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A structure-based approach was performed to design a novel thiazolone scaffold as HCV NS5B inhibitors. A focused library was designed and docked by GOLD. One of the top-scored molecules was synthesized and shown to have similar potency to the initial hit. The X-ray complex structure was determined and validated our design rationale.
Small-angle X-ray scattering (SAXS) has been widely used to investigate the organization of clay colloids in response to the particle concentration and ionic strength of the suspending medium. In such investigations, measuring the interparticle distance and/or spacing is usually attempted. In random or short-range ordered clay-water systems, the interparticle distances are often derived from the experimental structure factor maximum; however, the validity of such practice has never been theoretically or experimentally evaluated. The experimental structure factors of several clay-water systems with and without polyphosphate treatment to block the edge charges of clay particles were obtained from SAXS data in order to understand the physical meaning of this property. The results show that the polyphosphate treatment eliminated the experimental structure factor maximum and that the particle concentration effects were correlated with the depression on the curve in a random clay-water system (e.g., illite and laponite). For clay particles with greater anisotropy (i.e., montmorillonite), polyphosphate treatment enhanced the ordering of clay layers at high particle concentrations forming long-range ordered crystals showing Bragg reflections. In this ordered system, distinctive and symmetrical peaks representing the interparticle spacing were obtained by using a Fourier transform of the scattering curves. Thus, we conclude that the experimental structure factor maximum is induced by the edge-face oriented interactions, which may not be in direct contact as in a house-of-cards structure, and the position of the maximum should not be interpreted as an averaged interparticle distance in a clay-water system unless particles orient along the same direction.
BACKGROUND AND STUDY AIMS: Capsule endoscopy (CE) is an effective means of investigating the small bowel in patients with gastrointestinal diseases. Computerized reports are frequently used in endoscopy, and the Minimal Standard Terminology (MST) has been promoted by endoscopy societies as the official vocabulary for endoscopy. The aims of this study were to design a lexicon for CE reports based on the principles of the MST and to validate lists of terms for describing findings and reasons for performing a CE by cross-matching them with the results of CE procedures collected during ongoing clinical studies. MATERIALS AND METHODS: A consensus-based Capsule Endoscopy Structured Terminology (CEST) was developed by experts involved in CE studies. Lists of terms suitable for CE were designed for the various sections of an endoscopic report. They were then correlated with the corresponding MST lists for duodenal and intestinal endoscopy. The results of 766 CE procedures, collected in an electronic case record form (eCRF), were analyzed to provide lists of reasons for performing the procedures and of the findings. The eCRF provided only a limited number of items for each data field, along with free-text facilities. Only descriptions pertaining to the small bowel were analyzed. Lists of terms were then reviewed by two experts to group obvious synonyms. The accuracy of the CEST was defined beforehand as the capability to describe 90 % of entries. RESULTS: A total of 766 CE procedures were analyzed. The eCRF included 824 entries as reasons for the examination in 655 CEs (1.3 per procedure). These represented 122 different expressions. After grouping of synonyms, 28 expressions remained. Among them, 10 were matched with terms from the list of reasons for performing CE offered in the CEST. These were the most frequently used, accounting for 768 entries in this field (93.2 %). All eCRFs contained at least one description of findings. A total of 109 CE procedures were classified as normal (14.3 %). A total of 2624 entries for abnormal findings were recorded for 657 procedures (4.0 per procedure). In all, 213 different expressions were used to describe abnormal findings. After grouping of synonyms, 52 expressions remained. Among these, 27 were matched with terms from the list of findings in the CEST, covering 2403 entries (91.6 %). CONCLUSIONS: In this study, CEST terms were capable of describing more than 90 % of the reasons for performance and of the findings in an unselected set of CE procedures. CEST is therefore suitable for use as the standard lexicon for CE reports. Adopted as a standard, it could significantly improve the quality of the data collected and reported in CE studies.
OBJECTIVE: This study was conducted to determine the interrater reliability and predictive validity of a set of diagnostic criteria for the prodrome of the first episode of schizophrenic psychosis when based on the Structured Interview for Prodromal Syndromes. METHOD: The subjects were patients referred for evaluation because of a suspected schizophrenia prodromal syndrome. For the reliability study, two to four raters independently diagnosed 18 patients on the basis of face-to-face or videotaped interviews. For the validity study, 6- and 12-month outcome data were collected for 29 patients. RESULTS: Agreement in differentiating prodromal from nonprodromal patients was 93%. The prodromal features had converted to schizophrenic psychosis for 46% of the prodromal patients at 6 months and for 54% at 12 months. CONCLUSIONS: In small groups of subjects, these diagnostic criteria for the schizophrenic prodrome and the Structured Interview for Prodromal Syndromes showed promising interrater reliability and predictive validity.
This study concerns the development of a short version of a well-known and much used clinimetric instrument called the Sickness Impact Profile (SIP). The SIP is a generic measure of functional status. Based on findings of a principal components analysis of over 800 SIPs from a multi-diagnostic population, a selection of 68 items divided over 6 dimensions was made and initially tested. As no support was found for the statistical validity of the categorical structure of the original SIP, a new structure, discovered through principal components analysis, was used as the basis for selecting items. Comparison of the scores on the selection with information provided by the original SIP showed very promising results: the 68 item selection may serve as a valid short SIP-version.
Spatial structure of the membrane channel-forming hexadecapeptide, zervamicin IIB, was studied by NMR spectroscopy in mixed solvents of different polarity ranging from CDCl3/CD3OH (9:1, v/v) to CD3OH/H2O (1:1, v/v). The results show that in all solvents used the peptide has a very similar structure that is a bent amphiphilic helix with a mean backbone root mean square deviation (rmsd) value of ca. 0.3 A. Side chains of Trp1, Ile2, Gln3, Ile5 and Thr6 are mobile. The results are discussed in relation to the validity of the obtained structure to serve as a building block of zervamicin IIB ion channels.
Brownian dynamics (BD) and molecular dynamics (MD) simulations and electrostatic calculations were performed to study the binding process of kappa-PVIIA to the Shaker potassium channel and the structure of the resulting complex. BD simulations, guided by electrostatic interactions, led to an initial alignment between the toxin and the channel protein. MD simulations were then carried out to allow for rearrangements from this initial structure. After approximately 4 ns, a critical "induced fit" process was observed to last for approximately 2 ns. In this process, the interface was reorganized, and side chains were moved so that favorable atomic contacts were formed or strengthened, while unfavorable contacts were eliminated. The final complex structure was stabilized through electrostatic interactions with the positively charged side chain of Lys7 of kappa-PVIIA deeply inserted into the channel pore and other hydrogen bonds and by hydrophobic interactions involving Phe9 and Phe23 of the toxin. The validity of the predicted structure for the complex was assessed by calculating the effects of mutating charged and polar residues of both the toxin and the channel protein, with the calculated effects correlating reasonably well with experimental data. The present study suggests a general binding mechanism, whereby proteins are pre-aligned in their diffusional encounter by long-range electrostatic attraction, and nanosecond-scale rearrangements within the initial complex then lead to a specifically bound complex.
OBJECTIVE: To validate a semi-structured Revised Iowa Collateral Head Injury Interview (RICHII) to assess post-traumatic, psychosocial frontal symptoms. METHOD: 1. To revise the RICHII in the light of recent research findings and previous pilot studies. 2. External experts assure face and content validity. 3. Standard reliability and validity study in a sample of consecutive patients fulfilling inclusion and exclusion criteria of severe head trauma. 4. Principal component analysis and distribution of results of RICHII administration to the full sample (N= 55). RESULTS: Several original items were modified and two new items (inappropriate euphoria and affective unstableness) were incorporated, as well as a new, graded scoring system. Feasibility, internal consistency (Cronbach's alfa= 0.94), inter-rater reliability (n= 40, kappa= 0.60) and test-retest reliability (n= 25, kappa= 0.70) were quite acceptable. Four factors emerged in the factor analysis, explaining a high percentage of the variance; they tend to reflect modern knowledge in the field and are judged to support the construct validity of the RICHII. More than two thirds of patients (70.9%) scored high in at least one of the items. CONCLUSION: This is the first report about the reliability and validity of a collateral interview to assess post-traumatic, psychosocial frontal symptoms.
In a previous electron microscopic study of early fibrin polymers processed by freeze drying and rotatory shadowing, a large proportion of loosely constructed, frequently branching linear molecular chains was observed; their structural organization was inconsistent with a half-staggered double-stranded model for fibrin polymerization. These conflicting results prompted us to investigate the structure of early fibrin polymers prepared according to a large variety of methods currently used for electron microscopy of macromolecules. By use of a systematic random sampling procedure, fibrin polymers were photographically recorded. They were classified according to their morphological form, and the frequency of occurrence of each configuration was determined. Half-staggered double-stranded forms accounted for less than 1% of all types encountered. Interpretation of the structural organization manifested in the diverse polymer forms observed necessitated the construction of a new interlocked single-strand model for fibrin polymerization. The fibrin polymerization process combines simultaneous propagation of linear growth, branching, and lateral interlocking (leading to lateral association), resulting in the rapid formation of a fibrin network. The structural pattern developing during growth of fibrin polymers appears to be determined principally by the enzymatic mechanism and not solely by the intrinsic molecular structure of fibrinogen. The validity of the interlocked single-strand model was tested by selective fibrinopeptide-B-releasing experiments. Under such activation conditions, the polymer forms predicted according to this and the half-staggered double-strand models should differ; the structures observed were indeed consistent with the interlocked single-strand hypothesis. The compatibility of existing data with this model is discussed.
BACKGROUND: Bond et al. developed the Defense Style Questionnaire (DSQ), a self-questionnaire that aims at empirically measuring conscious derivatives of defense mechanisms. The original analysis yielded 4 factors called Defense Styles (DS). DSQ discriminates between mature and immature defense styles. OBJECTIVES: Determine if the French version of DSQ has (a) face validity, (b) a similar structure to the original version, (c) internal consistency, (d) grouping of defense mechanisms into clinically pertinent defense styles, (e) evidence of nonpatients using more mature defense styles, (f) correlation with Defensive Functioning Scale (DFS) (DSM-IV) [2]. METHODS: Reliability and validity study on 82 control subjects and 140 patients, 59 among them evaluated for defensive level. RESULTS: Factor analysis of controls sample yielded 4 factors ranging from immature to mature defense styles. DSQ scores on factor I (maladaptive style) are significantly higher in outpatients than in controls. Maladaptive style score correlates with clinical evaluation of defensive level of functioning (DFS). CONCLUSION: Psychometric features of the French version are similar to the original scale, although minor differences in individual defense mechanisms are present. Factor I (maladaptive defense style) remains more stable than other factors, accounts for most of variance contribution, has high internal consistency and applies to behaviors, i.e. conscious derivatives of defense mechanisms that can be easily identified. The French version of DSQ is (a) an easy and economical way to rate immature defense style in populations of 'neurotic' and borderline patients and (b) further provides a hierarchical grouping of defense mechanisms in defense styles.
The mapping of evoked cerebral activity is largely determined by the choice of the interpolation system used. When the number of electrodes is very large, practically any interpolation system is valid, but the geometrical and anatomical limitations imposed by the animals normally chosen for these experiments impede the use of a large number of electrodes; hence the overriding importance of a workable interpolation system. The polynomic interpolation method on the monomial structure is presented as valid, and compared with the pseudolineal interpolation method, which is more commonly used.
OBJECTIVES: To assess the structural, convergent, discriminant, and criterion validity of the Spanish version of the Child Health and Illness Profile-Adolescent Edition (CHIP-AE) and to compare results with the U.S. version. SUBJECTS: A sample of adolescents aged 12 to 19 attending schools and representative of the school-aged population in Barcelona, Spain (n = 902). MEASURES: Exploratory factor analyses were performed, and results compared with the U.S. version. The Child Depression Inventory (CDI) and the State-Trait Anxiety Inventory (STAIC) were administered to a subgroup of adolescents to assess convergent and discriminant validity. Criterion validity was assessed by using receiver operating characteristic (ROC) curves to examine the ability of the CHIP-AE academic performance subdomain to predict school grades. RESULTS: The Spanish version has 6 defined domains with a factor structure showing minor differences from the U.S. version. Higher correlations were found between the CDI and STAIC and CHIP-AE subdomains of emotional discomfort and self-esteem (range. 0.48-0.80, P<0.01) than with scales measuring dissimilar concepts. The area under the ROC curve was 0.83 (95% confidence interval, 0.75-0.92) for the number of failed subjects (none/one or more) related to academic performance. CONCLUSIONS: The underlying theoretical model of the Spanish version of the CHIP-AE functions well in Spain, and the Spanish version has acceptable levels of convergent, discriminant, and criterion validity. Sensitivity to change and the use of the health profiles need to be assessed.
Interferon-inducible p47 GTPases are critical mediators of cell-autonomous resistance against several intracellular pathogens. Here we present the first crystal structure of a member of this novel GTPase family, IIGP1, in its nucleotide-free, GDP-, and GppNHp-bound form. The structure shows a Ras-like G domain between an N-terminal three-helix bundle and a complex system of C-terminal helices and loops. Sequence comparison and secondary structure prediction suggest the IIGP1 structure to be a valid model for the p47 GTPase family. The IIGP1 crystals contain a noncrystallographic dimer. We show that the dimer is required for cooperative GTP hydrolysis and GTP-dependent oligomerization of IIGP1. We also present the GDP- and GppNHp-bound monomeric structures of two dimer interface mutants. Our structures direct approaches to the analysis of the catalytic mechanism of IIGP1 and provide a coherent basis for structure-function studies aimed at elucidating the mechanistic basis of pathogen resistance caused by these enigmatic GTPases.
OBJECTIVE: To develop and test a multi-item measure for general trust in physicians, in contrast with trust in a specific physician. DATA SOURCES: Random national telephone survey of 502 adult subjects with a regular physician and source of payment. STUDY DESIGN: Based on a multidimensional conceptual model, a large pool of candidate items was generated, tested, and revised using focus groups, expert reviewers, and pilot testing. The scale was analyzed for its factor structure, internal consistency, construct validity, and other psychometric properties. PRINCIPAL FINDINGS: The resulting 11-item scale measuring trust in physicians generally is consistent with most aspects of the conceptual model except that it does not include the dimension of confidentiality. This scale has a single-factor structure, good internal consistency (alpha = .89), and good response variability (range = 11-54; mean = 33.5; SD = 6.9). This scale is related to satisfaction with care, trust in one's physician, following doctors' recommendations, having no prior disputes with physicians, not having sought second opinions, and not having changed doctors. No association was found with race/ethnicity. While general trust and interpersonal trust are qualitatively similar, they are only moderately correlated with each other and general trust is substantially lower. CONCLUSIONS: Emerging research on patients' trust has focused on interpersonal trust in a specific, known physician. Trust in physicians in general is also important and differs significantly from interpersonal physician trust. General physician trust potentially has a strong influence on important behaviors and attitudes, and on the formation of interpersonal physician trust.
BACKGROUND: Selenium is an essential trace element that also elicits toxic effects at modest intakes. Investigations of selenium metabolites in urine can help our understanding of the transformations taking place in the body that produce these beneficial and detrimental effects. There is, however, considerable discord in the scientific literature regarding the selenium metabolites thought to play important roles in these biotransformation processes. APPROACH: We critically assessed the published reports on selenium urinary metabolites, from the first report in 1969 to the present, in terms of the rigor of the data on which structures have been proposed. CONTENT: We present and discuss data from approximately 60 publications reporting a total of 16 identified selenium metabolites in urine of humans or rats, a good model for human selenium metabolism. We assessed the analytical methods used and the validity of the ensuing structural assignments. SUMMARY: Many of the studies of selenium metabolites in urine appear to have assigned incorrect structures to the compounds. The long-held view that trimethylselenonium ion is a major human urinary metabolite appears unjustified. On the other hand, recent work describing selenosugars as major urinary metabolites looks sound and provides a firm basis for future studies.
Thirty-one gay male couples and 28 lesbian couples were compared with 36 cohabiting heterosexual couples using the Marital Satisfaction Inventory-Revised (MSI-R), a multidimensional measure of relationship functioning intended for use with both traditional and nontraditional couples. Analyses of scales' internal consistency and factor structure supported the construct validity of this measure with nontraditional couples. Analyses of mean profiles on the MSI-R indicated that cohabiting opposite-gender and same-gender couples were more alike than different, and were more similar to nondistressed samples of married heterosexual couples from the general community than to couples in therapy. Implications of current findings for clinical assessment and intervention are considered, and directions for future research are proposed.
BACKGROUND: Social phobia is an anxiety disorder of increasing interest in clinical psychiatric practice and research. The questionnaires most widely used in the psychometric evaluation of these patients are: Liebowitz Social Anxiety Scale (LSAS), Social Anxiety and Distress Scale (SADS) and Sheehan Disability Inventory (SDI). The objective of this study was to evaluate the validity and reproducibility of the Spanish versions. SUBJECTS AND METHODS: Convergent validity was analysed by correlating patients' scores on the LSAS, SADS and SDI with scores on the Global Activity Evaluation Scale (GAES), the Hamilton Anxiety Scale (HAM-A) and the Visual Analogue Scale (VAS) of the EuroQol. Validity of the internal structure was examined by analysing the correlations between the different sub-escales of the questionnaires. Internal consistency was analysed using Cronbach's alpha and Kuder-Richardson coefficients. Discriminative capability was analysed by comparing LSAS, SADS and SDI scores of patients with social phobia with scores from healthy subjects, and with that obtained on the HAM-A and the EuroQol VAS. Reproducibility was analysed by re-testing patients after 15 days. RESULTS: 57 patients and 57 healthy subjects were recruited in 4 psychiatric centres. The three questionnaires showed an adequate convergent validity with the GAES, the HAM-A and the EuroQol VAS (r = -0.24-0.40 and r = 0.29-0.52). The LSAS and SDI questionnaires showed a homogenous internal structure in terms of correlation between sub-scales (r = -0.61-0.93 for LSAS, and r = -0.04-0.61 for SDI). All the sub-scales of the questionnaires showed an adequate internal consistency (with coefficients between 0.72 and 0.88). The questionnaires discriminated between groups of patients with different levels of symptom severity and self-perceived overall health. They also discriminated between patients with social phobia and healthy subjects (area under the Receiver's Operating Characteristics curves = 0.95-0.99). All sub-scales from the questionnaires showed adequate reproducibility (with intraclass correlation coefficients between 0.63 and 0.88). CONCLUSIONS: The Spanish versions of the LSAS, SADS and SDI questionnaires have shown adequate validity and reproducibility for use in clinical research and the clinical assessment of patients with social phobia in Spain.
The structure-function paradigm claims that a specific function of a protein is determined by its unique and rigid three-dimensional (3D) structure. Thus, following its biosynthesis on the ribosome, a protein must fold to be functional. This idea represents one of the cornerstones of modern biology. Numerous cases when, due to the effect of environmental factors or because of genetic defects (mutations), a polypeptide chain has lost its capability to gain a proper functional 3D structure (i.e. became misfolded), seem to confirm this concept. Consequences of such misfolding are well known and represent lost of function, aggregation, development of conformational disorders and cell death. However, the recent revelation of countless examples of intrinsically disordered proteins has cast doubt on the general validity of the structure-function paradigm and revealed an intriguing route of functional disorder. Thus, in a living cell, a polypeptide chain chooses between three potential fates - functional folding, potentially deadly misfolding and mysterious nonfolding. This choice is dictated by the peculiarities of amino acid sequence and/or by the pressure of environmental factors. The aim of the present review is to outline some interesting features of these three routes.