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Influence of vessel distension and myogenic tone on pulmonary arterial input impedance. A study using a computer model of rabbit lung.

A computer model of the pulmonary arterial (PA) bed of rabbit lungs was designed in order to test experimental observations of changes in PA input impedance and pulsatile hydraulic power (cap.) during increased PA pressure. The computer model was based on a simple 3-component analog representation of single vessels (i.e. resistance, inertance and compliance). 16 generations of arterial vessels, from PA to 60 mum diameter, were combined to calculate PA input impedance. Input impedance was found to mimic closely that observed experimentally. Both venous pressure elevation and arteriolar constriction was found to reduce input impedance and Wp. By combining arteriolar constriction with increased myogenic tone of the larger arteries, Wp was found to show a minimum level at a certain PA pressure, dependent on the degree of arterial stiffening. Wp was found to follow changes in arterial volume and resistance during stimulated vasoconstriction. Wp dissipation in arterial vessels was calculated to approx. 50% of total imput Wp at physiological pressure conditions, and could be reduced by one half after PA pressure increase from 20 to 50 cm H2O, despite a concurrent halving of arterial compliance. Arterial vessels smaller than 200 mum diameter were found to have negligible direct influence on PA input impedance.

Animals

[Computer models of personality: implications for measurement].

Computer models of human behavior have long existed in the world of science fiction; however, in reality, progress has been slow. Research has concentrated, in recent years, on the simulation of memory and cognition. Computer models of personality, although fascinating and potentially useful, have been neglected. This paper reviewed the research done to date, categorizing it under five headings: (a) models of belief systems; (b) models of interpersonal behavior; (c) models of decision-making processes; (d) prediction models; and (e) theory-based simulations of specific processes. One practical application was then explored in depth, that of using the computer models in personality measurement. Although some practical development of the working simulations would have to precede their application to personality measurement, it was felt that such an application would be feasible and useful.

Attitude

Metabolism of the acutely ischemic dog heart. I. Construction of a computer model.

Construction of a computer model of glycolysis, the Krebs cycle, and related metabolism in acutely ischemic dog heart, involving 122 metabolites, 65 enzymes, and 406 chemical reactions, is described. A previous model of the same metabolism in normal-flow rat heart was modified to fit ischemic dog heart experimental data to within experimental error. The result resembles other models of ischemic heart preparations, implying common underlying mechanisms. The principal change made was reduction of enzyme amounts, consistent with the generally slower metabolism of large animals, suggesting that differing enzyme amounts are a major component of interspecies metabolic difference. Glycolytic intermediates oscillate, asynchronously and with large changes in level; pyridine nucleotides become highly reduced; pH falls, but mitochondria stay alkaline relative to cytoplasm even after oxidative phosphorylation stops.

Animals

Subsite mapping of enzymes. Depolymerase computer modelling.

We have developed a depolymerase computer model that uses a minimization routine. The model is designed so that, given experimental bond-cleavage frequencies for oligomeric substrates and experimental Michaelis parameters as a function of substrate chain length, the optimum subsite map is generated. The minimized sum of the weighted-squared residuals of the experimental and calculated data is used as a criterion of the goodness-of-fit for the optimized subsite map. The application of the minimization procedure to subsite mapping is explored through the use of simulated data. A procedure is developed whereby the minimization model can be used to determine the number of subsites in the enzymic binding region and to locate the position of the catalytic amino acids among these subsites. The degree of propagation of experimental variance into the subsite-binding energies is estimated. The question of whether hydrolytic rate coefficients are constant or a function of the number of filled subsites is examined.

Amino Acid Sequence

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

Subsite mapping of enzymes. Application of the depolymerase computer model to two alpha-amylases.

In the preceding paper (Allen and Thoma, 1976) we developed a depolymerase computer model, which uses a minimization routine to establish a subsite map for a depolymerase. In the present paper we show how the model is applied to experimental data for two alpha-amylases. Michaelis parameters and bond-cleavage frequencies for substrates of chain lengths up to twelve glucosyl units have been reported for Bacillus amyloliquefaciens, and a subsite map has been proposed for this enzyme [Thoma et al. (1971) J. Biol. Chem. 246, 5621-5635]. By applying the computer model to the experimental data, we have arrived at a ten-subsite map. We find that a significant improvement in this map is achieved by allowing the hydrolytic rate coefficient to vary as a function of the number of occupied subsites comprising the enzyme-binding region. The bond-cleavage frequencies, the enzyme is found to have eight subsites. A partial subsite map is arrived at, but the entire binding region cannot be mapped because Michaelis parameters are complicated by transglycosylation reactions. The hydrolytic rate coefficients for this enzyme are not constant.

Amino Acid Sequence

A computational model of cerebellar cortex and peripheral muscle.

A computational model, suitable for analytical or machine simulation studies, is developed for a specific cerebellar loop, the pathway from muscle fibre stretch receptors to the cerebellar cortex and back again. The model adheres to physiological data from the cat, and employs features from several existing models, including a single neuron model developed and tested earlier. Also included is a mechanical equivalent to an idealised muscle, in this case a rectangular array of muscle fibres which map 1-to-1 onto the array of compartments which form the cerebellar cortex. Much of the literature on cerebellar models is briefly reviewed, as are several key physiological experiments.

Animals

A computational model of pulmonary gas transport incorporating effective diffusion.

A computational model of gas transport in the lung is described which remedies many of the deficiencies of previous models, as listed by Chang and Farhi (1973), in that it allows for fluctuating lung dimensions, gas exchange, simultaneous convection and diffusion, and the enhanced effective diffusion that occurs when convective flow is also present. The results of calculations using the model are presented, showing the maximum effect of Taylor diffusion. The actual magnitude of Taylor diffusion, suitably modified to allow for the disturbed conditions within the lung, is considered in the light of recent experiments.

Carbon Dioxide

Metabolism of totally ischemic excised dog heart. I. Construction of a computer model.

Construction and fit to the experimental data of a computer model of glycolysis, the Krebs cycle, and related metabolism in an ischemic dog heart preparation, involving 122 metabolites, 65 enzymes, and 406 chemical reactions, is described. The experimental preparation simulated is a dog heart excised from the body, placed in a beaker of Tyrode's solution, and sampled for 100 min; the model required only moderate modification from models representing perfused rat hearts, and little modification from a model of another ischemic dog heart preparation. Common underlying mechanisms for the ischemia are indicated, although this preparation appears to evolve more slowly with time, perhpas owing to heavy sedation and diffusion-limited transport. Lactate is, at first, exported and then accumulates intracellularly; pH falls, but not as much in the mitochondria as the cytoplasm; redox couples go reduced, but with counterintuitive time courses; calcium phosphate is calculated to precipitate, as often observed in cardiac ischemia.

Adenine Nucleotides

A computer model in the selection of multiple channel analysers.

1. A simple computer model is described which was used to study possible test combinations on automated multichannel analysers. Specific objectives were minimisation of manpower and maximisation of throughput of the specimen preparation process. 2. In our case, by appropriate test combination selection, a staff saving of 50% in the aliquotting process is predicted. For tests that are available on multichannel analysers, a reduction from 198 to 121 aliquots per 100 patient specimens is expected on an 18 channel machine. With the use of filter separation systems, manual aliquotting would be required for 21 specimens per 100.

Autoanalysis

A computer model for hydrodynamic shearing of DNA.

A computer simulation model for the hydrodynamic shearing of DNA is presented. In this model the event space consists of a number of positions at which the DNA strand may break. The results of the model compared with the real world result are reported in this paper. Future endeavors to generalize the model would add significantly to the model's value.

Computers

The anterior cerebral artery. II. A computer model of its cortical branches estereotaxically obtained from anatomical specimens.

This article is a corrollary of a previously published anatomical study of the anterior cerebral artery. The authors propose a method to obtain a computer model of the anterior cerebral artery, based on a combined system of stereotaxic coordinates and a specially developed computer program. The graphic analysis, thus obtained, is projected on a model atlas brain and an ideal diagram of this anatomical structure is obtained. Forty anatomical specimens were used for this study.

Brain

A computational model for bacteriophage ϕX174 gene expression.

Bacteriophage ϕX174 has been widely used as a model organism to study fundamental processes in molecular biology. However, several aspects of ϕX174 gene regulation are not fully resolved. Here we construct a computational model for ϕX174 and use the model to study gene regulation during the phage infection cycle. We estimate the relative strengths of transcription regulatory elements (promoters and terminators) by fitting the model to transcriptomics data. We show that the specific arrangement of a promoter followed immediately by a terminator, which occurs naturally in the ϕX174 genome, poses a parameter identifiability problem for the model, since the activity of one element can be partially compensated for by the other. We also simulate ϕX174 gene expression with two additional, putative transcription regulatory elements that have been proposed in prior studies. We find that the activities of these putative elements are estimated to be weak, and that variation in ϕX174 transcript abundances can be adequately explained without them. Overall, our work demonstrates that ϕX174 gene regulation is well described by the canonical set of promoters and terminators widely used in the literature.

Gene Expression Regulation, Viral

Addressing current challenges in cancer immunotherapy with mathematical and computational modelling.

The goal of cancer immunotherapy is to boost a patient's immune response to a tumour. Yet, the design of an effective immunotherapy is complicated by various factors, including a potentially immunosuppressive tumour microenvironment, immune-modulating effects of conventional treatments and therapy-related toxicities. These complexities can be incorporated into mathematical and computational models of cancer immunotherapy that can then be used to aid in rational therapy design. In this review, we survey modelling approaches under the umbrella of the major challenges facing immunotherapy development, which encompass tumour classification, optimal treatment scheduling and combination therapy design. Although overlapping, each challenge has presented unique opportunities for modellers to make contributions using analytical and numerical analysis of model outcomes, as well as optimization algorithms. We discuss several examples of models that have grown in complexity as more biological information has become available, showcasing how model development is a dynamic process interlinked with the rapid advances in tumour-immune biology. We conclude the review with recommendations for modellers both with respect to methodology and biological direction that might help keep modellers at the forefront of cancer immunotherapy development.

Computer Simulation

Metabolism of palmitate in perfused rat liver. Computer models of subcellular triacylglycerol metabolism.

1. In the preceding paper [Kondrup (1979) Biochem. J.184, 63-71] the separation of two major fractions of hepatic triacylglycerol was described. One fraction contained triacylglycerol from the endoplasmic reticulum and from the Golgi apparatus. The other fraction contained triacylglycerol from the cytoplasmic lipid droplets. In the present paper possible precursor-product relationships between the two fractions were investigated by means of computer models. 2. The fatty acids present in di- and tri-acylglycerol in the fractions isolated in the time studies were analysed by gas chromatography. From this analysis the relative specific radioactivities, and contents, of palmitate in acylglycerols in the two fractions at the various time points were calculated. 3. A computer was used to predict relative specific radioactivities of pools in defined models of hepatic triacylglycerol metabolism. The acceptability of the models was evaluated by comparing predicted with measured relative specific radioactivities. 4. It is suggested that triacylglycerol in cytoplasmic lipid droplets does not originate (a) directly from triacylglycerol in the endoplasmic reticulum, (b) from a sub-pool of it or (c) directly from non-esterified fatty acids entering the cell. Rather, it is formed from diacylglycerol (and acyl-CoA) in the endoplasmic reticulum. Diacylglycerol, on the other hand, is furnished in part by hydrolysis of triacylglycerol in the endoplasmic reticulum. 5. This suggestion is discussed in relation to previous models of hepatic fatty acid metabolism.

Animals

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

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

Blood Circulation