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At least 343 records · Page 19Linked to original sources

PubMed2001

High intranuclear mobility and dynamic clustering of the splicing factor U1 snRNP observed by single particle tracking.

Uridine-rich small nuclear ribonucleoproteins (U snRNPs) are components of the splicing machinery that removes introns from precursor mRNA. Like other splicing factors, U snRNPs are diffusely distributed throughout the nucleus and, in addition, are concentrated in distinct nuclear substructures referred to as speckles. We have examined the intranuclear distribution and mobility of the splicing factor U1 snRNP on a single-molecule level. Isolated U1 snRNPs were fluorescently labeled and incubated with digitonin-permeabilized 3T3 cells in the presence of Xenopus egg extract. By confocal microscopy, U1 snRNPs were found to be imported into nuclei, yielding a speckled intranuclear distribution. Employing a laser video-microscope optimized for high sensitivity and high speed, single U1 snRNPs were visualized and tracked at a spatial precision of 35 nm and a time resolution of 30 ms. The single-particle data revealed that U1 snRNPs occurred in small clusters that colocalized with speckles. In the clusters, U1 snRNPs resided for a mean decay time of 84 ms before leaving the optical slice in the direction of the optical axis, which corresponded to a mean effective diffusion coefficient of 1 microm(2)/s. An analysis of the trajectories of single U1 snRNPs revealed that at least three kinetic classes of low, medium, and high mobility were present. Moreover, the mean square displacements of these fractions were virtually independent of time, suggesting arrays of binding sites. The results substantiate the view that nuclear speckles are not rigid structures but highly dynamic domains characterized by a rapid turnover of U1 snRNPs and other splicing factors.

3T3 Cells↗

PubMed2002

Ten-nanosecond molecular dynamics simulation of the motions of the horse liver alcohol dehydrogenase.PhCH2O- complex.

Molecular dynamics simulations have been carried out for a period of 10 ns with the dimeric enzyme horse liver alcohol dehydrogenase (HLADH) present as the reactive complex HLADH.NAD+. PhCH2O-. Cross-correlation analysis of the trajectory was carried out with the latter from 500 ps to 10 ns. The resulting cross-correlation map allowed the identification of the correlated and anticorrelated motions, which involve the entire protein. Anticorrelated and correlated motions are carried into the active site-aligned residues.

Alcohol Dehydrogenase↗

PubMed1993

Control of Three- and Four-Joint Arm Movement: Strategies for a Manipulator With Redundant Degrees of Freedom.

Control of arm movements when the number of joints exceeds the degrees of freedom necessary for the task requires a strategy for selecting specific arm configurations out of an infinite number of possibilities. This report reviews strategies used by human subjects to control the shoulder, elbow, and wrist (three degrees of freedom) while moving a pointer to positions in a horizontal plane (two degrees of freedom). Analysis of final arm configurations assumed when the pointer was at the target showed the following: (a) Final arm configurations were virtually independent of the configuration at the start of the pointing movement, (b) subjects avoided configurations subjectively felt to be uncomfortable (e.g., those with extreme flexion or extension of the wrist), and (c) the results could be simulated by assigning hypothetical cost functions to each joint and selecting the arm configuration that minimized the sum of the costs. The fitted cost functions qualitatively agreed with psychophysically determined comfort; they appeared to depend on joint angle and on muscular effort. Simple neural networks can learn implicit representations of these cost functions and use them to specify final arm configurations. The minimum cost principle can be extended to movements that use the fingers as a fourth movable segment. For this condition, however, experiments showed that final configurations of the arm depended upon initial configurations. Analysis of movement trajectories for arms with three degrees of freedom led to a control model in which the minimum cost principle is augmented by a mechanism that distributes required joint movements economically among the three joints and a mechanism that implements a degree of mass-spring control.

Journal Article↗

PubMed2005

Application of molecular dynamics simulations to spin-labeled oligonucleotides.

The EPR study of spin labeled macromolecules has provided insight into structural and dynamical properties of DNA, proteins, and related systems. While spin labeling has been useful, it is experimentally difficult to determine if the spin label significantly alters the conformation of the macromolecule to which it is attached. Molecular modeling has proven to be a powerful tool for studying structure and dynamics of biologically important molecules. Here, we have conducted molecular dynamics (MD) studies of spin labeled oligonucleotides (ONs) bearing a five (5sp) or six (6sp) membered ring nitroxide, and the corresponding unmodified ON using the suite of programs contained in Amber 5.0 with the Cornell et al. 94 force field (Cornell, W. D., Cieplak, P., Bayly, C. I., Gould, I. R., Merz, Jr., K. M. Ferguson, D. M., Spellmeyer, D. C., Fox, T., Caldwell, J. W., and Kollman, P. A. A Second Generation Force Field for the Simulation of Proteins and Nucleic Acids. J. Am. Chem. Soc. 117, 5179-5197 (1995)). Quantum mechanical calculations employing the B3LYP method with the standard 6-31G* basis set using Gaussian98 were performed and, together with available crystallographic data for analogous nitroxides, new parameters for the nitrogen, oxygen, nitroxide alpha-carbon, and sp-hybridized carbon atoms have been developed suitable for the Cornell et al. 94 force field. MD simulations on the double-stranded (ds) spin labeled ONs, along with the corresponding unmodified analogues, have been studied over the course of 4 ns and conformational properties of all ONs are described based on the analysis of the trajectories. The spin labels were found to alter the global conformation of the ONs to which they were attached to accommodate the spin labels. The major changes include widening the major groove, decreasing helical twist, and more negative X-displacement of the base pairs. The magnitude of the effect was dependent on the specific structure of the spin label. Average and 'most representative' structures derived from the molecular dynamics simulations correlate with the experimental data on the spin labeled ONs.

Computer Simulation↗

PubMed2002

cGMP-mediated signaling via cGKIalpha is required for the guidance and connectivity of sensory axons.

Previous in vitro studies using cGMP or cAMP revealed a cross-talk between signaling mechanisms activated by axonal guidance receptors. However, the molecular elements modulated by cyclic nucleotides in growth cones are not well understood. cGMP is a second messenger with several distinct targets including cGMP-dependent protein kinase I (cGKI). Our studies indicated that the alpha isoform of cGKI is predominantly expressed by sensory axons during developmental stages, whereas most spinal cord neurons are negative for cGKI. Analysis of the trajectories of axons within the spinal cord showed a longitudinal guidance defect of sensory axons within the developing dorsal root entry zone in the absence of cGKI. Consequently, in cGKI-deficient mice, fewer axons grow within the dorsal funiculus of the spinal cord, and lamina-specific innervation, especially by nociceptive sensory neurons, is strongly reduced as deduced from anti-trkA staining. These axon guidance defects in cGKI-deficient mice lead to a substantial impairment in nociceptive flexion reflexes, shown using electrophysiology. In vitro studies revealed that activation of cGKI in embryonic dorsal root ganglia counteracts semaphorin 3A-induced growth cone collapse. Our studies therefore reveal that cGMP signaling is important for axonal growth in vivo and in vitro.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed2003

Impairment of context-adapted movement selection in a primate model of presymptomatic Parkinson's disease.

The MPTP model allows the presymptomatic stage of parkinsonism to be studied in primates and hence specific behavioural manifestations of moderate nigrostriatal denervation to be identified. On the basis of the physiological literature, we hypothesized that depletion of striatal dopamine could impair the selection of context-relevant habits. To examine this hypothesis, we trained three African green monkeys to perform a simple reach-and-grasp task, including three contexts differing only in terms of the presence and position of transparent obstacles. At the end of training, the analysis of reaching trajectories showed that intact monkeys had built a repertoire of movements, from which they could select the appropriate one depending on the context. In the course of MPTP intoxication (0.3-0.4 mg/kg every 4-5 days) and before parkinsonian motor symptoms appeared, the reaction time (RT), movement time (MT) and variability of reaching trajectories increased in all monkeys. Frequently, the initial direction was not adapted to the context, and consequently the movement was either corrected online or restarted under visual assistance. These non-adapted trajectories appeared to be the main reason for the increase in both RT (because of difficulty in selecting) and MT (because of the need to make corrections). These observations indicate that moderate MPTP-induced dopamine depletion results in a deficit in the selection of context-adapted movement, which is compensated by corrections using either proprioceptive or visual feedback. Similar behavioural disorders might therefore occur in the presymptomatic stage of human Parkinson's disease.

Animals↗

PubMed1997

Reliability of electromagnetic articulography recording during speaking sequences.

For the development of malocclusions and speech disorders, major aetiological significance is attributed to orofacial malfunctions, especially of the tongue. The position of the tongue to the alveolar arch and teeth, particularly within the area of the tip of the tongue, is of special interest for orthodontists. Electromagnetic articulography is a new technique used to examine tongue function and to record its movement in the midsagittal plane. The aim of the study was to determine whether this procedure offers suitable and reliable results. Thirty-one subjects aged 14.3-37.3 years had to repeat speaking sequences five times. The German syllables they had to repeat were /asa/, /ascha/, /ata/, /ala/, /ana/, /aka/. The tongue movements were registered with an 'Articulograph AG 100'. Distances, angles and encircled planes were evaluated, and the proportion of intra-individual to overall variability was calculated in order to check the reliability of the courses of movement. Angles and distances especially showed, depending on the position of the receiver coils, strong reliability during speaking sequences, whereas area produced unfavourable results. The analysis of long trajectories and angles appeared favourable in order to describe the courses of movement. This required, however, a systematic assessment of functional movement with electromagnetic articulography.

Adolescent↗

PubMed2000

Effect of the reaction field electrostatic term on the molecular dynamics simulation of the activation domain of procarboxypeptidase B.

Molecular dynamics simulations of the activation domain of porcine procarboxypeptidase B (ADBp) were performed in order to examine the effects of the inclusion of a reaction field (RF) term into the calculation of electrostatics forces for highly charged proteins. Two simulations were performed with the GROMOS96 package, studying the influence of counterions on the final results. Comparison with previous results without the inclusion of the RF term (Martí-Renom, M.A., Mas,J.M., Oliva,B., Querol,E. and Avilés,F.X., Protein Engng, 1998, 11, 101-110) shows that the structure is well maintained when the RF term is included. Moreover, the analysis of the trajectories shows that simulations of solvated highly-charged proteins are sensitive to the presence of counterions, the secondary structures being more stable when their charges are neutralized.

Amino Acid Sequence↗

PubMed1992

A molecular dynamics simulation of bacteriophage T4 lysozyme.

An analysis of a 400 ps molecular dynamics simulation of the 164 amino acid enzyme T4 lysozyme is presented. The simulation was carried out with all hydrogen atoms modeled explicitly, the inclusion of all 152 crystallographic waters and at a temperature of 300 K. Temporal analysis of the trajectory versus energy, hydrogen bond stability, r.m.s. deviation from the starting crystal structure and radius of gyration, demonstrates that the simulation was both stable and representative of the average experimental structure. Average structural properties were calculated from the enzyme trajectory and compared with the crystal structure. The mean value of the C alpha displacements of the average simulated structure from the X-ray structure was 1.1 +/- 0.1 A; differences of the backbone phi and psi angles between the average simulated structure and the crystal structure were also examined. Thermal-B factors were calculated from the simulation for heavy and backbone atoms and both were in good agreement with experimental values. Relationships between protein secondary structure elements and internal motions were studied by examining the positional fluctuations of individual helix, sheet and turn structures. The structural integrity in the secondary structure units was preserved throughout the simulation; however, the A helix did show some unusually high atomic fluctuations. The largest backbone atom r.m.s. fluctuations were found in non-secondary structure regions; similar results were observed for r.m.s. fluctuations of non-secondary structure phi and psi angles. In general, the calculated values of r.m.s. fluctuations were quite small for the secondary structure elements. In contrast, surface loops and turns exhibited much larger values, being able to sample larger regions of conformational space. The C alpha difference distance matrix and super-positioning analyses comparing the X-ray structure with the average dynamics structure suggest that a 'hinge-bending' motion occurs between the N- and C-terminal domains.

Bacteriophage T4↗

PubMed1995

Clinical characteristics and prognostic value of acute retroviral syndrome among injecting drug users. Italian Seroconversion Study.

OBJECTIVE: To estimate the frequency of acute retroviral syndrome associated with HIV infection among injecting drug users (IDU), and to determine the extent to which acute retroviral syndrome predicts a faster rate of progression to AIDS and immunosuppression in this population. DESIGN: Prospective study of HIV seroconverters (median follow-up, 50.5 months). SETTING: Sixteen clinical centres throughout Italy established to study the natural history of HIV infection. PATIENTS: Three hundred and ninety-one IDU for whom the date of HIV seroconversion was established with a 9-month precision. MAIN OUTCOME MEASURES AND METHODS: Incidence of acute retroviral syndrome with signs and symptoms that included fever (temperature > 38 degrees C) occurring within 6 months prior to the time of first positive HIV test, progression to AIDS, crude and adjusted relative hazard of AIDS using survival analysis techniques, and trajectories of CD4+ cell counts using a piece-wise linear regression model incorporating the degree of dependency of within-person measurements. RESULTS: Of 391 HIV seroconverters, 39 (10.0%) were diagnosed with acute retroviral syndrome. During follow-up, 13 seroconverters with acute retroviral syndrome and 24 asymptomatic seroconverters developed AIDS. The Kaplan-Meier estimates for the cumulative AIDS incidence during 4.5 years of follow-up were 26.8 and 6.5%, respectively; the relative hazard of developing AIDS for acute retroviral syndrome was 5.59 (95% confidence interval, 2.79-11.20) after adjustment for age, sex and year of seroconversion. Although CD4+ level within the first year from seroconversion was similar, the rate of CD4+ cell decline after 1 year from seroconversion was faster in individuals with acute retroviral syndrome than in those without this syndrome (P < 0.001). CONCLUSIONS: Among HIV-infected IDU, a distinct acute retroviral syndrome is apparent and associated with a faster rate of clinical progression to AIDS and HIV-related immunosuppression.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Rotational viscosity in a nematic liquid crystal: a theoretical treatment and molecular dynamics simulation.

The rotational viscosity coefficient gamma(1) of 4-n-pentyl-4(')-cyanobiphenyl in the nematic phase is investigated by combination of existing statistical-mechanical approaches (SMAs), based on a rotational diffusion model and computer simulation technique. The SMAs rest on a model in which it is assumed that the reorientation of an individual molecule is a stochastic Brownian motion in a certain potential of mean torque. According to the SMAs, gamma(1) is found to be a function of temperature, density, rotational diffusion coefficient, and a number of order parameters (OPs). The diffusion coefficient and the OPs were obtained from an analysis of a trajectory generated in a molecular dynamics simulation using realistic atom-atom interactions. In addition, a set of experimentally determined diffusion coefficients and OPs was used for evaluation of gamma(1). Reasonable agreement between calculated and experimental values of gamma(1) is obtained. It is shown that near the clearing point gamma(1) is proportional to (-)P22, where (-)P2 is the second-rank OP. This limiting value of gamma(1) is in agreement with mean-field theory.

Journal Article↗

PubMed2005

Fluctuational transitions across different kinds of fractal basin boundaries.

We study fluctuational transitions in discrete and continuous dynamical systems that have two coexisting attractors in phase space, separated by a fractal basin boundary which may be either locally disconnected or locally connected. Theoretical and numerical evidence is given to show that, in each case, the transition occurs via a unique accessible point on the boundary, both in discrete systems and in flows. The complicated structure of the escape paths inside the locally disconnected fractal basin boundary is determined by a hierarchy of homoclinic points. The interrelation between the mechanism of transitions and the hierarchy is illustrated by consideration of fluctuational transitions in dynamical systems demonstrating "fractal-fractal" basin boundary metamorphosis at some value of a control parameter. The most probable escape path from an attractor, which can be either regular or chaotic, is found for each type of boundary using both statistical analysis of fluctuational trajectories and the Hamiltonian theory of fluctuations.

Journal Article↗

PubMed2005

Structural origin of negative thermal expansion in high-temperature silica polymorphs.

The alpha and beta modifications of quartz and cristobalite silica have been successfully simulated using molecular dynamics simulations based on a single parametrization of a charge transfer three-body potential. The simulated alpha forms exhibit positive thermal expansion; it is almost zero for beta cristobalite up to 1500 K and slightly negative at higher temperatures, while a negative thermal expansion of beta quartz is observed immediately above the alpha-to-beta transition. A detailed analysis of atomic trajectories reveals that the origin of negative thermal expansion in the high-temperature beta forms of silica is a gradual reactivation of the same displacement mode that underlies the transformation between the alpha and beta modifications.

Journal Article↗

PubMed1994

Mesoscopic theories for protein crystal growth.

A computer-simulation method is proposed for studying the hydrodynamic interactions of rigid protein molecules. It is a combination of Stokes dynamics and continuum hydrodynamics. The Stokes equations of motion for the protein molecules, the creeping-flow equation for the solvent together with the no-slip boundary conditions give a complete representation of the system. The resulting three-dimensional boundary-value problem can be rewritten in a two-dimensional form (without any loss of information) considering the surfaces of the particles only. Then, by solving the equations on discrete surface elements, the so-called mobility matrix is determined in which all hydrodynamic interactions are included. Finally, after calculation of the conservative forces and the stochastic force, the new velocities of the protein molecules can be determined. The simulation method can be applied to arbitrary particle shapes. It can also handle arbitrary flow fields, and the effects of applying a flow field to the system can be studied. From analysis of the trajectories, information can be gained on the kinetics and thermodynamics in the early stages of the crystallization process.

Journal Article↗

PubMed2003

Enhanced upper tropical tropospheric COS: impact on the stratospheric aerosol layer.

Carbonyl sulfide (COS) is considered to be a major source of the stratospheric sulfate aerosol during periods of volcanic quiescence. We measured COS at the tropical tropopause and find mixing ratios to be 20 to 50% larger than are assumed in models. The enhanced COS levels are correlated with high concentrations of biomass-burning pollutants like carbon monoxide (CO) and hydrogen cyanide (HCN). The analysis of backward trajectories and global maps of fire statistics suggest that biomass-burning emissions transported upward by deep convection are the source of the enhanced COS in the upper tropical troposphere.

Journal Article↗

PubMed2000

Direct observation of dynamical heterogeneities in colloidal hard-sphere suspensions

The real-space dynamics in a model system of colloidal hard spheres was studied by means of time-resolved fluorescence confocal scanning microscopy. Direct experimental evidence for the presence of dynamical heterogeneities in a dense liquid was obtained from an analysis of particle trajectories in two-dimensional slices of the bulk sample. These heterogeneities manifest themselves as a non-Gaussian probability distribution of particle displacements and also affect the onset of long-time diffusive behavior.

Journal Article↗

PubMed1999

Proprioceptive regulation of voluntary ankle movements, demonstrated using muscle vibration, is impaired by Parkinson's disease.

OBJECTIVE: To test the hypothesis that the proprioceptive regulation of voluntary movement is disturbed by Parkinson's disease, the effects of experimental stimulation of proprioceptors, using muscle vibration, on the trajectories of voluntary dorsiflexion movements of the ankle joint were compared between parkinsonian and control subjects. METHODS: Twenty one patients with Parkinson's disease, on routine medication (levodopa in all but one), and an equal number of age matched, neurologically intact controls, were trained initially to make reproducible ankle dorsiflexion movements (20 degrees amplitude with a velocity of 9.7 degrees /s) following a visual "go" cue while movement trajectories were recorded goniometrically. During 50% of the experimental trials, vibration (105 Hz; 0.7 mm peak to peak) was applied to the Achilles tendon during the ankle movement to stimulate antagonist muscle spindles; vibrated and non-vibrated trials were interspersed randomly. Subjects' performance was assessed by measuring end point position-that is, the ankle angle attained 2 seconds after the visual "go" cue, from averaged (20 trials) trajectories. RESULTS: Statistical analysis of the end point amplitudes of movement showed that, whereas the amplitudes of non-vibrated movements did not differ significantly between patients with Parkinson's disease and controls, antagonist muscle vibration produced a highly significant reduction in the amplitudes of ankle dorsiflexion movements in both the patient and control groups. However, the extent of vibration induced undershooting produced in the patients with Parkinson's disease was significantly less than that in the controls; the mean vibrated/non-vibrated ratios were 0.86 and 0.54 for, respectively, the patient and control groups. CONCLUSIONS: The present finding of a reduction of vibration induced ankle movement errors in parkinsonian patients resembles qualitatively previous observations of wrist movements, and suggests that Parkinson's disease may produce a general impairment of proprioceptive guidance.

Aged↗

PubMedDate not supplied

Characterization of endothelial cell locomotion using a Markov chain model.

A Markov chain model was developed to characterize the two-dimensional locomotion of bovine pulmonary artery endothelial (BPAE) cells cultured with or without basic fibroblast growth factor (bFGF). This model provides a detailed description of the migration process by computing the following locomotory parameters: (i) the speed of cell locomotion; (ii) the expected duration of cell movement in any given direction; (iii) the probability distribution of turn angles that will decide the next direction of cell movement; (iv) the frequency of cell stops; and (v) the duration of cell stops. Eight directional states and a stationary state were used in our Markov analysis. From cell trajectory data, the transition probabilities among the various states and the waiting times for the directional and the stationary states were computed. The steady-state probabilities were also calculated to obtain the ultimate direction of cell motion and, thus, determine whether cell motion was random. Our results showed how the addition of bFGF enhanced the locomotory capability of BPAE cells. Cells cultured with 30 ng/mL bFGF had lower probability of moving to the stationary state than those cultured without bFGF. In addition, cells cultured with 30 ng/mL bFGF remained in the stationary state for shorter periods of time than cells cultured without bFGF. In both these cases, however, the transition probabilities from the stationary state to any directional state were uniformly distributed and were not affected by the presence of bFGF.

Algorithms↗