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At least 145 records · Page 8Linked to original sources

PubMed1997

Modeling mechanical cardiopulmonary interactions for virtual environments.

We have developed a computer system for modeling mechanical cardiopulmonary behavior in an interactive, 3D virtual environment. The system consists of a compact, scalar description of cardiopulmonary mechanics, with an emphasis on respiratory mechanics, that drives deformable 3D anatomy to simulate mechanical behaviors of and interactions between physiological systems. Such an environment can be used to facilitate exploration of cardiopulmonary physiology, particularly in situations that are difficult to reproduce clinically. We integrate 3D deformable body dynamics with new, formal models of (scalar) cardiorespiratory physiology, associating the scalar physiological variables and parameters with corresponding 3D anatomy. Our approach is amenable to modeling patient-specific circumstances in two ways. First, using CT scan data, we apply semi-automatic methods for extracting and reconstructing the anatomy to use in our simulations. Second, our scalar models are defined in terms of clinically-measurable, patient-specific parameters. This paper describes our approach and presents a sample of results showing normal breathing and acute effects of pneumothoraces.

Computer Simulation↗

PubMed1994

Theoretical conformational analysis of the opioid delta antagonist H-Tyr-Tic-Phe-OH and the mu agonist H-Tyr-D-Tic-Phe-NH2.

A molecular mechanics study (grid search and energy minimization) of the highly delta receptor-selective delta opioid antagonist H-Tyr-Tic-Phe-OH (TIP; Tic: tetrahydroisoquinoline-3-carboxylic acid) resulted in four low energy conformers with energies within 2 kcal/mol of that of the lowest energy structure. These four conformers contain trans peptide bonds only and represent compact structures showing various patterns of aromatic ring stacking. The centrally located Tic residue imposes several conformational constraints on the N-terminal dipeptide segment; however, the results of molecular dynamics simulations indicated that this tripeptide still shows some structural flexibility, particularly at the Phe3 residue. Analogous studies performed with the structurally related mu receptor-selective mu agonist H-Tyr-D-Tic-Phe-NH2 resulted in low energy structures that were also compact but showed patterns of ring stacking different from those obtained with TIP. Superimposition of low energy conformers of TIP and H-Tyr-D-Tic-Phe-NH2 revealed that the Phe3 residues of the L-Tic- and the D-Tic peptide were always located on opposite sides of the plane defined by the Tic residue, thus providing an explanation for the distinct activity profiles of the two compounds in structural terms. Attempts to demonstrate spatial overlap between the pharmacophoric moieties of low energy conformers of TIP and the nonpeptide delta antagonist naltrindole were made by superimposing either the Tyr1 and Tic2 aromatic rings and the N-terminal amino group or the Tyr1 and Phe3 aromatic rings and the N-terminal amino group of the peptide with the corresponding aromatic rings and nitrogen atom in the alkaloid structure.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗

PubMed2000

Staphylococcal protein A: unfolding pathways, unfolded states, and differences between the B and E domains.

We present multiple native and denaturation simulations of the B and E domains of the three-helix bundle protein A, totaling 60 ns. The C-terminal helix (H3) consistently denatures later than either of the other two helices and contains residual helical structure in the denatured state. These results are consistent with experiments suggesting that the isolated H3 fragment is more stable than H1 and H2 and that H3 forms early in folding. Interestingly, the denatured state of the B domain is much more compact than that of the E domain. This sequence-dependent effect on the dimensions of the denatured state and the lack of correlation with structure suggest that the radius of gyration can be a misleading reaction coordinate for unfolding/folding. Various unfolding and refolding events are observed in the denaturation simulations. In some cases, the transitions are facilitated through interactions with other portions of the protein-contact-assisted helix formation. In the native simulations, the E domain is very stable: after 6 ns, the C(alpha) root-mean-square deviation from the starting structure is less than 1.4 A. In contrast, the native state of the B domain deviates more and its inter-helical angles fluctuate. In apparent contrast, we note that the B domain is thermodynamically more stable than the E domain. The simulations suggest that the increased stability of the B domain may be due to heightened mobility, and therefore entropy, in the native state and decreased mobility/entropy in the more compact denatured state.

Amino Acid Sequence↗

PubMed1992

Folding protein alpha-carbon chains into compact forms by Monte Carlo methods.

A method is presented for generating folded chains of specific amino acid sequences on a simple cubic lattice. Monte Carlo simulations are used to transform extended geometries of simplified alpha-carbon chains for eight small monomeric globular proteins into folded states. Permitted chain transitions are limited to a few types of moves, all restricted to occur on the lattice. Crude residue-residue potentials derived from statistical structure data are used to describe the energies for each conformer. The low resolution structures obtained by this procedure contain many of the correct gross features of the native folded architectures with respect to average residue energy per nonbonded contact, segment density, and location of surface loops and disulfide pairs. Rms deviations between these and the native X-ray structures and percentage of native long-range contacts found in these final folded structures are 7.6 +/- 0.7 A and 48 +/- 3%, respectively. This procedure can be useful for predicting approximate tertiary interactions from amino acid sequence.

Models, Molecular↗

PubMed1990

Cyclic fatigue-crack propagation, stress-corrosion, and fracture-toughness behavior in pyrolytic carbon-coated graphite for prosthetic heart valve applications.

Fracture-mechanics tests were performed to characterize the cyclic fatigue, stress-corrosion cracking, and fracture-toughness behavior of a pyrolytic carbon-coated graphite composite material used in the manufacture of cardiac valve prostheses. Testing was carried out using compact tension C(T) samples containing "atomically" sharp precracks, both in room-temperature air and principally in a simulated physiological environment of 37 degrees C Ringer's lactate solution. Under sustained (monotonic) loads, the composite exhibited resistance-curve behavior, with a fracture toughness (KIc) between 1.1 and 1.9 MPa square root of m, and subcritical stress-corrosion crack velocities (da/dt) which were a function of the stress intensity K raised to the 74th power (over the range approximately 10(-9) to over 10(-5) m/s). More importantly, contrary to common perception, under cyclic loading conditions the composite was found to display true (cyclic) fatigue failure in both environments; fatigue-crack growth rates (da/dN) were seen to be a function of the 19th power of the stress-intensity range delta K (over the range approximately 10(-11) to over 10(-8) m/cycle). As subcritical crack velocities under cyclic loading were found to be many orders of magnitude faster than those measured under equivalent monotonic loads and to occur at typically 45% lower stress-intensity levels, cyclic fatigue in pyrolytic carbon-coated graphite is reasoned to be a vital consideration in the design and life-prediction procedures of prosthetic devices manufactured from this material.

Biocompatible Materials↗

PubMed1999

Wear of composite resin veneering materials in a dual-axis chewing simulator.

The attritional wear of human enamel and four different composite resins for the veneering of crowns was evaluated in a dual-axis chewing simulator over up to 1200000 loading cycles. Enamel showed less wear than the composite resins. However, an ultrafine compact-filled composite resin (Targis) showed a wear not statistically significantly different from that of enamel. The other composite resins showed a statistically significantly higher wear than enamel regardless whether microfine, ultrafine midway-filled or ultrafine compact-filled.

Analysis of Variance↗

PubMed1994

Physiology, morphology and detailed passive models of guinea-pig cerebellar Purkinje cells.

1. Purkinje cells (PCs) from guinea-pig cerebellar slices were physiologically characterized using intracellular techniques. Extracellular caesium ions were used to linearize the membrane properties of PCs near the resting potential. Under these conditions the average input resistance, RN, was 29 M omega, the average system time constant, tau 0, was 82 ms and the average cable length, LN, was 0.59. 2. Three PCs were fully reconstructed following physiological measurements and staining with horseradish peroxidase. Assuming that each spine has an area of 1 micron 2 and that the spine density over the spiny dendrites is ten spines per micrometre length, the total membrane area of each PC is approximately 150,000 microns 2, of which approximately 100,000 microns 2 is in the spines. 3. Detailed passive cable and compartmental models were built for each of the three reconstructed PCs. Computational methods were devised to incorporate globally the huge number of spines into these models. In all three cells the models predict that the specific membrane resistivity, Rm, of the soma is much lower than the dendritic Rm (approximately 500 and approximately 100,000 omega cm2 respectively). The specific membrane capacitance, Cm, is estimated to be 1.5-2 muF cm-2 and the specific cytoplasm resistivity, Ri, is 250 omega cm. 4. The average cable length of the dendrites according to the model is 0.13 lambda, suggesting that under caesium conditions PCs are electrically very compact. Brief somatic spikes, however, are expected to attenuate 30-fold when spreading passively into the dendritic terminals. A simulated 200 Hz train of fast, 90 mV somatic spikes produced a smooth 12 mV steady depolarization at the dendritic terminals. 5. A transient synaptic conductance increase, with a 1 nS peak at 0.5 ms and a driving force of 60 mV, is expected to produce approximately 20 mV peak depolarization at the spine head membrane. This EPSP then attenuates between 200- and 900-fold into the soma. Approximately 800 randomly distributed and synchronously activated spiny inputs are required to fire the soma. 6. The passive model of the PC predicts a poor resolution of the spatio-temporal pattern of the parallel fibre input. An equally sized, randomly distributed group of approximately 1% of the parallel fibres, activated within a time window of a few milliseconds, would result in approximately the same composite EPSP at the soma.

Animals↗

PubMed1999

Progress and perspectives in computational neuroanatomy.

The tremendous increase in processing power of personal computers has recently allowed the construction of highly sophisticated models of neuronal function and behavior. Anatomy plays a fundamental role in supporting and shaping nervous system activity, yet to date most details of such a role have escaped the efforts of experimental and theoretical neuroscientists, mainly because of the problem's complexity. When accurate cellular morphologies are included in electrophysiological computer simulations, quantitative and qualitative effects of dendritic structure on firing properties can be extensively characterized. Complete models of dendritic morphology can be implemented to allow the computer generation of virtual neurons that model the anatomical characteristics of their real counterparts to a great degree of approximation. From a restricted and already available experimental database, stochastic and statistical algorithms can create an unlimited number of non-identical virtual neurons within several mammalian morphological classes, storing them in a compact and parsimonious format. When modeled neurons are distributed in three-dimensional and biologically plausible rules governing axonal navigation and connectivity are added to the simulations, entire portions of the nervous system can be "grown" as anatomically realistic neural networks. These computational constructs are useful to determine the influence of local geometry on system neuroanatomy, and to investigate systematically the mutual interactions between anatomical parameters and electrophysiological activity at the network level. A detailed computer model of a "virtual brain" that was truly equivalent to the biological structure could in principle allow scientists to carry out experiments that could not be performed on real nervous systems because of physical constraints. The computational approach to neuroanatomy is just at its beginning, but has a great potential to enhance the intuition of investigators and to aid neuroscience education. Anat Rec (New Anat): 257:195-207, 1999.

Animals↗

PubMedDate not supplied

Simulated epicardial potential maps during paced activation reflect myocardial fibrous structure.

Using a three-dimensional propagation model of the human ventricular myocardium, we studied the role of fibrous structure in generating epicardial potential maps. This model represents the myocardium as an anisotropic bidomain with an equal anisotropy ratio, and it incorporates a realistic representation of anatomical features, including epi-endocardial fiber rotation in the compact portion of the wall (compacta) and a distinct fiber arrangement of the trabeculated portion (trabeculata). Activation sequences were elicited at various intramural depths, and maps were calculated throughout a 60 ms sequence. The simulated maps closely resembled those measured by others in the canine heart. During the early stages of activation, a typical map featuring a central minimum flanked by two maxima emerged, with the axis joining these extrema approximately parallel to the fibers near the pacing site, and the axis joining the maxima rotated in the same direction as the fibers for different pacing depths; for endocardial and subendocardial pacing this map changed into one with an oblong positive area. During the later stages of activation, the positive areas of the maps expanded and rotated with the transmural fiber rotation. In concurrence with experiments, we saw a fragmentation and asymmetry of expanding and rotating positive areas. The latter features-apparently caused by the interface between the compacta and trabeculata, variable local thickness of the wall, or local undulations of the vetricular surface-could not be reproduced by more idealized, slab models.

Animals↗

PubMed1998

Tertiary contacts in alpha-lactalbumin at pH 7 and pH 2: a molecular dynamics study.

Molecular dynamics simulations of alpha-lactalbumin were performed under conditions of neutral pH and low pH in order to study the acid-induced molten globule state. Through the use of experimental techniques such as NMR and CD spectroscopy, molten globules have been characterized as being compact intermediates with secondary structure similar to that of the native protein but with tertiary structure that is disordered. The detailed structure of the molten globule state is unknown, however. Through the use of computer simulations we can study the structural changes which occur upon lowering pH. The simulations presented here differ from previous unfolding simulations in two important ways: the electrostatic interactions are treated more accurately than ever before, and artificially high temperatures are not used to force the protein to unfold. Simulations of 880 psec each were run at pH 7 (control simulation) and pH 2. We concentrate on the interesting changes in the tertiary interactions within the protein with lowering of pH. In particular, there is a loss of native tertiary contacts in the beta domain and interdomain region, and a large decrease in interdomain hydrogen bonds.

Computer Simulation↗

PubMed1993

Theoretical probes of conformational fluctuations in S-peptide and RNase A/3'-UMP enzyme product complex.

The dynamic properties of the RNase A/3'-UMP enzyme/product complex and the S-peptide of RNase A have been investigated by molecular dynamics simulations using suitable generalization of ideas introduced to probe the energy landscape in structural glasses. We introduce two measures, namely, the kinetic energy fluctuation metric and the force metric, both of which are used to calculate the time needed for sampling the conformation space of the molecules. The calculation of the fluctuation metric requires a single trajectory whereas the force metric is computed using two independent trajectories. The vacuum MD simulations show that for both systems the time required for kinetic energy equipartitioning is surprisingly long even at high temperatures. We show that the force metric is a powerful means of probing the nature and relative importance of conformational substates which determine the dynamics at low temperatures. In particular the time dependence of the non-bonded force metric is used to demonstrate that at low temperatures the system is predominantly localized in a single cluster of conformational substates. The force metric is used to show that relaxation of long range (in sequence space) interactions must be mediated by a sequence of local dihedral angle transitions. We also argue that the time needed for compact structure formation is intimately related to the time needed for the relaxation of the dihedral angle degrees of freedom. The time for non-bonded interactions, which drive protein molecules to fold under appropriate conditions, to relax becomes extremely long as the temperature is lowered suggesting that the formation of maximally compact structure in proteins must be a very slow process.

Computer Simulation↗

PubMed1998

Mapping the active site of factor Xa by selective inhibitors: an NMR and MD study.

The structure of two selective inhibitors, Ac-Tyr-Ile-Arg-Ile-Pro-NH2 and Ac-(4-Amino-Phe)-(Cyclohexyl-Gly)-Arg-NH2, in the active site of the blood clotting enzyme factor Xa was determined by using transferred nuclear Overhauser effect nuclear magnetic resonance (NMR) spectroscopy. They represent a family of peptidic inhibitors obtained by the screening of a vast combinatorial library. Each structure was first calculated by using standard computational procedures (distance geometry, simulated annealing, energy minimization) and then further refined by systematic search of the conformation of the inhibitor docked in the active site and repeating the simulated annealing and energy minimization. The final structure was optimized by molecular dynamics simulations of the inhibitor-complex in water. The NMR restraints were kept throughout the refinement. The inhibitors assume a compact, very well defined conformation, embedded into the substrate binding site not in the same way as a substrate, blocking thus the catalysis. The model allows to explain the mode of action, affinity, and specificity of the peptides and to map the active site.

Amino Acid Sequence↗

PubMed1985

The occurrence of copper, iron, zinc and other elements and the nature of some copper and iron complexes in humic substances from municipal refuse disposed of in a landfill.

Municipal refuse was allowed to decompose in a simulated landfill for 20 months. Three different models were studied in which the refuse, in 40 m3 lots, was either compacted or mixed 2:1 with sewage sludge, the latter being studied in both uncompacted and compacted states. At 2, 6, 12 and 20 months, humic substances were extracted from samples with 0.1 M Na2P4O7 and 0.1 M NaOH, and humic acids isolated by precipitation after acidification with HCl. The humic substances were examined by electron paramagnetic resonance (EPR) to determine the free radical content and the nature of some of the metal complexes present. The principal form of copper was present in either a square planar or a tetragonally-distorted octahedral environment, probably coordinated to two nitrogen and two oxygen atoms. Fe3+ was present in at least three different environments. In one, it was probably in a complex with rhombic symmetry; another showed Fe3+ in an axially-symmetric environment, most likely as a ferric porphyrin. No distinctions could be made between the concentrations or forms of metals present in the refuse humic substances as a result of adding sewage sludge, but the additions increased the yield of humic substances, particularly in the uncompacted landfill. Humic substances in the refuse retain metal elements in complexed forms which will restrict their release from the landfill.

Carbon↗

PubMed1989

Formulation studies of tableted oral rehydration salt mixtures.

Dehydration following non-specific diarrhoea may be prevented by oral administration of a simple glucose/salt mixture. A solution tablet of this mixture would have advantages of stability under environmental exposure and transport if the costs could be held within reasonable limits. The moisture adsorption and compression characteristics of Oral Rehydration Salts (ORS) ingredients have been studied. Combinations of ingredients resulted in a moisture adsorption higher than that of the individual components. This may be explained in terms of critical relative humidity, RHo, and environmental relative humidity RHi. Preparation of a stable ORS solution tablet therefore requires protection of moisture adsorbing components from the environment. The present UNICEF ORS mixture compacted easily by direct compression but gave fragile tablets, which were hygroscopic. This can be reduced by film coating the electrolyte component as granules with a resin (Eudragit L), or by simulating direct compression of the glucose as a compression-coating around the precompressed electrolytes. The packaging of compression-coated solution tablets in inexpensive polyethylene bags may lengthen the shelf-life and make the preparation less costly than the currently supplied ORS powders packed in laminated aluminium sachets. The increased dissolution lag time for the compacted tablet is a disadvantage that can be overcome by instructions to crush the product immediately before use.

Absorption↗

PubMed1997

The effect of ionic conditions on the conformations of supercoiled DNA. I. Sedimentation analysis.

We studied the conformations of supercoiled DNA as a function of superhelicity and ionic conditions by determining its sedimentation coefficient both experimentally and by calculation. To cancel out unknown parameters from both calculations and experiments, we determined the ratio of the sedimentation coefficient, s, to that of open circular DNA, s(oc). Calculations of the sedimentation coefficient were based on direct solution of the Burgers-Oseen problem for an equilibrium set of DNA conformations generated for each condition by the Metropolis Monte Carlo procedure. There were no adjustable parameters in the Monte Carlo simulations because all three parameters of the DNA model used, bending and torsional elasticity of DNA and DNA effective diameter specifying electrostatic interactions, were known from independent data. The good agreement between measured and calculated values of s/s(oc) allowed us to interpret the sedimentation results in terms of DNA conformations, with particular emphasis on the marked effect of ionic conditions. As NaCl concentration decreases, s/s(oc) increases because the superhelix becomes less regular and more compact. In the presence of just 10 mM MgCl(2), supercoiled DNA adopts essentially the same set of conformations as in moderate to high concentrations of NaCl. Our simulations showed that s is a strong function of the superhelix branching frequency. At near physiological ionic conditions, there are about four branches in the 7 kb DNA molecule used in this work. We found no indication of superhelix collapse in any ionic conditions even remotely approaching physiological ones. For all ionic conditions studied, we conclude that the electrostatic interaction of DNA segments specified by the DNA effective diameter is the primary determinant of supercoiled DNA conformations.

Centrifugation, Density Gradient↗

PubMedDate not supplied

[Dynamics of O2 and CO2 tensions in the brain (mathematical modeling)].

The mathematical model for description of the circulation and gas exchange dynamics in the brain is suggested. The model is based on a cell of two compact parallel capillary network with a brain tissue within. The equation system describing the model was calculated on a computer. The simulation showed that steady state pO2 in the cell during blood flow changes from 0.5 mm/sec to 0.25 or 1 mm/sec is reached within 2--5 sec. The dynamics of pCO2 is more inert. It was shown that the main factor in the dynamics of pO2 in the brain is the velocity of blood flow in capillaries. The dynamic pattern of pCO2 depends on haemodynamical condition, the structure of capillary network and physical properties of CO2.

Brain↗

PubMed1994

Hermite expansions of compact support waveforms: applications to myoelectric signals.

Nonstationary signals with finite time support are frequently encountered in electrophysiology and other fields of biomedical research. It is often desirable to have a compact description of their shape and of their time evolution. For this purpose, Fourier analysis is not necessarily the best tool. The Hermite-Rodriguez and Associated Hermite basis functions are applied in this work. Both are based on the product of Hermite polynomials and Gaussian functions. Their general properties relevant to biomedical signal processing are reviewed. Preliminary applications are described concerning the analysis and description of: a) test signals such as a square pulse and a single cycle of a sinewave, b) electrically evoked myoelectric signals, and c) power spectra of either voluntary or evoked signals. It is shown that expansions with only five to ten terms provide an excellent description of the computer simulated and real signals. It is shown that these two families of Hermite functions are well suited for the analysis of nonstationary biological evoked potentials with compact time support. An application to the estimation of scaling factors of electrically evoked myoelectric signals is described. The Hermite functions show advantages with respect to the more traditional spectral analysis, especially in the case of signal truncation due to stimulation with interpulse intervals smaller than the duration of the evoked response. Finally, the Hermite approach is found to be suitable for classification of spectral shapes and compression of spectral information of either voluntary or evoked signals. The approach is very promising for neuromuscular diagnosis and assessment because of its capability for information compression and waveform classification.

Electrophysiology↗

PubMed1999

Gradual development of protein-like global structures through functional selection.

This work focuses on streamlining the exploration of all possible sequences in an attempt to find polypeptides capable of folding into unique structures. Using a computer simulation, we have demonstrated the efficacy of constraining an 'active site' toward the correct configuration, in this case a particular conformation of a four-residue sequence, to bring about protein-like structure from a significant fraction of random sequences. The successive selections for a correct local configuration lead also to the gradual development of overall folding ability, helicity and compactness within 200 generations. The selection thus imposed alleviates an exhaustive search in sequence space.

Computer Simulation↗