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PubMed2006

Robustness and stability of flow-and-diffusion structures.

Reaction-diffusion-advection systems have revealed an interesting variety of pattern formation mechanism during the last years. Inside this field, flow-and-diffusion structures (FDSs) appear as a generalization of the mechanism of spatial symmetry breaking for different diffusion coefficients and flow rates of activator and inhibitor. The recent experimental validation of FDSs situates these structures in the focus of the actual research. We will report here an experimental and numerical analysis of the theoretically predicted robustness of these flow-and-diffusion structures by using different boundary profiles of illumination used to obtain FDSs. The results here shown reveal important characteristics related with the coexistence and interaction between these structures.

Journal Article↗
PubMed2006

The route to the structure determination of amorphous solids: a case study of the ceramic Si(3)B(3)N(7).

Si(3)B(3)N(7) is the parent compound of a new class of amorphous ceramics containing silicon, boron, nitrogen, and carbon that display a unique spectrum of properties. It consists of a random network in which the constituent elements are linked by predominantly covalent bonds. Similarly to quartz glass, the composition of amorphous Si(3)B(3)N(7) is virtually stoichiometric. As all three of its constituent elements can serve as the objects of various structural probes, Si(3)B(3)N(7) was selected as the basis of a systematic structural investigation, in which methods for the structure determination of solids without translational symmetry could be validated and improved. However, as the complete amorphous structure cannot be deduced from experimental data, these results must be complemented by computer simulations. Thus, five classes of structure models were generated and compared to experimental results. Only the models generated by following the actual synthesis route as closely as possible agreed well with the experimental data.

Journal Article↗
PubMed2007

Ensemble docking of multiple protein structures: considering protein structural variations in molecular docking.

One approach to incorporate protein flexibility in molecular docking is the use of an ensemble consisting of multiple protein structures. Sequentially docking each ligand into a large number of protein structures is computationally too expensive to allow large-scale database screening. It is challenging to achieve a good balance between docking accuracy and computational efficiency. In this work, we have developed a fast, novel docking algorithm utilizing multiple protein structures, referred to as ensemble docking, to account for protein structural variations. The algorithm can simultaneously dock a ligand into an ensemble of protein structures and automatically select an optimal protein structure that best fits the ligand by optimizing both ligand coordinates and the conformational variable m, where m represents the m-th structure in the protein ensemble. The docking algorithm was validated on 10 protein ensembles containing 105 crystal structures and 87 ligands in terms of binding mode and energy score predictions. A success rate of 93% was obtained with the criterion of root-mean-square deviation <2.5 A if the top five orientations for each ligand were considered, comparable to that of sequential docking in which scores for individual docking are merged into one list by re-ranking, and significantly better than that of single rigid-receptor docking (75% on average). Similar trends were also observed in binding score predictions and enrichment tests of virtual database screening. The ensemble docking algorithm is computationally efficient, with a computational time comparable to that for docking a ligand into a single protein structure. In contrast, the computational time for the sequential docking method increases linearly with the number of protein structures in the ensemble. The algorithm was further evaluated using a more realistic ensemble in which the corresponding bound protein structures of inhibitors were excluded. The results show that ensemble docking successfully predicts the binding modes of the inhibitors, and discriminates the inhibitors from a set of noninhibitors with similar chemical properties. Although multiple experimental structures were used in the present work, our algorithm can be easily applied to multiple protein conformations generated by computational methods, and helps improve the efficiency of other existing multiple protein structure(MPS)-based methods to accommodate protein flexibility.

Algorithms↗
PubMed2004

The learning curve for a colonoscopy simulator in the absence of any feedback: no feedback, no learning.

BACKGROUND: The hypothesis of this study is that working on the simulator without a structured feedback does not change performance; hence, any effects shown after structured feedback would amount to useful learning of the procedure. The aim was to investigate the learning curve for the HT Immersion Medical Colonoscopy Simulator without any structured feedback. This could then be potentially applied to validate the learning curve on the simulator when structured feedback is provided. There are no previous studies on this matter. METHODS: Candidates were asked to perform colonoscopy on the HT Immersion Medical Colonoscopy Simulator. Modules 3 and 4 were used at random. In total, each candidate was asked to perform five consecutive virtual colonoscopies on the same module. These five episodes were collectively referred to as one trial. A time result of 3,600 sec (1 h) was used to denote perforation. No guidance or feedback was given to candidates before, during, or after each procedure. A total of 26 postgraduate doctors were recruited, including nine research fellows, five preregistration house officers, six specialist registrars, and six consultants. Fourteen candidates recorded five attempts each (i.e., one trial each) on the same module of the colonoscopy simulator (14 trials over 70 episodes). Another 12 candidates recorded five attempts (i.e., one trial each) on two modules of the colonoscopy simulator (24 trials over 120 episodes). Hence, 190 episodes were recorded in total, representing 38 trials. RESULTS: There was no improvement in performance on the simulator from first attempt to the fifth in the absence of feedback. If there was any initial gain in any measurable outcome, this was lost in subsequent attempts indicating lack of learning. The outcomes measured included time taken to complete the test, percentage of the mucosa visualized, depth of the instrument inserted, and the path length used. The results were statistically significant for all outcomes. CONCLUSIONS: This study demonstrates that in the absence of feedback, it is not possible to improve performance on the HT Immersion Medical Colonoscopy Simulator. Thus, there is no learning curve for the machine. The information from this study is vital for using the simulators in training and assessment because any improvement in learning curves shown after training on simulators can be presumed to be due to learning the procedure and not the simulator.

Clinical Competence↗
PubMed2005

Psychometric properties of the Toronto Alexithymia Scale (TAS-20) for substance users.

OBJECTIVE: To determine the psychometric properties of the Toronto Alexithymia Scale (TAS-20), an established self-report measure of alexithymia, for a substance user sample participating in a clinical trial of outpatient cognitive-behavioral therapies (N=230). METHODS: Confirmatory and exploratory factor analyses were used to determine the number and nature of the factors underlying the TAS-20 in a sample of substance users. Structural equation modeling was used to determine the predictive validity of the TAS-20. RESULTS: A factor structure comparable, but not identical, with TAS-20 psychometric results with other populations was found; alpha coefficients were .88 for the feelings factor, .62 for the external thinking factor, and .87 for the total score. Although, on average, the substance users did not appear to have elevated alexithymia scores compared with the undergraduate students, alexithymia predicted less treatment engagement, i.e., fewer sessions attended and weaker helping alliance. Alexithymia also predicted alcohol use outcomes but not drug use outcomes. The relation between alexithymia and drinking outcome was conditional on whether the patient was using solely alcohol at baseline. CONCLUSION: The TAS-20 has reasonably good psychometric properties in this sample, which might be improved by dropping several marginal questionnaire items. Alexithymia appears to attenuate substance abuse treatment engagement. More clinical and research experience with this construct and specific instrument in substance user samples is needed.

Adult↗
PubMed1998

High-resolution crystal structures of human hemoglobin with mutations at tryptophan 37beta: structural basis for a high-affinity T-state,.

The high-resolution X-ray structures of the deoxy forms of four recombinant hemoglobins in which Trp37(C3)beta is replaced with Tyr (betaW37Y), Ala (betaW37A), Glu (betaW37E), or Gly (betaW37G) have been refined and analyzed with superposition methods that partition mutation-induced perturbations into quaternary structure changes and tertiary structure changes. In addition, a new cross-validation statistic that is sensitive to local changes in structure (a "local Rfree" parameter) was used as an objective measure of the significance of the tertiary structure changes. No significant mutation-induced changes in tertiary structure are detected at the mutation site itself for any of the four mutants studied. Instead, disruption of the intersubunit contacts associated with Trp37(C3)beta results in (1) a change in quaternary structure at the alpha1beta2 interface, (2) alpha subunit tertiary structure changes that are centered at Asp94(G1)alpha-Pro95(G2)alpha, (3) beta subunit tertiary structure changes that are located between residues Asp99(G1)beta and Asn102(G4)beta, (4) increased mobility of the alpha subunit COOH-terminal dipeptide, and (5) shortening of the Fe-Nepsilon2His(F8) bond in the alpha and beta subunits of the betaW37G and betaW37E mutants. In each case, the magnitude of the change in a particular structural parameter increases in the order betaW37Y < betaW37A < betaW37E approximately betaW37G, which corresponds closely to the degree of functional disruption documented in the preceding papers.

Amino Acid Substitution↗
PubMed2003

Structure and reactivity in the non-mevalonate pathway of isoprenoid biosynthesis.

The function, structure and mechanism of two Escherichia coli enzymes involved in the non-mevalonate route of isoprenoid biosynthesis, 2C-methyl-D-erythritol 4-phosphate cytidylyltransferase and 2C-methyl-D-erythritol 2,4-cyclodiphosphate synthase, are reviewed. Comparisons of each with enzymes from microbial pathogens highlight important conservation of sequence suggestive of similarities in secondary structure, subunit folds, quaternary structure and active sites. Since both enzymes are validated drug targets, the models provide templates for structure-based design of anti-microbial agents targeting a number of serious human diseases.

Amino Acid Sequence↗
PubMed1992

Extended x-ray absorption fine structure studies of a retrovirus: equine infectious anemia virus cysteine arrays are coordinated to zinc.

Zinc finger arrays have been established as a critical structural feature of proteins involved in DNA recognition. Retroviral nucleocapsid proteins, which are involved in the binding of viral RNA, contain conserved cysteine-rich arrays that have been suggested to coordinate zinc. We provide metalloprotein structural data from an intact virus preparation that validate this hypothesis. Extended x-ray absorption fine structure (EXAFS) spectroscopy of well-characterized and active preparations of equine infectious anemia virus, compared with a peptide with known coordination and in combination with available biochemical and genetic data, defines a Cys3His1 coordination environment for zinc. The average of the Zn-S distances is 2.30(1) A and that of the Zn-N distance (to histidine) is 2.01(3) A.

Absorptiometry, Photon↗
PubMed2002

Structural and functional characterization of the human DNA repair helicase XPD by comparative molecular modeling and site-directed mutagenesis of the bacterial repair protein UvrB.

A molecular model for the human nucleotide excision repair protein, XPD, was developed based on the structural and functional relationship of the protein with a bacterial nucleotide excision repair (NER) protein, UvrB. Whereas XPD does not share significant sequence identity with UvrB, the proteins share seven highly conserved helicase motifs that define a common protein structural template. They also have similar functional roles in their ATPase activity and the ability to unwind DNA and verify damaged strands in the process of NER. The validity of using the crystal structure of UvrB as a template for the development of an XPD model was tested by mimicking human disease-causing mutations (XPD: R112H, D234N, R601L) in UvrB (E110R, D338N, R506A) and by mutating two highly conserved residues (XPD, His-237 and Asp-609; UvrB, H341A and D510A). The XPD structural model can be employed in understanding the molecular mechanism of XPD human disease causing mutations. The value of this XPD model demonstrates the generalized approach for the prediction of the structure of a mammalian protein based on the crystal structure of a structurally and functionally related bacterial protein sharing extremely low sequence identity (<15%).

Amino Acid Sequence↗
PubMed1985

The effects of sodium and magnesium-ion interactions on chromatin structure and solubility.

The effects of sodium and magnesium-ion interactions on chromatin structure and solubility were examined in isolated mouse liver nuclei. To facilitate this study, a simple assay of chromatin structure was developed, based on the absorbances at 260 nm (A260) and 320 nm (A320) of nuclei in test solutions. By subtracting the A320 from the A260, a single "spectral index" was obtained which served as a useful, but not absolute, indicator of chromatin structure. Electron microscopy verified the validity of this approach. The results indicate that either 200 mM NaCl or 0.5 mM MgCl2 were capable of preserving the native 20 to 30 nm chromatin fiber structure. Below 200 mM NaCl, the native fiber progressively uncoiled to the 10 nm unit fiber. The presence of 0.5 mM MgCl2 inhibited this uncoiling. Only divalent cations stabilized condensed chromatin (heterochromatin) within the nucleus. Monovalent and divalent cations interacted with one another at critical concentrations and modified their individual effects on chromatin structure; e.g., 10 to 25 mM NaCl interfered with the action of 0.5 to 1.5 mM MgCl2, causing a complete loss of condensed chromatin. Maximum solubility of micrococcal nuclease-digested chromatin occurred at 10 mM NaCl, which treatment allowed the chromatin to unfold to the 10 nm fiber. However, ionic conditions that disrupted condensed chromatin but maintained the native chromatin fiber morphology still resulted in relatively high yields of soluble chromatin. Minimum solubility occurred under conditions which preserved the structure of condensed chromatin.

Animals↗
PubMed2006

Structural transitions of confined model proteins: molecular dynamics simulation and experimental validation.

Proteins fold in a confined space not only in vivo, i.e., folding assisted by molecular chaperons and chaperonins in a crowded cellular medium, but also in vitro as in production of recombinant proteins. Despite extensive work on protein folding in bulk, little is known about how and to what extent the thermodynamics and kinetics of protein folding are altered by confinement. In this work, we use a Gō-like off-lattice model to investigate the folding and stability of an all beta-sheet protein in spherical cages of different sizes and surface hydrophobicity. We find whereas extreme confinement inhibits correct folding, a hydrophilic cage stabilizes the protein due to restriction of the unfolded configurations. In a hydrophobic cage, however, strong attraction from the cage surface destabilizes the confined protein because of competition between self-aggregation and adsorption of hydrophobic residues. We show that the kinetics of protein collapse and folding is strongly correlated with both the cage size and the surface hydrophobicity. It is demonstrated that a cage of moderate size and hydrophobicity optimizes both the folding yield and kinetics of structural transitions. To support the simulation results, we have also investigated the refolding of hen-egg lysozyme in the presence of cetyltrimethylammoniumbromide (CTAB) surfactants that provide an effective confinement of the proteins by micellization. The influence of the surfactant hydrophobicity on the structural and biological activity of the protein is determined with circular dichroism spectrum, fluorescence emission spectrum, and biological activity assay. It is shown that, as predicted by coarse-grained simulations, CTAB micelles facilitate the collapse of denatured lysozyme, whereas the addition of beta-cyclodextrin-grafted-PNIPAAm, a weakly hydrophobic stripper, dissociates CTAB micelles and promotes the conformational rearrangement and thereby gives an improved recovery of lysozyme activity.

Acrylic Resins↗
PubMed1998

Echocardiographic evaluation of cardiac structure and function in broiler and Leghorn chickens.

This study was conducted to validate echocardiography in chickens, and to compare cardiac structure and function between broiler and Leghorn chickens. Diameters of the right and left ventricles, and thicknesses of the left ventricular free wall and the interventricular septum were measured echocardiographically in 5- and 7-wk-old chickens from both lines. Images were obtained from minimally restrained, standing birds using a 7.5 MHz probe placed in a parasternal position. End-systolic and end-diastolic echocardiographic measurements were compared with post-mortem measurements of the same variables. Comparisons resulted in correlation coefficients greater than 0.70 between in vivo (echocardiographic) and post-mortem measurements of the same variables, with post-mortem measurements more closely resembling end-diastolic echocardiographic measurements. After being normalized to body weight, post-mortem myocardial thicknesses, aortic and left ventricular diameters, heart weight at 5 wk of age, and left ventricular weight at 7 wk of age were smaller in broiler than in Leghorn chickens. Echocardiographic parameters, including ventricular wall thicknesses, ventricular diameters, and left ventricular fractional shortening, were also smaller in the broiler chicken. Right ventricular fractional shortening did not differ between the chicken lines. These results indicate that echocardiography is a useful noninvasive technique for in vivo evaluation of cardiac structure and function in the chicken, and that broiler chickens have a relatively smaller structural and functional heart than Leghorn chickens.

Aging↗
PubMed2004

Designing for beam propagation in periodic and nonperiodic photonic nanostructures: extended Hamiltonian method.

We use Hamiltonian optics to design and analyze beam propagation in two-dimensional (2D) periodic structures with slowly varying nonuniformities. We extend a conventional Hamiltonian method, adding equations for calculating the width of a beam propagating in such structures, and quantify the range of validity of the extended Hamiltonian equations. For calculating the beam width, the equations are more than 10(3) times faster than finite difference time domain (FDTD) simulations. We perform FDTD simulations of beam propagation in large 2D periodic structures with slowly varying nonuniformities to validate our method. Beam path and beam width calculated using the extended Hamiltonian method show good agreement with FDTD simulations. By contrasting the method with ray tracing of the bundle of rays, we highlight and explain the limitations of the extended Hamiltonian method. Finally, we use a frequency demultiplexing device optimization example to demonstrate the potential applications of the method.

Journal Article↗
PubMed2005

Validity of the Spanish version of the Scoliosis Research Society-22 (SRS-22) Patient Questionnaire.

STUDY DESIGN: A cross-sectional multicenter study was performed to validate the Spanish version of the Scoliosis Research Society-22 (SRS-22) Patient Questionnaire. OBJECTIVES: To determine the construct validity and convergent validity of the instrument. METHODS: The Spanish version of the SRS-22 was given to 175 patients with scoliosis (mean age, 19 years old and 86% women). A subgroup of 31 patients also received the Quality of Life for Spine Deformities Profile (QLSDP). Construct validity was studied by factor analysis. Discriminant validity was assessed analyzing the relation between SRS-22 scores and the variables of deformity severity. Convergent validity as related to the QLSDP was studied with a multitrait-multimethod matrix analysis. RESULTS: Factor analysis offered a solution of four factors coherent with the dimensions of the original instrument. SRS-22 scores were worse in older patients (r = -0.34); patients using analgesics demonstrated lower scores (P < 0.001). Patients treated with a brace had a poorer self-image and were less satisfied with their treatment (P < 0.001) than the other treatment groups. Angular improvement of the curves was associated with better self-image scores (r = 0.34). The SRS-22 and QLSDP demonstrated high correlation coefficients in the convergent validity tests (r = 0.84). CONCLUSION: The Spanish version of the SRS-22 is valid. It has a factorial structure similar to that of the original questionnaire. Moreover, it relates to known severity characteristics of the disease, distinguishes among scoliosis patient groups, and shows concordant values with another valid instrument for measuring self-perceived health.

Adult↗
PubMed2003

3D structure of Sulfolobus solfataricus carboxypeptidase developed by molecular modeling is confirmed by site-directed mutagenesis and small angle X-ray scattering.

Sulfolobus solfataricus carboxypeptidase (CPSso) is a thermostable zinc-metalloenzyme with a M(r) of 43,000. Taking into account the experimentally determined zinc content of one ion per subunit, we developed two alternative 3D models, starting from the available structures of Thermoactinomyces vulgaris carboxypeptidase (Model A) and Pseudomonas carboxypeptidase G2 (Model B). The former enzyme is monomeric and has one metal ion in the active site, while the latter is dimeric and has two bound zinc ions. The two models were computed by exploiting the structural alignment of the one zinc- with the two zinc-containing active sites of the two templates, and with a threading procedure. Both computed structures resembled the respective template, with only one bound zinc with tetrahedric coordination in the active site. With these models, two different quaternary structures can be modeled: one using Model A with a hexameric symmetry, the other from Model B with a tetrameric symmetry. Mutagenesis experiments directed toward the residues putatively involved in metal chelation in either of the models disproved Model A and supported Model B, in which the metal-binding site comprises His(108), Asp(109), and His(168). We also identified Glu(142) as the acidic residue interacting with the water molecule occupying the fourth chelation site. Furthermore, the overall fold and the oligomeric structure of the molecule was validated by small angle x-ray scattering (SAXS). An ab initio original approach was used to reconstruct the shape of the CPSso in solution from the experimental curves. The results clearly support a tetrameric structure. The Monte Carlo method was then used to compare the crystallographic coordinates of the possible quaternary structures for CPSso with the SAXS profiles. The fitting procedure showed that only the model built using the Pseudomonas carboxypeptidase G2 structure as a template fitted the experimental data.

Amino Acid Sequence↗
PubMed2005

Human cytidine deaminase: a three-dimensional homology model of a tetrameric metallo-enzyme inferred from the crystal structure of a distantly related dimeric homologue.

Cytidine deaminase (CDA) is a cytosolic metalloprotein whose functional unit can be either a homotetramer (T-CDA) or a homodimer (D-CDA), depending on the species. In 1994, the first crystal structure of the dimeric Escherichia coli CDA has been published. However, a crystal structure of a tetrameric CDA was not determined until 2002. Prior to the disclosure of the experimentally elucidated structure of a tetrameric CDA, we derived a homology model of the human T-CDA employing the crystal structure of the dimeric E. coli CDA as a template. The comparison of our theoretical model with the crystal structure of the human T-CDA, subsequently published in 2004, validates our prediction: not only of the structural features of the monomer and the details of the binding site, but also the multimeric arrangement of the subunits were determined with high accuracy in our model. By means of a phylogenetic analysis conducted on CDAs from various organisms, we demonstrate that the E. coli CDA is one of the furthest known homologues of the human enzyme. Nonetheless, despite the evolutionary distance and, more importantly, the different multimeric arrangement of their functional units, the E. coli CDA proved to have all the necessary information to accurately infer the structure of its human homologue.

Amino Acid Sequence↗
PubMed2004

A covariance structure analysis of employees' response to performance feedback.

This longitudinal study used D. R. Ilgen, C. D. Fisher, and M. S. Taylor's (1979) feedback process model as a theoretical framework to determine whether a sequential chain of cognitive variables mediates an individual's response to performance feedback. One hundred two employees were surveyed 2 weeks after their performance appraisal, and performance was assessed 11 months later at the end of the review cycle. Covariance structure analysis supported the convergent and discriminant validity of the constructs underlying the model and the constellation of structural relationships. A set of cognitive variables was found to completely mediate the relationship between an individual's receipt and response to feedback. Implications for the feedback process and future research are discussed.

Employee Performance Appraisal↗
PubMed2000

Effects of mechanical stress/strain and estrogen on cancellous bone structure predicted by fuzzy decision.

A theoretical model was developed on the basis of fuzzy decision to predict cancellous bone structure following changes in mechanical stress/strain and estrogen. The model was validated experimentally by simulation of the normal structure of a rat distal femur, and further used to predict the structural alterations following ovarian hormone deficiency. The results show that net bone resorption after ovariectomy occurs in the metaphysis at locations where trabecula were subjected to the lowest mechanical stress/strain. These findings, consistent with experimental results, suggest that estrogen deficiency increase the mechanostat set point at which bone cells perceive mechanical stress/strain. Additionally, the results show that changes in bone architecture which are due to alterations in bone remodeling can be simulated by fuzzy decision without precise mathematical description, and multiple factors can also be readily incorporated into the model.

Animals↗