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Results for “Structural validation”

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At least 163 records · Page 9Linked to original sources
PubMed1994

Stabilization of beta-ribbon structures in peptides using disulfide bonds.

The effect of a disulfide crosslink between two peptide chains on the stability of beta-ribbon secondary structures formed by these peptides has been investigated. Based on structural principles, we hypothesized that introduction of an unstrained disulfide crosslink at appropriate locations on two peptide chains should have a stabilizing effect on the beta-ribbon structure formed by these two peptide chains. To test this hypothesis, we designed and synthesized two sets of 9-residue peptides incorporating cysteine in one and (S)-alpha-amino-epsilon-mercaptohexanoic acid in the other. Comparison of the CD data clearly show that the dimer containing a disulfide bond between the longer sidechains of (S)-alpha-amino-epsilon-mercaptohexanoic acid shows dramatically higher beta-ribbon character as compared to the dimer with cystine disulfide bond, thus validating our structural hypothesis.

Amino Acid Sequence↗
PubMed1991

Structure-activity relationships of chemical mutagens and carcinogens.

In recent years, octanol-water partition coefficients (P) have been used in toxicology studies to correlate chemical structure and biological activity. Generally, only limited attempts are made to show how a new correlation equation relates to those previously published, especially when different activities are involved. Evidence is presented to show that there is often a high degree of self-consistency between the dependence of activity on hydrophobicity (defined by log P) from different systems. Examples are drawn from nonspecific toxicity, mutagenicity and carcinogenicity. It is suggested that this kind of lateral correlation is an important means for validating structure-activity relationships.

Alcohols↗
PubMed1995

Accurate prediction of protein secondary structural class with fuzzy structural vectors.

The prerequisites for accurate prediction of protein secondary structural class (all-alpha, all-beta, alpha+beta, alpha/beta or multidomain) were studied, and a new similarity-based method is presented for the prediction of the secondary structural class of a protein from its sequence. The new method uses representatives of nuclear families as a learning set. For the sequence to be predicted, the method produces a vector of certainty factors called a fuzzy structural vector. Validation with independent test sets shows that the prediction accuracy of the proposed method has clear dependency on the representativity of the learning set. The representatives obtained from the nuclear families of the Brookhaven Protein Data Bank (PDB) were shown to give accurate predictions for PDB proteins, whilst the amino acid composition-based methods used previously achieve their maximum predictability with relatively limited learning sets, and they remain inaccurate even with highly representative learning sets. The usability of the new method is increased further by the fuzzy structural vectors, which substantially reduce the risk of misclassification and realistically describe vague secondary structural tendencies.

Algorithms↗
PubMed2026

Sperm subpopulations differing in mitochondrial abundance show divergent nuclear allele frequencies.

Mammalian ejaculates contain heterogeneous sperm subpopulations that differ in subcellular architecture and developmental history, despite appearing morphologically uniform. The extent to which this cellular heterogeneity reflects underlying nuclear genomic structure within a sire remains largely unexplored. Mitochondrial architecture in sperm is established during spermatogenesis, with final assembly and organization occurring during spermiogenesis under nuclear genomic control, positioning variation in mitochondrial abundance and organization as a potential phenomic indicator of within-sire allelic segregation. Here, we tested whether sperm subpopulations defined by differing mitochondrial abundance exhibit systematic differences in nuclear allele representation. Boar sperm were resolved into low and high mitochondrial subpopulations using fluorescence-activated cell sorting based on MitoTracker™ Green fluorescence while excluding debris, doublets, and non-viable cells. Epifluorescence microscopy confirmed that high MitoTracker™ Green fluorescence sperm possessed longer mitochondrial sheaths, validating a structural distinction between subpopulations. Whole-genome sequencing of paired mitochondrial subpopulations from three boars was performed, and allelic ratio distortion was evaluated relative to heterozygous baseline populations. Analyses across heterozygous loci genome-wide identified candidate allele frequency shifts between mitochondrial-defined subpopulations, suggesting non-random segregation of alleles within ejaculates. Using a minimum sequencing depth of 30 reads in both sorted fractions, 182 candidate SNPs were identified with evidence of allele-frequency differences between mitochondrial fluorescence-defined subpopulations. These findings suggest that sperm mitochondrial abundance can potentially serve as an indirect, high-throughput marker of nuclear genomic heterogeneity within sires. This proof-of-concept framework establishes a foundation for future studies integrating sperm phenotyping, genome-wide allele-frequency analysis and functional validation to better characterize gamete-level heterogeneity.

Male↗
PubMed1985

Epidemiology: reflections on testing the validity of psychiatric interviews.

Laboratory tests that validate psychiatric disorder are unavailable. Accordingly, the validity of structured diagnostic interviews such as the Diagnostic Interview Schedule have been assessed through a double-blind test-retest design. This approach compares the Diagnostic Interview Schedule to a clinician's assessment and evaluates its results by three statistics: sensitivity and specificity, for which the clinician's interview serves as the standard, and K, which measures concordance between the two interviews. This design is found wanting on several counts: the reinterview may be answered differently because of clinical change or because of its meaning to the respondent; the clinician's interview may be an erratic standard; and the statistics are affected by both prevalence and severity of disorder. Furthermore, the statistics may not predict the accuracy of prevalence estimates made by the interview or its ability to detect correlates of disorder. Some alternative approaches are suggested.

Clinical Trials as Topic↗
PubMed1978

Wechsler Memory Scale: a selective review of the literature.

Research on the Wechsler Memory Scale (WMS) is reviewed with respect to questions of its reliability, factor structure, construct validity, and utility. The relationship of Memory Quotient to Full Scale IQ is explored and the conditions under which disparity between the two scores may be clinically useful indicated. Despite its numerous limitations, the WMS has been a sensitive test of short-term verbal memory. As such, it may be helpful in identifying impairment of the dominant (left) temporal lobe and its medial hippocampal connections. The test is badly in need of re-standardization, however, and suggestions for improving the instrument are made.

Adult↗
PubMed1996

The effect of concentration on the structure of alpha-crystallin.

Several models have been proposed for arrangement of the subunits in alpha-crystallin. These include the contrasting proposals that subunits are arranged in three layers and that subunits assemble into micelle-like structures. The validity of the micelle model was investigated by examining the effects of variations in protein concentration on the surface tension, conductivity, molecular weight and conformation of alpha-crystallin. The data were compared with those obtained for bovine serum albumin (BSA) and sodium dodecyl sulphate (SDS). Measurements of surface tension were conducted in the range, 10 micrograms ml-1 to 130 mg ml-1, in low and high ionic strength buffers. An apparent point of inflection, independent of ionic strength, was seen in alpha-crystallin's surface tension at around 1.9 mg ml-1 (95 microM). The surface tension did not plateau beyond this point, as is the case with surfactants, but continued to decrease up to 130 mg ml-1. BSA exhibited similar surface tension properties with an apparent inflection at 0.9 mg ml-1 (13 microM). The conductivity of alpha-crystallin and BSA solutions increased smoothly with no sign of any transition up to 96 mg ml-1 and 60 mg ml-1, respectively. In contrast, SDS showed a clear transition in this property at the concentration corresponding to its CMC. The aggregation state of the alpha-crystallin aggregates was examined by comparing molecular masses and Stokes radii. The size of the protein remained uniform over a wide concentration range and was unaffected by variations in ionic strength. Protein conformation, which was monitored by examining the microenvironment of tryptophan residues, was also found to be independent of protein concentration. It is concluded that over the concentration range that was investigated, alpha-crystallin does not exhibit any of the properties associated with classical micelles formed from small amphiphilic molecules.

Animals↗
PubMed1995

A local lymph-node assay validation study of a structure-activity relationship model for contact allergens.

A structure-activity relationship model for prediction of contact allergenic potential of chemicals had previously been developed. The model had been shown to be able to classify known allergens and nonallergens using data on physicochemical and reactivity parameters of functional groups by discriminant two-value multiple regression analysis. To investigate the model, six selected chemicals which had not been previously investigated for allergenicity were studied with both the model and a murine local lymph-node assay. The same compounds were predicted to be allergens (3-bromo-2-coumaranone, 1-nitrocyclohexene and alpha-acryloyloxy-beta, beta-dimethyl-beta-butyrolactone) and nonallergens (1-carbethoxy-4-piperidone, 6,7-dimethoxy-2-tetralone and 9-acetylanthracene) by both the model and the local lymph-node assay.

Allergens↗
PubMed1989

Effect of neuroleptics on positive and negative symptoms and the deficit state.

The concept of negative symptoms tries to operationalize a deficit syndrome observed in schizophrenia, but also in other disorders. The instruments for the measurement developed so far are unclear in their dimensional structure and validity. Further methodological development is needed. A new scale for measuring negative symptoms was derived from the AMDP-system and applied to results of drug trials with clozapine, fluperlapine, and haloperidol. The three drugs were equally effective on negative symptoms of acute and chronic schizophrenics.

Antipsychotic Agents↗
PubMed1992

Development of a computer application for headache diagnosis: the Headache Diagnostic System.

A computer-assisted decision support system for headache classification and diagnosis is presented. The system provides: structured headache data collection, automated data quality control and management, and automated headache classification. The system is based upon headache classification and diagnostic criteria recently developed by the International Headache Society. Development, logical structure and validation of the system are discussed. The system is shown to provide a general improvement in headache classification reliability and has utility for validation and improvement of present headache classification criteria.

Adult↗
PubMed1996

Heteroligation of a mouse monoclonal IgE antibody (La2) with small molecules, analysed by computer-aided automated docking.

A mouse monoclonal anti-TNP IgE antibody (IgE-La2) was screened by a competitive-binding ELISA with a random pool of over 2000 small molecules, mostly drugs, drug derivatives and metabolites. Thirteen of these (naproxene, beta-carboxy-chi-naphthol, oxolinic acid, hymecromone, 8-aminoquinoline, beta-naphthylamine, chi-nitrilo-cinnamic acid, 1,5-diaminonaphthaline, prolonium iodide, diaspirin, 3,4,5-trimethoxy-cinnamic acid, cycrimine, hemimellitic acid) were found to bind as strongly, or stronger, to the antibody as the immunizing hapten. We have used a Monte Carlo search technique for simulated docking of the DNP and non-DNP ligands to a model of the Fv region of IgE(La2). The validity of structural predictions made by the AutoDock program were tested on IgG(ANO2), the three-dimensional structure of which had been obtained previously by X-ray crystallography and 2D-NMR. The rms differences between the experimentally determined and auto-docked complexes in the energetically most favored binding modes were 0.31-0.44 A. Evaluation of structures of IgE(La2)-ligand complexes [including 2,4-dinitrophenol (DNP), 16 DNP amino acids, and the 13 non-DNP ligands listed above] obtained by computer-aided automated docking, suggested the existence of two subsites within an approximately 12 x 18 A2 groove extending between the H and L CDRs. Some of the ligands (DNP-Glu, 8-aminoquinoline, prolonium-I, beta-naphthylamine) were found to bind exclusively to subsite 1, others (DNP-Ala, chi-nitrilo-cinnamic acid, hemimellitic acid, beta-carboxy-chi-naphthol) to subsite 2. The majority of DNP amino acids and other ligands (oxolinic acid, 3,4,5-trimethoxy-cinnamic acid, diaspirin, [R]-cycrimine) were found to occupy an overlapping area including subsites 1 and 2, while some of the compounds (DNP-Asn, DNP-Pro, hymecromone, 1,5-naphthylenediamine) were predicted to interact with either of these subsites with comparable probabilities. When all of the docked La2-ligand complexes were taken into account, five tyrosine residues (H33, L32, L91, L92, L96) were found to provide the majority (53.4%) of all observed contact points. Thus, a multitude of interactions with aromatic residues, and a combinatorial type of interaction within the binding region, seem to be the major factors to explain the mechanism of heteroligation by IgE(La2).

Amino Acid Sequence↗
PubMed1987

Reconstruction of NOESY maps. A requirement for a reliable conformational analysis of biomolecules using 2D NMR.

The modelling of the conformation of a biomolecule in solution is based mainly on the internuclear distances deduced from measurements of nuclear Overhauser effects (nOe) in NOESY correlation maps. The distances are then used as restraints in the energy minimization procedure, which leads to one or several optimized conformations. A general and safe technique for validating these structures with respect to the experimental data is here proposed: from the internuclear distances, the relaxation matrix can be computed under the assumption of a unique rotational correlation time. By stepwise integration of these relaxation equations, the NOESY maps can be accurately reconstructed for any mixing time. Because multi-spin effects are correctly taken into account, any difference between the experimental and theoretical maps can be easily interpreted in terms of conformation, and possible inconsistencies due to conformational averaging can be pointed out. The technique is illustrated for a bacterial lipopeptide, mycosubtilin, the spectrum of which is completely assigned.

Biopolymers↗
PubMed1995

Towards eradication of measles virus: global progress and strategy evaluation.

Despite an increase in global measles vaccine coverage from under 20% in 1980 to around 80% in 1990, measles remains a major cause of morbidity and mortality world-wide. This paper addresses a number of issues relating to efforts to control measles, namely, (i) at the global level, how might we assess the impact of measles vaccination on the incidence of infection and associated disease, and, (ii), at the strategic level, how can we utilise an understanding of the transmission dynamics of childhood viral infections to aid the design of optimal immunisation programmes? Based on WHO vaccine coverage data, and organising countries according to similarities in demographic and epidemiological parameters, an age-structured model of measles transmission is used to capture the non-linear dynamics of infection and mass vaccination and to generate projections of the impact of measles immunization world-wide. The results provide a crude indication of the percentage reduction in measles cases by year 2000 (compared with no immunization) and suggest an approximately 70% reduction in cases over all ages, and 77% reduction in cases under 5 years (where there is the greatest risk of case fatality); these suggest that WHO targets for 1995 are unlikely to be achieved. In the second part of the paper, examples are given to illustrate the usefulness of a modelling approach in evaluating measles immunization policy. The introduction of MMR vaccine in the UK in 1988 has resulted in measles incidence falling to an all time low and attention has turned to the requirements of elimination. A realistic age structured model, validated using extensive serological data, is used to compare the merits of single or two dose strategies. Based upon recent estimates of vaccine efficacy (90%) and coverage (92% by end of second year of life) it is suggested that a two-dose policy with a pre-school second dose given irrespective of vaccine history is required to prevent the build up of susceptibles to epidemic proportions in the longer term. In a second example, prompted by the success of the campaign approach to polio and measles elimination in Central and South America, simple models are used to explore and quantify the process by which pulse vaccination programmes (i.e. repeated application across a wide age range) act to control transmission.

England↗
PubMed1983

An assessment of the evidence for the role of ribonucleoprotein particles in the maturation of eukaryote mRNA.

This article has sought to draw together, on the one hand, what is known of mRNA processing and its control and, on the other hand, what is known of the structure and validity of hnRNP and snRNP particles. At the same time, it has attempted to synthesize these two themes into a critical assessment of the evidence which suggests that the particles are intimately involved in processing. It cannot be said that the case is proven. The evidence is compelling but circumstantial. The last few years have seen the development of the first in vitro splicing systems (Weingartner and Keller, 1981; Goldenberg and Raskus, 1981; Kole and Weissman, 1982), the isolation of monoclonal antibodies to defined snRNP (Lerner et al., 1981a; Billings et al., 1982) and hnRNP proteins (Hugle et al., 1982), and the ability to use artificial lipid vesicles to transfer antisera (Lenk et al., 1982) and radioactive snRNA (Gross and Cetron, 1982) into cells. It is to be hoped that further refinements of these and other techniques will allow us to solve this, one of the major outstanding problems of molecular biology.

Animals↗
PubMed1988

Sensitive quantification of pseudoephedrine in human plasma and urine by high-performance liquid chromatography.

An assay for the selective quantification of pseudoephedrine in human plasma and urine was developed using high-performance liquid chromatography with UV detection at 205 nm. Analyte and internal standard were extracted from alkaline plasma or urine into a mixture of n-hexane and diethyl ether, and the organic phase was back-extracted into dilute acid. The chromatographic system comprises microparticulate cyanopropyl-silica as stationary phase and a ternary solvent mixture with ion-pair reagents as mobile phase. Using 0.25 ml plasma, the lower limit of quantification was 25 ng/ml with excellent linearity up to 1000 ng/ml. In urine, the calibration ranged from 2.5 to 100 micrograms/ml. The selectivity of the method was demonstrated for several pharmaceuticals with similar structures. The validated method was applied to a pharmacokinetic study with a single oral dose of 100 mg of pseudoephedrine in two galenic formulations. Precision and accuracy data of the assay and calculated pharmacokinetic parameters are presented.

Adolescent↗
PubMed1994

The development and validation of an age-structured model for the evaluation of disease control strategies for intestinal helminths.

Epidemiological modelling can be a useful tool for the evaluation of parasite control strategies. An age-structured epidemiological model of intestinal helminth dynamics is developed. This model includes the explicit representation of changing worm distributions between hosts as a result of treatment, and estimates the morbidity due to heavy infections. The model is used to evaluate the effectiveness of different programmes of age-targeted community chemotherapy in reducing the amount of morbidity due to helminth infection. The magnitude of age-related heterogeneities is found to be very important in determining the results of age-targeted treatment programmes. The model was verified using field data from control programmes for Ascaris lumbricoides and Trichuris trichiura, and was found to provide accurate predictions of prevalence and mean intensities of infection during and following different control regimes.

Adult↗
PubMed1982

Sequences of three molluscan 5 S ribosomal RNAs confirm the validity of a dynamic secondary structure model.

The collection of known 5 S rRNA primary structures is enriched with the sequences from three mollusca, the snails Helix pomatia and Arion rufus, and the mussel Mytilus edulis. The three sequences can be fitted in a five-helix secondary structure model previously shown (De Wachter et al. (1982) Biochimie 64, 311-329) to apply to all 5 S RNAs regardless of their origin. One of the helices in this model can undergo a bulge-internal loop transition. Within the metazoan kingdom, the dimensions of each helix and loop are rigidly conserved, except for one helix which can comprise either 6 or 7 base pairs.

Animals↗