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PubMed2001

Three-dimensional model of the cyclin-dependent kinase 1 (CDK1): Ab initio active site parameters for molecular dynamics studies of CDKS.

Cyclin-dependent kinase 1 (CDK1) is an interesting target for potential anticancer drugs, and its three-dimensional (3D) structure is presently unknown. The purpose of this work was to build a 3D model of CDK1, which could be used in drug design studies. The protein 3D structure was homology modeled, based on the known crystal structure of CDK2, and new nonbonded parameters for the Mg(2+) coordination complex were developed by means of ab initio quantum chemical calculations. These parameters were both obtained and validated using the CDK2 structure as reference, and then they were used for the refinement of the CDK1 model. The resulting CDK1 structure was satisfactory and stable at room temperature, as shown by the molecular dynamics simulations carried out over a 1-ns time interval on the entire protein. A number of representative kinases in the active and inactive form, including the inactive CDK1 modeled in this work, were compared. The results illustrate the conformational variability of the activation loop of the inactive form of the kinases and suggest a way for selectively targeting the single CDKs.

Amino Acid Sequence↗

PubMed2007

Does subtle screening for substance abuse work? A review of the Substance Abuse Subtle Screening Inventory (SASSI).

AIM: Through a complex combination of direct (face-valid) and indirect (subtle) subscales, the Substance Abuse Subtle Screening Inventory (SASSI) is purported to detect substance use disorders with a high degree of validity regardless of respondent honesty or motivation. This review evaluates empirical evidence regarding the reliability and validity of this widely used screening instrument. METHODS: Source documents were 36 peer-reviewed reports yielding data regarding the SASSI's internal consistency, test-retest reliability, psychometric structure, convergent and divergent validity and criterion (predictive) validity. RESULTS: The total N of the studies reviewed equaled 22 110. Internal consistency is high for the overall SASSI and for its direct but not its indirect (subtle) subscales, suggesting that the instrument taps a single face-valid construct. SASSI classifications converged with those from other direct screening instruments, and were also correlated with ethnicity, general distress and social deviance. Studies found test-retest reliability lower than that reported in the test manuals. Sensitivity was found to be similar to that for public domain screening instruments, but on specificity the SASSI appears to yield a high rate of false positives. CONCLUSION: No empirical evidence was found for the SASSI's claimed unique advantage in detecting substance use disorders through its indirect (subtle) scales to circumvent respondent denial or dishonesty. Recommendations for screening and for future research with the SASSI are offered.

Adolescent↗

PubMed1996

Prediction of rodent carcinogenicity bioassays from molecular structure using inductive logic programming.

The machine learning program Progol was applied to the problem of forming the structure-activity relationship (SAR) for a set of compounds tested for carcinogenicity in rodent bioassays by the U.S. National Toxicology Program (NTP). Progol is the first inductive logic programming (ILP) algorithm to use a fully relational method for describing chemical structure in SARs, based on using atoms and their bond connectivities. Progol is well suited to forming SARs for carcinogenicity as it is designed to produce easily understandable rules (structural alerts) for sets of noncongeneric compounds. The Progol SAR method was tested by prediction of a set of compounds that have been widely predicted by other SAR methods (the compounds used in the NTP's first round of carcinogenesis predictions). For these compounds no method (human or machine) was significantly more accurate than Progol. Progol was the most accurate method that did not use data from biological tests on rodents (however, the difference in accuracy is not significant). The Progol predictions were based solely on chemical structure and the results of tests for Salmonella mutagenicity. Using the full NTP database, the prediction accuracy of Progol was estimated to be 63% (+/- 3%) using 5-fold cross validation. A set of structural alerts for carcinogenesis was automatically generated and the chemical rationale for them investigated- these structural alerts are statistically independent of the Salmonella mutagenicity. Carcinogenicity is predicted for the compounds used in the NTP's second round of carcinogenesis predictions. The results for prediction of carcinogenesis, taken together with the previous successful applications of predicting mutagenicity in nitroaromatic compounds, and inhibition of angiogenesis by suramin analogues, show that Progol has a role to play in understanding the SARs of cancer-related compounds.

Animals↗

PubMed1995

The Aberrant Behavior Checklist-Community: factor validity and effect of subject variables for adults in group homes.

The factor validity of the new Aberrant Behavior Checklist-Community (ABC-C) was determined with 1,040 group home residents. Exploratory factor analysis indicated that the factor structure derived from the original ABC appears to be valid for the ABC-C when used with this population. Coefficients of congruence showed a high level of concordance with the original factor structure, and internal consistency continued to be high for each of the five subscales. Analyses for the effects of age, gender, and level of mental retardation indicated that some correction is appropriate for each of these variables when scoring the ABC-C. Further analyses explored the effects of subjects variables such as visual and auditory handicaps and the presence of epilepsy or Down syndrome. Psychotropic medication use was often associated with subscale score differences. The original ABC factor structure appears valid for scoring the ABC-C with community-based adults, at least those living in group homes.

Adolescent↗

PubMed1999

Discourse structures in medical reports--watch out! The generation of referentially coherent and valid text knowledge bases in the MEDSYNDIKATE system.

The automatic analysis of medical narratives currently suffers from neglecting text structure phenomena such as referential relations between discourse units. This has unwarranted effects on the descriptional adequacy of medical knowledge bases automatically generated from texts. The resulting representation bias can be characterized in terms of incomplete, artificially fragmented and referentially invalid knowledge structures. We focus here on four basic types of textual reference relations, viz. pronominal and nominal anaphora, textual ellipsis and metonymy and show how to deal with them in an adequate text parsing device. Since the types of reference relations we discuss show an increasing dependence on conceptual background knowledge, we stress the need for formally grounded, expressive conceptual representation systems for medical knowledge. Our suggestions are based on experience with MEDSYNDIKATE, a medical text knowledge acquisition system designed to properly deal with various sorts of discourse structure phenomena.

Artificial Intelligence↗

PubMed2005

Antibodies against Gag are diagnostic markers for feline foamy virus infections while Env and Bet reactivity is undetectable in a substantial fraction of infected cats.

Spumaretroviruses or foamy viruses constitute a distinct subfamily of retroviruses. The biology of foamy viruses within the authentic host, their mode of transmission, and disease potential in the authentic host or after zoonotic transmission into human or other species are almost unknown. Using feline foamy virus (FFV) as model system, we established modular enzyme-linked immunosorbent assays (ELISA) suited to determine feline IgG and IgM antibody responses against structural and non-structural FFV proteins. We validated the ELISAs with standard reference sera. In 99 cats admitted to a Swiss veterinary hospital, overall FFV Gag antibody prevalence was 36%, reactivity against Env and the non-structural protein Bet each was about 25%, and 19% of the sera were directed against all three FFV antigens. With one exception, all Bet- and/or Env-positive sera were also positive for Gag. In this small epidemiological pilot study, FFV antibodies were not significantly associated with clinical disease.

Animals↗

PubMedDate not supplied

Thermolytical techniques to characterize fungal polysaccharides and bacterial lipopolysaccharides.

The present work constitutes an entirely novel contribution in the scope of microbiology and especially in taxonomy, introducing thermolysis curves as a rapid method of characterization of fungal polysaccharides and bacterial lipopolysaccharides. The thermal analysis techniques applied were thermogravimetry and derivative thermogravimetry (TG-DTG), differential thermal analysis (DTA), and differential scanning calorimetry (DSC). Each thermogram of a sample is represented by one or a few temperatures and, in DSC, by complementary enthalpy data. The temperatures of the thermograms from structurally unknown polysaccharides are compared with those used as references, and thus, information on their composition, linkage types, and anomeric configuration can be deduced. The situation is more complicated for bacterial lipopolysaccharides, but in whatever mode, a structural estimation is always possible. In the course of the development and validation of the thermal method, structural findings on relative stabilities of linkage types (valuable in carbohydrate research) have been recognized and are therefore also described in this work.

Biotechnology↗

PubMed2000

Motivational and cognitive influences on affective priming in adulthood.

This research examined age differences in the impact of affective primes on judgments about neutral stimuli. When participants were unaware that the primes had been presented, age differences were nonexistent, with individuals of all ages producing likability judgments consistent with the valence of the prime. In contrast, when awareness of the primes was maximized, prime influences were virtually nonexistent in the youngest participants, but prime influences increased with participants' age. In addition, the impact of the primes was differentially affected by an individual's need for simple structure. Need for structure did not influence the performance of young and middle-aged participants, but prime effects increased with need in the oldest participants. It is argued that the stronger predictive validity of need for structure with age is due to aging-related changes in personal resources (both social and cognitive) and/or a closer mapping of individual characteristics onto need with age. Regardless of source, the results argue for closer consideration of motivational factors in determining age differences in performance.

Adult↗

PubMed2004

Statistical-mechanical theory of the overall magnetic properties of mesocrystals.

The mesocrystal showing both electrorheological and magnetorheological effects is called electro-magnetorheological (EMR) solids. Prediction of the overall magnetic properties of the EMR solids is a challenging task due to the coexistence of the uniaxially anisotropic behavior and structural transition as well as long-range interaction between the suspended particles. To consider the uniaxial anisotropy effect, we present an anisotropic Kirkwood-Fröhlich equation for calculating the effective permeabilities by adopting an explicit characteristic spheroid rather than a characteristic sphere used in the derivation of the usual Kirkwood-Fröhlich equation. Further, by applying an Ewald-Kornfeld formulation we are able to investigate the effective permeability by including the structural transition and long-range interaction explicitly. Our theory can reduce to the usual Kirkwood-Fröhlich equation and Onsager equation naturally. To this end, the numerical simulation shows the validity of monitoring the structure of EMR solids by detecting their effective permeabilities.

Journal Article↗

PubMed2001

Automated measurement of latent morphological features in the human corpus callosum.

Our objective was to develop a novel factor-based analysis of the morphology of the corpus callosum and assess its applicability to the study of normal development, intelligence, and other subject characteristics. The contour of the corpus callosum was defined in the midsagittal planes of the MRI scans of 325 subjects, 6 to 88 years of age. The contours were coregistered, rescaled, and resampled to 50 points that were then entered into a principal components analysis with varimax rotation. The analysis yielded 8 factors for the contours of 138 healthy subjects. A second analysis of contours from 187 subjects in a patient group extracted 8 similar factors. Correlations of factor scores with conventional measures of callosum shape supported the construct validity of the assignment of morphological features to each of the factors. Correlations of factor scores with age, sex, handedness, ventricular volume, and IQ demonstrated the predictive validity of the factor structure and helped to define the neural correlates of these subject characteristics. We conclude that factor-based measures capture latent morphological features of the corpus callosum that are reliable and valid. Future studies will determine whether these novel measures are more closely related to neurobiologically important features of the corpus than are conventional measures of callosum size and shape.

Adolescent↗

PubMed2000

Validation of nuclear texture, density, morphometry and tissue syntactic structure analysis as prognosticators of cervical carcinoma.

OBJECTIVE: To evaluate the performance of karyometry and histometry in the prediction of survival, recurrence and response of early-stage invasive cervical carcinoma. STUDY DESIGN: Nuclear morphometry, chromatin texture and tissue architecture (characterized by syntactic structure analysis) were measured using a semiautomated image analysis system on 46 cases of Feulgen-stained tissue sections. The performance of the features was compared to that of clinical features, reported to be the best prognosticators until now, such as age, lympho-vascular permeation, histologic type, stage and grade. A K nearest neighbor classifier was used for classification. RESULTS: In the prediction of three-year survival, recurrence and response, syntactic structure analysis proved to be the best performer. Classification rates were, respectively, 100%, 94.4% and 94.5%. In all classifications, karyometric and histometric features outperformed clinical features. In general, the best performing features described differences in second-order population statistics (standard deviations). CONCLUSION: The results show that a quantitative analysis based on nuclear morphology, chromatin texture and histology can be considered an excellent aid in the prognosis of invasive cervical carcinoma. The measurements are not hampered by the need to undertake complete resections and are suited to daily practice when implemented in a semiautomated image analysis system.

Adult↗

PubMed2006

Modeling of Cdc25B dual specifity protein phosphatase inhibitors: docking of ligands and enzymatic inhibition mechanism.

The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signalling processes and cell proliferation. It has been reported that an improper amplification or activation of these enzymes is a distinctive feature of a number of human cancers, including breast cancers. Thus, the inhibition of Cdc25 phosphatases might provide a novel approach for the discovery of new and selective antitumor agents. By using the crystal structure of the catalytic domain of Cdc25B, structural models for the interaction of various Cdc25B inhibitors (1-13) with the enzyme were generated by computational docking. The parallel use of two efficient and predictive docking programs, AutoDock and GOLD, allowed mutual validation of the predicted binding poses. To evaluate their quality, the models were validated with known structure-activity relationships and site-directed mutagenesis data. The results provide an improved basis for structure-based ligand design and suggest a possible explanation for the inhibition mechanism of the examined Cdc25B ligands. We suggest that the recurring motif of a tight interaction between the inhibitor and the two arginine residues, 482 and 544, is of prime importance for reversible enzyme inhibition. In contrast, the irreversible inhibition mechanism of 1-4 seems to be associated with the close vicinity of the quinone ring and the Cys473 catalytic thiolate. We believe that this extensive study might provide useful hints to guide the development of new potent Cdc25B inhibitors as novel anticancer drugs.

Cell Cycle Proteins↗

PubMed2003

Flexible ligand docking using evolutionary algorithms: investigating the effects of variation operators and local search hybrids.

The docking of ligands to proteins can be formulated as a computational problem where the task is to find the most favorable energetic conformation among the large space of possible protein-ligand complexes. Stochastic search methods such as evolutionary algorithms (EAs) can be used to sample large search spaces effectively and is one of the commonly used methods for flexible ligand docking. During the last decade, several EAs using different variation operators have been introduced, such as the ones provided with the AutoDock program. In this paper we evaluate the performance of different EA settings such as choice of variation operators, population size, and usage of local search. The comparison is performed on a suite of six docking problems previously used to evaluate the performance of search algorithms provided with the AutoDock program package. The results from our investigation confirm that the choice of variation operators has an impact on the search-capabilities of EAs. The introduced DockEA using the best settings found obtained the overall best docking solutions compared to the Lamarckian GA (LGA) provided with AutoDock. Furthermore, the DockEA proved to be more robust than the LGA (in terms of reproducing the results in several runs) on the more difficult problems with a high number of flexible torsion angles.

Algorithms↗

PubMed2003

Computer-aided modeling of pentachlorophenol 4-monooxygenase and site-directed mutagenesis of its active site.

Homology modeling was used to construct a model of the three-dimensional structure of pentachlorophenol 4-monooxygenase (PcpB). A PSI-BLAST homology search was initially performed to identify the 3D structure of proteins homologous with PcpB. The feasibility of modeled structures of PcpB was evaluated by Verify3D, which calculated structural compatibility scores based on 3D-1D profiles. The predicted structure of PcpB had an acceptable 3D-1D self-compatibility score, beyond the incorrect fold score threshold. A PcpB-pentachlorophenol (PCP) complex was then constructed utilizing the modeled PcpB structure. After energy minimization of the complex, and successive minimizations of the system that consisted of the complex and the water layer surrounding the complex, the molecular dynamics of the system were simulated. The active-site residues of PcpB were identified on the basis of the modeled structure, and PcpB mutants were then designed to change the active site residues, expressed, and purified by affinity chromatography. The mutant activity was compared with that of the wild-type to investigate the validity of the modeled structure. The experimental results suggested that Phe85, Tyr216, and Arg235 were relevant to enzyme activity, and that Tyr397 and Phe87 were important for stabilization of the structure of PcpB.

Binding Sites↗

PubMed2004

Psychometric Properties of the Posttraumatic Cognitions Inventory (PTCI): a replication with motor vehicle accident survivors.

This study examined the factor structure, internal consistency, concurrent validity, discriminant validity, and discriminative validity of the Posttraumatic Cognitions Inventory (PTCI; E. B. Foa, A. Ehlers, D. M. Clark, D. F. Tolin, and S. M. Orsillo, 1999) in a sample of 112 individuals who had experienced a serious motor vehicle accident. Results generally supported the 3-factor structure of the PTCI: (a) Negative Cognitions About Self, (b) Negative Cognitions About the World, and (c) Self-Blame. Subscales reflecting negative thoughts of the self and world showed adequate internal consistency, as well as good concurrent, discriminant, and discriminative validity. However, difficulties with the subscale representing self-blame emerged, specifically poor concurrent and discriminant validity. Potential reasons for this finding are discussed. The PTCI seems to be a promising measure of negative and dysfunctional posttrauma cognitions, which deserves continuing attention.

Accidents, Traffic↗

PubMed2006

Factor structure of the alcohol urge questionnaire under neutral conditions and during a cue-elicited urge state.

BACKGROUND: The Alcohol Urge Questionnaire (AUQ) is a promising multi-item measure of self-reported urges to drink in human laboratory studies; however, its factor structure has not been examined during an acute urge state. This study sought to validate the AUQ's factor structure under neutral conditions and during a cue-elicited urge state in heavy drinkers. METHODS: Participants (248 heavy drinkers; 70% male) completed the AUQ, the Alcohol Dependence Scale (ADS), and the Positive and Negative Affect Scale (PANAS) under neutral conditions. A randomly selected subsample (n=61; 74% male) then underwent a multimodal alcohol cue exposure and completed the AUQ and PANAS a second time. RESULTS: Under neutral conditions, confirmatory factor analysis (CFA) replicated the previously reported single-factor structure, on which all items significantly loaded (p<0.001). Alcohol urges, as measured by the AUQ, exhibited significant positive associations with drinks per week and severity of dependence. Following the alcohol cue exposure, participants exhibited a significant increase in urge on the AUQ. Confirmatory factor analysis of the AUQ during the cue-elicited urge state also supported the single factor structure, on which all items significantly loaded (p<0.001). Positive and negative affect were positively associated with urges across the experimental protocol, but at greater magnitudes during an acutely elevated urge state. CONCLUSIONS: These results further validate the use of the AUQ for real-time measurement of alcohol craving in human laboratory research.

Adult↗

PubMed1994

Consistency and stability of recombinant fermentations.

Production of proteins of consistent quality in heterologous, genetically-engineered expression systems is dependent upon identifying the manufacturing process parameters which have an impact on product structure, function, or purity, validating acceptable ranges for these variables, and performing the manufacturing process as specified. One of the factors which may affect product consistency is genetic instability of the primary product sequence, as well as instability of genes which code for proteins responsible for post-translational modification of the product. Approaches have been developed for mammalian expression systems to assure that product quality is not changing through mechanisms of genetic instability. Sensitive protein analytical methods, particularly peptide mapping, are used to evaluate product structure directly, and are more sensitive in detecting genetic instability than is direct genetic analysis by nucleotide sequencing of the recombinant gene or mRNA. These methods are being employed to demonstrate that the manufacturing process consistently yields a product of defined structure from cells cultured through the range of cell ages used in the manufacturing process and well beyond the maximum cell age defined for the process. The combination of well designed validation studies which demonstrate consistent product quality as a function of cell age, and rigorous quality control of every product lot by sensitive protein analytical methods provide the necessary assurance that product structure is not being altered through mechanisms of mutation and selection.

Biotechnology↗

PubMedDate not supplied

Reliability and validity of a measure of perceived diabetes and dietary competence in African American women with type 2 diabetes.

PURPOSE: A general measure of perceived diabetes and dietary competence (PDDC) was developed to assess a person's sense of confidence and perceived behavioral control in diabetes and dietary self-management. Internal structure, reliability, and construct validity were evaluated. METHODS: There were 2 samples of African American women with type 2 diabetes; 226 patients in the development sample and 225 patients in the validation sample. Factor analysis, Cronbach's coefficient alpha, and correlation analysis were used to assess reliability and validity of the PDDC measure. RESULTS: Three subscales were empirically determined by factor analysis: positive competence, negative dietary competence, and negative control. Cronbach's alphas for all subscales were good. Predicted relationships with measures of perceived health competence, self-efficacy, social support, and perceived dietary barriers were largely supported in construct validation. CONCLUSIONS: This study provides initial support for the internal reliability and validity of a perceived diabetes and dietary competence measure. Further research is needed to determine its validity in other samples of African Americans with type 2 diabetes and its clinical utility in evaluating diabetes self-management training.

Adult↗