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PubMed1997

Strategies for hematopoietic stem cell gene therapy: insights from computer simulation studies.

We simulated gene therapy using parameters derived from the analysis of autologous transplantation studies in glucose-6-phosphate dehydrogenase heterozygous cats to determine how hematopoietic stem cell (HSC) biology might influence outcomes. Simulation illustrates that a successful experiment can result by chance and may not be the repeated outcome of a specific protocol design or technical approach. As importantly, in many simulated gene therapy experiments where 1, 2, or 6 of 30 transplanted HSC were labeled, there was significant variation in the contribution from marked clones over time. Variability was minimized in simulations in which large numbers of HSC were transplanted. Strategies that may permit consistent clinically successful results are presented. Taken together, these simulation studies demonstrate that the in vivo behavior of HSC must be considered when optimizing approaches to gene therapy in large animals, and perhaps by extension, in humans.

Animals↗

PubMed1988

Computer simulation of DNA ligation: determination of initial DNA concentrations favouring the formation of recombinant molecules.

A computer program was used to simulate the dynamic process of a ligation of DNA fragments. More specifically, the influence of the initial DNA fragments lengths and concentrations on the relative abundance of the various end-products was systematically investigated. Depending on the nature of the DNA extremities (asymmetric or symmetric, dephosphorylated or not), sets of initial conditions could be found that optimized the yield of active recombinant molecules. These results can be directly used to increase the efficiency of the ligation step, in particular for the construction of cDNA or genomic libraries.

Algorithms↗

PubMed2004

Conformational sampling and dynamics of membrane proteins from 10-nanosecond computer simulations.

In the current report, we provide a quantitative analysis of the convergence of the sampling of conformational space accomplished in molecular dynamics simulations of membrane proteins of duration in the order of 10 nanoseconds. A set of proteins of diverse size and topology is considered, ranging from helical pores such as gramicidin and small beta-barrels such as OmpT, to larger and more complex structures such as rhodopsin and FepA. Principal component analysis of the C(alpha)-atom trajectories was employed to assess the convergence of the conformational sampling in both the transmembrane domains and the whole proteins, while the time-dependence of the average structure was analyzed to obtain single-domain information. The membrane-embedded regions, particularly those of small or structurally simple proteins, were found to achieve reasonable convergence. By contrast, extra-membranous domains lacking secondary structure are often markedly under-sampled, exhibiting a continuous structural drift. This drift results in a significant imprecision in the calculated B-factors, which detracts from any quantitative comparison to experimental data. In view of such limitations, we suggest that similar analyses may be valuable in simulation studies of membrane protein dynamics, in order to attach a level of confidence to any biologically relevant observations.

Computer Simulation↗

PubMed2000

Segmental composition of whole-body impedance cardiogram estimated by computer simulations and clinical experiments.

Whole-body impedance cardiography (ICGWB) has been proposed as a feasible means of measuring cardiac output (CO). However, the source distribution of heart-related impedance variations in the whole body is not known. To establish how much of a signal originates in each segment of the body and what the contribution of each is to stroke volume (SV) in ICGWB, impedance in the extremities and trunk were investigated in 15 healthy volunteers. In addition, the theoretical measurement properties of ICGWB were studied using a computer model of the whole-body anatomy as a volume conductor. The model confirmed the expected result that most of the basal impedance originates from the extremities. Clinical experiments revealed that the heart-related amplitude variations in the ICGWB signal originate more evenly from various body segments, the trunk slightly more than the arms or legs. The heart-related ICGWB signal represents a weighted sum of segmental pulsatile events in the body yielding physiologically meaningful data on almost the whole circulatory system.

Adolescent↗

PubMed1995

Tissue spectroscopy with electrical impedance tomography: computer simulations.

A method is proposed by which bioelectrical spectroscopy could be combined with electrical impedance tomography (EIT) to provide noninvasive characterization of tissue. Multifrequency (2-200 kHz) EIT measurements were simulated with a numerical model for a volume of porcine liver immersed in an electrolytic tank. From the reconstructed EIT images the tissue characterization method was then applied enabling a plot of complex resistivity to be drawn for any selected pixel in the image. Simulations were performed for a small volume of degraded tissue embedded in the normal tissue to examine its effect on the derived spectroscopic parameters. The method could have an application in transplant surgery for screening organs for tissue degradation.

Animals↗

PubMed1996

Exponential growth, random transitions and progress through the G1 phase: computer simulation of experimental data.

At a time of increasing knowledge of gene and molecular regulation of cell cycle progression, a re-evaluation is presented concerning a phenomenon discussed before the present expanding era of cell cycle research. 'Random transition' and exponential slopes of alpha- and beta-curves were conceived in the 1970s and early 1980s to explain cell cycle progression. An exponential behaviour of the beta-curve was claimed as being necessary and sufficient for a 'random transition' in the cell cycle. In our present work, similar slopes of those curves were shown to materialize when the increase in mass of single cells was set as exponential in a structured cell cycle model where DNA replication and increase in cell mass were postulated to be two loosely coupled subcycles of the cell cycle, without introducing any 'random transition'. Findings published in the 1980s demonstrating the effect of serum depletion of 3T3 Balb-c cells were simulated and the shallower slope of the alpha- and beta-curves found experimentally could be attributed to the reduced rate of exponential growth in cell mass, rather than to a reduced 'transition probability'.

3T3 Cells↗

PubMed2002

Computer simulations of protein folding with a small number of distance restraints.

A high coordination lattice model was used to represent the protein chain. Lattice points correspond to amino-acid side groups. A complicated force field was designed in order to reproduce a protein-like behavior of the chain. Long-distance tertiary restraints were also introduced into the model. The Replica Exchange Monte Carlo method was applied to find the lowest energy states of the folded chain and to solve the problem of multiple minima. In this method, a set of replicas of the model chain was simulated independently in different temperatures with the exchanges of replicas allowed. The model chains, which consisted of up to 100 residues, were folded to structures whose root-mean-square deviation (RMSD) from their native state was between 2.5 and 5 A. Introduction of restrain based on the positions of the backbone hydrogen atoms led to an improvement in the number of successful simulation runs. A small improvement (about 0.5 A) was also achieved in the RMSD of the folds. The proposed method can be used for the refinement of structures determined experimentally from NMR data.

Algorithms↗

PubMed1993

A computer simulation of the blood flow at the aortic bifurcation with flexible walls.

To understand the role of fluid dynamics in atherogenesis, especially the effect of the flexibility of arteries, a two-dimensional numerical model for blood flow at the aortic bifurcation with linear viscoelastic walls is developed. The arbitrary Lagrangian-Eulerian method is adopted to deal with the moving boundary problem. The wall expansion induces flow reversals or eddies during the decelerating systole while the wall contraction restricts them during the diastole. A flexible bifurcation experiences the shear stresses about 10 percent lower than those of a rigid one.

Aorta, Abdominal↗

PubMed2003

Stochastic fluctuations of the quantal EPSC amplitude in computer simulated excitatory synapses of hippocampus.

The postsynaptic response in glutamatergic synapses of hippocampus, produced by the release of a single presynaptic vesicle, shows a large variability in amplitude not only among the synapses, but also for a single synapse. A mathematical modelling based on a Brownian motion for the diffusion of glutamate molecules and receptor binding was applied to study the possible sources of the quantal variability. Detailed, geometric and functional, descriptions of the vesicle, of the fusion pore and of the synaptic cleft were used and quantal (or miniature) EPSCs were computed. Our results show non-saturation of AMPA receptors, attributable to the small number of molecules contained in the glutamate vesicles of hippocampus. NMDA receptor saturation was obtained rarely, only in very specific instances. We concluded that the lack of AMPA saturation and intrinsic random variations in basic presynaptic elements, such as the vesicle volume and the vesicle docking position, are the main causes of the observed stochastic variability of the quantal EPSC amplitude. Only minor effects can be ascribed to postsynaptic sources.

Animals↗

PubMed1999

Computer simulations for the optimization of magnetic resonance phase imaging applied in the study of trabecular bone.

A new technique for the evaluation of bone trabeculation using magnetic resonance (MR) phase images has been recently presented. This technique calculates the phase variance in a region of interest (ROI) on the phase images of a gradient echo sequence. In this study, a computer program was developed which simulates the phase distribution in gradient echo acquired phase images of a structure that mimics trabecular bone, consisting of a three-dimensional connected network of orthogonal bone struts. Several tests were performed in order to assess the influence of imaging parameters such as the echo time, the pixel size and the slice width on phase variance. The results from this work show that with selection of appropriate imaging parameters, phase variance strongly reflects variations in trabecular bone density. Representative MR experiments were performed in the distal radius to verify the simulation results.

Bone and Bones↗

PubMed1994

Computer simulation of electrocortical activity at millimetric scale.

We report a simulation of electrocortical wave activity at millimetric scale, during the "desynchronised" state. Asymmetric sigmoid pulse/wave relations, short-range excitatory/inhibitory interactions and long-range excitatory couplings of pools of cortical cells were modelled. Frequency/wave number analysis of cat electrocorticogram was compared with the results of simulation. Local standing waves, with wave numbers from about 0.25/mm to 3.3/mm independent of temporal frequency, appeared in real and simulated ECoG. These arise from interactions of excitatory and inhibitory cells and reciprocal excitation of pyramidal cells. The simulation also exhibits long wave length activity consistent with that of the real ECoG. Serial relay of excitation gives rise to travelling waves with a velocity of about 0.6 m/sec, which approximates earlier experimental estimates based on coherence. Interaction of the local and travelling waves results in group waves with high phase velocities (32 m/sec at 5 Hz, to 0.6 m/sec at 50 Hz). Such group waves have not yet been experimentally identified and would be readily confused with effects of volume conduction. However, the frequency response characteristics of the simulation, along with the group waves, may account for experimental findings of action potential correlation with local field potentials at 40-50 Hz and long-range synchronisation of action potentials.

Animals↗

PubMed2005

Computer simulation of polypeptide adsorption on model biomaterials.

When biomaterials are inserted in a biological environment, for instance in a body implant, proteins do quickly adsorb on the exposed surface. Such process is of fundamental importance, since it directs the subsequent cell adhesion. Here we review recent advances in this field obtained with molecular simulations. While coarse-grained models can provide important general results, as it has long been recognized in polymer science, the hierarchical structure of a very complex copolymer such as a protein, together with the nature of the biomaterial surface suggest that atomistic models are better suited to investigate these phenomena. Thus, after briefly mentioning some common features of coarse-grained and atomistic force fields, we first discuss early theoretical and coarse-grained simulation results about protein adsorption, and then we highlight the main results recently obtained by us with atomistic models. In particular, we discuss some conformational and energetic aspects of the adsorption of protein fragments with different secondary structure on surfaces of different wettability, including hydrophobic graphite and hydrophilic poly(vinylalcohol). We also consider other features, such as the simulation of the materials wettability, the hydration of the adsorbed fragments, their kinetics of spreading, and the sequential adsorption of two protein fragments on top of each other, highlighting the results of general interest.

Adsorption↗

PubMed1987

Logic operations are properties of computer-simulated interactions between excitable dendritic spines.

Neurons in the central nervous system of mammals and many other species receive most of their synaptic inputs in their dendritic branches and spines, but the precise manner in which this information is processed in the dendrites is not understood. In order to gain insight into these mechanisms, simulations of interactions between distal dendritic spines with an excitable membrane have been carried out, using an electrical circuit analysis program for the compartmental representation of a dendrite and several spines. Interactions between responses to single and paired excitatory and inhibitory synaptic inputs have been analyzed. Basic logic operations, including AND gates, OR gates and AND-NOT gates, arise from these interactions. The results suggest the computational power and precision of excitable spines in distal branches of neuronal dendrites, especially those of pyramidal neurons in the cerebral cortex. The applicability to information processing in distal dendrites is discussed.

Computer Simulation↗

PubMed1989

Sensitivity analysis of the systemic circulation with a view to computer simulation and parameter estimation.

A sensitivity analysis study has been performed on a seven-parameter model of the systemic vascular bed in order to obtain structure reductions appropriate for simulation and estimation. This analysis considers separately the systolic and diastolic transfer functions between arterial and venous pressures in order to divide a non-linear problem in two distinct linear problems. The results obtained refer to nominal parameter values corresponding to normal circulatory conditions in man and supply guide-lines for an application-oriented selection of reduced models. Simple resistance-compliance models are preferred because the inertial effects appear to have only slight influence. In particular, the choice of a five-parameter model seems to be convenient for simulation purposes. An additional structure reduction is suggested to reach reliable results in parameter estimation problems. The resulting model is characterized by three elements: peripheral resistance, arterial compliance and venous compliance.

Blood Circulation↗

PubMed2000

Computer simulation of ion channel gating: the M(2) channel of influenza A virus in a lipid bilayer.

The transmembrane fragment of the influenza virus M(2) protein forms a homotetrameric channel that transports protons. In this paper, we use molecular dynamics simulations to help elucidate the mechanism of channel gating by four histidines that occlude the channel lumen in the closed state. We test two competing hypotheses. In the "shuttle" mechanism, the delta nitrogen atom on the extracellular side of one histidine is protonated by the incoming proton, and, subsequently, the proton on the epsilon nitrogen atom is released on the opposite side. In the "water-wire" mechanism, the gate opens because of electrostatic repulsion between four simultaneously biprotonated histidines. This allows for proton transport along the water wire that penetrates the gate. For each system, composed of the channel embedded in a hydrated phospholipid bilayer, a 1.3-ns trajectory was obtained. It is found that the states involved in the shuttle mechanism, which contain either single-protonated histidines or a mixture of single-protonated histidines plus one biprotonated residue, are stable during the simulations. Furthermore, the orientations and dynamics of water molecules near the gate are conducive to proton transfer. In contrast, the fully biprotonated state is not stable. Additional simulations show that if only two histidines are biprotonated, the channel deforms but the gate remains closed. These results support the shuttle mechanism but not the gate-opening mechanism of proton gating in M(2).

Algorithms↗

PubMed2005

Computer simulation of the linear and nonlinear optical susceptibilities of p-nitroaniline in cyclohexane, 1,4-dioxane, and tetrahydrofuran in quadrupolar approximation. I. Molecular polarizabilities and hyperpolarizabilities.

This is the first part of a study of the local field effects on (non)linear optical susceptibilities of solutions of para-nitroaniline (pNA) in three different solvents, cyclohexane (CH), 1,4-dioxane (DI), and tetrahydrofuran (THF), using a discrete molecular representation of the condensed phase. To account for dipolar and quadrupolar effects, the latter of which are especially important for DI solution, all the electric properties necessary to compute the local fields and local field gradients in quadrupolar approximation as well as the dipolar hyperpolarizabilities for the four molecules are computed, including frequency dispersion and vibrational contributions to the dipolar properties. The convergence of the perturbation treatment for the pure vibrational (PV) contributions is examined by comparison of the values obtained at the lowest order with those of partially computed second order in mechanical and electrical anharmonicity. For pNA, for which previous computations of the hyperpolarizabilities have generally found poor agreement with experimental results, a thorough investigation of the effects of solvent-induced geometry changes, dynamic and static correlation, frequency dispersion, and classical thermal averaging over the torsional modes of the substituent groups and the inversion mode of the amino group on the dipolar properties is carried out. Computations using self-consistent continuum reaction field models show that the amino group is substantially less pyramidalized in polar solvents than in the gas phase. With all the effects taken into account, reasonable agreement with the experimental electric-field induced second harmonic generation (EFISH) result on pNA vapor of Kaatz, Donley, and Shelton is obtained.

Aniline Compounds↗

PubMed2001

Computer simulation of non-newtonian effects on blood flow in large arteries.

The influence of viscoelastic effects on blood flow in large arteries is studied numerically. The description of the blood flow uses the conservation of mass and momentum and a constitutive relation of Jeffreys' type (Oldroyd-B) and appropriate relations to describe the shear thinning behaviour. The steady flow studies are carried out in an axisymmetric tube with a local constriction modelling a stenosed blood vessel and in a three-dimensional 90 degrees curved tube. The numerical approach applies a decoupled technique where the computation of kinematics and stresses is separated. The governing equations are solved by means of an upwind stabilised Galerkin finite element method. The numerical results indicate significant influence of viscoelastic effects in the stenosed model. The flow through the curved tube shows minor quantitative viscoelastic influence. The influence of the shear thinning effect can be observed in both geometries. The results demonstrate that the viscoelastic behaviour of the local flow patterns in large arteries is dependent on the shape of the flow domain.

Arteries↗

PubMed1997

Waveform changes due to conduction block and their underlying mechanism in spinal somatosensory evoked potential: a computer simulation. Technical note.

Based on a square-wave solid-angle analysis, a simplified mathematical model was produced for computing a sequence of potential change in a volume conductor generated by an impulse traveling along a nerve fiber. A conduction block was simulated as a phenomenon in which a depolarization wavefront stops traveling when it reaches a certain point, although the following repolarization wavefront continues to travel until it reaches the same point. The spinal somatosensory evoked potential (SSEP) was produced as an algebraic sum of simulated nerve fiber action potentials (NFAPs). With a conduction block, an NFAP that was normally triphasic showed a positive-negative diphasic wave with reduced negativity at the point of the block, diphasic waves with enhanced negativity at points immediately preceding the block, and initial-positive waves alone or abolition of any wave at points beyond the block. The absence of their terminal-positive phases paradoxically enhanced the negative peak of the spinal SSEPs in a partial block that involved only the constituent fastest fibers, because phase cancellation of the phases between the terminal-positive phases of the fastest fibers and the negative phases of the slower fibers, which normally happens, failed to occur. At the points immediately preceding the block, the identical mechanism sustained the spinal SSEP enhancement even when every fiber was included in the block. The computer model predicted that localization of the precise site of conduction block can be achieved by demonstrating an abrupt reduction in the amplitude of the spinal SSEP, which is accompanied by an increased negative wave caudally and an enhanced monophasic positive wave rostrally.

Computer Simulation↗