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At least 55 records · Page 3Linked to original sources
PubMed1990

The use of selective inhibitors and computer modelling to evaluate the role of specific high affinity cyclic AMP phosphodiesterases in the hormonal regulation of hepatocyte intracellular cyclic AMP concentrations.

Using experimentally derived data for the activities and kinetic constants of hepatocyte cyclic AMP phosphodiesterase isoenzymes together with the derived changes in adenylate cyclase activity, due to stimulation and subsequent desensitization by glucagon, a computer model was established to simulate hepatocyte cyclic AMP metabolism. The established ability of glucagon to activate the 'dense-vesicle' cyclic AMP phosphodiesterase by eliciting its cyclic AMP-dependent phosphorylation was shown on the model to be capable of eliciting a profound reduction in the glucagon-stimulated increase in intracellular cyclic AMP. This was consistent with experimentally derived observations using the compound ICI 118233 which was used to inactivate the 'dense-vesicle' enzyme selectively. The non-hydrolysable adenosine agonist N6 (phenylisopropyl)-adenosine (PIA), which prevents glucagon pre-treatment of hepatocytes blocking the ability of insulin to stimulate the peripheral plasma membrane cyclic AMP phosphodiesterase, is shown here to accentuate the ability of insulin to decrease glucagon-elevated intracellular cyclic AMP concentrations. This effect was obliterated using the compound ICI 63197, a selective inhibitor of the peripheral plasma membrane phosphodiesterase. Computer modelling studies, taking into account experimentally derived actions in insulin in activating the peripheral plasma membrane phosphodiesterase, confirmed the potential of this enzyme to decrease intracellular cyclic AMP concentrations. Modelling of the putative effect of an insulin 'mediator' in activating the two cyclic GMP-stimulated cyclic AMP phosphodiesterase isoenzymes was shown to elicit a decrease in intracellular cyclic AMP concentrations which was comparable to that caused by insulin's action on intact hepatocytes. The relative contribution of each phosphodiesterase form to the metabolism of hepatocyte intracellular cyclic AMP, together with an assessment of the potential effect of inhibition and activation of specific species, was evaluated using the computer model. These experimental and stimulation studies indicate that alterations in the phosphodiesterase activity of the 'dense-vesicle' enzyme, the peripheral plasma membrane enzyme, the cyclic GMP-stimulated cyclic AMP isoforms and the IBMX-insensitive PDE-MQ-II can elicit profound effects upon hepatocyte intracellular cyclic AMP concentrations.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1976

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↗
PubMed1991

3-D computer model of subcortical structures of human brain.

Three-dimensional computer model of thalamus and adjacent formations of human brain has been elaborated on the basis of sagittal slices from the Schaltenbrand-Bailey stereotactic atlas. The model includes 120 morphologically distinguishable structures and consists of more than 16 million points (volume elements) each of them being associated with the particular structure in the brain. The model is stored in the long-term computer memory. A special software has been developed to facilitate utilizing the model obtained. The software facilitates synthesizing arbitrary cross-sections through the brain and provides the correspondence between the stereotactic coordinates of any point and its position on the screen of monitor. The coordinates of the point in the system of stereotactic atlas and the name of the structure, the point belongs to, are also supplied. It is also possible to get magnified images of cross-sections and to get isometrical images. The system enables the neurosurgeon to improve the planning and execution of stereotactic operations, and will also be helpful for education.

Brain↗
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↗
PubMed1991

Stereochemical complementarity of progesterone and cavities between base pairs in partially unwound double stranded DNA using computer modeling and energy calculations to determine degree of fit.

Computer modeling was applied for the first time to investigate previously reported complementarity of progesterone and cavities formed between base pairs in partially unwound double stranded DNA. Computer graphics enabled a more objective assessment of complementarity; energy calculations provided a rigorous method to evaluate degree of fit. Graphics confirmed that the complementarity was virtually "lock and key", i.e. close contacts were formed between van der Waals surfaces in the progesterone/DNA complexes and hydrogen bonds were formed between the two carbonyl groups on opposite ends of the steroid and phosphate groups on adjacent strands of DNA. Molecular mechanics calculations revealed that insertion of the steroid resulted in a relatively stable complex i.e. both van der Waals and electrostatic energies were lowered due to favorable steric interactions and stereospecific hydrogen bonds, respectively. Three published X-ray crystal structures of progesterone exhibited similar complementarity. Ent-progesterone which does not occur naturally possessed very poor complementarity. These findings confirm that the structure of progesterone is directly reflected in the stereochemistry of DNA. While no mechanistic explanation for these results is proffered, we hypothesize that such complementarity must have played a decisive role in the evolution of steroid hormone structure and function.

Base Composition↗
PubMed1977

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↗
PubMed1992

Intra-blood-brain barrier synthesis of IgG: comparison of IgG synthesis formulas in a computer model and in 1,629 consecutive specimens.

We evaluated four formulas for estimating the intra-blood-brain barrier (IBBB) synthesis of IgG in a computer model of two types of BBB damage and in 1,629 consecutively received pairs of CSF and serum. These four formulas were the IgG synthesis rate (SR), IgG(loc) (ie, local), IgG index, and IgG extended index. Results from the 1,629 specimens and the computer model of type 2 BBB damage (partial or total loss of selective filtration) accurately predicted problems encountered with the IgG SR in clinical practice. In both the model and with the results from the 1,629 specimens, the combination of the IgG(loc) and IgG index formulas minimized the possibility of false-positive and false-negative results and yielded the most reliable results for IBBB synthesis of IgG in the presence or absence of increased permeability of the BBB. Additional studies with detailed clinical correlations will allow an accurate assessment of how effectively this combination of formulas can help to rule in or out the diagnosis of a particular disease or inflammatory condition of the CNS.

Albumins↗
PubMedDate not supplied

Computer modelling studies of ribonuclease T1-2'-deoxy-2'-fluoroguanylyl- (3',5')-cytidine complex.

The mode of binding of the substrate analog 2'-deoxy-2'-fluoroguanylyl- (3',5')-cytidine (GfpC) to RNase T1 was determined by computer modelling studies. The results obtained are in good agreement with the observations of 1H-nmr studies. The modes of binding of the substrate analog GfpC and the substrate GpC to the enzyme RNase T1 have been compared. Though the guanine base favours to occupy the same site of the enzyme in both the complexes, significant differences are observed in the local environment around the 2'-substituent group of guanosine ribose moiety. In the RNase T1-GpC complex, the 2'-OH group is in close proximity to the side chain carboxylic acid of Glu58 which leads to the formation of a hydrogen bond. However, in the RNase T1-GfpC complex, 2'-fluorine is positioned away from Glu58 due to electrostatic repulsion and instead forms a hydrogen bond with His40 imidazolium group. The results obtained rule out the possibility of His40 serving as the base group in catalysis as suggested by 1H-nmr studies and further support the primary role assigned to Glu58 as the general base group by earlier computer modelling and the recent site directed mutagenesis studies. This study also implies that the 2'-deoxy-2'-fluoro substrate analog may not serve as a good model for determining the amino acid residue which serves as the general base group in ribonuclease catalysed reactions.

Binding Sites↗
PubMed1977

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↗
PubMed1991

Computer modelling of neural tube defects.

Neurulation, the curling of the neuroepithelium to form the neural tube, is an essential component of the development of animal embryos. Defects of neural tube formation, which occur with an overall frequency of one in 500 human births, are the cause of severe and distressing congenital abnormalities. However, despite the fact that there is increasing information from animal experiments about the mechanisms which effect neural tube formation, much less is known about the fundamental causes of neural tube defects (NTD). The use of computer models provides one way of gaining clues about the ways in which neurulation may be compromised. Here we employ one computer model to examine the robustness of different cellular mechanisms which are thought to contribute to neurulation. The model, modified from that of Odell et al (Odell, G.M., Oster, G., Alberch, P. and Burnside, B., (1981)) mimics neurulation by laterally propagating a wave of apical contraction along an active zone within a ring of cells. We link the results to experimental evidence gained from studies of embryos in which neurulation has been perturbed. The results indicate that alteration of one of the properties of non-neural tissue can delay or inhibit neurulation, supporting the idea, gained from observation of embryos bearing genes which predispose to NTD, that the tissue underlying the neuroepithelium may contribute to the elevation of the neural folds. The results also show that reduction of the contractile properties of a small proportion of the neuroepithelial cell population may have a profound effect on overall tissue profiling. The results suggest that the elevation of the neural folds, and hence successful neurulation, may be vulnerable to relatively minor deficiencies in cell properties.

Animals↗
PubMed1990

The solution conformations of ferrichrome and deferriferrichrome determined by 1H-NMR spectroscopy and computational modeling.

We have applied computational procedures that utilize nmr data to model the solution conformation of ferrichrome, a rigid microbial iron transport cyclohexapeptide of known x-ray crystallographic structure [D. van der Helm et al. (1980) J. Am. Chem. Soc. 102, 4224-4231]. The Al3+ and Ga3+ diamagnetic analogues, alumichrome and gallichrome, dissolved in d6-dimethylsulfoxide (d6-DMSO), were investigated via one- and two-dimensional 1H-nmr spectroscopy at 300, 600, and 620 MHz. Interproton distance constraints derived from proton Overhauser experiments were input to a distance geometry algorithm [T. F. Havel and K. Wüthrich (1984) Bull. Math. Biol. 46, 673-691] in order to generate a family of ferrichrome structures consistent with the experimental data. These models were subsequently optimized through restrained molecular dynamics/energy minimization [B. R. Brooks et al. (1983) J. Comp. Chem. 4, 187-217]. The resulting structures were characterized in terms of relative energies and conformational properties. Computations based on integration of the generalized Bloch equations for the complete molecule, which include the 14N-1H dipolar interaction, demonstrate that the x-ray coordinates reproduce the experimental nuclear Overhauser effect time courses very well, and indicate that there are no significant differences between the crystalline and solution conformations of ferrichrome. A similar study of the metal free peptide, deferriferrichrome, suggests that at least two conformers are present in d6-DMSO at 23 degrees C. Both are different from the ferrichrome structure and explain, through conformational averaging, the observed amide NH and CH alpha multiplet splittings. The occurrence of interconverting peptide backbone conformations yields an increased number of sequential NH-CH alpha and NH-NH Overhauser connectivities, which reflects the mean value of r-6 dependence of the dipolar interaction. Our results support the idea that, in the case of structurally rigid peptides, moderately accurate distance constraints define a conformational subspace encompassing the "true" structure, and that energy considerations reduce the size of this subspace. For flexible peptides, however, the straight-forward approach can be misleading since the nmr parameters are averaged over substantially different conformational states.

Amino Acid Sequence↗
PubMed1991

Cardiac electrophysiological experiments in numero, Part I: Concepts and strategies of mathematical and computer models.

This article is the first of three articles that review mathematical and computer models of the heart and describe their construction, development, research potential, and clinical utility. This article explains the methodological principles of mathematical and computer simulation of biomedical systems. The strategies of model construction, testing, and application are presented; the advantages and limitations of computer simulation studies are explained, and the basic value of computer simulation for cardiological research and practice is discussed.

Cardiac Pacing, Artificial↗
PubMed1979

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↗
PubMed1990

Computer model of an inhomogeneous human torso.

Based on the atlas of sectional human anatomy, a three dimensional computer model of a human torso, including four cavities of the heart (LV, RV, LA, RA), two lobes of the lung and the body surface, and a three dimensional model of the myocardium is introduced. The torso model, with more than 10,000 surface triangles, depicts the structures and appropriate proportions of the internal organs, especially of the heart. Algorithms for the model construction are given in detail and the validity of the models for the purpose of simulation research into the electrocardiogram is discussed.

Algorithms↗
PubMed1992

Initial results for automated computational modeling of patient-specific electromagnetic hyperthermia.

Developments in finite-difference time-domain (FD-TD) computational modeling of Maxwell's equations, super-computer technology, and computed tomography (CT) imagery open the possibility of accurate numerical simulation of electromagnetic (EM) wave interactions with specific, complex, biological tissue structures. One application of this technology is in the area of treatment planning for EM hyperthermia. In this paper, we report the first highly automated CT image segmentation and interpolation scheme applied to model patient-specific EM hyperthermia. This novel system is based on sophisticated tools from the artificial intelligence, computer vision, and computer graphics disciplines. It permits CT-based patient-specific hyperthermia models to be constructed without tedious manual contouring on digitizing pads or CRT screens. The system permits in principle near real-time assistance in hyperthermia treatment planning. We apply this system to interpret actual patient CT data, reconstructing a 3-D model of the human thigh from a collection of 29 serial CT images at 10 mm intervals. Then, using FD-TD, we obtain 2-D and 3-D models of EM hyperthermia of this thigh due to a waveguide applicator. We find that different results are obtained from the 2-D and 3-D models, and conclude that full 3-D tissue models are required for future clinical usage.

Computer Simulation↗
PubMed1991

A massively parallel computer model of propagation through a two-dimensional cardiac syncytium.

A computer model of electrical propagation through a two-dimensional (2D) sheet of cardiac tissue has been developed to run on the massively parallel processor Connection Machine (CM-2) computer. The transmembrane ionic currents in each of 16,384 (128 x 128) 100 x 100 microns 2 patches of cardiac tissue are described by modified Beeler-Reuter membrane equations. These equations, along with the parabolic differential equation derived from 2D cable theory, are solved in parallel to study normal and abnormal 2D propagation. The sheet is paced with planar waves at a basic cycle length of 500 msec (control). When a premature ectopic stimulus of sufficient strength and appropriate timing is then applied to a local region of the syncytium, one of two types of reentry is observed: (a) stable figure-of-eight reentry, or (b) unstable but self-sustaining "fibrillation-like" reentry. During this fibrillatory activity, action potential durations are 79.8 +/- 36.8 msec (control = 244.9 +/- 0.9 msec) and coupling intervals average 96.7 +/- 31.3 msec (control = 500 +/- 0 msec). We also observed that passive electrotonically-induced depolarization of already refractory tissue extended the refractory period of that tissue, and that the duration of this extension depended on the magnitude of the electrotonic effect.

Action Potentials↗
PubMed1990

A computer model of the heart that obeys Starling's law.

We developed a computer model of the heart that accurately reproduces human left ventricular pressure wave morphology. The model factors beat-to-beat venous return in generating cardiac output and simulates congestive heart failure when the venous return exceeds the heart's pumping capacity. The blood pressure waveform produced by our model resembles experimental data with a greater than 98% correlation and the model incorporates Starling's transfer function. The model is useful for simulations of cardiovascular hemodynamics where accurate waveforms and venous return feedback or modeling failing hearts are important.

Blood Pressure↗