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Results for “Structural validation”

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At least 397 records · Page 22Linked to original sources

PubMed2006

Predictions of CCR1 chemokine receptor structure and BX 471 antagonist binding followed by experimental validation.

A major challenge in the application of structure-based drug design methods to proteins belonging to the superfamily of G protein-coupled receptors (GPCRs) is the paucity of structural information (1). The 19 chemokine receptors, belonging to the Class A family of GPCRs, are important drug targets not only for autoimmune diseases like multiple sclerosis but also for the blockade of human immunodeficiency virus type 1 entry (2). Using the MembStruk computational method (3), we predicted the three-dimensional structure of the human CCR1 receptor. In addition, we predicted the binding site of the small molecule CCR1 antagonist BX 471, which is currently in Phase II clinical trials (4). Based on the predicted antagonist binding site we designed 17 point mutants of CCR1 to validate the predictions. Subsequent competitive ligand binding and chemotaxis experiments with these mutants gave an excellent correlation to these predictions. In particular, we find that Tyr-113 and Tyr-114 on transmembrane domain 3 and Ile-259 on transmembrane 6 contribute significantly to the binding of BX 471. Finally, we used the predicted and validated structure of CCR1 in a virtual screening validation of the Maybridge data base, seeded with selective CCR1 antagonists. The screen identified 63% of CCR1 antagonists in the top 5% of the hits. Our results indicate that rational drug design for GPCR targets is a feasible approach.

Animals↗

PubMed1991

Reliability and validity of the objective structured clinical examination in paediatrics.

The assessment of clinical competence has traditionally been carried out through standard evaluations such as multiple choice question and bedside oral examinations. The attributes which constitute clinical competence are multidimensional, and we have modified the objective structured clinical examination (OSCE) to measure these various competencies. We have evaluated the validity and reliability of the OSCE in a paediatric clinical clerkship. We divided the examination into the four components of competence (clinical skills, problem-solving, knowledge, and patient management) and evaluated the performance of 77 fourth-year medical students. The skill and content domains of the OSCE were carefully defined, agreed upon, sampled and reproduced. This qualitative evaluation of the examination was both adequate and appropriate. We achieved both acceptable interstation and intertask reliability. When correlated with concurrent methods of evaluation we found the OSCE to be an accurate measure of paediatric knowledge and patient management skills. The OSCE did not correlate, however, with traditional measures of clinical skills including history-taking and physical examination. Our OSCE, as outlined, offers an objective means of identifying weaknesses and strengths in specific areas of clinical competence and is therefore an important addition to the traditional tools of evaluation.

Clinical Clerkship↗

PubMedDate not supplied

Construct validity of instruments measuring impairments in body structures and function in rheumatic disorders: which constructs are selected for validation? A systematic review.

PURPOSE: This paper focuses on the construct validity of instruments measuring impairments in body structures and function in rheumatic disorders. The objective is: 1) to make an inventory of constructs, based on the domains of the International Classification of Functioning, Disabilities and Health problems (ICF), against which instruments measuring impairments in body structures and function were validated; 2) to analyse whether validation against a similar construct resulted in higher correlation coefficients than validation against a dissimilar construct. METHODS: In a systematic review papers were identified in which instruments measuring impairments in body structures and function for patients with rheumatic disorders were validated. The instruments identified were assessed on their methodological properties and the constructs against which they were validated. Subsequently, pooled (interclass) correlations of similar constructs and dissimilar constructs against which was validated were compared. An instrument was decided to have good construct validity, if the correlation coefficient was 0.50 or higher, and the measurement instrument in question is validated against similar constructs. RESULTS: In total 216 papers were identified analysing the validity of 42 different instruments. Only 16% of these instruments were validated against instruments that represent the most similar construct. In general, estimates of construct validity were lower when validated against dissimilar constructs, except for instruments measuring impairments in mental functions. CONCLUSION: There is a trend that validation against a similar construct yields higher correlation coefficients than validation against a dissimilar construct. If an instrument measuring impairments is validated against the most similar construct, and a criterion of r > 0.50 is applied, only 10 out of the 42 identified instruments turned out to be valid.

Humans↗

PubMed1997

Asymmetric Synthesis of Sesaminone: Confirmation of Its Structure and Determination of Its Absolute Configuration.

An asymmetric synthesis of the naturally occurring antipode of the tetrahydrofuran lignan sesaminone ((-)-1) has been achieved. An X-ray crystal structure of the synthetic material validated the structure proposed in the literature for this lignan. Additionally, the absolute configuration of the natural product was established by correlation of the synthetic tetrahydrofuran with the known absolute configuration of L-Phe. The opening of the synthesis was a diastereoselective Evans aldol reaction between N-4-pentenoyloxazolidinone 6 and piperonal. Reduction of the major diastereomer of the aldol product provided enantiomerically pure diol 4. The primary and secondary hydroxyl groups of 4 were protected in tandem to generate silyl ether-MOM ether 9. The vinyl group contained in 9 was then elaborated, via a series of four steps, to aryl ketone 10. This aryl ketone was transformed to a mixture of silyl enol ether stereoisomers (11a,b); TiCl(4)-mediated activation of the MOM ethers contained in this mixture of enol ethers yielded tetrahydrofuran 12 as the major product. Treatment of 12 with fluoride provided synthetic (-)-1.

Journal Article↗

PubMed2006

Tetratricopeptide repeats in the type III secretion chaperone, LcrH: their role in substrate binding and secretion.

Non-flagellar type III secretion systems (T3SSs) transport proteins across the bacterial cell and into eukaryotic cells. Targeting of proteins into host cells requires a dedicated translocation apparatus. Efficient secretion of the translocator proteins that make up this apparatus depends on molecular chaperones. Chaperones of the translocators (also called class-II chaperones) are characterized by the possession of three tandem tetratricopeptide repeats (TPRs). We wished to dissect the relations between chaperone structure and function and to validate a structural model using site-directed mutagenesis. Drawing on a number of experimental approaches and focusing on LcrH, a class-II chaperone from the Yersinia Ysc-Yop T3SS, we examined the contributions of different residues, residue classes and regions of the protein to chaperone stability, chaperone-substrate binding, substrate stability and secretion and regulation of Yop protein synthesis. We confirmed the expected role of the conserved canonical residues from the TPRs to chaperone stability and function. Eleven mutations specifically abrogated YopB binding or secretion while three mutations led to a specific loss of YopD secretion. These are the first mutations described for any class-II chaperone that allow interactions with one translocator to be dissociated from interactions with the other. Strikingly, all mutations affecting the interaction with YopB mapped to residues with side chains projecting from the inner, concave surface of the modelled TPR structure, defining a YopB interaction site. Conversely, all mutations preventing YopD secretion affect residues that lie on the outer, convex surface of the triple-TPR cluster in our model, suggesting that this region of the molecule represents a distinct interaction site for YopD. Intriguingly, one of the LcrH double mutants, Y40A/F44A, was able to maintain stable substrates inside bacteria, but unable to secrete them, suggesting that these two residues might influence delivery of substrates to the secretion apparatus.

Amino Acid Sequence↗

PubMed1991

The solution structures of Escherichia coli trp repressor and trp aporepressor at an intermediate resolution.

We have determined the solution structures and examined the dynamics of the Escherichia coli trp repressor (a 25-kDa dimer), with and without the co-repressor L-tryptophan, from NMR data. This is the largest protein structure thus far determined by NMR. To obtain a set of data sufficient for a structure determination it was essential to resort to isotopic spectral editing. Line broadening observed in this molecular mass range precludes for the most part the measurement of coupling constants and stereospecific assignments, with the inevitable result that the attainable resolution of the final structure will be somewhat lower than the resolution reported for smaller proteins and peptides. Nevertheless the general topology of the protein can be deduced from the subsets of NOEs defining the secondary and tertiary structure, providing a basis for further refinement using the full set of NOEs and energy minimization. We report here (a) an intermediate resolution structure that can be deduced from NMR data, covalent, angular and van-der-Waals constraints only, without resort to detailed energy calculations, and (b) the limits of uncertainty within which this structure is valid. An examination of these structures combined with backbone amide exchange data shows that even at this resolution three important conclusions can be drawn: (a) the protein structure changes upon binding tryptophan; (b) the putative DNA binding region is much more flexible than the core of the molecule, with backbone amide proton exchange rates 1000 times faster than in the core; (c) the binding of tryptophan stabilizes the repressor molecule, which is reflected in both the appearance of additional NOEs, and in the slowing of backbone proton exchange rates by factors of 3-10. Sequence-specific 1H-NMR assignments and the secondary structure of the holopressor (L-tryptophan-bound form) have been reported previously [C. H. Arrowsmith, R. Pachter, R. B. Altman, S. B. Iyer & O. Jardetzky (1990) Biochemistry 29, 6332-6341]. Those for the trp aporepressor (L-tryptophan-free form), made using the same methods and conditions as described in the cited paper, are reported here. The secondary structure of the aporepressor was calculated from sequential and medium-range NOEs and is the same as reported for the holorepressor except that helix E is shorter. The tertiary solution structures for both forms of the repressor were calculated from long-range NOE data.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed2006

Measuring safety climate in health care.

AIM: To review quantitative studies of safety climate in health care to examine the psychometric properties of the questionnaires designed to measure this construct. METHOD: A systematic literature review was undertaken to study sample and questionnaire design characteristics (source, no of items, scale type), construct validity (content validity, factor structure and internal reliability, concurrent validity), within group agreement, and level of analysis. RESULTS: Twelve studies were examined. There was a lack of explicit theoretical underpinning for most questionnaires and some instruments did not report standard psychometric criteria. Where this information was available, several questionnaires appeared to have limitations. CONCLUSIONS: More consideration should be given to psychometric factors in the design of healthcare safety climate instruments, especially as these are beginning to be used in large scale surveys across healthcare organisations.

Attitude of Health Personnel↗

PubMed1998

Verbal aggressiveness: conceptualization and measurement a decade later.

Verbally aggressive messages attack an individual's self-concept to inflict psychological pain. Infante and Wigley developed a trait measure of Verbal aggressiveness; however, the psychometric qualities and validity of the Verbal Aggressiveness scale were not fully explored. In Study I, 119 targets (Mage = 46.2, SDage = 14.1) and 238 observers (Mage = 42.9, SD age = 14.4) participated. In Study II, 112 targets (Mage = 39.9, SDage = 12.9) and 236 observers (Mage = 37.7 SDage = 11.1) participated. In Study III, 153 college students participated (Mage = 25.9, SDage = 4.6). In these studies, temporal stability over two months, criterion-related validity (target-observer agreement), discriminant validity (employing structural equation models), and construct validity (correlations with the facet and domain scales of the NEO-Personality Inventory-R) were investigated. The results justify considering Verbal Aggressiveness as a personality trait and the Verbal Aggressiveness scale as a valid measure.

Adult↗

PubMed1992

Obsessions and compulsions: dimensional structure, reliability, convergent and divergent validity of the Padua Inventory.

This study presents data on dimensional structure, reliability, convergent and divergent validity of the Padua Inventory (PI). In a sample (n = 430) of normal Dutch subjects. The dimensional structure and the strength of the factors were comparable to those found in the Italian sample. The reliability of the PI was found to be satisfactory. As hypothesized substantial correlations were found between the PI and related scales of the Maudsley Obsessive-Compulsive Inventory (MOCI) and between the PI and the subscales Sensitivity, Hostility and Depression of the revised version of the Symptom Checklist. Low correlations were found between the PI on the one side and the Eysenck Personality Questionnaire revised Extraversion, Psychoticism and Social Desirability scale on the other side. Finally, the mean score of the PI differs across the Italian, American and Dutch samples. This is of theoretical interest and deserves further study.

Adolescent↗

PubMed2004

Criterion and content validity of a novel structured haggling contingent valuation question format versus the bidding game and binary with follow-up format.

Contingent valuation question formats that will be used to elicit willingness to pay for goods and services need to be relevant to the area they will be used in order for responses to be valid. A novel contingent valuation question format called the "structured haggling technique" (SH) that resembles the bargaining system in Nigerian markets was designed and its criterion and content validity compared with those of the bidding game (BG) and binary-with-follow-up (BWFU) technique. This was achieved by determining the willingness to pay (WTP) for insecticide-treated nets (ITNs) in Southeast Nigeria. Content validity was determined through observation of actual trading of untreated nets together with interviews with sellers and consumers. Criterion validity was determined by comparing stated and actual WTP. Stated WTP was determined using a questionnaire administered to 810 household heads and actual WTP was determined by offering the nets for sale to all respondents one month later. The phi (correlation) coefficient was used to compare criterion validity across question formats. The phi coefficients were SH (0.60: 95% C.I. 0.50-0.71), BG (0.42: 95% C.I. 0.29-0.54) and the BWFU (0.32: 95% C.I. 0.20-0.44), implying that the BG and SH had similar levels of criterion-validity while the BWFU was the least criterion-valid. However, the SH was the most content-valid. It is necessary to validate the findings in other areas where haggling is common. Future studies should establish the content validity of question formats in the contexts in which they will be used before administering questionnaires.

Attitude to Health↗

PubMed2002

The Dutch Childhood Anxiety Sensitivity Index: psychometric properties and factor structure.

Examined the reliability, validity, and factor structure of the Childhood Anxiety Sensitivity Index (CASI; Silverman, Fleisig, Rabian, & Peterson, 1991) in a Dutch sample. Five hundred forty-four Dutch schoolchildren between 8 and 16 years of age completed Dutch translations of the CASI; the State-Trait Anxiety Inventory for Children (Spielberger, Edwards, Lushene, Montuori, & Platzek, 1973); and the Fear Survey Schedule for Children-Revised (Ollendick, 1983). The Dutch CASI was found to have adequate internal consistency for use with children as well as adolescents. Results reveal that the CASI predicted fear beyond a measure of trait anxiety in this Dutch sample. Both exploratory and confirmatory factor analyses comparing different models were undertaken. The model with 3 first-order factors found in previous studies showed an acceptable fit in this cross-validation sample. Loadings on the 3 factors (Physical Concerns, Mental Concerns, and Publicly Observable Concerns) did not differ between children and adolescents. Results are compared with previous research on the CASI. Directions for future research are discussed.

Adolescent↗

PubMedDate not supplied

Age differences in personality structure revisited: Studies in validity, stability, and change.

Construct validity and longitudinal stability evidence for three cluster dimensions of personality identified as Anxiety, Extraversion, and Openness is examined in a sample of adult males. Correlations with Allport-Vernon-Lindsay Value scales, Cornell Medical Index scores, Eysenck E and N scales, and factors from the SVIB are presented in support of the interpretation of the three clusters. Nine-year longitudinal evidence of stability is presented for Anxiety and Extraversion scores. Previous evidence for change in the structure of Openness to Experience is reconsidered in the light of eleven-year longitudinal data. While the earlier structural differences were not longitudinally replicated, a pattern of external correlates provided evidence for validity of an Openness dimension. Finally, the structural approach to personality development is illustrated by examining the differing relations between field-dependence and tendermindedness in younger and older men.

Adult↗

PubMed2004

Toward the detection and validation of repeats in protein structure.

We present a method called DAVROS to detect, localize, and validate repeating motifs in protein structure allowing for insertions and deletions. DAVROS uses the score matrix from a structural alignment program (SAP) to search for repeating motifs using an algorithm based on concepts from signal processing and the statistical properties of the alignments. The method was tested against a nonredundant Protein Data Bank, and each chain was assigned a score. For the top 50 chains ranked by score, 70% contain repeating motifs detected without error. These represent 14 types of fold covering alpha, beta, and alphabeta protein classes. A second data set comprising protein chains in different sequence families for triosephosphate isomerase (TIM) barrel, leucine-rich repeat (LRR), trefoil, and alpha-alpha barrel folds was used to assess the ability of DAVROS to detect all motifs within a specific fold. For the second test set, the percentage of motifs detected was highest for the LRR chains (88.7%) and least for the TIM barrels (60%). This variability results from the regularity of the LRR motif compared to the alphabeta units of the TIM barrel, which generally have many more indels. These reduce the strength of the repeat signal in the SAP matrix, making repeat detection more difficult.

Amino Acid Motifs↗

PubMed2003

Evaluation of a model of violence risk assessment among forensic psychiatric patients.

OBJECTIVE: This study tested the interrater reliability and criterion-related validity of structured violence risk judgments made by using one application of the structured professional judgment model of violence risk assessment, the HCR-20 violence risk assessment scheme, which assesses 20 key risk factors in three domains: historical, clinical, and risk management. METHODS: The HCR-20 was completed for a sample of 100 forensic psychiatric patients who had been found not guilty by reason of a mental disorder and were subsequently released to the community. Violence in the community was determined from multiple file-based sources. RESULTS: Interrater reliability of structured final risk judgments of low, moderate, or high violence risk made on the basis of the structured professional judgment model was acceptable (weighted kappa=.61). Structured final risk judgments were significantly predictive of postrelease community violence, yielding moderate to large effect sizes. Event history analyses showed that final risk judgments made with the structured professional judgment model added incremental validity to the HCR-20 used in an actuarial (numerical) sense. CONCLUSIONS: The findings support the structured professional judgment model of risk assessment as well as the HCR-20 specifically and suggest that clinical judgment, if made within a structured context, can contribute in meaningful ways to the assessment of violence risk.

Actuarial Analysis↗

PubMed1998

Revision and restandardization of the Conners Teacher Rating Scale (CTRS-R): factor structure, reliability, and criterion validity.

The Conners Teacher Rating Scale (CTRS) is a commonly used research and clinical tool for assessing children's behavior in the classroom. The present study introduces the revised CTRS (CTRS-R) which improves on the original CTRS by (1) establishing normative data from a large, representative North American sample, (2) deriving a factor structure using advanced statistical techniques, and (3) updating the item content to reflect current conceptualizations of childhood disorders. Using confirmatory factor analysis, a six-factor structure was found which includes Hyperactivity-Impulsivity, Perfectionism, Inattention/Cognitive Problems, Social Problems, Oppositionality, and Anxious/Shy factors. The reliability of the scale, as measured by test-retest correlations and internal consistency, is generally satisfactory. Using all of the scale factors to discriminate between attention deficit hyperactivity disordered and normal children, 85 percent of children were correctly classified, supporting the validity of the scale and indicating excellent clinical utility. Similarities and differences between the original CTRS factor structure and the CTRS-R factor structure are discussed.

Attention Deficit Disorder with Hyperactivity↗

PubMedDate not supplied

Correct bond order assignment in a molecular framework using integer linear programming with application to molecules where only non-hydrogen atom coordinates are available.

We describe a method based on linear programming, for deducing the correct bond orders in small molecules, which only needs the sigma bonds connectivity and atom symbols as input. The procedure checks whether the current structure can be written as a valid Lewis structure by assigning double and triple bonds by translating the octet equations into an integer linear program that is solved by an external solver. The procedure was intensively tested on some ligands from the protein data bank as well as some other exotic molecules, for which first the hydrogen topology is generated by a standard procedure from literature. The most stable Lewis structure is retained for which hydrogen coordinates are generated.

Databases, Protein↗

PubMed1999

Crystal structure of a 14 bp RNA duplex with non-symmetrical tandem GxU wobble base pairs.

Adjacent GxU wobble base pairs are frequently found in rRNA. Atomic structures of small RNA motifs help to provide a better understanding of the effects of various tandem mismatches on duplex structure and stability, thereby providing better rules for RNA structure prediction and validation. The crystal structure of an RNA duplex containing the sequence r(GGUAUUGC-GGUACC)2 has been solved at 2.1 A resolution using experimental phases. Novel refinement strategies were needed for building the correct solvent model. At present, this is the only short RNA duplex structure containing 5'-U-U-3'/3'-G-G-5' non-symmetric tandem GxU wobble base pairs. In the 14mer duplex, the six central base pairs are all displaced away from the helix axis, yielding significant changes in local backbone conformation, helix parameters and charge distribution that may provide specific recognition sites for biologically relevant ligand binding. The greatest deviations from A-form helix occur where the guanine of a wobble base pair stacks over a purine from the opposite strand. In this vicinity, the intra-strand phosphate distances increase significantly, and the major groove width increases up to 3 A. Structural comparisons with other short duplexes containing symmetrical tandem GxU or GxT wobble base pairs show that nearest-neighbor sequence dependencies govern helical twist and the occurrence of cross-strand purine stacks.

Base Pairing↗

PubMed2002

Validating the measurement and structure of self-concept: snapshots of past, present, and future research.

Although the study of self-concept has been a topic of great interest and much study in the social sciences for many decades, it is really only in the past 30 years that any fruitful expansion in knowledge of both its theoretical structure and its related measurement has been forthcoming. From three perspectives--past, present, and future--the author presents abbreviated and selected highlights of important construct validity findings related to this research and postulates possible trends and areas of self-concept research yet to be explored.

Awards and Prizes↗