Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Structural validation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,531 records · Page 85Linked to original sources
PubMed2006

Chemically engineered extracts as an alternative source of bioactive natural product-like compounds.

The access to libraries of molecules with interesting biomolecular properties is a limiting step in the drug discovery process. By virtue of a long molecular evolution process, natural products are recognized as biologically validated starting points in structural space for library development. We introduce here a strategy to generate natural product-like libraries. A semisynthetic mixture of compounds was produced by diversification of a natural product extract through the chemical transformation of common chemical functionalities in natural products into chemical functionalities rarely found in nature. The resulting mixture showed antifungal activity against Candida albicans, whereas the starting extract did not show such activity. Bioguided fractionation led to the isolation of a previously undescribed active semisynthetic pyrazole. The result illustrates how biological activity can be generated by designed chemical diversification of a natural product mixture, and represents the proof of principle of an alternative strategy for producing natural product-like libraries from natural products libraries.

Antifungal Agents↗
PubMed2002

Conceptualization and measurement of clinical competence of residents: a brief rating form and its psychometric properties.

Conceptualization and measurement of clinical competence of residents are of interest to medical educators. Yet there is a scarcity of operational tools with satisfactory psychometric support for measuring clinical competence. In this study, we investigated the underlying structure, criterion-related validity and alpha reliability of a brief rating form (20 items) developed to assess clinical competence of residents. The study sample consisted of 882 physicians (654 men, 228 women) in postgraduate training at Thomas Jefferson University Hospital between 1998 and 2000. Construct validity of the form was supported by factor analysis. Two relevant factors emerged: 'Knowledge, Data-Gathering and Processing Skills', and 'Interpersonal Skills and Attitudes'. Criterion-related validity was supported by significant linear associations between factor scores and performance on the medical licensing examinations. Alpha reliability coefficients for the two factors were 0.98 and 0.97, respectively. This brief rating form can be employed as one measure to evaluate clinical competence of residents with reasonable confidence in its measurement properties.

Clinical Competence↗
PubMed1998

Parametric image reconstruction using spectral analysis of PET projection data.

Spectral analysis is a general modelling approach that enables calculation of parametric images from reconstructed tracer kinetic data independent of an assumed compartmental structure. We investigated the validity of applying spectral analysis directly to projection data motivated by the advantages that: (i) the number of reconstructions is reduced by an order of magnitude and (ii) iterative reconstruction becomes practical which may improve signal-to-noise ratio (SNR). A dynamic software phantom with typical 2-[11C]thymidine kinetics was used to compare projection-based and image-based methods and to assess bias-variance trade-offs using iterative expectation maximization (EM) reconstruction. We found that the two approaches are not exactly equivalent due to properties of the non-negative least-squares algorithm. However, the differences are small (< 5%) and mainly affect parameters related to early and late time points on the impulse response function (K1 and, to a lesser extent, VD). The optimal number of EM iteration was 15-30 with up to a two-fold improvement in SNR over filtered back projection. We conclude that projection-based spectral analysis with EM reconstruction yields accurate parametric images with high SNR and has potential application to a wide range of positron emission tomography ligands.

Algorithms↗
PubMed1996

Implementing a validation program in a cord blood bank.

The regulatory climate surrounding cord blood banking has been slowly evolving since the publication of the FDA notice, Applications of Current Statutory Authorities to Human Somatic Cell Therapy in the October 14, 1993, Federal Register. The pace of establishing regulatory policy for cord blood banking is about to quicken dramatically. Cord blood banking will most likely be regulated as a new blood product within the Office of Blood Research and Review in the Center for Biologics Evaluation and Research (CBER) and would then be subject to licensing preapproval inspections. Validation is a critical element of the approval process. Fundamental elements of structuring and implementing a scientifically sound validation program are discussed.

Blood Banks↗
PubMed2003

A computational pipeline for protein structure prediction and analysis at genome scale.

MOTIVATION: Experimental techniques alone cannot keep up with the production rate of protein sequences, while computational techniques for protein structure predictions have matured to such a level to provide reliable structural characterization of proteins at large scale. Integration of multiple computational tools for protein structure prediction can complement experimental techniques. RESULTS: We present an automated pipeline for protein structure prediction. The centerpiece of the pipeline is our threading-based protein structure prediction system PROSPECT. The pipeline consists of a dozen tools for identification of protein domains and signal peptide, protein triage to determine the protein type (membrane or globular), protein fold recognition, generation of atomic structural models, prediction result validation, etc. Different processing and prediction branches are determined automatically by a prediction pipeline manager based on identified characteristics of the protein. The pipeline has been implemented to run in a heterogeneous computational environment as a client/server system with a web interface. Genome-scale applications on Caenorhabditis elegans, Pyrococcus furiosus and three cyanobacterial genomes are presented. AVAILABILITY: The pipeline is available at http://compbio.ornl.gov/proteinpipeline/

Algorithms↗
PubMed2006

NQ-Flipper: validation and correction of asparagine/glutamine amide rotamers in protein crystal structures.

The error rate of asparagine (Asn) and glutamine (Gln) amide rotamers in protein crystal structures is in the order of 20% and as a consequence the current Protein Database (PDB) contains approximately half a million incorrect Asn and Gln side-chain rotamers. Here we present NQ-Flipper, a web service based on knowledge-based potentials of mean force to automatically detect and correct erroneous rotamers. We achieve excellent agreement with expert curated data.

Asparagine↗
PubMed2004

Recirculatory model of fentanyl disposition with the brain as the target organ.

BACKGROUND: The factors affecting the concentrations of fentanyl in the brain after intravenous administration have not been completely quantified. METHODS: A model integrating the role of brain, lung and systemic kinetics was developed based on data from conscious instrumented sheep. Brain kinetics were inferred from arterio-sagittal sinus concentration gradients and cerebral blood flow, and lung kinetics from the pulmonary artery-aortic gradient and cardiac output. The best models of the lung and brain were incorporated into a recirculatory model of the whole-body disposition of fentanyl. The validity of the model structure was tested by its ability to describe published data on the effect of hypo-, normo- and hypercarbia on the blood and brain concentrations of fentanyl in anaesthetized dogs. RESULTS: The cerebral kinetics of fentanyl were consistent with partial membrane limitation: the time to 50% equilibration with arterial blood was 10.0 min. Lung kinetics had two distinct components: a shallow compartment that was 50% equilibrated with blood in 0.72 min, and a loss term probably representing sequestration. Despite its simplicity, the recirculatory model was an adequate description of the sheep data. The dog data could be described if cerebral blood flow and cardiac output in the model were allowed to differ between hypo-, normo- and hypercarbic states. The required flow changes were in good agreement with the known effect of these states in the dog. CONCLUSIONS: A recirculatory model with the brain as a target organ defined the quantitative relationship between the brain concentrations of fentanyl and the circulatory state.

Analgesics, Opioid↗
PubMed2006

Sequence-dependent enhancement of hydrolytic deamination of cytosines in DNA by the restriction enzyme PspGI.

Hydrolytic deamination of cytosines in DNA creates uracil and, if unrepaired, these lesions result in C to T mutations. We have suggested previously that a possible way in which cells may prevent or reduce this chemical reaction is through the binding of proteins to DNA. We use a genetic reversion assay to show that a restriction enzyme, PspGI, protects cytosines within its cognate site, 5'-CCWGG (W is A or T), against deamination under conditions where no DNA cleavage can occur. It decreases the rate of cytosine deamination to uracil by 7-fold. However, the same protein dramatically increases the rate of deaminations within the site 5'-CCSGG (S is C or G) by approximately 15-fold. Furthermore, a similar increase in cytosine deaminations is also seen with a catalytically inactive mutant of the enzyme showing that endonucleolytic ability of the protein is dispensable for its mutagenic action. The sequences of the mutants generated in the presence of PspGI show that only one of the cytosines in CCSGG is predominantly converted to thymine. Our results are consistent with PspGI 'sensitizing' the cytosine in the central base pair in CCSGG for deamination. Remarkably, PspGI sensitizes this base for damage despite its inability to form stable complexes at CCSGG sites. These results can be explained if the enzyme has a transient interaction with this sequence during which it flips the central cytosine out of the helix. This prediction was validated by modeling the structure of PspGI-DNA complex based on the structure of the related enzyme Ecl18kI which is known to cause base-flipping.

Base Sequence↗
PubMed1998

The herbicide-resistant species of the cyanobacterial D1 protein obtained by thorough and random in vitro mutagenesis.

Random mutations were introduced into the DNA fragment of the psbA2 gene of Synechocystis sp. PCC 6803, which encodes the carboxyl-terminal 178 amino acid region of the D1 protein of the PSII reaction center, by in vitro random mutagenesis to obtain D1 species resistant to herbicides and to understand the protein-herbicide interactions. The mutants were screened on the criterion of resistance to either 1 microM DCMU or 10 microM atrazine. In these mutants, amino acid substitutions were distributed throughout the entire area of the targeted region in the D1 protein. However, in every mutant, except for one case, the substitution was present in the region described as the "herbicide-binding niche", i.e., between Phe211 and Leu275, although some amino acid substitutions which were not previously described were found at residues known to be involved with herbicide affinity. Thus, the result of random mutagenesis basically supports the validity of the proposed structural model for the D1 protein, as well as of the herbicide-binding niche. Preliminary characterization of the herbicide-resistant mutants obtained in this study has also been conducted.

Amino Acid Sequence↗
PubMed2002

Proteo-chemometrics analysis of MSH peptide binding to melanocortin receptors.

The published data for six melanocortin peptides binding to wild-type and chimeric melanocortin MC(1)/MC(3) receptors were analysed using the novel proteo-chemometrics modelling approach. The chimeric receptors and the peptides were coded using binary descriptors and used to correlate with the experimental data for affinity or selectivity for peptides binding to receptors. Correlations were achieved using partial least squares projection to latent structures (PLS) and statistically valid models were obtained. The models were further improved by adding cross-terms and applying orthogonal signal correction. The models were validated using external prediction, with half of the data being excluded from the modelling. Interpretation of the results using PLS coefficient plots revealed that the binding pocket for the melanocortins is located between the first, second, third, sixth and seventh transmembrane regions of the melanocortin receptors, in good agreement with previous three-dimensional models for the interactions of melanocortins with melanocortin receptors. Further, analysis of cross-terms between peptide descriptors indicated that the proteo-chemometrics modelling is able to distinguish between differences in the conformational space of the peptides that affect binding affinity and selectivity.

Humans↗
PubMed2005

Modeling membrane proteins based on low-resolution electron microscopy maps: a template for the TM domains of the oxalate transporter OxlT.

The availability of both EM and high-resolution crystallographic data for several membrane proteins (MPs) permits a detailed evaluation of the ability of molecular modeling techniques to complement EM data in the development of models of MPs. A protocol for this purpose is presented, consisting of (1) identifying transmembrane (TM) domains from sequence; (2) assigning buried and lipid-exposed faces of the TM domains; and (3) assembling the TM domains into a bundle, based on geometric restraints obtained from the EM data. The protocol is validated by predicting the structures of several 7- and 12-TM MPs to within 3-5 A r.m.s.d. from their crystal structures. The protocol is applied to generate a model of the oxalate transporter OxlT, for which a high-resolution structure is not yet available.

Algorithms↗
PubMedDate not supplied

Relationship of blood coagulation and fibrinolysis to vital exhaustion.

OBJECTIVE: Acute physical and psychological stressors affect blood coagulation and fibrinolysis, but little is known about hemostatic factors associated with chronic psychological stress. Prolonged psychological stress may end in a state of vital exhaustion, which has been shown to be a risk factor for first myocardial infarction and recurrent events after coronary angioplasty. The present study tested the hypothesis that vital exhaustion resulting from chronic psychological stress is associated with impaired fibrinolytic capacity and increased coagulation factors. METHODS: On the basis of a validated questionnaire and subsequent structured interview, a well-defined group of otherwise healthy exhausted men was recruited (N = 15) and compared with age-matched not-exhausted controls (N = 15). Fibrinolytic measures included tissue plasminogen activator (TPA) antigen and plasminogen activator inhibitor (PAI-1) activity, and as coagulation factors we examined factors VIIc, factor VIIIc, and fibrinogen. Control variables were: blood pressure, smoking status, triglycerides, cholesterol, and standard hematological measures. Samples were collected twice to correct for intraindividual fluctuations. Statistical analyses were performed using 2 x 2 mixed model analysis of variance with subsequent univariate testing. RESULTS: Vital exhaustion was associated with significantly elevated levels of PAI-1 activity (p = .023). The higher PAI-1 activity in exhausted subjects (median = 13.0 U/ml vs. 6.0 U/ml) was not accounted for by smoking status or serum lipids. No significant differences were observed in TPA antigen, factor VIIc, factor VIIIc, and fibrinogen. The groups did not differ in blood pressure, smoking status, triglycerides, cholesterol, or standard hematological measures. CONCLUSION: These data suggest a reduced fibrinolytic capacity in exhausted individuals. Therefore, the relationship between vital exhaustion and risk of myocardial infarction may be mediated in part by an imbalance between blood coagulation and fibrinolysis.

Adult↗
PubMedDate not supplied

Measuring subclinical disability in older mexican americans.

OBJECTIVE: The purpose of this study was to develop a comprehensive list of adaptive strategies to prevent disability and use this information to devise a preliminary measure of subclinical disability (state of sustained independence in the presence of latent or manifest functional limitations) suitable for older Mexican Americans. METHOD: Semistructured interviews were conducted with 24 community-dwelling Mexican American elders (> or =65 years old) to elicit information about adaptations in performance of daily living tasks (eg, walking, dressing, and shopping) that may indicate presence of subclinical disability. This information was used to construct a quantitative self-report measure of subclinical disability administered to 207 older Mexican Americans. Item and factor analyses were performed to reduce the number of items and establish their underlying structure. Construct and discriminant validity of the reduced instrument was determined. RESULTS: A framework comprised of nine categories of daily living tasks, three functional levels, and five adaptation types was generated from the qualitative data. The initial 133-item measure (named the ADAPT) was reduced to a 44-item scale with three subscales (physical, household, and social). ADAPT scores correlated significantly in the expected direction with standard functional status measures, but the shared variance was modest, indicating that the ADAPT captured substantial, unique variance. Mean ADAPT scores differed significantly and were monotonically lower across subgroups classified as independent, subclinically disabled, and disabled, respectively. CONCLUSIONS: The ADAPT seems to have construct and discriminant validity as a measure of subclinical disability. Additional research is required to determine sensitivity to change and clinically significant cut points for varying risk of frank disability.

Activities of Daily Living↗
PubMed1991

Reliability of interpretation of plain lumbar spine radiographs in benign, mechanical low-back pain.

A study was conducted to investigate the variability of interpretation of plain lumbar spine radiographs by rheumatologists in benign low-back pain (LBP). Intra- and interobserver agreement in classifying the presence of primary radiologic abnormalities according to pre-established criteria was assessed by the Kappa statistic in 115 anteroposterior and lateral radiograms. A significant variability of interpretation was observed for many findings often considered important in benign LBP. Particularly, low levels of agreement were observed for apophyseal joint abnormalities. Schmorl's nodes, spondylolysis, and structural deviations. Elaboration and validation of better standardized criteria for the main radiologic abnormalities is needed to improve the reliability of interpretation of lumbar spine radiographs.

Back Pain↗
PubMed2006

Identifying interactions in mixed and noisy complex systems.

We present a technique that identifies truly interacting subsystems of a complex system from multichannel data if the recordings are an unknown linear and instantaneous mixture of the true sources. The method is valid for arbitrary noise structure. For this, a blind source separation technique is proposed that diagonalizes antisymmetrized cross-correlation or cross-spectral matrices. The resulting decomposition finds truly interacting subsystems blindly and suppresses any spurious interaction stemming from the mixture. The usefulness of this interacting source analysis is demonstrated in simulations and for real electroencephalography data.

Action Potentials↗
PubMed2006

Bias in cross-validated free R factors: mitigation of the effects of non-crystallographic symmetry.

Current methods of free R factor cross-validation assume that the structure factors of the test and working sets are independent of one another. This assumption is only an approximation when the modeled structure occupies anything less than the full asymmetric unit. Through progressive elimination of reflections from the working set, starting with those expected to be most correlated to the test set, small biases in free R can be measured, presumably because of over-sampling of the Fourier transform owing to bulk solvent in the crystal. This level of bias may be of little practical importance, but it rises to significant levels with increasing non-crystallographic symmetry owing to wider correlations between structure factors than hitherto appreciated. In the presence of 15-fold non-crystallographic symmetry, with resolutions commonly attainable in macromolecular crystallography, it may not be possible to calculate an unbiased free R factor. Methods are developed for the calculation of reduced-bias free R factors through elimination of the strongest correlations between test and working sets. With 180-fold non-crystallographic symmetry they may not be an accurate indicator of absolute quality, but they do yield the correct optimal weighting for stereochemical restraints.

Algorithms↗
PubMed2003

Median-based robust algorithms for tracing neurons from noisy confocal microscope images.

This paper presents a method to exploit rank statistics to improve fully automatic tracing of neurons from noisy digital confocal microscope images. Previously proposed exploratory tracing (vectorization) algorithms work by recursively following the neuronal topology, guided by responses of multiple directional correlation kernels. These algorithms were found to fail when the data was of lower quality (noisier, less contrast, weak signal, or more discontinuous structures). This type of data is commonly encountered in the study of neuronal growth on microfabricated surfaces. We show that by partitioning the correlation kernels in the tracing algorithm into multiple subkernels, and using the median of their responses as the guiding criterion improves the tracing precision from 41% to 89% for low-quality data, with a 5% improvement in recall. Improved handling was observed for artifacts such as discontinuities and/or hollowness of structures. The new algorithms require slightly higher amounts of computation, but are still acceptably fast, typically consuming less than 2 seconds on a personal computer (Pentium III, 500 MHz, 128 MB). They produce labeling for all somas present in the field, and a graph-theoretic representation of all dendritic/axonal structures that can be edited. Topological and size measurements such as area, length, and tortuosity are derived readily. The efficiency, accuracy, and fully-automated nature of the proposed method makes it attractive for large-scale applications such as high-throughput assays in the pharmaceutical industry, and study of neuron growth on nano/micro-fabricated structures. A careful quantitative validation of the proposed algorithms is provided against manually derived tracing, using a performance measure that combines the precision and recall metrics.

Algorithms↗
PubMed2004

A novel neural network for nonlinear convex programming.

In this paper, we present a neural network for solving the nonlinear convex programming problem in real time by means of the projection method. The main idea is to convert the convex programming problem into a variational inequality problem. Then a dynamical system and a convex energy function are constructed for resulting variational inequality problem. It is shown that the proposed neural network is stable in the sense of Lyapunov and can converge to an exact optimal solution of the original problem. Compared with the existing neural networks for solving the nonlinear convex programming problem, the proposed neural network has no Lipschitz condition, no adjustable parameter, and its structure is simple. The validity and transient behavior of the proposed neural network are demonstrated by some simulation results.

Neural Networks, Computer↗