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At least 487 records · Page 27Linked to original sources

PubMed2006

Calculation of the vibronic structure of the X2Pi photoelectron spectra of XCN, X=F, Cl, and Br.

The vibronic structure of the photoelectron spectra of the X (2)Pi state of XCN(+) (X=F, Cl, and Br) has been calculated, assuming that the X (2)Pi state can be considered as an isolated electronic state. The Renner-Teller coupling of the two components of the (2)Pi state via the degenerate bending mode as well as spin-orbit coupling effects are taken into account. The two stretching modes are treated within the so-called linear vibronic-coupling model. The vibronic and spin-orbit parameters have been determined by accurate ab initio electronic-structure calculations. While spin-orbit effects are small in FCN(+), the large spin-orbit splitting of the X (2)Pi state of the BrCN(+) leads to a complete quenching of the Renner-Teller effect. The X (2)Pi state of the ClCN(+) is shown to be of particular interest: here the resonance condition for linear-relativistic Renner-Teller coupling is approximately fulfilled. This coupling mechanism leads to a significant intensity transfer to vibronic levels with odd quanta of the bending mode. The calculated spectrum indicates that this novel relativistic vibronic-coupling effect should be observable in high-resolution (electron energy resolution of the order of a few meV) photoelectron spectra of ClCN.

Journal Article↗

PubMed1997

Identification of a novel bond between a histidine and the essential tyrosine in catalase HPII of Escherichia coli.

A bond between the N delta of the imidazole ring of His 392 and the C beta of the essential Tyr 415 has been found in the refined crystal structure at 1.9 A resolution of catalase HPII of Escherichia coli. This novel type of covalent linkage is clearly defined in the electron density map of HPII and is confirmed by matrix-assisted laser desorption/ionization mass spectrometry analysis of tryptic digest mixtures. The geometry of the bond is compatible with both the sp3 hybridization of the C beta atom and the planarity of the imidazole ring. Two mutated variants of HPII active site residues, H128N and N201H, do not contain the His 392-Tyr 415 bond, and their crystal structures show that the imidazole ring of His 392 was rotated, in both cases, by 80 degrees relative to its position in HPII. These mutant forms of HPII are catalytically inactive and do not convert heme b to heme d, suggesting a relationship between the self-catalyzed heme conversion reaction and the formation of the His-Tyr linkage. A model coupling the two processes and involving the reaction of one molecule of H2O2 on the proximal side of the heme with compound 1 is proposed.

Amino Acid Sequence↗

PubMed2001

Hydrodynamic modeling of cerebrospinal fluid motion within the spinal cavity.

The fluid that resides within cranial and spinal cavities, cerebrospinal fluid (CSF), moves in a pulsatile fashion to and from the cranial cavity. This motion can be measured hy magnetic resonance imaging (MRI) and may he of clinical importance in the diagnosis of several brain and spinal cord disorders such as hydrocephalus, Chiari malformation, and syringomyelia. In the present work, a geometric and hydrodynamic characterization of an anatomically relevant spinal canal model is presented. We found that inertial effects dominate the flow field under normal physiological flow rates. Along the length of the spinal canal, hydraulic diameter was found to vary significantly from 5 to 15 mm. The instantaneous Reynolds number at peak flow rate ranged from 150 to 450, and the Womersle number ranged from 5 to 17. Pulsatile flow calculations are presented for an idealized geometric representation of the spinal cavity. A linearized Navier-Stokes model of the pulsatile CSF flow was constructed based on MRI flow rate measurements taken on a healthy volunteer. The numerical model was employed to investigate effects of cross-sectional geometry and spinal cord motion on unsteady velocity, shear stress, and pressure gradientfields. The velocity field was shown to be blunt, due to the inertial character of the flow, with velocity peaks located near the boundaries of the spinal canal rather than at the midpoint between boundaries. The pressure gradient waveform was found to be almost exclusively dependent on the flow waveform and cross-sectional area. Characterization of the CSF dynamics in normal and diseased states may be important in understanding the pathophysiology of CSF related disorders. Flow models coupled with MRI flow measurements mnay become a noninvasive tool to explain the abnormal dynamics of CSF in related brain disorders as well as to determine concentration and local distribution of drugs delivered into the CSF space.

Anatomy, Cross-Sectional↗

PubMed2004

Quantitative effects of thermal injury and insulin on the metabolism of the skeletal muscle using the perfused rat hindquarter preparation.

Injury from a severe burn or trauma can propel the body into a hypermetabolic state that can lead to the significant erosion of lean muscle mass. Investigations describing this process have been somewhat limited due to the lack of adequate experimental models. Here we report the use of a perfused rat hindquarter preparation to study the consequences of a moderate burn injury (approximately 20% total body surface area), with or without the addition of exogenous insulin (12.5 mU/mL), on the fluxes of major metabolites across the isolated skeletal muscle. The metabolic flux data was further analyzed using metabolic flux analysis (MFA), which allows for the estimation of the impact of these conditions on the intracellular muscle metabolism. Results indicate that this model is able to capture the increased rate of proteolysis, glutamine formation, and the negative nitrogen balance associated with the burn-induced hypermetabolic state. The inclusion of exogenous insulin resulted in significant changes in several fluxes, including an increase in the metabolism of glucose and the flux through the pentose phosphate pathway, as well as a reduction in the metabolism of glutamine, alanine, and leucine. However, insulin administration did not affect the nitrogen balance or the rate of proteolysis in the muscle, as has been suggested using other techniques. The use of the perfused hindquarter model coupled with MFA is a physiologically relevant and experimentally flexible platform for the exploration of skeletal muscle metabolism under catabolic conditions, and it will be useful in quantifying the specific metabolic consequences of other therapeutic advances.

Animals↗

PubMed1976

The parent-therapist program: an innovative approach to treating emotionally disturbed children.

The authors describe the parent-therapist program, an innovative alternative to residential treatment for emotionally disturbed children. In the program, which is based on the extended family model, couples not only provide a residential milieu for a child placed with them, but also are trained to be therapists who can deal with specific emotional and behavioral problems. The parent-therapists work together in three treatment teams, each consisting of five couples. Education and supervision are ongoing. A total of 27 children have been treated in the program since it got under way in May 1972. Clinical impressions indicate that the children have made substantial gains in developing social and interpersonal skills and in their academic acievement.

Canada↗

PubMed1994

Carrier screening for cystic fibrosis.

A number of different models of CF carrier screening have now been tested in pilot trials. Apart from opportunistic and cascade testing (which are strictly speaking not true forms of screening), the major programmes have been directed either to young adults in primary care or to pregnant women in antenatal clinics. Only in the latter form of screening has sufficient data been collected to allow conclusions to be reached on the optimum mode of delivery. It seems very probable that when CF carrier screening passes into routine service, it will be the antenatal couple model that is used.

Cystic Fibrosis↗

PubMed2004

Antisymmetric exchange in [2Fe-2S]1+ clusters: EPR of the Rieske protein from Thermus thermophilus at pH 14.

[2Fe-2S] clusters found in the xanthine oxidase family of proteins exhibit an S = 1/2 EPR feature, called signal II, for which one g-value is significantly above g = 2.0. The g-values of signal II cannot be explained with the standard spin coupling model that has been so successful in describing the g = 1.94 signals of [2Fe-2S] ferredoxins. We have studied the EPR spectra of the Rieske protein from Thermus thermophilus at pH 14 and observed a signal II-type EPR spectrum, with g-values at 1.81, 1.94, and 2.14. It is shown that the g-values of signal II can be explained by including an antisymmetric exchange term, d.S1xS2, in the spin Hamiltonian. The presence of this term is sensed by EPR if the isotropic exchange coupling constant J is sufficiently small. For the Rieske protein we determined J = 43 cm-1 which is at least 4 times smaller than the J values reported for [2Fe-2S] clusters that yield standard g = 1.94 signals.

Electron Spin Resonance Spectroscopy↗

PubMed1995

Carrier screening in the community.

A number of different models of cystic fibrosis (CF) carrier screening have now been tested in pilot trials. Apart from opportunistic and cascade testing (which are strictly speaking not true forms of screening), the major programmes have been directed either to young adults in primary care or to pregnant women in antenatal clinics. Only in the latter form of screening has sufficient data been collected to allow conclusions to be reached on the optimum mode of delivery. It seems very probable that when CF carrier screening passes into routine service, it will be the antenatal couple model that is used.

Adult↗

PubMed2003

Dynamical and integrative cell signaling: challenges for the new biology.

Years of careful experimental analysis have revealed that signaling molecules are organized into complex networks of biochemical reactions exquisitely regulated in time and space to provide a cell with high-fidelity information about an extremely noisy and volatile environment. A new view of signaling networks as systems consisting of multiple complex elements interacting in a multifarious fashion is emerging, a view that conflicts with the single-gene or protein-centric approach common in biological research. The postgenomic era has brought about a different, network-centric methodology of analysis, suddenly forcing researchers toward the opposite extreme of complexity, where the networks being explored are, to a certain extent, intractable and uninterpretable. Both the cartoons of simple pathways and the very large "hair-ball" diagrams of large intracellular networks are also representations of static worlds, superficially devoid of dynamics and chemistry. These representations are often viewed as being analogous to stably linked computer and neural networks rather than dynamically changing networks of chemical interactions, where the notions of concentration, compartmentalization, and diffusion may be the primary determinants of connectivity. Arguably, the systems biology approach, relying on computational modeling coupled with various experimental techniques and methodologies, will be an essential component of analysis of the behavior of signal transduction pathways. Combining the dynamical view of rapidly evolving responses and the structural view arising from high-throughput analyses of the interacting species will be the best approach toward efforts toward greater understanding of intracellular signaling processes.

Cell Communication↗

PubMed2005

Kinetics of cell spreading.

Cell spreading is a fundamental event where the contact area with a solid substrate increases because of actin polymerization. We propose in this Letter a physical model to study the growth of the contact area with time. This analysis is compared with experimental data using the ameoba Dictyostelium discoideum. Our model couples the stress, which builds up at the margin of the contact area when the cell spreads, to the biochemical processes of actin polymerization. This leads to a scaling analysis of experimental data with a characteristic time whose order of magnitude compares well with our experimental results.

Actins↗

PubMed1990

Diffusion in porous materials above the percolation threshold.

The diffusion of water-soluble solutes in water-soaked porous media was studied by following the release of benzoic acid from poly(vinyl stearate) matrices. The results were analyzed using a pseudo-steady-state diffusion model coupled with the fundamental concepts of percolation theory. The results of the study indicated that the relationship between the bulk diffusion coefficient of benzoic acid in the polymer matrix and the porosity was well described by percolation scaling laws. A very low percolation threshold (0.07) was experimentally observed for this system.

Benzoates↗

PubMed1992

Cardiac muscle fiber force versus length determined by a cardiac muscle crossbridge model.

A mathematical model incorporating Huxley's sliding filament crossbridge muscle model coupled with parallel and series elastic components was simulated to examine force-length relations under different external calcium concentrations. Several researchers have determined experimentally in both papillary muscle preparations and in situ heart experiments that the calcium concentration (or effective concentration from inotropic agents) will affect the strength and convexity of the cardiac muscle fiber force-length relations. Simulations were performed over a several-order-of-magnitude range of calcium concentrations in isometric contractions and these showed that the force-length curve convexity was changed. Simulation results demonstrated that increasing the stiffness in the model contractile element or series elasticity element did not change the force-length convexity. Increasing the series elasticity element stiffness did slightly change the shape of the force-length curve. The model predicts that the curve convexity changes as a result of the calcium-troponin interactions.

Calcium↗

PubMed2005

Free energy of solvation from molecular dynamics simulation applying Voronoi-Delaunay triangulation to the cavity creation.

The free energy of solvation for a large number of representative solutes in various solvents has been calculated from the polarizable continuum model coupled to molecular dynamics computer simulation. A new algorithm based on the Voronoi-Delaunay triangulation of atom-atom contact points between the solute and the solvent molecules is presented for the estimation of the solvent-accessible surface surrounding the solute. The volume of the inscribed cavity is used to rescale the cavitational contribution to the solvation free energy for each atom of the solute atom within scaled particle theory. The computation of the electrostatic free energy of solvation is performed using the Voronoi-Delaunay surface around the solute as the boundary for the polarizable continuum model. Additional short-range contributions to the solvation free energy are included directly from the solute-solvent force field for the van der Waals-type interactions. Calculated solvation free energies for neutral molecules dissolved in benzene, water, CCl4, and octanol are compared with experimental data. We found an excellent correlation between the experimental and computed free energies of solvation for all the solvents. In addition, the employed algorithm for the cavity creation by Voronoi-Delaunay triangulation is compared with the GEPOL algorithm and is shown to predict more accurate free energies of solvation, especially in solvents composed by molecules with nonspherical molecular shapes.

Journal Article↗

PubMed2002

Coherent and robust modulation of a metabolic network by cytoskeletal organization and dynamics.

In order to investigate the influence of cytoskeletal organization and dynamics on cellular biochemistry, a mathematical model was formulated based on our own experimental evidence. The model couples microtubular protein (MTP) dynamics to the glycolytic pathway and its branches: the Krebs cycle, ethanolic fermentation, and the pentose phosphate (PP) pathway. Results show that the flux through glycolysis coherently and coordinately increases or decreases with increased or decreased levels of polymerized MTP, respectively. The rates of individual enzymatic steps and metabolite concentrations change with the polymeric status of MTP throughout the metabolic network. Negative control is exerted by the PP pathway on the glycolytic flux, and the extent of inhibition depends inversely on the polymerization state of MTP, i.e. a high degree of polymerization relieves the negative control. The stability of the model's steady state dynamics for a wide range of variation of metabolic parameters increased with the degree of polymerized MTP. The findings indicate that the organization of the cytoskeleton bestows coherence and robustness to the coordination of cellular metabolism.

Cytoskeleton↗

PubMed1997

Calculation of diffusion-limited kinetics for the reactions in collision coupling and receptor cross-linking.

Both enzyme (e.g., G-protein) activation via a collision coupling model and the formation of cross-linked receptors by a multivalent ligand involve reactions between two molecules diffusing in the plasma membrane. The diffusion of these molecules is thought to play a critical role in these two early signal transduction events. In reduced dimensions, however, diffusion is not an effective mixing mechanism; consequently, zones in which the concentration of particular molecules (e.g., enzymes, receptors) becomes depleted or enriched may form. To examine the formation of these depletion/ accumulation zones and their effect on reaction rates and ultimately the cellular response, Monte Carlo techniques are used to simulate the reaction and diffusion of molecules in the plasma membrane. The effective reaction rate at steady state is determined in terms of the physical properties of the tissue and ligand for both enzyme activation via collision coupling and the generation of cross-linked receptors. The diffusion-limited reaction rate constant is shown to scale with the mean square displacement of a receptor-ligand complex. The rate constants determined in the simulation are compared with other theoretical predictions as well as experimental data.

Animals↗

PubMed2006

Modeling the HIV/AIDS epidemic among injecting drug users and sex workers in Kunming, China.

This paper presents a mathematical model of the HIV/AIDS epidemic in Kunming, the provincial capital of Yunnan, China. The population is divided into several groups, with individuals possibly changing group. Two transmission routes of HIV are considered: needle sharing between injecting drug users (IDUs) and commercial sex between female sex worker (FSWs) and clients. The model includes male IDUs who are also clients and female IDUs who are also FSWs. Groups are split in two--risky and safe--according to condom use and needle sharing. A system of partial differential equations is derived to describe the spread of the disease. For the simulation, parameters are chosen to fit as much as possible data publicly available for Kunming. Some mathematical properties of the model--in particular the epidemic threshold R0 which determines the goal of public health interventions--are also presented. Though the model couples two transmission routes of HIV, the approximation R0 approximately = max[R0(IDU), R0(sex)], with closed formulas for R0(IDU) and R0(sex), appears to be quite good. The critical levels of condom use and clean needle use necessary to stop both the sexual transmission and the transmission among IDUs can therefore be determined independently.

Acquired Immunodeficiency Syndrome↗

PubMed2002

3D QSAR (COMFA) of a series of potent and highly selective VLA-4 antagonists.

The integrin VLA-4 (alpha4,beta1) is involved in the migration of white blood cells to sites of inflammation, and is implicated in the pathology of a variety of diseases including asthma and multiple sclerosis. We report the structure-activity relationships of a series of VLA-4 antagonists that were based upon the integrin-binding sequence of the connecting segment peptide of fibronectin (Leu-Asp-Val), and of VCAM-1 (Ile-Asp-Ser), both natural ligands of VLA-4. We explore variation in the ligand derived peptide portion of these antagonists and also in the novel N-terminal cap, which have discovered through chemical optimization, and which confers high affinity and selectivity. Using the X-ray derived conformation of the Ile-Asp-Ser region of VCAM-1, we rationalize the structure-activity relationships of these antagonists using 3D QSAR (COMFA). The COMFA model was found to be highly predictive with a cross-validated R2CV of 0.7 and a PRESS of 0.49. The robustness of the model was confirmed by testing the influence of various parameters, including grid size, column filtering, as well as the role of orientation of the aligned molecules. Our results suggest that the VCAM-1 structure is useful in generating highly predictive models of our VLA-4 antagonists. The COMFA model coupled with the knowledge that the peptide amides are tolerant to methylation should prove useful in future peptidomimetic design studies.

Binding Sites↗

PubMed2004

A patient-specific computer model to predict outcomes of the balloon occlusion test.

OBJECT: Balloon occlusion tests (BOTs) are performed to identify patients who are at risk for ischemia and stroke following permanent internal carotid artery (ICA) occlusion. The object of this work was to determine whether patient-specific blood flow modeling can be used to identify patients in whom the BOT would not be tolerated. METHODS: The test was performed in 16 patients who underwent BOT with continuous neurological and electroencephalographic monitoring, followed by a hypotensive challenge. During hypotension a tracer was injected so that single-photon emission tomography (SPECT) scans could be obtained. Each individual brain circulation was modeled using information gained from phase-contrast magnetic resonance (MR) angiography and digital subtraction (DS) angiography, and the predicted effect of the BOT was evaluated. Six patients did not tolerate the BOT; in these patients, decreases in middle cerebral artery (M1 segment) blood flow of 41 +/- 27% (mean +/- standard deviation), anterior cerebral artery (A3 segment) flow of 56 +/- 33%, and posterior cerebral artery (P2 segment) flow of 4 +/- 13% ipsilateral to the site of occlusion were found with modeling; these changes were significantly greater than the percentage of changes measured in the contralateral hemisphere (p < 0.05). Ten patients who tolerated the BOT well had calculated decreases in ipsilateral flows of only 9 +/- 6% for the M1 segment, 12 +/- 40% for the A3 segment, and 17 +/- 21% for the P2 segment during BOT modeling. CONCLUSIONS: A decrease in blood flow in both the ipsilateral M1 and A3 segments that was greater than 20%, calculated by flow modeling of the BOT, was 100% sensitive and 100% specific in identifying patients who could not tolerate the BOT. Blood flow modeling, coupled with DS angiography and noninvasive phase-contrast MR angiography measurements to make calculations patient specific, can be used to identify patients who have an elevated risk of ischemia during the BOT.

Adult↗