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PubMed1987

Mapping of epitopes on human tissue-type plasminogen activator with recombinant deletion mutant proteins.

An antigen assay based on a monoclonal antibody directed against the light chain of tissue-type plasminogen activator (t-PA) was developed to quantify seven recombinant (r) t-PA deletion mutant proteins. These recombinant proteins were then employed to map different epitopes on t-PA which interact with a panel of twenty-three monoclonal anti-t-PA antibodies. Twenty were directed against domains on the heavy chain, two against the "finger" domain, three against the "epidermal growth factor-like" domain, five against the kringle 1 domain, and ten against the kringle 2 domain. Only three monoclonal anti-t-PA antibodies interact with the light chain. The finding that the epitopes of each of the monoclonals could be determined with the deletion mutant proteins supports the hypothesis of autonomous folding of structural domains and emphasizes the validity of the use of the recombinant t-PA-deletion mutant proteins for structure-function studies.

Antibodies, Monoclonal↗

PubMed2002

Measuring leader perceptions of school readiness for reforms: use of an iterative model combining classical and Rasch methods.

This study examines validity of data generated by the School Readiness for Reforms: Leader Questionnaire (SRR-LQ) using an iterative procedure that combines classical and Rasch rating scale analysis. Following content-validation and pilot-testing, principal axis factor extraction and promax rotation of factors yielded a five factor structure consistent with the content-validated subscales of the original instrument. Factors were identified based on inspection of pattern and structure coefficients. The rotated factor pattern, inter-factor correlations, convergent validity coefficients, and Cronbach's alpha reliability estimates supported the hypothesized construct properties. To further examine unidimensionality and efficacy of the rating scale structures, item-level data from each factor-defined subscale were subjected to analysis with the Rasch rating scale model. Data-to-model fit statistics and separation reliability for items and persons met acceptable criteria. Rating scale results suggested consistency of expected and observed step difficulties in rating categories, and correspondence of step calibrations with increases in the underlying variables. The combined approach yielded more comprehensive diagnostic information on the quality of the five SRR-LQ subscales; further research is continuing.

Calibration↗

PubMed2005

Protein structure similarity clustering and natural product structure as guiding principles in drug discovery.

The identification of new chemical entities that are capable of altering protein function lies at the heart of the hit and lead finding process, for which combinatorial chemistry has emerged as a powerful tool. Following the maturation of combinatorial chemistry and compound library development, it was soon recognized that biological relevance, design and diversity of a library are more important than library size. The universe of conceivable compounds is almost infinite, therefore, the decisive question arises: where is a biologically validated starting point in structural space from which to build a compound library to be found? As a new approach to address this complex problem, a synergistic strategy is presented, which is based on protein structure similarity clustering and natural product structure as guiding rationales.

Biological Factors↗

PubMedDate not supplied

Development of the drug abuse screening test for adolescents (DAST-A).

The development and initial validation of the Drug Abuse Screening Test for Adolescents (DAST-A) is summarized. The DAST-A, derived from a modification of the original adult version called the Drug Abuse Screening Test (DAST: Skinner, 1982), was psychometrically tested in a study group of adolescent inpatients. The DAST-A demonstrated good internal consistency, high test-retest reliability, unidimensional factor structure, and good concurrent validity. Using the classification system of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association 1994), DAST-A scores of greater than 6 yielded sensitivity, specificity, and positive predictive powers of 78.6%, 84.5%, and 82.3%, respectively, in differentiating adolescent psychiatric inpatients with and without drug-related disorders. These findings suggest that the DAST-A holds promise as a drug abuse screening measure in psychiatrically impaired adolescent populations.

Adolescent↗

PubMed2005

QSAR study for mycobacterial promoters with low sequence homology.

The general belief is that quantitative structure-activity relationship (QSAR) techniques work only for small molecules and, protein sequences or, more recently, DNA sequences. However, with non-branched graph for proteins and DNA sequences the QSAR often have to be based on powerful non-linear techniques such as support vector machines. In our opinion, linear QSAR models based on RNA could be useful to assign biological activity when alignment techniques fail due to low sequence homology. The idea bases the high level of branching for the RNA graph. This work introduces the so-called Markov electrostatic potentials (k)xi(M) as a new class of RNA 2D-structure descriptors. Subsequently, we validate these molecular descriptors solving a QSAR classification problem for mycobacterial promoter sequences (mps), which constitute a very low sequence homology problem. The model developed (mps=-4.664.(0)xi(M)+0. 991.(1)xi(M)-2.432) was intended to predict whether a naturally occurring sequence is an mps or not on the basis of the calculated (k)xi(M) value for the corresponding RNA secondary structure. The RNA-QSAR approach recognises 115/135mps (85.2%) and 100% of control sequences. Average predictability and robustness were greater than 95%. A previous non-linear model predicts mps with a slightly higher accuracy (97%) but uses a very large parameter space for DNA sequences. Conversely, the (k)xi(M)-based RNA-QSAR encodes more structural information and needs only two variables.

Bacterial Proteins↗

PubMed2001

The validation of a nursing nutritional assessment tool for use on acute elderly wards.

BACKGROUND: Elderly people are at great risk of poor nutritional status. Identifying those at nutritional risk is complex owing to its multifactorial nature and highlights the need for an easily administered nutritional screening tool. AIM: To test the robustness of a tool used to identify those patients who require further dietetic assessment. METHOD: The tool was tested on an 'acute elderly' ward to assess its statistical robustness, i.e. test-retest reliability, inter-rater reliability, internal consistency and factor structure, concurrent and construct validity. The research was carried out by a dietitian and two nurses on an overall sample of 185 consecutive admissions. RESULTS: Test-retest results reflect that the tool is capable of yielding consistent assessments over time. Inter-rater reliability results revealed that when comparisons of agreement between nurses and dietitians were examined there was consistent disagreement. Internal consistency was found to be low but the rotated factor analysis suggested a relationship between the items in the tool. Concurrent validity was exhibited with body mass index, albumin and American Nutrition Risk Index only. Construct validity was not sufficiently exhibited with any of the measures used. CONCLUSION: The tool has not demonstrated reliability as determined by the statistical measures and hence validity at this stage. Issues which need to be addressed to allow this tool to be used appropriately are discussed.

Aged↗

PubMed1996

The SIP68: a measure of health-related functional status in rehabilitation medicine.

OBJECTIVE: To demonstrate the usefulness of the SIP68, a recently developed short version of the sickness impact profile (SIP), for measuring health-related functional status in rehabilitation medicine. DESIGN: Survey, oral interviews. SETTING: Patient's homes. PATIENTS: 315 persons (out of 423 that could be reached) with a spinal cord injury whose mean average age was 39.4 years and who were living in the community at the time of the interview. MAIN OUTCOME MEASURES: Internal consistency is tested by computing Cronbach's alpha. Construct validity is tested by principal components analysis and computing Cattell's similarity index. Criterion validity is tested by comparing SIP68 results with the level of the spinal cord lesion and with results of specific measures of disability (Barthel Index) and life satisfaction (Life Satisfaction Questionnaire), and with vocational status. RESULTS: SIP68 scores and subscale scores indicate that our spinal cord injured group falls well within the scope of this instrument. Internal consistency figures are good and the proposed six-dimensional structure is confirmed. Criterion validity figures are also satisfactory. Barthel Index scores show high agreement with the scores of the subscale "somatic autonomy," moderate agreement with the other physically related and socially related subscales, and low agreement with the mentally related subscales of the SIP68. LSQ scores show low agreement with the physically related subscales and moderate agreement with the mentally and socially related subscales. Figures of vocational status show strongest agreement with the socially oriented subscales. CONCLUSION: The SIP68 is recommended as a useful generic outcome measure for research in rehabilitation medicine.

Activities of Daily Living↗

PubMed2002

A new molecular mechanics force field for the oxidized form of blue copper proteins.

A molecular mechanics force field for blue copper proteins has been developed, based on a rigid potential energy surface scan of the Cu(II)/His/His/Cys/Met chromophore, using DFT (B3LYP) calculations and the AMBER force field for the protein backbone. The strain-energy-minimized structures of the model chromophore alone are in excellent agreement with the DFT-optimized structure, and those of the entire set of cupredoxins (five structures are considered) are, within the experimental error limits, in good agreement with the single crystal structural data. However, the structural variation in the computed structures is much smaller than those in the experimental structures. It is shown that, due to the large error limits in the experimental data, a validation of the force field with experimental structural data is impossible because, within the error limits, all experimental structures considered are virtually identical. A validation on the basis of spectroscopic data and their correlation with experimental and computed structural data is proposed, and, as a first example, the correlation of intensity ratios of the charge transfer transitions with a specific distortion mode is presented. The quality of the correlation, using the computed structures, is higher than that with the X-ray structures, and this indicates that the computed structures are meaningful.

Azurin↗

PubMed1997

Validating risk-adjusted surgical outcomes: site visit assessment of process and structure. National VA Surgical Risk Study.

BACKGROUND: Risk-adjusted mortality and morbidity rates are often used as measures of the quality of surgical care. This study was conducted to determine the validity of risk-adjusted surgical morbidity and mortality rates as measures of quality of care by assessing the process and structure of care in surgical services with higher-than-expected and lower-than-expected risk-adjusted 30-day mortality and morbidity rates. STUDY DESIGN: A structural survey of 44 Veterans Affairs Medical Center surgical services and site visits to 20 surgical services with higher-than-expected and lower-than-expected risk-adjusted outcomes were conducted. Main outcome measures included assessment of technology and equipment, technical competence of staff, leadership, relationship with other services, monitoring of quality of care, coordination of work, relationship with affiliated institutions, and overall quality of care. RESULTS: Surgical services with lower-than-expected risk-adjusted surgical morbidity and mortality rates had significantly more equipment available in surgical intensive care units than did services with higher-than-expected outcomes (4.3 versus 2.9, p < 0.05). Site-visitor ratings of overall quality of care were significantly higher for surgical services with lower-than-expected morbidity and mortality rates (6.1 versus 4.5 for high outliers, p < 0.05); technology and equipment were rated significantly better among low-outlier services (7.1 versus 4.8 for high outliers, p < 0.001). Masked site-visit teams correctly predicted the outlier status (high versus low) of 17 of the 20 surgical services visited (p < 0.001). CONCLUSIONS: Significant differences in several dimensions of process and structure of the delivery of surgical care are associated with differences in risk-adjusted surgical morbidity and mortality rates among 44 Veterans Affairs Medical Centers.

Hospital Mortality↗

PubMed2006

A novel computational model of the circadian clock in Arabidopsis that incorporates PRR7 and PRR9.

In plants, as in animals, the core mechanism to retain rhythmic gene expression relies on the interaction of multiple feedback loops. In recent years, molecular genetic techniques have revealed a complex network of clock components in Arabidopsis. To gain insight into the dynamics of these interactions, new components need to be integrated into the mathematical model of the plant clock. Our approach accelerates the iterative process of model identification, to incorporate new components, and to systematically test different proposed structural hypotheses. Recent studies indicate that the pseudo-response regulators PRR7 and PRR9 play a key role in the core clock of Arabidopsis. We incorporate PRR7 and PRR9 into an existing model involving the transcription factors TIMING OF CAB (TOC1), LATE ELONGATED HYPOCOTYL (LHY) and CIRCADIAN CLOCK ASSOCIATED (CCA1). We propose candidate models based on experimental hypotheses and identify the computational models with the application of an optimization routine. Validation is accomplished through systematic analysis of various mutant phenotypes. We introduce and apply sensitivity analysis as a novel tool for analyzing and distinguishing the characteristics of proposed architectures, which also allows for further validation of the hypothesized structures.

Arabidopsis↗

PubMedDate not supplied

The Algase Wandering Scale: initial psychometrics of a new caregiver reporting tool.

This paper reports on the Algase wandering scale (AWS), a 28-item questionnaire, based on five dimensions of wandering. With factor analysis, an eight-factor solution explained nearly 70 percent of the variance in ratings for 151 long-term care subjects and confirmed three of the structuring dimensions. Reliability of the AWS was examined for internal consistency and for inter-rater reliability. The AWS had an alpha of .86; subscale alphas ranged between .88 (persistent walking) and .57 (routinized walking). Inter-rater reliabilities, estimated through cross-rater comparisons of the AWS and subscales with a four-point judgement of wandering status, were moderately strong and no significant differences existed between two sets of raters. Validity of the AWS and its subscales was supported by examining their ability to differentiate wanderers and nonwanderers, by positive correlation with measures of cognitive impairment and with multiple parameters of observed wandering, and by negative or no correlations with nonwandering locomotion. Although the AWS may be a useful measure of wandering in long-term care settings, validation of its factor structure and evaluation in cross-cultural samples is needed.

Aged↗

PubMed1994

An objective selection system to identify the qualities for a career in nursing.

This article describes a research programme commissioned by the NHS in four health authorities to define the qualities that characterise successful nurses. A structured interview designed and validated by SRI Limited to objectively measure these qualities in those applying to be trained for the nursing profession is outlined. This interview has been piloted as an aid to the selection of student nurses by the Bloomsbury and Islington College of Nursing and Midwifery for over 3 years. A survey has been conducted with those who have been selected by Bloomsbury and Islington College, whose results indicate that these applicants found the structured interview to be a positive experience and many viewed it as a more objective selection than others that they had experienced in pursuing their aspirations for a nursing career. This research provides some initial indications of the potential value of the interview as a positive objective aid to the selection of student nurses and to identifying objectively those with the potential to find fulfilment in the profession.

Career Choice↗

PubMed2000

Novel variable selection quantitative structure--property relationship approach based on the k-nearest-neighbor principle

A novel automated variable selection quantitative structure-activity relationship (QSAR) method, based on the kappa-nearest neighbor principle (kNN-QSAR) has been developed. The kNN-QSAR method explores formally the active analogue approach, which implies that similar compounds display similar profiles of pharmacological activities. The activity of each compound is predicted as the average activity of K most chemically similar compounds from the data set. The robustness of a QSAR model is characterized by the value of cross-validated R2 (q2) using the leave-one-out cross-validation method. The chemical structures are characterized by multiple topological descriptors such as molecular connectivity indices or atom pairs. The chemical similarity is evaluated by Euclidean distances between compounds in multidimensional descriptor space, and the optimal subset of descriptors is selected using simulated annealing as a stochastic optimization algorithm. The application of the kNN-QSAR method to 58 estrogen receptor ligands as well as to several other groups of pharmacologically active compounds yielded QSAR models with q2 values of 0.6 or higher. Due to its relative simplicity, high degree of automation, nonlinear nature, and computational efficiency, this method could be applied routinely to a large variety of experimental data sets.

Journal Article↗

PubMed2006

How well does Poisson-Boltzmann implicit solvent agree with explicit solvent? A quantitative analysis.

We have quantitatively studied the performance of a finite-difference Poisson-Boltzmann implicit solvent with respect to the TIP3P explicit solvent in a range of systems of biochemical interest. An overall agreement was found between the tested implicit and explicit solvents for hydrogen-bonding/salt-bridging dimers and peptide monomers and dimers of different conformations and different lengths. These comparative analyses also indicate a good transferability of empirically optimized parameters for the implicit solvent from small training molecules to large testing peptides. However, deviations between the two tested solvents are also apparent. Specifically, a consistent deviation was observed when hydrogen-bonding or salt-bridging dimers are within 4-6 A. The deviation reaches a maximum at about 5.5 A, the so-called water-bridging distance. The tested implicit solvent, even with optimized parameters, cannot capture the subtle fluctuation in the distance-dependent reaction field energy profiles, although smoothed profiles can still be obtained and are in overall agreement with those in the explicit solvent. Interestingly, the same mechanism underlining the above discrepancy is also responsible for the larger deviations of certain peptide conformations, such as parallel beta-strand dimers. It is likely that the observed discrepancy may cause improper conformational distributions in simulations with the implicit solvent when hydrogen-bonding or salt-bridging interactions are crucial, such as secondary structure populations in proteins. Validation of the implicit solvent with optimized parameters in dynamics simulations will be the next step to study the influences of the observed discrepancy at biological conditions.

Alanine↗

PubMed1996

Factor analysis of the Frankfurt Complaint Questionnaire in a Spanish sample.

The Frankfurt Complaint Questionnaire (FCQ) is a self-assessment instrument designed to evaluate the subjective experiences (SE) of psychotic patients. It is composed of 98 yes-no items grouped in ten phenomenological subscales. The original validation of the FCQ included a factor analysis with a four-factor structure. No further studies of factor validity have been carried out. The present study aimed to replicate the factor structure of the FCQ in a Spanish sample. The sample was composed of 286 consecutively admitted patients due to a recrudescence of their psychotic symptoms. They were evaluated through a semistructured interview for schizophrenia and diagnosed according to DSM-III-R criteria. Organic mental disorders were excluded. Sixteen patients who failed to fulfill the FCQ were excluded. The sample finally comprised 270 patients. A factor structure of FCQ items comprising 25 factors was found. The first factor obtained the highest explained variance, and most items obtained their highest load on the first factor. These results strongly suggest a unidimensionality underlying FCQ items. A new scale composed of 18 items was derived from those with higher weights in the first factor. The new scale of SE was presented in a Likert format to demonstrate their frequency and intensity more clearly.

Adult↗

PubMed2001

Active site structure and mechanism of human glyoxalase I-an ab initio theoretical study.

The structure of the active site of human glyoxalase I and the reaction mechanism of the enzyme-catalyzed conversion of the thiohemiacetal, formed from methylglyoxal and glutathione, to S-D-lactoylglutathione has been investigated by ab initio quantum chemical calculations. To realistically represent the environment of the reaction center, the effective fragment potential methodology has been employed, which allows systems of several hundred atoms to be described quantum mechanically. The methodology and the active site model have been validated by optimizing the structure of a known enzyme-inhibitor complex, which yielded structures in good agreement with the experiment. The same crystal structure has been used to obtain the quantum motif for the investigation of the glyoxalase I reaction. The results of our study confirm that the metal center of the active site zinc complex plays a direct catalytic role by binding the substrate and stabilizing the proposed enediolate reaction intermediate. In addition, our calculations yielded detailed information about the interactions of the substrate, the reaction intermediates, and the product with the active site of the enzyme and about the mechanism of the glyoxalase I reaction. The proton transfers of the reaction proceed via the two highly flexible residues Glu172 and Glu99. Information about the structural and energetic effect of the protein on the first-shell complex has been attained by comparison of the structures optimized in the local protein environment and in a vacuum. The environment of the zinc complex disturbs the Cs symmetry found for the complex in a vacuum, which suggests an explanation for the stereochemical behavior of glyoxalase I.

Catalytic Domain↗

PubMed2004

Combining evolutionary and structural information for local protein structure prediction.

We study the effects of various factors in representing and combining evolutionary and structural information for local protein structural prediction based on fragment selection. We prepare databases of fragments from a set of non-redundant protein domains. For each fragment, evolutionary information is derived from homologous sequences and represented as estimated effective counts and frequencies of amino acids (evolutionary frequencies) at each position. Position-specific amino acid preferences called structural frequencies are derived from statistical analysis of discrete local structural environments in database structures. Our method for local structure prediction is based on ranking and selecting database fragments that are most similar to a target fragment. Using secondary structure type as a local structural property, we test our method in a number of settings. The major findings are: (1) the COMPASS-type scoring function for fragment similarity comparison gives better prediction accuracy than three other tested scoring functions for profile-profile comparison. We show that the COMPASS-type scoring function can be derived both in the probabilistic framework and in the framework of statistical potentials. (2) Using the evolutionary frequencies of database fragments gives better prediction accuracy than using structural frequencies. (3) Finer definition of local environments, such as including more side-chain solvent accessibility classes and considering the backbone conformations of neighboring residues, gives increasingly better prediction accuracy using structural frequencies. (4) Combining evolutionary and structural frequencies of database fragments, either in a linear fashion or using a pseudocount mixture formula, results in improvement of prediction accuracy. Combination at the log-odds score level is not as effective as combination at the frequency level. This suggests that there might be better ways of combining sequence and structural information than the commonly used linear combination of log-odds scores. Our method of fragment selection and frequency combination gives reasonable results of secondary structure prediction tested on 56 CASP5 targets (average SOV score 0.77), suggesting that it is a valid method for local protein structure prediction. Mixture of predicted structural frequencies and evolutionary frequencies improve the quality of local profile-to-profile alignment by COMPASS.

Algorithms↗

PubMed1986

Estimation of surface area from vertical sections.

'Vertical' sections are plane sections longitudinal to a fixed (but arbitrary) axial direction. Examples are sections of a cylinder parallel to the central axis; and sections of a flat slab normal to the plane of the slab. Vertical sections of any object can be generated by placing the object on a table and taking sections perpendicular to the plane of the table. The standard methods of stereology assume isotropic random sections, and are not applicable to this kind of biased sampling. However, by using specially designed test systems, one can obtain an unbiased estimate of surface area. General principles of stereology for vertical sections are outlined. No assumptions are necessary about the shape or orientation distribution of the structure. Vertical section stereology is valid on the same terms as standard stereological methods for isotropic random sections. The range of structural quantities that can be estimated from vertical sections includes VV, NV, SV and the volume-weighted mean particle volume vV, but not LV. There is complete freedom to choose the vertical axis direction, which makes the sampling procedure simple and 'natural'. Practical sampling procedures for implementation of the ideas are described, and illustrated by examples.

Animals↗