PubMed Health⌕ Search

Biomedical subjects

C A Reynolds

Publications and source records attributed to C A Reynolds.

At least 19 recordsLinked to original sources
PubMed1997

A new approach to docking in the beta 2-adrenergic receptor that exploits the domain structure of G-protein-coupled receptors.

A novel technique for docking ligands to the beta 2-adrenergic receptor is described which exploits the domain structure of this class of receptors. The ligands (norepinephrine, an agonist; pindolol, a partial agonist; and propranolol, an antagonist) were docked into the receptor using the key conserved aspartate on helix 3 (D113) as an initial guide to the placement of the amino group and GRID maps (Goodford, P. J. J. Med. Chem, 1985, 28, 849) to identify the likely binding regions of the hydrophobic (and hydroxyl) moieties on the A domain (comprising of helices 1-5). The essence of the new approach involved pulling the B domain, which includes helices 6 and 7, away from the other domain by 5-7 A. During the subsequent minimization and molecular dynamics, the receptor ligand complex reformed to yield structures which were very well supported by site-directed mutagenesis data. In particular, the model predicted a number of important interactions between the antagonist and key residues on helix 7 (notably Leu311 and Asn312) which have not been described in many previous computer simulation studies. The justification for this new approach is discussed in terms of (a) phase space sampling and (b) mimicking the natural domain dynamics which may include domain swapping and dimerization to form a 5,6-domain-swapped dimer. The observed structural changes in the receptor when pindolol, the partial agonist, was docked were midway between those observed for propranolol and norepinephrine. These structural changes, particularly the changes in helix-helix interactions at the dimer interface, support the idea that the receptors have a very dynamic structure and may shed some light on the activation process. The receptor model used in these studies is well supported by experiment, including site-directed mutagenesis (helices 1-7), zinc binding studies (helices 2, 3, 5, and 6), the substituted cysteine accessibility method (helices 3, 5, and 7), and site-directed spin-labeling studies (helices 3-6).

Amino Acid Sequence↗
PubMed1997

Inclusion of conserved buried water molecules in the model structure of rat submaxillary kallikrein.

A new approach to the molecular modelling of homologous serine proteases is adopted, by including a set of 21 buried waters known to be preserved in enzymes sharing the primary specificity of trypsin, in the homology modelling of rat submaxillary gland kallikrein. Buried waters--water molecules sequestered from bulk solvent within a protein matrix--appear to be integral conserved components of all serine proteases of known structure and should be incorporated into serine protease models built on the basis of sequence/structural homology to this family. The absence of such waters might induce errors in a force field simulation, favouring the formation of nonexistent hydrogen bonds and locally inaccurate structure. The kallikrein model refinement has led to the conclusion that an additional buried water should be added to the original rigid matrix of 21 conserved water molecules. The structurally preserved protein cavities of such waters validate the modelled structure.

Amino Acid Sequence↗
PubMed1997

Genetics and developmental psychopathology: 1. Phenotypic assessment in the Virginia Twin Study of Adolescent Behavioral Development.

We introduce an overlapping cohort sequential longitudinal study of behavioral development and psychopathology in a representative sample of 1412 pairs of twins aged 8 through 16 years. Multiple phenotypic assessments involve a full psychiatric interview with each child and each parent, and supplementary parental, teacher, and child interview material and questionnaires. For the first wave of assessments, the numbers of reported DSM-III-R symptoms of Major Depressive Disorder (MDD), Separation Anxiety Disorder (SAD), Overanxious Disorder (OAD), Oppositional Defiant Disorder (ODD), Conduct Disorder (CD), and Attention Deficit Hyperactivity Disorder (ADHD), assessed through interviews, confirm patterns of age and sex trends found in other epidemiological samples, but underscore their dependence on whether the child or the parent is the informant. Correlations across domains for symptoms reported by the same informant are often as large as correlations across informants for the same domain of symptoms. Factor analyses of these symptom counts, taking account of informant view and unreliability of assessment, show the high degree of correlation between SAD and OAD, between MDD and OAD, and between CD and ODD. ADHD symptoms are relatively independent of the other domains, but show moderate correlations with CD, ODD, and MDD. Factorially derived dimensional questionnaire scales, based on child, parental, and teacher reports, show patterns of relationship to symptom counts consistent with both convergent and discriminant validity as indices of liability to clinical symptoms. Across informants, questionnaire scales provide as good a prediction of symptoms as do clinical interviews. Multitrait-multimethod confirmatory factor analysis reveals the patterns of relationship between symptoms of psychiatric disorder in children taking due account of informant and unique sources of variance. Gender differences are consistent within the correlated clusters of ODD/CD and MDD/SAD/OAD, although there are disorder-specific age trends. There are large informant-specific influences on the reporting of symptoms in clinical interviews. Dimensional questionnaire scales provide a useful source of additional information. In subsequent analyses of genetic and environmental etiology of childhood psychopathology we must expect that results may differ by informant and method of assessment. Multivariate and developmental analyses that explore the sources of these differences will shed new light on the relationship between genetic and environmentally influenced vulnerability and the manifestation of psychopathology in specific circumstances.

Adolescent↗
PubMed1997

Genetics and developmental psychopathology: 2. The main effects of genes and environment on behavioral problems in the Virginia Twin Study of Adolescent Behavioral Development.

Little is known about the contribution of genetic and environmental factors to risk for juvenile psychopathology. The Virginia Twin Study of Adolescent Behavioral Development allows these contributions to be estimated. A population-based, unselected sample of 1412 Caucasian twin pairs aged 8-16 years was ascertained through Virginia schools. Assessment of the children involved semi-structured face-to-face interviews with both twins and both parents using the Child and Adolescent Psychiatric Assessment (CAPA). Self-report questionnaires were also completed by parents, children, and teachers. Measures assessed DSM-III-R symptoms of Attention Deficit Hyperactivity Disorder (ADHD). Conduct Disorder, Oppositional Defiant Disorder, Overanxious Disorder, Separation Anxiety, and Depressive Disorder. Factorially derived questionnaire scales were also extracted. Scores were normalized and standardized by age and sex. Maximum likelihood methods were used to estimate contributions of additive and nonadditive genetic effects, the shared and unique environment, and sibling imitation or contrast effects. Estimates were tested for heterogeneity over sexes. Generally, monozygotic (MZ) twins correlated more highly than dizygotic (DZ) twins, parental ratings more than child ratings, and questionnaire scales more highly than interviews. DZ correlations were very low for measures of ADHD and DZ variances were greater than MZ variances for these variables. Correlations sometimes differed between sexes but those for boy-girl pairs were usually similar to those for like-sex pairs. Most of the measures showed small to moderate additive genetic effects and moderate to large effects of the unique individual environment. Measures of ADHD and related constructs showed marked sibling contrast effects. Some measures of oppositional behavior and conduct disorder showed shared environmental effects. There were marked sex differences in the genetic contribution to separation anxiety, otherwise similar genetic effects appear to be expressed in boys and girls. Effects of rater biases on the genetic analysis are considered. The study supports a widespread influence of genetic factors on risk to adolescent psychopathology and suggests that the contribution of different types of social influence may vary consistently across domains of measurement.

Adolescent↗
PubMed1997

Breast MR imaging: interpretation model.

PURPOSE: To develop an interpretation model based on architectural features of suspicious breast findings on magnetic resonance (MR) images. MATERIALS AND METHODS: One hundred ninety-two patients with mammographically visible or palpable findings underwent T1- and fat-saturated T2-weighted spin-echo and contrast agent-enhanced fat-saturated gradient-echo MR imaging. Patients underwent subsequent excisional biopsy for histopathologic confirmation. An interpretation model was constructed by using 98 cases and was tested prospectively and expanded by using 94 different cases. Sensitivity, specificity, predictive values, and receiver operating characteristic curves were computed for all models. RESULTS: Individual features with high predictive values were MR visibility, enhancement degree and pattern, focal mass border characteristics, and focal mass internal septations. Feature combinations with high negative predictive values for malignancy were absence of an MR-visible abnormality, focal masses with smooth borders, lobulated or irregular masses with nonenhancing internal septations, and focal masses with no (or minimal) enhancement. The validated- and revised-model performance characteristics were, respectively, as follows: sensitivity, 100% and 96%; specificity, 69% and 79%; positive predictive value, 75% and 76%; negative predictive value, 100% and 97%; and overall accuracy, 83% and 86%. CONCLUSION: An interpretation model that incorporates breast MR architectural features can achieve high sensitivity and improve specificity for diagnosing breast cancer.

Adult↗
PubMed1997

Fibroadenomas: MR imaging appearances with radiologic-histopathologic correlation.

PURPOSE: To identify histopathologic correlates for the varied magnetic resonance (MR) imaging appearances of fibroadenomas. MATERIALS AND METHODS: Twenty-three fibroadenomas in 21 patients (aged 23-66 years) examined with gadolinium-enhanced MR imaging were graded for signal intensity on T2-weighted images, contrast material enhancement, shape, and internal septations and were correlated with histopathologic findings. RESULTS: Fibroadenomas demonstrated high T2 signal intensity with enhancement (n = 11), low T2 signal intensity with enhancement (n = 3), or low T2 signal intensity without enhancement (n = 9). Low T2 signal intensity and lack of enhancement were associated with more sclerotic stroma and older patient age. Lesion shape was lobular, oval, or round in 19 of 23 fibroadenomas (83%). Internal septations were identified within nine of 14 enhancing fibroadenomas (64%) and appeared to correlate with collagenous bands at histopathologic analysis. CONCLUSION: Fibroadenomas demonstrate marked histopathologic variability. The resultant variability in the MR appearance limits the ability to distinguish between benign and malignant masses on the basis of signal intensity and enhancement alone. Lobulation and internal septation, which appear to reflect intrinsic growth patterns of fibroadenomas, may provide a more reliable basis for distinction.

Adult↗
PubMed1997

Diagnostic performance characteristics of architectural features revealed by high spatial-resolution MR imaging of the breast.

OBJECTIVE: Our objective was twofold: to determine which architectural features revealed by high spatial-resolution MR imaging of the breast contribute to diagnostic accuracy and to evaluate the diagnostic performance characteristics of those architectural features. MATERIALS AND METHODS: Eligible patients with suspicious mammographic or palpable findings or both underwent MR imaging. Ninety-three patients whose MR images revealed lesions that corresponded to the mammographically visible or palpable findings were included in the study. Patients were examined with sagittal T1-weighted spin-echo MR imaging, fat-saturated T2-weighted fast spin-echo MR imaging, and dynamically enhanced fat-saturated fast gradient-echo MR imaging. All patients underwent subsequent excisional biopsy or cyst aspiration. Lesions were identified initially by an experienced radiologist who was aware of the patient's clinical or mammographic information. Two radiologists who were unaware of the patients' histories and who had less experience in MR imaging of the breast then independently evaluated each lesion for the architectural-features and predicted each lesion's potential for malignancy. RESULTS: Architectural features that were highly predictive of benign disease included smooth or lobulated borders (97-100%), the absence of mass enhancement (100%), and enhancement that was less than the enhancement of surrounding breast fibroglandular tissue (93-100%). Nonenhancing internal septations were specific for the diagnosis of fibroadenoma. Architectural features that were highly predictive of malignant disease included spiculated borders (76-88%) and peripheral rim enhancement in the presence of central lesion enhancement (79-92%). CONCLUSION: Architectural features revealed by high spatial-resolution MR imaging of the breast can help distinguish benign from malignant disease.

Adult↗
PubMed1996

Models of spouse similarity: applications to fluid ability measured in twins and their spouses.

Genetic influences have consistently been reported to be the principal explanation for resemblance among relatives for intelligence, with shared environmental effects playing a much smaller role. However, crucial to understanding the nature of environmental influences are the mechanisms of assortative mating. Phenotypic assortment, albeit widely assumed or modeled in biometrical analyses, may be less important than other assortment processes, such as social homogamy. Consequently, effects of shared environment may play a greater role than prior studies have suggested. The goal of this study was to resolve environmental and genetic influences on fluid ability based on alternative models of assortment by examining the similarity of monozygotic (MZ) and dizygotic (DZ) twins and their spouses. Raven's Progressive Matrices scores were available from a population-based Swedish sample of 138 twin kinships. The effects of both social homogamy and phenotypic assortment were tested simultaneously in each of two alternate assortment models. A factor/delta path model represented social homogamy as a common factor and phenotypic assortment as a delta path, while a delta/delta path model represented both social homogamy and phenotypic assortment as delta paths. Overall, the factor/delta path model was found to be superior. Results suggested that social homogamy completely explained spouse similarity; phenotypic assortment was not significant. The results of these analyses suggest the presence of shared environmental effects among twins and their spouses, which would have been underestimated if only phenotypic modeled phenotypic assortment may have underestimated the effects of environment.

Adult↗
PubMed1996

Genetics of educational attainment in Australian twins: sex differences and secular changes.

The relative effects of genetic and environmental factors in producing individual differences in educational achievement are compared across women and men and over birth cohorts. In a large sample of Australian twin pairs, the heritability of self-reported educational attainment did not vary among women and men born before and after 1950. In a "psychometric" model of twin resemblance, based on separate self-reports in 1981 and 1989, genetic factors explained 57% of the stable variance in educational achievement, while environmental factors shared by twins accounted for 24% of the variance. Corrections for phenotypic assortative mating for educational level, however, suggested that estimated common-environmental effects could be entirely explained by the correlation between additive genetic values for mates. Taking this into account, heritability "true" educational attainment in Australia may be as high as 82% with the remaining variation being due to individual environments or experiences. Unlike previous studies in Scandinavian countries, results in Australia suggest that factors influencing educational success are comparable between women and men and for individuals born at different points during this century.

Adult↗
PubMed1996

Sources of covariation among Mini-Mental State Examination scores, education, and cognitive abilities.

An adoption/twin design was used to address issues concerning the relationship between education and Mini-Mental State Examination (MMSE) performance. Data on general cognitive abilities, education, and MMSE from 110 identical twin pairs and 177 fraternal pairs aged 50 through 88 were analyzed using multivariate quantitative genetic methods. Genetic influences account for 32% and 19% of the variation in MMSE for men and women, respectively. Furthermore, all of the genetic variation in MMSE is in common with genetic variation for cognitive abilities and education. Finally, correlations between education and MMSE (.21 and .16 for men and women, respectively), which were reduced to near zero when cognitive abilities were partialed out, are primarily attributable to genetic effects for cognitive abilities. These results support the hypothesis that the association between education and MMSE performance predominantly reflects genetically mediated cerebral capacity rather than test bias or health-endangering life styles in less educated individuals.

Cognition↗
PubMed1996

The genetics of children's oral reading performance.

Measures of reading achievement and verbal ability have been shown to be heritable. Additionally, recent evidence has been suggestive of a major gene effect on reading disability and for problem reading in a sample of normal readers. We report on the etiology of individual differences in oral reading performance, the Slosson Oral Reading Test (SORT), for which biometrical analyses have not been reported in the literature previously. Oral reading performance was measured in a large population-based sample of twins of the Virginia Twin Study of Adolescent Behavioral Development. Biometrical analyses of the SORT suggested that, in both males and females, 69% of the phenotypic variation was due to heritable influences and 13% of the variation due to shared environmental effects. While the relative importance of genetic and environmental influences is equivalent for males and females, males showed greater phenotypic variability than females.

Achievement↗
PubMed1996

The effect of nontraumatic immobilization on ankle dorsiflexion stiffness in rats.

Experimental evidence supports the general conclusion that 6 or more weeks of immobilization will cause joint contractures due to changes in the capsules of animals whose limbs have been traumatized. There is controversy whether contractures will form in 6 weeks in limbs which are free of trauma. The purpose of this study was to determine if range of motion would be lost in ankle joints of rats following nontraumatic immobilization of the hindlimb for 2 or 6 weeks. The right hindlimb of each animal was immobilized in a plaster cast for 2 or 6 weeks with the left hindlimb serving as a matched control (N = 8). Nonimmobilized rats served as additional controls (N = 4). Following 2 or 6 weeks of immobilization, each rat was sacrificed and the lower leg removed at the knee. An electrogoniometer measured the change in dorsiflexion as torque was applied in increasing increments to the ankle. Load-deformation tests were performed to determine: 1) torque to end range of dorsiflexion, 2) joint excursion with application of 3.57 mNm torque for 2.5 seconds, and 3) joint excursion with prolonged application of 3.57 mNm torque. Only the group casted for 6 weeks demonstrated a significant (p < 0.05) decrease in both degrees of dorsiflexion and joint compliance. The group casted for 6 weeks required five times more torque to achieve end range than the other groups and had a 70% decrease in ankle dorsiflexion when a fixed torque of 3.57 mNm was applied. No significant differences were noted among the remaining groups. These findings suggest that in nontraumatically immobilized joints of rats, dense connective tissue remodels in such a way that mobility is unaffected after 2 weeks, but becomes quite limited by 6 weeks.

Animals↗
PubMed1995

A molecular dynamics approach to receptor mapping: application to the 5HT3 and beta 2-adrenergic receptors.

A molecular dynamics-based approach to receptor mapping is proposed, based on the method of Rizzi (Rizzi, J. P.; et al. J. Med. Chem. 1990, 33, 2721). In Rizzi's method, the interaction energy between a series of drug molecules and probe atoms (which mimic functional groups on the receptor, such as hydrogen bond donors) was calculated. These interactions were calculated on a three-dimensional grid within a molecular mechanics parameters, were placed at these minima. The distances between the dummy atom sites were monitored during molecular dynamics simulations and plotted as distance distribution functions. Important distances within the receptor became apparent, as drugs with a common mode of binding share similar peaks in the distance distribution functions. In the case of specific 5HT3 ligands, the important donor--acceptor distance within the receptor has a range of ca. 7.9--8.9 A. In the case of specific beta 2-adrenergic ligands, the important donor--acceptor distances within the receptor lie between ca. 7--9 A and between 8 and 10 A. These distances distribution functions were used to assess three different models of the beta 2-adrenergic G-protein-coupled receptor. The comparison of the distance distribution functions for the simulation with the actual donor--acceptor distances in the receptor models suggested that two of the three receptor models were much more consistent with the receptor-mapping studies. These receptor-mapping studies gave support for the use of rhodopsin, rather than the bacteriorhodopsin template, for modeling G-protein-coupled receptors but also sounded a warning that agreement with binding data from site-directed mutagenesis experiments does not necessarily validate a receptor model.

Adrenergic Agonists↗