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At least 1,711 records · Page 95Linked to original sources
PubMed1998

The coefficient of error of optical fractionator population size estimates: a computer simulation comparing three estimators.

The optical fractionator is a design-based two-stage systematic sampling method that is used to estimate the number of cells in a specified region of an organ when the population is too large to count exhaustively. The fractionator counts the cells found in optical disectors that have been systematically sampled in serial sections. Heretofore, evaluations of optical fractionator performance have been made by performing tests on actual tissue sections, but it is difficult to evaluate the coefficient of error (CE), i.e. the precision of a population size estimate, by using biological tissue samples because they do not permit a comparison of an estimated CE with the true CE. However, computer simulation does permit making such comparisons while avoiding the observational biases inherent in working with biological tissue. This study is the first instance in which computer simulation has been applied to population size estimation by the optical fractionator. We used computer simulation to evaluate the performance of three CE estimators. The estimated CEs were evaluated in tests of three types of non-random cell population distribution and one random cell population distribution. The non-random population distributions varied by differences in 'intensity', i.e. the expected cell counts per disector, according to both section and disector location within the section. Two distributions were sinusoidal and one was linearly increasing; in all three there was a six-fold difference between the high and low intensities. The sinusoidal distributions produced either a peak or a depression of cell intensity at the centre of the simulated region. The linear cell intensity gradually increased from the beginning to the end of the region that contained the cells. The random population distribution had a constant intensity over the region. A 'test condition' was defined by its population distribution, the period between consecutive sampled sections and the spacing between consecutive sampled disectors. There were 1000 independently simulated cell populations for each test condition, and a 'trial' was conducted for each of these cell populations. In each trial we calculated the (unique) true CE of the population size estimate and the three CE estimates obtained by applying the Scheaffer-Mendenhall-Ott (SMO) and both Gundersen-Jensen (GJ) estimators. We compared the estimated CEs with the true CEs for each population distribution. We found that the CE estimates obtained by the SMO estimator were closer to the true CEs and had less scatter than those of the nugget-modified GJ estimator. Both had small positive bias. The CE estimates obtained by the unmodified GJ estimator exhibited widely varying bias and large scatter. In all the population distributions we tested, the average true CE was very nearly proportional to 1/square root of QT, where QT is the average number of cells counted in the two-stage systematic sample.

Cell Count↗
PubMed1994

Simulation of susceptibility artifacts in 2D and 3D Fourier transform spin-echo and gradient-echo magnetic resonance imaging.

A method is presented for simulating susceptibility artifacts in 2D and 3D spin-echo and gradient-echo imaging of arbitrary susceptibility distributions. The method incorporates object induced field perturbations in the time domain (k-space) and is demonstrated for spherical nonuniformities in susceptibility. Both simulations and experimental results for multi-slice 2D and 3D imaging of phantoms and human subjects are provided.

Artifacts↗
PubMed1998

Synchronization of pacemaker cell firing by weak ELF fields: simulation by a circuit model.

Entrainment of output action potentials from repetitively firing pacemaker cells, brought about by regularly spaced excitatory or inhibitory postsynaptic inputs, is a well-known phenomenon. Synchronization of neural firing patterns by extremely low frequency (ELF) external electric fields has also been observed. Whereas current densities of approximately 10 A-m(-2) are required for direct excitation of otherwise quiescent neural tissue, much lower peak current densities (approximately 10[-2] A-m2) have been reported to entrain spontaneously firing molluscan pacemaker cells. We have developed a neural spike generator circuit model that simulates repetitive spike generation by a space clamped patch (area approximately 10[-7] m2) of excitable membrane subjected to depolarizing current. Picoampere (pA) range variation of DC depolarizing current causes a corresponding smooth variation of neural spike frequency, producing a physiologically realistic stimulus-response (S-R) characteristic. When lower pA range 60 Hz AC current is superposed upon the DC depolarizing current, smooth variation of the S-R characteristic is distorted by subharmonic locking of the spike generator at 30, 20, 15, 12, 10 Hz, and higher order subharmonic frequencies. Although the additional superposition of a physiologically realistic level of "white" current noise, covering the bandwidth 4-200 Hz, suffices to obscure higher order subharmonic locking, locking at 30, 20, and 15 Hz is still clearly evident in the presence of noise. Subharmonic locking is observed at an root mean square AC simulated tissue current density of approximately 10(-5) A-m(-2).

Action Potentials↗
PubMed1997

Torsion angle dynamics for NMR structure calculation with the new program DYANA.

The new program DYANA (DYnamics Algorithm for Nmr Applications) for efficient calculation of three-dimensional protein and nucleic acid structures from distance constraints and torsion angle constraints collected by nuclear magnetic resonance (NMR) experiments performs simulated annealing by molecular dynamics in torsion angle space and uses a fast recursive algorithm to integrate the equations of motions. Torsion angle dynamics can be more efficient than molecular dynamics in Cartesian coordinate space because of the reduced number of degrees of freedom and the concomitant absence of high-frequency bond and angle vibrations, which allows for the use of longer time-steps and/or higher temperatures in the structure calculation. It also represents a significant advance over the variable target function method in torsion angle space with the REDAC strategy used by the predecessor program DIANA. DYANA computation times per accepted conformer in the "bundle" used to represent the NMR structure compare favorably with those of other presently available structure calculation algorithms, and are of the order of 160 seconds for a protein of 165 amino acid residues when using a DEC Alpha 8400 5/300 computer. Test calculations starting from conformers with random torsion angle values further showed that DYANA is capable of efficient calculation of high-quality protein structures with up to 400 amino acid residues, and of nucleic acid structures.

Algorithms↗
PubMed1995

A velocity k-space analysis of flow effects in echo-planar and spiral imaging.

A velocity k-space formalism facilitates the analysis of flow effects for imaging sequences involving time-varying gradients such as echo-planar and spiral. For each sequence, the velocity k-space trajectory can be represented by kv(kr); that is, its velocity-frequency (kv) position as a function of spatial-frequency (kr) position. In an echo-planar sequence, kv is discontinuous and asymmetric. However, in a spiral sequence, kv is smoothly varying, circularly symmetric, and small near the kr origin. To compare the effects of these trajectory differences, simulated images were generated by computing the k-space values for an in-plane vessel with parabolic flow. Whereas the resulting echo-planar images demonstrate distortions and ghosting that depend on the vessel orientation, the spiral images exhibit minimal artifacts.

Artifacts↗
PubMed2006

Folding kinetics of a lattice protein via a forward flux sampling approach.

We implement a forward flux sampling approach [R. J. Allen et al., J. Chem. Phys. 124, 194111 (2006)] for calculating transition rate constants and for sampling paths of protein folding events. The algorithm generates trajectories for the transition between the unfolded and folded states as chains of partially connected paths, which can be used to obtain the transition-state ensemble and the properties that characterize these intermediates. We apply this approach to Monte Carlo simulations of a model lattice protein in open space and in confined spaces of varying dimensions. We study the effect of confinement on both protein thermodynamic stability and folding kinetics; the former by mapping free-energy landscapes and the latter by the determination of rate constants and mechanistic details of the folding pathway. Our results show that, for the range of temperatures where the native state is stable, confinement of a protein destabilizes the unfolded state by reducing its entropy, resulting in increased thermodynamic stability of the folded state. Relative to the folding in open space, we find that the kinetics can be accelerated at temperatures above the temperature at which the unconfined protein folds fastest and that the rate constant increases with the number of constrained dimensions. By examining the statistical properties of the transition-state ensemble, we detect signs of a classical nucleation folding mechanism for a core of native contacts formed at an early stage of the process. This nucleus acts as folding foci and is composed of those residues that have higher probability to form native contacts in the transition-state intermediates, which can vary depending on the confinement conditions of the system.

Computer Simulation↗
PubMed2005

Vestibular-Podokinetic interaction without vestibular perception.

After prolonged stepping in place relative to space over the center of a rotating turntable, blindfolded subjects cannot step on the stationary platform without unknowingly turning themselves relative to space, a phenomenon termed podokinetic after rotation (PKAR). We asked what role the resulting vestibular stimulation might play in the expression of this form of PKAR. A method of servo-stabilizing the body relative to space during PKAR was devised to compare PKAR expression with and without significant vestibular stimulation. Simulated estimates of average central vestibular response profiles were obtained by passing the averaged unidirectional body angular velocity profiles relative to space through a first-order model of the canal system (tau=15 s). Such simulation results suggested that during normal PKAR performed on a stationary platform, the average central vestibular response would likely rise to peak levels equivalent to that induced by about 9 degrees /s within the frequency range of natural head movement. In the servo-stabilized condition, the simulated response was reduced to insignificant levels. Experimental results demonstrated that in the unstabilized condition the rate of rise of PKAR angular velocity was roughly four times slower than in the stabilized condition. We conclude that the normal expression of PKAR conducted on a stationary platform tends to be substantially slowed by interaction with an unperceived vestibular response.

Biomechanical Phenomena↗
PubMed2005

CD4 binding partially locks the bridging sheet in gp120 but leaves the beta2/3 strands flexible.

The structure of the free form HIV gp120, critical for therapeutic agent development, is unavailable due to its high flexibility. Previous thermodynamic data, structural analysis and simulation results have suggested a large conformational change in the core domain upon CD4 binding. The bridging sheet, which consists of four beta-strands with beta20/21 nestling against the inner/outer domains and beta2/3 facing outward, more exposed to the solvent, was proposed to be unfolded in the native state. In order to test this proposition and to characterize the native conformations, we performed potential mean force (PMF) molecular dynamics (MD) simulations on the CD4-bound crystal structure. We pushed the bridging sheet away from the inner and outer domain to explore the accessible conformational space for the bridging sheet. In addition, we performed conventional MD simulations on structures with the bridging sheet partially unfolded to investigate the stability of the association between the inner and outer domains. Based on the free energy profiles, we find that the whole bridging sheet is unlikely to unfold without other concurrent conformational changes. On the other hand, the partial bridging sheet, beta strands 2/3, can switch its conformation from the folded to the unfolded state. Furthermore, relaxation of conformation with partially unfolded bridging sheet through MD simulations leads to a conformation with beta strands 20/21 quickly re-anchoring against the inner and outer domains. Such a conformation, although lacking some of the hydrophobic interactions present in the CD4-bound structure, displayed high stability as further indicated by other restrained MD simulations. The relevance of this conformation to the free form structure and the pathway for conformational change from the free form to the CD4-bound structure is discussed in detail in light of the available unliganded SIV gp120 crystal structure.

Amino Acid Motifs↗
PubMed2006

The free energy landscape of small peptides as obtained from metadynamics with umbrella sampling corrections.

There is considerable interest in developing methodologies for the accurate evaluation of free energies, especially in the context of biomolecular simulations. Here, we report on a reexamination of the recently developed metadynamics method, which is explicitly designed to probe "rare events" and areas of phase space that are typically difficult to access with a molecular dynamics simulation. Specifically, we show that the accuracy of the free energy landscape calculated with the metadynamics method may be considerably improved when combined with umbrella sampling techniques. As test cases, we have studied the folding free energy landscape of two prototypical peptides: Ace-(Gly)(2)-Pro-(Gly)(3)-Nme in vacuo and trialanine solvated by both implicit and explicit water. The method has been implemented in the classical biomolecular code AMBER and is to be distributed in the next scheduled release of the code.

Algorithms↗
PubMed2005

Numerical analysis of electroosmotic flow in dense regular and random arrays of impermeable, nonconducting spheres.

We present a numerical scheme for analyzing steady-state isothermal electroosmotic flow (EOF) in three-dimensional random porous media, involving solution of the coupled Poisson, Nernst-Planck, and Navier-Stokes equations. While traditional finite-difference methods were used to resolve the Poisson-Nernst-Planck problem, the (electro)hydrodynamics has been addressed with high efficiency using the lattice-Boltzmann method. The developed model allows simulation of electrokinetic transport under most general conditions, including arbitrary value and distribution of electrokinetic potential at the solid-liquid interface, electrolyte composition, and pore space morphology. The approach provides quantitative information on a spatial distribution of simulated velocities. This feature was utilized to characterize EOF fields in regular and random, confined and bulk packings of hard (i.e., impermeable, nonconducting) spheres. Important aspects of pore space morphology (sphere size distribution), surface heterogeneity (mismatch in electrokinetic potentials at confining wall and sphere surface), and fluid phase properties (electrical double layer thickness) were investigated with respect to their influence on the EOF dynamics over microscopic and macroscopic spatial domains. Most important is the observation of a generally nonuniform pore-level EOF velocity profile in the sphere packings (even in the thin double layer limit) which is caused by pore space morphology and which is in contrast to the pluglike velocity distribution in a single, straight capillary under the same conditions.

Journal Article↗
PubMed2004

Conformational subspace in simulation of early-stage protein folding.

A probability calculus was used to simulate the early stages of protein folding in ab initio structure prediction. The probabilities of particular phi and psi angles for each of 20 amino acids as they occur in crystal forms of proteins were used to calculate the amount of information necessary for the occurrence of given phi and psi angles to be predicted. It was found that the amount of information needed to predict phi and psi angles with 5 degrees precision is much higher than the amount of information actually carried by individual amino acids in the polypeptide chain. To handle this problem, a limited conformational space for the preliminary search for optimal polypeptide structure is proposed based on a simplified geometrical model of the polypeptide chain and on the probability calculus. These two models, geometric and probabilistic, based on different sources, yield a common conclusion concerning how a limited conformational space can represent an early stage of polypeptide chain-folding simulation. The ribonuclease molecule was used to test the limited conformational space as a tool for modeling early-stage folding.

Amino Acids↗
PubMed2004

Hydrodynamic properties of carbon nanotubes.

We study water flowing past an array of single walled carbon nanotubes using nonequilibrium molecular dynamics simulations. For carbon nanotubes mounted with a tube spacing of 16.4 x 16.4 nm and diameters of 1.25 and 2.50 nm, respectively, we find drag coefficients in reasonable agreement with the macroscopic, Stokes-Oseen solution. The slip length is -0.11 nm for the 1.25 nm carbon nanotube, and 0.49 for the 2.50 nm tube for a flow speed of 50 m/s, respectively, and 0.28 nm for the 2.50 nm tube at 200 m/s. A slanted flow configuration with a stream- and spanwise velocity component of 100 ms(-1) recovers the two-dimensional results, but exhibits a significant 88 nm slip along the axis of the tube. These results indicate that slip depends on the particular flow configuration.

Computer Simulation↗
PubMed2006

Filament compliance effects can explain tension overshoots during force development.

Spatially explicit stochastic simulations of myosin S1 heads attaching to a single actin filament were used to investigate the process of force development in contracting muscle. Filament compliance effects were incorporated by adjusting the spacing between adjacent actin binding sites and adjacent myosin heads in response to cross-bridge attachment/detachment events. Appropriate model parameters were determined by multi-dimensional optimization and used to simulate force development records corresponding to different levels of Ca(2+) activation. Simulations in which the spacing between both adjacent actin binding sites and adjacent myosin S1 heads changed by approximately 0.06 nm after cross-bridge attachment/detachment events 1), exhibited tension overshoots with a Ca(2+) dependence similar to that measured experimentally and 2), mimicked the observed k(tr)-relative tension relationship without invoking a Ca(2+)-dependent increase in the rate of cross-bridge state transitions. Tension did not overshoot its steady-state value in control simulations modeling rigid thick and thin filaments with otherwise identical parameters. These results underline the importance of filament geometry and actin binding site availability in quantitative theories of muscle contraction.

Actins↗
PubMed1996

Acceleration-sensitivity threshold of Physarum.

Free-living cells show distinct gravisensitivities and often use the gravity ('g') vector for their spatial orientation. The rhythmic contractions of the ameboid Myxomycete (acellular slime mold) Physarum polycephalum are a sensitive parameter which can be modified by external stimuli. Space experiments and ground-based 0 x g simulation studies established that the contraction period transiently decreases after a transition from 1 x g to 0 x g with a back-regulating process starting after 30 min. For determination of the threshold of acceleration sensitivity, a slow-rotating centrifuge microscope (NIZEMI--Niedergeschwindigkeits-Zentrifugenmikroskop) was used, providing in space accelerations from 0 x g to 1.5 x g. A stepwise acceleration increase revealed that the lowest acceleration level capable of inducing a response was 0.1 x g. The response to the acceleration increase was an increase in contraction period, in contrast to a stimulus deprivation, which led to a period decrease. The time schedule of the acceleration responses and back-regulating process seems to be fixed, suggesting that every acceleration being above the threshold can induce a complete response-regulation process. The low acceleration-sensitivity threshold favors rather large and dense cell organelles as candidates for the gravity receptor in Physarum.

Acceleration↗
PubMedDate not supplied

Gravity perception and signal transduction in single cells.

Cellular signal processing in multi-, as well as in unicellular organisms, has to rely on fundamentally similar mechanisms. Free-living single cells often use the gravity vector for their spatial orientation (gravitaxis) and show distinct gravisensitivities. In this investigation the gravisensitive giant ameboid cell Physarum polycephalum (Myxomycetes, acellular slime molds) is used. Its gravitaxis and the modulation of its intrinsic rhythmic contraction activity by gravity was demonstrated in 180 degrees-turn experiments and in simulated, as well as in actual, near-weightlessness studies (fast-rotating clinostat; Spacelab D1, IML-1). The stimulus perception was addressed in an IML-2 experiment, which provided information on the gravireceptor itself by the determination of the cell's acceleration-sensitivity threshold. Ground-based experiments designed to elucidate the subsequent steps in signal transduction leading to a motor response, suggest that an acceleration stimulus induces changes in the level of second messenger, adenosine 3',5'-cyclic monophosphate (cAMP), indicating also that the acceleration-stimulus signal transduction chain of Physarum uses an ubiquitous second messenger pathway.

Acceleration↗
PubMed2003

[Continuous target of China's manned space project and research direction of space medico-engineering].

The subject of space medico-engineering which takes manned space flight as its own task, played an important role in China's manned space project, and developed rapidly. According to China's next three manned space objectives: 1) to develop the technology of extra-vehicle activity (EVA) and test the astronauts' performance ability of EVA; 2) to develop the technology of docking with other object spacecraft in space; 3) to found a relatively large space lab, the research directions and key technology of space medico-engineering have been given, including astronaut's selection and training; requirements and evaluation of medicine and ergonomics of the space lab design; the researches of fields in astronauts' medical monitoring and space medicine; technology of environmental control and life support system in space module; technology of EVA or docking; and technology of simulation of astronaut's training.

Aerospace Medicine↗
PubMed1984

The Life Sciences Programme of the European Space Agency, and opportunities for radiation biology experiments.

With the advent of Europe's commitment to contribute the European Space Agency (ESA) to the NASA Space Transportation System (STS) by means of the Spacelab programme, a new area for research opportunities on Life Sciences has been created for the European scientific community. Although considered as a young and new discipline, the goals of Life Sciences research in space had soon been defined by the ESA advising Life Sciences Working Group in the beginning of 1977. The programme proposals of the various subdisciplines concentrated on the advantageous use of the microgravity environment, to study in more depth the gravity relevance of biological systems. It included, however, also the use of other factors during space flight which cannot be reproduced or adequately simulated on the ground: cosmic radiation in its total spectrum, particularly HZE particles, solar and UV radiation, vacuum, and the combination of radiation and weightlessness, etc. On this basis, call for proposals in the various subdisciplines resulted in experiments also in the field of radiation biology which were flown on the Spacelab 1 mission and which were selected for later missions. In particular, ESA is providing the science community with mission opportunities on Spacelab, either European or International, with platforms to be launched by STS, and with so called multi-user facilities (e.g. Biorack). Typically, the experiments will be the responsibility of the scientists, the integration and mission phase the responsibility of ESA. Both mission definition and experiment selection rests with the ultimate decision of the responsible ESA Programme Board. A further description of missions envisioned, the Spacelab facility, platforms, multi-user facilities and areas of research applicable to radiobiology will be given. ESA's continuing interaction with the scientific community through the Life Sciences Working Group, and the advice on future programmes will be stressed as a vital factor contributing to a European Life Sciences Programme in Space.

Adaptation, Physiological↗
PubMed1998

Constant-pressure molecular dynamics investigation of cholesterol effects in a dipalmitoylphosphatidylcholine bilayer.

We report a 1.4-ns constant-pressure molecular dynamics simulation of cholesterol at 12.5 mol% in a dipalmitoylphosphatidylcholine (DPPC) bilayer at 50 degrees C and compare the results to our previous simulation of a pure DPPC bilayer. The interlamellar spacing was increased by 2.5 A in the cholesterol-containing bilayer, consistent with x-ray diffraction results, whereas the bilayer thickness was increased by only 1 A. The bilayer/water interface was more abrupt because the lipid headgroups lie flatter to fill spaces left by the cholesterol molecules. This leads to less compensation by the lipid headgroups of the oriented water contribution to the membrane dipole potential and could explain the experimentally observed increase in the magnitude of the dipole potential by cholesterol. Our calculations suggested that 12.5 mol% cholesterol does not significantly affect the conformations and packing of the hydrocarbon chains and produces only a slight reduction in the empty free volume. However, cholesterol has a significant influence on the subnanosecond time scale lipid dynamics: the diffusion constant for the center-of-mass "rattling" motion was reduced by a factor of 3, and the reorientational motion of the methylene groups was slowed along the entire length of the hydrocarbon chains.

1,2-Dipalmitoylphosphatidylcholine↗