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PubMed1999

Structural characterization by computer experiments of the lipid-free LDL-receptor-binding domain of apolipoprotein E.

The structure and dynamics of the lipid-free LDL-receptor-binding domain of apolipoprotein E (apoE-RBD) has been investigated by Molecular Dynamics Simulations. ApoE-RBD in its monomeric lipid-free form is a singular four-helix bundle made up of four elongated amphipathic helices. Analysis of one 1.5 ns molecular dynamics trajectory of apoE-RBD performed in water indicates that the lipid-free domain adopts a structure that exhibits characteristics found in native proteins: it has very stable helices and presents a compact structure. Yet its interior exhibits a larger number of transient atomic-size cavities relative to that found in other proteins of similar size and its apolar side chains are more mobile. The latter features distinguish the elongated four-helix bundle as a slightly disordered structure, which shows a structural likeness with some de novo designed four-helix bundle proteins and shares with the latter a leucine-rich residue composition. We anticipate that these unique properties compared with other native helix bundles may be related to the postulated ability of apoE-RBD to undergo an opening of its bundle upon interaction with phospholipids. The distribution of empty cavities computed along the trajectory in the interface regions between the different pairs of helices reveals that the tertiary contacts in one of the interfaces are weaker suggesting that this particular interface could be more easily ruptured upon lipid association.

Algorithms↗
PubMed1993

Substrate mobility in thiocamphor-bound cytochrome P450cam: an explanation of the conflict between the observed product profile and the X-ray structure.

Thiocamphor is an unusual substrate for P450cam in that in the X-ray structure it binds in the active site pocket in two distinct orientations and neither of these orientations are consistent with the 5-alcohol being the primary product. Other camphor analogs such as norcamphor or camphane bind in a single orientation consistent with the 5-alcohol being a major product. We present an analysis of four 175 ps molecular dynamics trajectories of thiocamphor-bound cytochrome P450cam. The first two trajectories were calculated for cytochrome P450cam with thiocamphor bound in both its major and minor crystallographic orientations. In the second set of simulations, a single oxygen atom was added as a distal ligand to the heme group in order to model the putative ferryl oxygen reaction intermediate. Trajectories were again calculated starting with thiocamphor in its major and minor orientations. While the protein dynamics were quite similar in all four trajectories, the substrate showed distinctly different motions in each of the trajectories. In particular, the preferred substrate orientations were very different in the presence of the ferryl oxygen than in the absence of that oxygen. The preferred orientations in the absence of the distal oxygen were consistent with the 3-alcohol being the major product, while the preferred orientations in the presence of the distal oxygen were consistent with the 5-alcohol being a major product. These simulations offer an explanation for the inconsistency between the X-ray data and the product profile.

Binding Sites↗
PubMed2004

A three-dimensional kinematic and dynamic study of the lower limb during the stance phase of gait using an homogeneous matrix approach.

This paper presents a method to analyze three dimensional kinematics and dynamics of lower limb during walking. The proposed method is based on a homogeneous matrix concept, derived from robotics and using compact, expressive notation convenient for computer applications. The major advantage of this method is that no hypothesis is required on the joint model, which makes it applicable to complex and pathologic joints. Kinematic data are computed from 3-D trajectories of markers collected by a motion analysis system. External forces applied on the leg are measured synchronously during the stance phase of gait. Angular velocity components obtained using the homogeneous matrix method are displayed for three subjects and compared with those obtained from the same experimental data using a helical axis method. Then, intersegmental moments calculated from the inverse dynamic part of the homogeneous matrix method are shown on the same subjects. Kinematic results indicate that there are no significant differences between the methods, thus demonstrating the reproducibility of the stance phase of gait in the sagittal plane. Use of this synthetic homogeneous method developed for both kinematics and dynamics of rigid bodies demonstrates good promise for applications in biomechanics.

Adult↗
PubMed1999

Assignment of side-chain conformation using adiabatic energy mapping, free energy perturbation, and molecular dynamic simulations.

NMR spectroscopic analysis of the C-terminal Kunitz domain fragment (alpha3(VI)) from the human alpha3-chain of type VI collagen has revealed that the side chain of Trp21 exists in two unequally populated conformations. The major conformation (M) is identical to the conformation observed in the X-ray crystallographic structure, while the minor conformation (m) cannot structurally be resolved in detail by NMR due to insufficient NOE data. In the present study, we have applied: (1) rigid and adiabatic mapping, (2) free energy simulations, and (3) molecular dynamic simulations to elucidate the structure of the m conformer and to provide a possible pathway of the Trp21 side chain between the two conformers. Adiabatic energy mapping of conformations of the Trp21 side chain obtained by energy minimization identified two energy minima: One corresponding to the conformation of Trp21 observed in the X-ray crystallographic structure and solution structure of alpha3(VI) (the M conformation) and the second corresponding to the m conformation predicted by NMR spectroscopy. A transition pathway between the M and m conformation is suggested. The free-energy difference between the two conformers obtained by the thermodynamic integration method is calculated to 1.77+/-0.7 kcal/mol in favor of the M form, which is in good agreement with NMR results. Structural and dynamic properties of the major and minor conformers of the alpha3(VI) molecule were investigated by molecular dynamic. Essential dynamics analysis of the two resulting 800 ps trajectories reveals that when going from the M to the m conformation only small, localized changes in the protein structure are induced. However, notable differences are observed in the mobility of the binding loop (residues Thr13-Ile18), which is more flexible in the m conformation than in the M conformation. This suggests that the reorientation of Trp2 might influence the inhibitory activity against trypsin, despite the relative large distance between the binding loop and Trp21.

Collagen↗
PubMed2003

Integrins modulate Sog activity in the Drosophila wing.

Morphogenesis of the Drosophila wing depends on a series of cell-cell and cell-extracellular matrix interactions. During pupal wing development, two secreted proteins, encoded by the short gastrulation (sog) and decapentaplegic (dpp) genes, vie to position wing veins in the center of broad provein territories. Expression of the Bmp4 homolog dpp in vein cells is counteracted by expression of the Bmp antagonist sog in intervein cells, which results in the formation of straight veins of precise width. We screened for genetic interactions between sog and genes encoding a variety of extracellular components and uncovered interactions between sog and myospheroid (mys), multiple edematous wing (mew) and scab (scb), which encode betaPS, alphaPS1 and alphaPS3 integrin subunits, respectively. Clonal analysis reveals that integrin mutations affect the trajectory of veins inside the provein domain and/or their width and that misexpression of sog can alter the behavior of cells in such clones. In addition, we show that a low molecular weight form of Sog protein binds to alphaPS1betaPS. We find that Sog can diffuse from its intervein site of production into adjacent provein domains, but only on the dorsal surface of the wing, where Sog interacts functionally with integrins. Finally, we show that Sog diffusion into provein regions and the reticular pattern of extracellular Sog distribution in wild-type wings requires mys and mew function. We propose that integrins act by binding and possibly regulating the activity/availability of different forms of Sog during pupal development through an adhesion independent mechanism.

Animals↗
PubMed2004

Individual growth curve analysis illuminates stability and change in personality disorder features: the longitudinal study of personality disorders.

BACKGROUND: The long-term stability of personality pathology remains an open question. Its resolution will come from prospective, multiwave longitudinal studies using blinded assessments of personality disorders (PD). Informative analysis of multiwave data requires the application of statistical procedures, such as individual growth curve modeling, that can detect and describe individual change appropriately over time. The Longitudinal Study of Personality Disorders, which meets contemporary methodological design criteria, provides the data for this investigation of PD stability and change from an individual growth curve perspective. METHODS: Two hundred fifty subjects were examined for PD features at 3 different time points using the International Personality Disorders Examination during a 4-year study. Stability and change in PD features over time were examined using individual growth modeling. RESULTS: Fitting of unconditional growth models indicated that statistically significant variation in PD features existed across time in the elevation and rate of change of the individual PD growth trajectories. Fitting of additional conditional growth models, in which the individual elevation and rate-of-change growth parameters were predicted by subjects' study group membership (no PD vs possible PD), sex, and age at entry into the study, showed that study group membership predicted the elevation and rate of change of the individual growth curves. Comorbid Axis I psychopathology and treatment during the study period were related to elevations of the individual growth trajectories, but not to rates of change. CONCLUSIONS: From the perspective of individual growth curve analysis, PD features show considerable variability across individuals over time. This fine-grained analysis of individual growth trajectories provides compelling evidence of change in PD features over time and does not support the assumption that PD features are traitlike, enduring, and stable over time.

Adolescent↗
PubMed1999

The primate neocortex in comparative perspective using magnetic resonance imaging.

In this study we use neuroanatomic data from living anthropoid primate subjects to test the following three hypotheses: (1) that the human neocortex is significantly larger than expected for a primate of our brain size, (2) that the human prefrontal cortex is significantly more convoluted than expected for our brain size, and (3) that increases in cerebral white matter volume outpace increases in neocortical gray matter volume among anthropoid primates. Whole brain MRI scans were obtained from 44 living primate subjects from 11 different species. Image analysis software was used to calculate total brain volume, neocortical gray matter volume, cerebral white matter volume, and the cross sectional area of the spinal cord in each scan. Allometric regression analyses were used to compare the relative size of these brain structures across species, with an emphasis on determining whether human brain proportions correspond with predictions based on nonhuman primate allometric trajectories. All three hypotheses were supported by our analysis. The results of this study provide additional insights into human brain evolution beyond the important observation that brain volume approximately tripled in the hominid lineage by demonstrating that the neocortex was uniquely modified throughout hominid evolution. These modifications may constitute part of the neurobiological substrate that supports some of our species most distinctive cognitive abilities.

Animals↗
PubMed2007

New insights into the efficacy of naltrexone based on trajectory-based reanalyses of two negative clinical trials.

BACKGROUND: The heterogeneity of clinical findings in studies evaluating the efficacy of naltrexone in the treatment of alcohol dependence has led to growing efforts to explore novel approaches to data analysis. The objective of this study was to identify distinct trajectories of daily drinking over time in two negative clinical trials and to determine whether naltrexone affected the probability to follow a particular trajectory. METHODS: The Veterans Affairs (VA) Cooperative Study #425 and the Women's Naltrexone Study failed to demonstrate efficacy on primary outcome variables. Separately for each study, we analyzed daily indicators of any drinking and heavy drinking using a semiparametric group-based approach. RESULTS: We estimated three distinct trajectories of daily drinking (both any and heavy drinking) which we described as "abstainer," "sporadic drinker," and "consistent drinker." Naltrexone doubled the odds of following the abstainer trajectory instead of the consistent drinker trajectory but did not significantly change the odds of following the abstainer trajectory as contrasted with the sporadic drinker trajectory. CONCLUSIONS: Naltrexone may have a clinically meaningful effect for alcohol-dependent patients with a high chance of consistent drinking, even in studies where it failed to show efficacy in planned analyses.

Adult↗
PubMed1992

Effects of chamber depth on the motion pattern of human spermatozoa in semen or in capacitating medium.

The computer-aided sperm analysis system (CASA) permits precise calculation of the trajectory characteristics of human spermatozoa. Comparison between different chamber depths (10, 20 and 100 microns) revealed variations in the results, which were more evident as the magnitude of the spermatozoon flagellar beat increased. In seminal spermatozoa, the reduced amplitude of movement, linked to the relatively short flagellum and high viscosity of seminal plasma, indicates that the 10 microns-deep chamber can be used for motion analysis without involving extensive modifications. On the other hand, analysis of quicker movement, such as in capacitated spermatozoa, revealed large variations; in particular the proportion of non-progressive hyperactivated spermatozoa was higher in the 20 microns than in the 10 microns chamber (17.9 +/- 14% and 6.9 +/- 4.5% respectively, P < 0.01). In fact the distribution of non-progressive and progressive hyperactivated spermatozoa is depth-dependent. It is therefore necessary to use a chamber of at least 20 microns in depth for sperm analysis in capacitated medium.

Computers↗
PubMed2003

Optoelectronic measures in the analysis of running target shooting.

In this study, we examined the construct validity and practical significance of an optoelectronic shooting training system (Noptel ST 2000 Sport) for the technical analysis of running target shooting. A total of 37 male shooters of three different skill levels participated in the study. Principal component analysis revealed four common factors of 16 variables describing the aiming trajectory of the rifle barrel: (i) Holding area, (ii) Accuracy of aiming, (iii) Cleanness of triggering and (iv) Time on target. These factors were suggested to describe the essential components of running target shooting. According to the discriminant analysis, the shooters of various skill levels seemed to discriminate successfully into three groups when the aiming trajectory data were analysed. Finally, the aiming trajectory variables represented a 43% of the total variance in the shooting score. In summary, the present data indicated that the optoelectronic shooting training system had practical significance and supported the technical analysis of rifle barrel movement in running target shooting. A sub-set of variables, which reflect the essential information of running target shooting performance, were outlined for training and coaching purposes.

Adult↗
PubMed2005

Long dynamics simulations of proteins using atomistic force fields and a continuum representation of solvent effects: calculation of structural and dynamic properties.

Long dynamics simulations were carried out on the B1 immunoglobulin-binding domain of streptococcal protein G (ProtG) and bovine pancreatic trypsin inhibitor (BPTI) using atomistic descriptions of the proteins and a continuum representation of solvent effects. To mimic frictional and random collision effects, Langevin dynamics (LD) were used. The main goal of the calculations was to explore the stability of tens-of-nanosecond trajectories as generated by this molecular mechanics approximation and to analyze in detail structural and dynamical properties. Conformational fluctuations, order parameters, cross correlation matrices, residue solvent accessibilities, pKa values of titratable groups, and hydrogen-bonding (HB) patterns were calculated from all of the trajectories and compared with available experimental data. The simulations comprised over 40 ns per trajectory for ProtG and over 30 ns per trajectory for BPTI. For comparison, explicit water molecular dynamics simulations (EW/MD) of 3 ns and 4 ns, respectively, were also carried out. Two continuum simulations were performed on each protein using the CHARMM program, one with the all-atom PAR22 representation of the protein force field (here referred to as PAR22/LD simulations) and the other with the modifications introduced by the recently developed CMAP potential (CMAP/LD simulations). The explicit solvent simulations were performed with PAR22 only. Solvent effects are described by a continuum model based on screened Coulomb potentials (SCP) reported earlier, i.e., the SCP-based implicit solvent model (SCP-ISM). For ProtG, both the PAR22/LD and the CMAP/LD 40-ns trajectories were stable, yielding C(alpha) root mean square deviations (RMSD) of about 1.0 and 0.8 A respectively along the entire simulation time, compared to 0.8 A for the EW/MD simulation. For BPTI, only the CMAP/LD trajectory was stable for the entire 30-ns simulation, with a C(alpha) RMSD of approximately 1.4 A, while the PAR22/LD trajectory became unstable early in the simulation, reaching a C(alpha) RMSD of about 2.7 A and remaining at this value until the end of the simulation; the C(alpha) RMSD of the EW/MD simulation was about 1.5 A. The source of the instabilities of the BPTI trajectories in the PAR22/LD simulations was explored by an analysis of the backbone torsion angles. To further validate the findings from this analysis of BPTI, a 35-ns SCP-ISM simulation of Ubiquitin (Ubq) was carried out. For this protein, the CMAP/LD simulation was stable for the entire simulation time (C(alpha) RMSD of approximately 1.0 A), while the PAR22/LD trajectory showed a trend similar to that in BPTI, reaching a C(alpha) RMSD of approximately 1.5 A at 7 ns. All the calculated properties were found to be in agreement with the corresponding experimental values, although local deviations were also observed. HB patterns were also well reproduced by all the continuum solvent simulations with the exception of solvent-exposed side chain-side chain (sc-sc) HB in ProtG, where several of the HB interactions observed in the crystal structure and in the EW/MD simulation were lost. The overall analysis reported in this work suggests that the combination of an atomistic representation of a protein with a CMAP/CHARMM force field and a continuum representation of solvent effects such as the SCP-ISM provides a good description of structural and dynamic properties obtained from long computer simulations. Although the SCP-ISM simulations (CMAP/LD) reported here were shown to be stable and the properties well reproduced, further refinement is needed to attain a level of accuracy suitable for more challenging biological applications, particularly the study of protein-protein interactions.

Alanine↗
PubMed1994

The effects of family cohesiveness and peer encouragement on the development of adolescent alcohol use: a cohort-sequential approach to the analysis of longitudinal data.

This article demonstrates a latent growth curve methodology for analyzing longitudinal data for adolescent alcohol use by combining information from different overlapping age cohorts to form a single developmental trajectory. Hypotheses concerning the form of growth in alcohol use, the extent of individual differences in the common trajectory over time, and covariates influencing both initial status and the form of growth were tested. Utilizing five separate age cohorts each measured over the same 4-year period, results suggested a common trajectory existed across the 8 years represented by the cohort-sequential analysis, with alcohol use increasing more rapidly during the adolescents' transition to high school. Family cohesion and peer encouragement for alcohol use were hypothesized to influence both initial status and the trajectory of alcohol consumption during adolescence. While family cohesion served to suppress initial levels of consumption delaying the upward trajectory of alcohol use, peer encouragement was related not only to initial, and elevated, levels of use, but was predictive of those changes that occurred during adolescence. Discussion involves the importance of family and peer influences in the development of adolescent alcohol use and the utility of the cohort-sequential approach in the analysis of longitudinal data.

Adolescent↗
PubMed1994

Canonical analysis of correlated atomic motions in DNA from molecular dynamics simulation.

We report a method for analyzing atomic correlated motions in biopolymers from trajectories obtained by molecular dynamics simulation. A correlation coefficient based on the canonical analysis of data is defined which is independent on the relative orientation of atomic displacement. To illustrate the method we studied correlation between positional fluctuations of protons in the double-stranded self complementary oligonucleotide d(CTGAT-CAG), deduced from a 200 ps molecular dynamics simulation in the presence of explicit water molecules and counterions. It is found that on this time scale the motions of protons belonging to different residues are poorly coupled while the motion of a base proton is correlated to the motion of the sugar ring protons of the same nucleotide. Such a method may be generalized to study correlated motions of two distinct domains of a macro-molecule.

Computer Simulation↗
PubMed1995

Does Paramecium sense gravity?

In order to get an insight into the cellular mechanisms for the integration of the effects of gravity, we investigated the gravitactic behaviour in Paramecium. There are two main categories for the model of the mechanism of gravitaxis; one is derived on the basis of the mechanistic properties of the cell (physical model) and the other of the physiological properties including cellular gravireception (physiological model). In this review article, we criticized the physical models and introduced a new physiological model. Physical models postulated so far can be divided into two; one explaining the negative gravitactic orientation of the cell in terms of the static torque generated by the structural properties of the cell (gravity-buoyancy model by Verworn, 1889 and drag-gravity model by Roberts, 1970), and the other explaining it in terms of the dynamic torque generated by the helical swimming of the cell (propulsion-gravity model by Winet and Jahn, 1974 and lifting-force model by Nowakowska and Grebecki, 1977). Among those we excluded the possibility of dynamic-torque models because of their incorrect theoretical assumptions. According to the passive orientation of Ni(2+)-immobilized cells, the physical effect of the static torque should be inevitable for the gravitactic orientation. Downward orientation of the immobilized cells in the course of floating up in the hyper-density medium demonstrated the gravitactic orientation is not resulted by the nonuniform distribution of cellular mass (gravity-buoyancy model) but by the fore-aft asymmetry of the cell (drag-gravity model). A new model explaining the gravitactic behaviour is derived on the basis of the cellular gravity sensation through mechanoreceptor channels of the cell membrane. Paramecium is known to have depolarizing receptor channels in the anterior and hyperpolarizing receptors in the posterior of the cell. The uneven distribution of the receptor may lead to the bidirectional changes of the membrane potential by the selective deformation of the anterior and posterior cell membrane responding to the orientation of the cell in the gravity field; i.e. negative- and positive-going shift of the potential due to the upward and downward orientation, respectively. The orientation dependent changes in membrane potential with respect to gravity, in combination with the close coupling of the membrane potential and the ciliary locomotor activity, may allow the changes in swimming direction along with those in the helical nature of the swimming path; upward shift of axis of helix by decreasing the pitch angle due to hyperpolarization in the upward-orienting cell, and also the upward shift by increasing the pitch angle due to depolarization in the downward-orienting cell. Computer simulation of the model demonstrated that the cell can swim upward along the "super-helical" trajectory consisting of a small helix winding helically an axis parallel to the gravity vector, after which the model was named as "Super-helix model". Three-dimensional recording of the trajectories of the swimming cells demonstrated that about a quarter of the cell population drew super-helical trajectory under the unbounded, thermal convection-free conditions. In addition, quantitative analysis of the orientation rate of the swimming cell indicated that gravity-dependent orientation of the swimming trajectory could not be explained solely by the physical static torque but complementarily by the physiological mechanism as proposed in the super-helix model.

Animals↗
PubMed1998

Gradient characterization using a Fourier-transform technique.

This paper describes a technique for characterizing the gradient subsystem of a magnetic resonance (MR) system. The technique uses a Fourier-transform analysis to directly measure the k-space trajectory produced by an arbitrary gradient waveform. In addition, the method can be easily extended to multiple dimensions and can be adapted to measuring residual gradient effects such as eddy currents. Several examples of gradient waveform and eddy-current measurements are presented. Also, it is demonstrated how the eddy-current measurements can be parameterized with an impulse-response formalism for later use in system tuning. When compared to a peak-fitting analysis, this technique provides a more direct extraction of the k-space measurements, which reduces the possibility of analysis error. This approach also has several advantages as compared to the conventional eddy-current measurement technique, including the ability to measure very short time constant effects.

Fourier Analysis↗
PubMed1996

H-bond stability in the tRNA(Asp) anticodon hairpin: 3 ns of multiple molecular dynamics simulations.

Multiple molecular dynamics trajectories of the solvated and neutralized 17-residue tRNA(Asp) anticodon hairpin were generated for a total of 3 ns. Explicit treatment of all long-ranged electrostatic interactions by the particle mesh Ewald algorithm, as implemented in the AMBER MD software package, effected a degree of structural stabilization not previously achieved by use of a long 16-A solvent interaction truncation scheme. The increased stability of this multiple molecular dynamics set was appropriate for an in-depth analysis of the six 500-ps-long trajectories and allowed the characterization of a number of key structural interactions. The dynamical behavior of the standard Watson-Crick base pairs, the noncanonical G30-U40 "wobble" base pair, and the psi 32-C38 pseudo-base pair is presented as well as that of two C--H... O hydrogen bonds found to contribute to the array of tertiary interactions that stabilize the seven-nucleotide native loop conformation. The least mobile residue in the loop is U33, which forms the U-turn motif and which participates in several hydrogen-bonding interactions, whereas the most mobile residue is the apical residue G34 at the wobble position, a factor undoubtedly important in its biological function. The set of multiple molecular dynamics trajectories obtained does not converge on a 500-ps time scale to a unique dynamical model but instead describes an ensemble of structural microstates accessible to the system under the present simulation protocol, which is the result of local structural heterogeneity rather than of global conformational changes.

Anticodon↗
PubMedDate not supplied

An analytic strategy for modeling multiple-item responses: a breast cancer symptom example.

BACKGROUND: Item Response Theory (IRT) is increasingly applied in health research to combine information from multiple-item responses. IRT posits that a person's susceptibility to a symptom is driven by the interaction of the characteristics of the symptom and person. This article describes the statistical background of incorporating IRT into a multilevel framework and extends this approach to longitudinal health outcomes, where the self-report method is used to construct a multi-item scale. METHODS: A secondary analysis of data from 2 descriptive longitudinal studies is performed. The data include 21 symptoms reported across time by 350 women with breast cancer. A 3-level hierarchical linear model (HLM) was used for the analysis. Level 1 models the item responses, consisting of symptom presence or absence. Level 2 models the trajectory of each individual, representing change over time of the IRT-created latent variable symptom experience. Level 3 explains that trajectory using person-specific characteristics such as age and location of care. The purpose of the analysis is to examine if older and younger women with breast cancer differ in their symptom experience trajectory after controlling for location of care. RESULTS: Fatigue and pain were the most prevalent symptoms. The symptom experience of women with breast cancer was found to improve over time. Neither age nor location of care was significantly associated with the symptom experience trajectory. DISCUSSION: Embedding IRT into an HLM framework produces several benefits. The example provided demonstrates benefits through the creation of a latent symptom experience variable that can be used either as an outcome or as a covariate in another model, examining the latent symptom experience trajectory and its relationship with covariates at the individual level, and managing symptom nonresponse.

Adult↗