from the left heart model were compared to clinically observed diastolic flow conditions for validation. The inflow velocities through the mitral valve corresponded with clinical values (E-wave = 74.4 cm/s, A-wave = 43 cm/s, and E/A = 1.73). The pressure traces for the atrium and ventricle, and the appearance of the ventricular flow fields throughout filling, agreed with those observed in the heart. In addition, the atrial flow fields could be observed in this model and showed the conduit and pump functions that current theory suggests. The ability to examine atrial function in the present model is something not described previously in computational simulations of cardiac function.

Biomedical Engineering↗

PubMedDate not supplied

Regional myocardial mechanics: integrative computational models of flow-function relations.

Many cardiac disorders result in regionally altered myocardial mechanics. Although myocardial strain distributions can be measured experimentally and clinically, regional wall stresses must be computed from computational models. Combining these approaches can provide insight into the structural basis of regional dysfunction under conditions such as acute myocardial infarction and ischemia-reperfusion. Recently, 3-dimensional computational models have helped to elucidate the structural basis of the functional border zone adjacent to acutely ischemic myocardium. They have also shown that heterogeneous dysfunction in ischemic-reperfused stunned myocardium does not necessarily imply heterogeneous myofilament injury. Now that computational models are able to reproduce many complex features of the 3-dimensional patterns of regional myocardial deformation observed experimentally, we suggest possible roles for such integrative models in clinical diagnosis.

Animals↗

PubMed1998

Human factors project: development of computer models of anatomy as an aid to risk management.

Behavioral studies and reports in the pediatric medical literature suggest that children, particularly those younger than 4 years, frequently place foreign objects such as toys and small parts of consumer products in their mouths, nasal cavities and ear canals. These actions not infrequently lead to injury or death. Accurate models of the anatomical areas most often severely injured by foreign body impaction (oral cavity, orbit, ear canal and nasal passages) would greatly facilitate assessment of the risks of impaction. Because models of these anatomic regions in children of the ages when they are most at risk are not widely available, Intertek Testing Services, Risk Analysis and Management (ITS RAM), in association with faculty at the University of Pittsburgh and the Pittsburgh Supercomputing Center at Carnegie Mellon University, developed computerized models of these anatomical areas of interest in children at the critical stages of child development. Computer models were also developed of proposed or existing products and of objects represented in the ITS RAM Small Parts Aspiration and Ingestion Database (comprised of data from 17 children's hospitals) and fatality data from the Consumer Product Safety Commission. The computer models of products and computer anatomical models can be used to assess the possible hazards inherent in the product designs and to communicate the risks associated with product designs to manufacturers and marketing groups.

Child, Preschool↗

PubMedDate not supplied

TCM-1: a nonlinear dynamical computational model to simulate cellular changes in the T cell system; conceptional design and validation.

Based upon a previously developed theory of dysregulative lymphoma pathogenesis, a computer model is designed in order to simulate cell changes occurring in disturbances of the T cell immune system and in lymphoproliferative diseases. The model is based upon the concept that factors identified as proliferation factors, differentiation factors and inhibition factors exert a network regulation upon development and function of the T cell system, and that selective disturbances of these factors may lead to hyperplastic, aplastic or neoplastic diseases. The resulting computer model (TCM-1) was validated by comparing it with data from human diseases such as acute HHV-6 (viral) infection, chronic persistent HHV-6 infection, progressive HIV1 infection and HTLV-1 infection, and comparing the simulation results with the actual cell data in the human patients. All these infections target the same T cell population (i.e. CD4 + T helper cells), yet cause different prototypical reactions (hyperplastic, aplastic, neoplastic). The described computer model, which was successfully used to simulate changes in the benign lymphoproliferative disease, Canale-Smith syndrome, will serve as the basis model for further supplementation to accommodate identified factorial influences such as by cytokines, chemokines and others.

Adult↗

PubMed2005

Computational models of working memory: putting long-term memory into context.

Detailed computational modeling of human memory has typically been aimed at either short-term (working) memory or long-term memory in isolation. However, recent research highlights the importance of interactions between these systems for both item and order information. At the same time, computational models of both systems are beginning to converge onto a common framework in which items are associated with an evolving "context" signal and subsequently compete with one another at recall. We review some of these models, and discuss a common mechanism capable of modelling working memory and its interaction with long-term memory, focussing on memory for verbal sequences.

Attention↗

PubMed1984

Sensitivity and specificity of the computational model for maximal expiratory flow.

The computational model for forced expiratory flow from human lungs of Lambert and associates (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 52: 44-56, 1982) was used to investigate the sensitivity of maximal expiratory flow to lung properties. It was found that maximal flow is very sensitive to recoil pressure and airway areas but not very sensitive to lung volume, airway compliance, and airway length. Linear programming was used to show that a given air flow-pressure curves was compatible with a fairly wide range of airway properties. Additional data for maximal flow with a He-O2 mixture narrowed the range somewhat. It was shown that the flow-pressure curve contains more information about central than peripheral airways and that information about the latter is obtainable only from flows at recoils less than 2 cmH2O. Parameter ranges compatible with individual flow-pressure curves showed differences that demonstrated that such curves give some indication of individual central airway properties.

Airway Resistance↗

PubMed1977

A Monte Carlo computer model to investigate patient scheduling.

A Monte Carlo computer model was developed to investigate various types of patient appointment schedules for a single channel queue. Input parameters included the incidence of no-shows, the rate of unscheduled walk-ins, the frequency distribution of physician examination times, and the string of appointment times. The results included the frequency distributions of physician utilization rates and the total waiting time of all patients. Five hospital clinics were simulated. Even increment schedules yielded the best trade-off between physician utilization and patient waiting.

Appointments and Schedules↗

PubMed2004

Computational modeling of cardiac ventricular action potentials in rat and mouse: review.

Little is known about the ionic mechanisms underlying the action potential heterogeneity in ventricle-associated healthy and disease conditions, even though five decades of histological, electrophysiological, pharmacological, and biochemical investigations exist. The computational modeling in murine ventricular myocytes can complement our knowledge of the experimental data and provide us with more quantitative descriptions in understanding different conditions related to normal and disease conditions. This paper initially reviews the theoretical modeling for cardiac ventricular action potentials of various species and the related experimental work. It then presents the progress of the computational modeling of cardiac ventricular cells for normal, diabetic, and spontaneously hypertensive rats. The paper also introduces recent modeling efforts for the action potential heterogeneity in mouse ventricular cells. The computational insights gained into the ionic mechanisms in rodents will continue to enhance our understanding of the heart and provide us with new knowledge for future studies to treat cardiac diseases in children and adults. Because the dissemination of computational models is very important, we continue to disseminate these models by iCell, the interactive cell modeling resource. iCell (http://ssd1.bme.memphis.edu/icell/) has been developed as a simulation-based teaching and learning tool for electrophysiology and contains JAVA applets that present models of various cardiac cells and neurons and simulation data of their bioelectric activities at cellular level.

Action Potentials↗

PubMed2005

Radiofrequency ablation: importance of background tissue electrical conductivity--an agar phantom and computer modeling study.

PURPOSE: To determine whether radiofrequency (RF)-induced heating can be correlated with background electrical conductivity in a controlled experimental phantom environment mimicking different background tissue electrical conductivities and to determine the potential electrical and physical basis for such a correlation by using computer modeling. MATERIALS AND METHODS: The effect of background tissue electrical conductivity on RF-induced heating was studied in a controlled system of 80 two-compartment agar phantoms (with inner wells of 0.3%, 1.0%, or 36.0% NaCl) with background conductivity that varied from 0.6% to 5.0% NaCl. Mathematical modeling of the relationship between electrical conductivity and temperatures 2 cm from the electrode (T2cm) was performed. Next, computer simulation of RF heating by using two-dimensional finite-element analysis (ETherm) was performed with parameters selected to approximate the agar phantoms. Resultant heating, in terms of both the T2cm and the distance of defined thermal isotherms from the electrode surface, was calculated and compared with the phantom data. Additionally, electrical and thermal profiles were determined by using the computer modeling data and correlated by using linear regression analysis. RESULTS: For each inner compartment NaCl concentration, a negative exponential relationship was established between increased background NaCl concentration and the T2cm (R2= 0.64-0.78). Similar negative exponential relationships (r2 > 0.97%) were observed for the computer modeling. Correlation values (R2) between the computer and experimental data were 0.9, 0.9, and 0.55 for the 0.3%, 1.0%, and 36.0% inner NaCl concentrations, respectively. Plotting of the electrical field generated around the RF electrode identified the potential for a dramatic local change in electrical field distribution (ie, a second electrical peak ["E-peak"]) occurring at the interface between the two compartments of varied electrical background conductivity. Linear correlations between the E-peak and heating at T2cm (R2= 0.98-1.00) and the 50 degrees C isotherm (R2= 0.99-1.00) were established. CONCLUSION: These results demonstrate the strong relationship between background tissue conductivity and RF heating and further explain electrical phenomena that occur in a two-compartment system.

Agar↗

PubMed2003

Steps toward building mathematical and computer models from cognitive task analyses.

Typically, detailed quantitative and computer models of human operators performing real world tasks cannot easily be developed. We propose a technique that more easily allows for that development. We propose that when a cognitive task analysis has been carried out, a computer simulation model useful for approximations of task completion time is often within reach. The first step is to construct an activity network or order-of-processing diagram from the task analysis. Second, activity durations are found in the literature or approximated through multidimensional scaling. Finally, equations are written for calculating task completion time, or a program is written for simulations to estimate this time. Resulting models can be useful for optimizing system design. The approach is illustrated with an activity network by W. D. Gray, B. E. John, and M. E. Atwood (1993) for a telephone operator task. Simulations demonstrate the feasibility of using multidimensional scaling to obtain approximate activity durations. The approach is also illustrated with an order-of-processing diagram representing drivers reading roadside message displays. We point out that if a more detailed picture of unobservable mental processes in a task is needed, techniques have been developed for this through analysis of response times. Actual or potential applications of this research include system design, human-computer interaction, message comprehension, and simulation of information-processing tasks.

Cognition↗

PubMed2002

A method to quantify the dynamics and complexity of re-entry in computational models of ventricular fibrillation.

Ventricular fibrillation is a deadly cardiac arrhythmia. There is evidence that electrical activity in cardiac tissue is sustained during fibrillation by re-entrant waves that rotate around filaments. In this paper we develop a method for identifying and tracking filaments in a computational model of ventricular fibrillation. This method identifies the birth, death, bifurcation and amalgamation of filaments and these events are summarized on a directed graph. The approach described in this study provides ways to quantify the complex patterns of electrical activity seen in computational models of fibrillation, to relate the behaviour of computational models to experimental data and thus to gain insights into the underlying mechanisms of this dangerous arrhythmia.

Anisotropy↗

PubMed2004

Computational models of the basal ganglia: from robots to membranes.

With the rapid accumulation of neuroscientific data comes a pressing need to develop models that can explain the computational processes performed by the basal ganglia. Relevant biological information spans a range of structural levels, from the activity of neuronal membranes to the role of the basal ganglia in overt behavioural control. This viewpoint presents a framework for understanding the aims, limitations and methods for testing of computational models across all structural levels. We identify distinct modelling strategies that can deliver important and complementary insights into the nature of problems the basal ganglia have evolved to solve, and describe methods that are used to solve them.

Animals↗

PubMed1989

Computer model of cardiac repolarization processes and of the recovery sequence.

A computer model simulating both excitation and recovery processes within a block of heart muscle tissue has been developed and implemented on different IBM PC AT compatible computers. The model incorporates blocks of tissue consisting of several thousand elements and introduces phenomena which are completely or partly omitted in other existing cardiac electrophysiology models. These phenomena include the electric anisotropy of the tissue, different durations of repolarization in different layers of tissue, and the different shapes of action potential which correspond to cells excited when not fully recovered. Implementation of the model on small personal computers requires the use of a special data structure management and an effective algorithmic background. The program of the model is written in PASCAL and uses dynamically allocated data structures and the asynchronous simulation technique of event planing. These techniques are described in detail. The model has been used in various experiments. Results of simulation studies are presented in the form of modeled three-lead electrocardiographic records. The experimental series which are described include basic patterns of regular activation sequences, modeling of premature beats, simulation of effects due to fast pacing, models of ischemia and infarction, simulation of reentry mechanisms with a special reference to the initiation of ventricular fibrillation, and models of late potentials. The future development of more realistic models of the cardiac recovery process is also discussed.

Action Potentials↗

PubMedDate not supplied

[Computer modeling of mechanisms of the information processing in the olfactory bulb. I. Model of the structure-functional organizations of neuronal elements in the olfactory bulb and receptor epithelium].

A computer model of the olfactory bulb was constructed. The paper describes: 1) the general architecture of a model neuron network that reflects the neurophysiological experimental and theoretical data on the structural and functional organization of the peripheral part of the olfactory system, the olfactory bulb with inputs from olfactory receptor neurons; 2) the organization of each of three levels of the model: receptors, olfactory glomeruli, and basic neurons; and 3) a scenario of the computer model work. In some aspects, in particular, in the principle of information presentation, the treatment of the role of basic neurons (mitral and tufted cells), and their interrelations in modules, the model favorably differs from the available olfactory bulb models. The model is basic and provides further refinement of the architecture, an increase in the number of modules, and the modeling of the learning process.

Animals↗

PubMed2004

Simulating complex intracellular processes using object-oriented computational modelling.

The aim of this paper is to give an overview of computer modelling and simulation in cellular biology, in particular as applied to complex biochemical processes within the cell. This is illustrated by the use of the techniques of object-oriented modelling, where the computer is used to construct abstractions of objects in the domain being modelled, and these objects then interact within the computer to simulate the system and allow emergent properties to be observed. The paper also discusses the role of computer simulation in understanding complexity in biological systems, and the kinds of information which can be obtained about biology via simulation.

Animals↗

PubMed1987

A computer model of hemorrhagic shock in domestic swine.

We used a modified version of the computer model of the circulation developed by C.V. Greenway (Pharmacol Rev 33:213-251, 1982) to study the volume-pressure relationship of the systemic venous circulation during and immediately after massive blood loss. Our theoretical predictions were based on experimental measurements performed in conscious, chronically instrumented swine subjected to massive and rapid loss of a predetermined amount of blood. These animals were subjected to an exponential removal of either 50% of their calculated blood volume in 1 hour or a linear removal of 60% in 15 minutes. Our computer model indicates a hysteresis effect between the volume-pressure curves during and immediately following hemorrhage. The results emphasize the importance of venous capacitance changes as a compensatory response to blood loss.

Animals↗