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PubMed2005

Segmented polyurethane modified by photopolymerization and cross-linking with 2-methacryloyloxyethyl phosphorylcholine polymer for blood-contacting surfaces of ventricular assist devices.

To improve the biocompatibility of pulsatile ventricular assist devices (VADs), the blood-contacting surface of the segmented polyurethane (SPU) diaphragm employed in an electromechanical VAD was modified by introducing 2-methacryloyloxyethyl phosphorylcholine (MPC) units into its surface and forming an interpenetrating polymer network (IPN) structure, which contained independently cross-linked MPC polymer and SPU. The SPU diaphragm modified with an IPN structure was then assembled into a target test pump and underwent continuous pump operation at 37 degrees C for 2 weeks in a simulated systemic circulation using a mock circulatory loop. The surface characteristics of the pump diaphragm after 2 weeks of pump operation were then analyzed with an X-ray photoelectron spectroscope (XPS) and gold-colloid-labeled immunoassay. The XPS surface analysis of the IPN-modified SPU indicated the firm anchoring of MPC units even after 2 weeks of pump operation (the phosphor : carbon ratio was reduced by only 0.09%). The IPN-modified diaphragm prevented protein adsorption as well as cell adhesion in comparison to the unmodified SPU surface. This result thus validated that (1) the IPN structure could firmly secure MPC units to the SPU surface even in a high-mechanical-stress and high-shear environment, (2) the antithrombogenic power of MPC units remained unchanged after 2 weeks of continuous exposure to a high-shear environment, and (3) the IPN modified SPU cross-linked with MPC could be a powerful antithrombogenic surface for blood pumps used for chronic circulatory support of cardiac patients.

Biocompatible Materials↗
PubMed2000

The use of chemical shift temperature gradients to establish the paramagnetic susceptibility tensor orientation: implication for structure determination/refinement in paramagnetic metalloproteins.

The use of dipolar shifts as important constraints in refining molecular structure of paramagnetic metalloproteins by solution NMR is now well established. A crucial initial step in this procedure is the determination of the orientation. of the anisotropic paramagnetic susceptibility tensor in the molecular frame which is generated interactively with the structure refinement. The use of dipolar shifts as constraints demands knowledge of the diamagnetic shift. which, however, is very often not directly and easily accessible. We demonstrate that temperature gradients of dipolar shifts can serve as alternative constraints for determining the orientation of the magnetic axes, thereby eliminating the need to estimate the diamagnetic shifts. This approach is tested on low-spin, ferric sperm whale cyanometmyoglobin by determining the orientation, anisotropies and anisotropy temperature gradients by the alternate routes of using dipolar shifts and dipolar shift gradients as constraints. The alternate routes ultimately lead to very similar orientation of the magnetic axes, magnetic anisotropies and magnetic anisotropy temperature gradients which, by inference, would lead to an equally valid description of the molecular structure. It is expected that the use of the dipolar shift temperature gradients, rather than the dipolar shifts directly, as constraints will provide an accurate shortcut in a solution structure determination of a paramagnetic metalloprotein.

Animals↗
PubMed1993

Structure of Sesbania mosaic virus at 4.7 A resolution and partial sequence of the coat protein.

Sesbania mosaic virus (SMV) is a plant virus infecting Sesbania grandiflora plants in Andhra Pradesh, India. Amino acid sequence of the tryptic peptides of SMV coat protein were determined using a gas phase sequenator. These sequences showed identical amino acids at 69% of the positions when aligned with the corresponding residues of southern bean mosaic virus (SBMV). Crystals diffracting to better than 3 A resolution were obtained by precipitating the virus with ammonium sulphate. The crystals belonged to rhombohedral space group R3 with a = 291.4 A and alpha = 61.9 degrees. Three-dimensional X-ray diffraction data on these crystals were collected to a resolution of 4.7 A, using a Siemens-Nicolet area detector system. Self-rotation function studies revealed the icosahedral symmetry of the virus particles, as well as their precise orientation in the unit cell. Cross-rotation function and modelling studies with SBMV showed that it is a valid starting model for SMV structure determination. Low resolution phases computed using a polyalanine model of SBMV were subjected to refinement and extension by real-space electron density averaging and solvent flattening. The final electron density map revealed a polypeptide fold similar to SBMV. The single disulphide bridge of SBMV coat protein is retained in SMV. Four icosahedrally independent cation binding sites have been tentatively identified. Three of these sites, related by a quasi threefold axis, are also found in SBMV. The fourth site is situated on the quasi threefold axis. Aspartic acid residues, which replace Ile218 of SBMV from the quasi threefold-related subunits are suitable ligands to the cation at this site.

Amino Acid Sequence↗
PubMed2006

Characterization of trabecular bone structure from high-resolution magnetic resonance images using fuzzy logic.

The purpose of this work was to apply fuzzy logic image processing techniques to characterize the trabecular bone structure with high-resolution magnetic resonance images. Fifteen ex vivo high-resolution magnetic resonance images of specimens of human radii at 1.5 T and 12 in vivo high-resolution magnetic resonance images of the calcanei of peri- and postmenopausal women at 3 T were obtained. Soft segmentation using fuzzy clustering was applied to MR data to obtain fuzzy bone volume fraction maps, which were then analyzed with three-dimensional (3D) fuzzy geometrical parameters and measures of fuzziness. Geometrical parameters included fuzzy perimeter and fuzzy compactness, while measures of fuzziness included linear index of fuzziness, quadratic index of fuzziness, logarithmic fuzzy entropy, and exponential fuzzy entropy. Fuzzy parameters were validated at 1.5 T with 3D structural parameters computed from microcomputed tomography images, which allow the observation of true trabecular bone structure and with apparent MR structural indexes at 1.5 T and 3 T. The validation was statistically performed with the Pearson correlation coefficient as well as with the Bland-Altman method. Bone volume fraction correlation values (r) were up to .99 (P<.001) with good agreements based on Bland-Altman analysis showing that fuzzy clustering is a valid technique to quantify this parameter. Measures of fuzziness also showed consistent correlations to trabecular number parameters (r>.85; P<.001) and good agreements based on Bland-Altman analysis, suggesting that the level of fuzziness in high-resolution magnetic resonance images could be related to the trabecular bone structure.

Aged↗
PubMed1994

Probing structure-function relationships in human immunodeficiency virus type 1 protease via molecular dynamics simulation.

This chapter has focused on the application of molecular dynamics computer simulations and related molecular modeling techniques to the study of HIV protease structure and structure-function relationships. The abundance of crystallographic data provides ample experimental quantities (average structures, temperature factors, and hydrogen bond topography) to validate the computational techniques employed. Furthermore, these studies provide insight into the structure and functional energetics of HIV-1 protease that would be difficult or impossible to study experimentally. This chapter covers studies that investigate correlated motion between and within subunits of the protease, mutants of the protease that disrupt the tertiary structure and dimer formation, and studies of HIV-1 protease-inhibitor complexes that rationalize both the protonation state of the active site and the observed binding strength of these complexes. These studies demonstrate that MD is capable of contributing to our understanding of structure-function relationships and may aid in the design of potential therapeutics.

Amino Acid Sequence↗
PubMed2002

Transmembrane topology of the NuoL, M and N subunits of NADH:quinone oxidoreductase and their homologues among membrane-bound hydrogenases and bona fide antiporters.

Nicotinamide adenine dinucleotide-reduced form (NADH):quinone oxidoreductase (respiratory Complex I), F420H2 oxidoreductase and complex, membrane-bound NiFe-hydrogenase contain protein subunits homologous to a certain type of bona fide antiporters. In Complex I, these polypeptides (NuoL/ND5, NuoM/ND4, NuoN/ND2) are most likely core components of the proton pumping mechanism, and it is thus important to learn more about their structure and function. In this work, we have determined the transmembrane topology of one such polypeptide, and built a 2D structural model of the protein valid for all the homologous polypeptides. The experimentally determined transmembrane topology was different from that predicted by majority vote hydrophobicity analyses of members of the superfamily. A detailed phylogenetic analysis of a large set of primary sequences shed light on the functional relatedness of these polypeptides.

Amino Acid Sequence↗
PubMedDate not supplied

Modeling the structural basis of human CCR5 chemokine receptor function: from homology model building and molecular dynamics validation to agonist and antagonist docking.

This article describes the construction and validation of a three-dimensional model of the human CCR5 receptor using a homology-based approach starting from the X-ray structure of the bovine rhodopsin receptor. The reliability of the model is assessed through molecular dynamics and docking simulations using both natural agonists and a synthetic antagonist. Some important structural and functional features of the receptor cavity and the extracellular loops are identified, in agreement with data available from site-directed mutagenesis. The results of this study help to explain the structural basis for the recognition, activation, and inhibition processes of CCR5 and may provide fresh insights for the design of HIV-1 entry blockers.

CCR5 Receptor Antagonists↗
PubMed1998

Structure-based prediction of the conductance properties of ion channels.

The HOLE procedure allows the prediction of the absolute conductance of an ion channel model from its structure. The original prediction method uses an empirically corrected Ohmic method. It is most successful, with predictions being reliable to within a factor of two. A new modification of the procedure is presented in which the self-diffusion coefficients of water molecules from molecular dynamics simulation are used to replace the empirical correction factor. A "prediction" of the conductance for the porin OmpF by the new method is made and shown to be very close to the experimental value. HOLE also allows the prediction of the effect that the addition of non-electrolyte polymers will have on channel conductance. The method has great potential to yield structural information from data provided by single channel recordings but needs further validation by making measurements on channels of known structure. Preliminary results are given of single channel records establishing the effects of non-electrolytes on the conductance of gramicidin D channels. As an example of the potential uses of the procedure application is made to examine the oligomerization of alpha-toxin (alpha-hemolysin) channels. A model for the alpha-toxin hexamer, based on the crystal structure for the heptamer, is generated using molecular mechanics methods. The compatibility of the structures with single channel conductance data is assessed using HOLE.

Computer Simulation↗
PubMed2001

A comparative trial of paper-and-pencil versus computer administration of the Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire.

BACKGROUND: Although most health-related quality of life questionnaires are self-administered by means of paper and pencil, new technologies for automated computer administration are becoming more readily available. Novel methods of instrument administration must be assessed for score equivalence in addition to consistency in reliability and validity. OBJECTIVES: The present study compared the psychometric characteristics (score equivalence and structure, internal consistency, and reproducibility reliability and construct validity) of the Quality of Life in Reflux And Dyspepsia (QOLRAD) questionnaire when self-administered by means of paper and pencil versus touch-screen computer. The influence of age, education, and prior experience with computers on score equivalence was also examined. RESEARCH DESIGN: This crossover trial randomized 134 patients with gastroesophageal reflux disease to 1 of 2 groups: paper-and-pencil questionnaire administration followed by computer administration or computer administration followed by use of paper and pencil. To minimize learning effects and respondent fatigue, administrations were scheduled 3 days apart. A random sample of 32 patients participated in a 1-week reproducibility evaluation of the computer-administered QOLRAD. RESULTS: QOLRAD scores were equivalent across the 2 methods of administration regardless of subject age, education, and prior computer use. Internal consistency levels were very high (alpha = 0.93-0.99). Interscale correlations were strong and generally consistent across methods (r = 0.7-0.87). Correlations between the QOLRAD and Short Form 36 (SF-36) were high, with no significant differences by method. Test-retest reliability of the computer-administered QOLRAD was also very high (ICC = 0.93-0.96). CONCLUSIONS: Results of the present study suggest that the QOLRAD is reliable and valid when self-administered by means of computer touch-screen or paper and pencil.

Age Factors↗
PubMed1989

Factor structure of perceptual-motor attributes in normal children: a cross-validation.

The scores on 22 items of the Purdue Perceptual-motor Survey, administered to 567 normal school children of mean IQ 103 and mean age of 116 mo., were subjected to R-factor analysis by the method of principal factoring with orthogonal varimax rotation. The analysis led to the definition of 10 factors: J, ocular control; K, dynamic balance; L, visual-motor fluency; M, chalkboard; N, unilateral-bilateral coordination; O, upper-lower body differentiation; P, form perception; Q, developmental maturation; R, sex; and S, spatial body perception. The results provide cross-validation for previous studies on the perceptual-motor attributes of normal school children.

Child↗
PubMedDate not supplied

[Biopolymers and evolution].

Biopolymers are usually studied being extracted from the whole system of a cell or of an organism. Some important features are lost during such a procedure. It is necessary to take into account the behavior of proteins and nucleic acids in metabolic networks and to investigate their evolution. The substitutions of amino-acids metabolic networks residues are biologically possible in the polypeptides and proteins if they do not influence their spatial structure and function. The correlations of the primary structure with these properties are degenerate. The protein can be treated as "an edited statistical copolymer" (Ptitsyn). In the process of "edition" an important role is played by the ions of transient metals. Nucleic acids possess similar properties. It can be shown that the deleterious mutations of proteins can be compensated by the changes of their amount, spatial and temporal characteristics of the synthesis. Not only the structure of the protein is important but also the exact answers of the questions: how much, when and where? The contemporary theory of evolution unites phylogeny and onthogeny. The directionality of evolution is determined both by natural selection and by the already existing structure of an organism. Hence many characters are not adaptive. This is valid also for the molecular level of the structure. Thus three independent groups of facts and suggestions are presented, which confirm the neutral theory of evolution (Kimura) and elucidate its physical meaning. The molecular evolution does not coincide with the biological evolution.

Amino Acid Sequence↗
PubMed1994

[Difficulties encountered in the evaluation of prognostic criteria of breast cancer: apropos of the experience of the René Huguenin center].

The use of prognostic factors to help select breast cancer patients for adjuvant therapy is of considerable concern to the oncology community. This need for selection of prognostically less favorable cases is stimulating investigators to identify new and more powerful prognostic factors. Unfortunately however, this identification process is becoming more confusing because of a lack of guidelines for investigators to use to study new factors and for reviewers and readers to use to evaluate papers on this topic. In this paper, we will describe across our experience the main problems encountered in the study of biological prognostic studies. Considering evaluation criteria to be developed in the future, it appears that only multicentric and multidisciplinary structures are able to define decisional trees based on technically and clinically validated parameters in particular patients subgroups. Such a structure exists at the european level ("Receptor Study Group" of the EORTC) and a similar structure has now been created in France to answer these questions.

Breast Neoplasms↗
PubMed2003

Surface descriptors for protein-ligand affinity prediction.

Molecular descriptors calculated by the VolSurf program have been extensively used to model pharmacokinetic properties, e.g., passive permeability through the gastrointestinal tract or through the blood-brain barrier. These descriptors quantify steric, hydrophobic, and hydrogen bond interactions between model compounds and different environments. Since these interactions are the same as those involved in the ligand-receptor binding, VolSurf descriptors could potentially be relevant in modeling this process as well. We obtained a significant model (r(2) = 0.85, q(2) = 0.75) using VolSurf descriptors derived from the ligand, the protein, and the ligand-protein complex for a diverse set of 38 structures previously used in the VALIDATE (ref 23) training set. Furthermore, a statistically significant model (r(2) = 0.94, q(2) = 0.89) was obtained using the same type of descriptors for a homogeneous set of glycogen phosphorylase inhibitors (ref 25). Using the VolSurf computational framework, both ligand-receptor binding and the ligand's pharmacokinetic behavior can be modeled simultaneously during the preclinical aspects of drug discovery.

Ligands↗
PubMed2004

Second eigenvalue of the Laplacian matrix for predicting RNA conformational switch by mutation.

MOTIVATION: Conformational switching in RNAs is thought to be of fundamental importance in several biological processes, including translational regulation, regulation of self-cleavage in viruses, protein biosynthesis and mRNA splicing. Current methods for detecting bi-stable RNAs that can lead to structural switching when triggered by an outside event rely on kinetics, energetics and properties of the combinatorial structure space of RNAs. Based on these properties, tools have been developed to predict whether a given sequence folds to a structure characterized by a bi-stable conformation, or to design multi-stable RNAs by an iterative algorithm. A useful addition is in developing a local procedure to prescribe, given an initial sequence, the least amount of mutations needed to drive the system into an optimal bi-stable conformation. RESULTS: We introduce a local procedure for predicting mutations, by generating and analyzing eigenvalue tables, that are capable of transforming the wild-type sequence into a bi-stable conformation. The method is independent of the folding algorithms but relies on their success. It can be used in conjunction with existing tools, as well as being incorporated into more general RNA prediction packages. We apply this procedure on three well-studied structures. First, the method is validated on the mutation leading to a conformational switch in the spliced leader RNA from Leptomonas collosoma, a mutation that has already been confirmed by an experiment. Second, the method is used to predict a mutation that can lead to a novel conformational switch in the P5abc subdomain of the group I intron ribozyme in Tetrahymena thermophila. Third, the method is applied on Hepatitis delta virus to predict mutations that transform the wild-type into a bi-stable conformation, a configuration assessed by calculating the free energies using folding prediction algorithms. The predictions in the final examples need to be verified experimentally, whereas the mutation predicted in the first example complies with the experiment. This supports the use of our proposed method on other known structures, as well as genetically engineered ones. AVAILABILITY: An eigenvalue application will be available in the near future attached to one of the existing tools.

Algorithms↗
PubMedDate not supplied

Food safety: risk assessment methodology and decision-making criteria.

As our scientific technology grows, risk assessment methods become more complex and, therefore, open to greater scientific debate. Risk assessment has always been a part of the regulatory notification and approval process for foods. However, the methodologies applied to risk assessment and decision-making have become diverse, dependent on a number of features, including the areas of the world in which one operates, the need to use cumulative risk assessment for pesticides and other ingredients or alternative risk assessment considerations for evaluating nontraditional or bioengineered foods. Diverse institutional structures within a single federal regulatory authority may tend to lead to diversity in risk outcomes that creates policy decisions that complicate and confuse the risk management process. On top of this challenge, decisions become more complicated by the need to examine beneficial factors of foods rather than the adverse effects of foods and food additives. Foods are a complex mixture of ingredients. Regulatory groups recognize the need to use new approaches for evaluating the safety and risks associated with foods and food additives, and to do so in a timely manner. The United States Food and Drug Administration (US FDA) in its need to ensure standards of "reasonable certainty of no harm" continues to explore alternative means to be responsive to petitioners as well as continue to examine scientifically validated means, e.g., quantitative structure-activity relationship (QSAR), and computer-assisted programs, within the approval process to assist in the evaluation of risks. Another means to improve the risk management process would include the cumulative risk assessment of pesticides that will, no doubt, be the beginning of more intensive efforts to understand cumulative exposures and the inherent risks from multiple pathways of exposure. The passage of the Food Quality Protection Act (FQPA) resulted in developing additional risk assessment methodologies and approaches to assess the potential for multiple exposures and risks. Addressing the international criteria used in decision-making related to foods safety assessment has resulted in acceptable intake values for food ingredients for carcinogens and noncarcinogens that, in general, tend to be more stringent in the United States compared to Europe. Clearly, the need for harmonization of risk assessment criteria and the impact of the decision process on regulatory approvals and safety assessment is a future need for the continued assurances of food safety. The topics presented in this paper are based on a symposium held in November 2002 at the annual meeting of the American College of Toxicology.

Animals↗
PubMed2003

Covalent modification of cysteine 193 impairs ATPase function of nucleotide-binding domain of a Candida drug efflux pump.

N-ethylmaleimide (NEM) impairs the ATPase function of N-terminal NBD of Candida drug resistance gene product Cdr1p. To identify the reactive cysteine(s) for such a contribution, we adopted a three-arm approach that included covalent modification, cysteine mutagenesis, and structure homology modeling. The covalent modification results clearly indicate the ability of NEM and iodoacetic acid (IAA) to potently inhibit the ATPase activity of N-terminal NBD. Since this domain contains five cysteine residues in its sequence, we mutated each and found four of these (C325A, C363A, C402A, and C462A) to stay sensitive to NEM/IAA modification and influence ATPase activity, while C193A mutation completely abrogated the catalytic function. The structural homology modeling data further validate these biochemical findings by ruling out any plausible interactions within the cysteine residues, and deriving the importance of Cys-193 in lying at a bond length clearly feasible to interact with ATP and divalent cation to critically influence ATP hydrolysis.

Adenosine Triphosphatases↗
PubMed2006

Mobile computing acceptance factors in the healthcare industry: a structural equation model.

OBJECTIVE: This paper presents a revised technology acceptance model to examine what determines mobile healthcare systems (MHS) acceptance by healthcare professionals. METHOD: Conformation factor analysis was performed to test the reliability and validity of the measurement model. The structural equation modeling technique was used to evaluate the causal model. RESULTS: The results indicated that compatibility, perceived usefulness and perceived ease of use significantly affected healthcare professional behavioral intent. MHS self-efficacy had strong indirect impact on healthcare professional behavioral intent through the mediators of perceived usefulness and perceived ease of use. Yet, the hypotheses for technical support and training effects on the perceived usefulness and perceived ease of use were not supported. CONCLUSION: This paper provides initial insights into factors that are likely to be significant antecedents of planning and implementing mobile healthcare to enhance professionals' MHS acceptance. The proposed model variables explained 70% of the variance in behavioral intention to use MHS; further study is needed to explore extra significant antecedents of new IT/IS acceptance for mobile healthcare. Such as privacy and security issue, system and information quality, limitations of mobile devices; the above may be other interesting factors for implementing mobile healthcare and could be conducted by qualitative research.

Attitude of Health Personnel↗
PubMed2000

[Psychometric properties of the French version of the Effort-Reward Imbalance model].

BACKGROUND: Two main models are currently used to evaluate psychosocial factors at work: the Job Strain model developed by Karasek and the Effort-Reward Imbalance model. A French version of the first model has been validated for the dimensions of psychological demands and decision latitude. As regards the second one evaluating three dimensions (extrinsic effort, reward, and intrinsic effort), there are several versions in different languages, but until recently there was no validated French version. The objective of this study was to explore the psychometric properties of the French version of the Effort-Reward Imbalance model in terms of internal consistency, factorial validity, and discriminant validity. METHODS: The present study was based on the GAZEL cohort and included the 10 174 subjects who were working at the French national electric and gas company (EDF-GDF) and answered the questionnaire in 1998. A French version of Effort-Reward Imbalance was included in this questionnaire. This version was obtained by a standard forward/backward translation procedure. RESULTS: Internal consistency was satisfactory for the three scales of extrinsic effort, reward, and intrinsic effort: Cronbach's Alpha coefficients higher than 0.7 were observed. A one-factor solution was retained for the factor analysis of the scale of extrinsic effort. A three-factor solution was retained for the factor analysis of reward, and these dimensions were interpreted as the factor analysis of intrinsic effort did not support the expected four-dimension structure. The analysis of discriminant validity displayed significant associations between measures of Effort-Reward Imbalance and the variables of sex, age, education level, and occupational grade. CONCLUSION: This study is the first one supporting satisfactory psychometric properties of the French version of the Effort-Reward Imbalance model. However, the factorial validity of intrinsic effort could be questioned. Furthermore, as most previous studies were based on male samples working in specific occupations, the present one is also one of the first to show strong associations between measures of this model and social class variables in a population of men and women employed in various occupations.

Adult↗

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