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PubMed1995

Three-dimensional quantitative structure-activity relationships of dioxins and dioxin-like compounds: model validation and Ah receptor characterization.

In the present study we have utilized comparative molecular field analysis (CoMFA), a three-dimensional quantitative structure-activity relationship paradigm, to explore the physico-chemical requirements for binding to the Ah (dioxin) receptor. Recent developments by Gillner et al. [(1993) Mol. Pharmacol. 44, 336-345] prompted us to review and revise our previous CoMFA/QSAR model [Waller, C. L., and McKinney, J. D. (1992) J. Med. Chem. 36, 3660-3666] to include a structurally-diverse training set of Ah receptor ligands ranging in size from naphthalene to indolo[3,2-b]carbazole nuclei. An exhaustive validation process utilizing external test sets and hierarchical cluster analysis routines was employed during model construction and is discussed herein. The limitations of the approach presented herein are discussed with respect to predictive ability of the CoMFA/QSAR models, which is demonstrated to be dependent on a balance between structural diversity and redundancy in the molecules comprising the training set. The results of our modified CoMFA/QSAR model are consistent with and unify all previously established structure-activity relationships established for less structurally-diverse training sets of Ah receptor ligands. As a result of the more complete nature of the series of molecules under examination in the present study, the CoMFA/QSAR steric and electrostatic field contour plots as well as the essential and excluded volume plots provide for a more detailed characterization of the molecular binding domain of the Ah receptor. The implications of the CoMFA/QSAR model presented herein are explored with respect to quantitative hazard identification of potential toxicants.

Binding Sites↗
PubMed1997

Three-dimensional quantitative structure-activity relationships from molecular similarity matrices and genetic neural networks. 1. Method and validations.

The utility of genetic neural network (GNN) to obtain quantitative structure-activity relationships (QSAR) from molecular similarity matrices is described. In this application, the corticosteroid-binding globulin (CBG) binding affinity of the well-known steroid data set is examined. Excellent predictivity can be obtained through the use of either electrostatic or shape properties alone. Statistical validation using a standard randomization test indicates that the results are not due to chance correlations. Application of GNN on the combined electrostatic and shape matrix produces a six-descriptor model with a cross-validated r2 value of 0.94. The model is superior to those obtained from partial least-squares and genetic regressions, and it also compares favorably with the results for the same data set from other established 3D QSAR methods. The theoretical basis for the use of molecular similarity in QSAR is discussed.

Algorithms↗
PubMed2005

Fine-scale structural variation of the human genome.

Inversions, deletions and insertions are important mediators of disease and disease susceptibility. We systematically compared the human genome reference sequence with a second genome (represented by fosmid paired-end sequences) to detect intermediate-sized structural variants >8 kb in length. We identified 297 sites of structural variation: 139 insertions, 102 deletions and 56 inversion breakpoints. Using combined literature, sequence and experimental analyses, we validated 112 of the structural variants, including several that are of biomedical relevance. These data provide a fine-scale structural variation map of the human genome and the requisite sequence precision for subsequent genetic studies of human disease.

Base Pairing↗
PubMed2003

The different biological effects of telomestatin and TMPyP4 can be attributed to their selectivity for interaction with intramolecular or intermolecular G-quadruplex structures.

Demonstration of the existence of G-quadruplex structures in telomeres of Stylonychia macronuclei and in the promoter of c-myc in human cells has validated these secondary DNA structures as potential targets for drug design. The next important issue is the selectivity of G-quadruplex-interactive agents for the different types of G-quadruplex structures. In this study, we have taken an important step in associating specific biological effects of these drugs with selective interaction with either intermolecular or intramolecular G-quadruplex structures formed in telomeres. Telomestatin is a natural product isolated from Streptomyces anulatus 3533-SV4 and has been shown to be a very potent telomerase inhibitor through its G-quadruplex interaction. We have demonstrated that telomestatin interacts preferentially with intramolecular versus intermolecular G-quadruplex structures and also has a 70-fold selectivity for intramolecular G-quadruplex structures over duplex DNA. Telomestatin is able to stabilize G-quadruplex structures that are formed from duplex human telomeric DNA as well as from single-stranded DNA. Importantly, telomestatin stabilizes these G-quadruplex structures in the absence of monovalent cations, which is a unique characteristic among G-quadruplex-interactive compounds. At noncytotoxic concentrations, telomestatin suppresses the proliferation of telomerase-positive cells within several weeks. In contrast, TMPyP4, a compound that preferentially facilitates the formation of intermolecular G-quadruplex structures, suppresses the proliferation of alternative lengthening of telomeres (ALT)-positive cells as well as telomerase-positive cells. We have also demonstrated that TMPyP4 induces anaphase bridges in sea urchin embryos, whereas telomestatin did not have this effect, leading us to conclude that the selectivity of telomestatin for intramolecular G-quadruplex structures and TMPyP4 for intermolecular G-quadruplex structures is important in mediating different biological effects: stabilization of intramolecular G-quadruplex structures produces telomerase inhibition and accelerated telomere shortening, whereas facilitation of the formation of intermolecular G-quadruplex structures induces the formation of anaphase bridges.

Anaphase↗
PubMed1996

Membrane fluidity of blood cells.

Plasma membranes are fluid structures and the maintenance of fluidity is a prerequisite for function, viability, growth and reproduction of cells. Membrane fluidity is the reciprocal of membrane microviscosity, which in turn is inversely proportional to rotational and lateral diffusion rates of membrane components. In the absence of constraints most lipids and unrestrained integral proteins freely diffuse in the plane of the membrane with high diffusion coefficients. The fluid mosaic model of plasma membrane structure is essentially still valid but this model is by its nature a macroscopic one. At present, attention is focused on molecular structural details of protein-lipid interactions and on the static and dynamic structure of membrane proteins. Highly potent new macroscopic and microscopic methods have been developed to measure translational diffusion of membrane lipids and proteins. The microscopic methods can reveal diffusion via encounters between labeled molecules. Fluorescence anisotropy measurements are the most widely used techniques in biological research. The use of different permeant and non-permeant fluorophores have contributed much to a better understanding of the changes in the ordered states and motional freedom of the membrane phospholipids in different cells during development, aging and physiological functions as well as in pathological conditions. The application of fluorophores with non-random distribution have shed light on the asymmetrical changes between the outer and inner domain of the lipid bilayer and on the dynamics of 'flip-flop' in signal transduction. Membrane fluidity was shown to have a decisive role in the efficiency of ligand binding, in the outcome of direct cell to cell contacts and in the modulation of the activity of membrane enzymes. Cell filtrability reflects whole cell viscosity that can not always be correlated with the fine changes in membrane fluidity. Cell viscosity depends inter alia on the size and shape of the cells as well as on membrane rigidity. In contrast to this, membrane fluidity is only dependent on the freedom of mobility of the membrane constituents. Increased release of free radicals and reactive oxygen specie (ROS) affect membrane fluidity, cellular Ca2+ homeostasis, induce lipid peroxidation and finally cell death. Investigation of membrane fluidity proved to be a useful and sensitive additional method to obtain a better insight into the mechanisms by which different compounds, drugs and contact with foreign surfaces are affecting cellular functions. The measurements of membrane fluidity may gain more widespread use for monitoring the safety and efficacy of these actions. During the last few years, changes in membrane fluidity of blood cells have been reported during development and aging and as a result of physiological cell functions. Membrane fluidity changes have been described in thrombocythaemia, hyperlipidaemia, hypercholesterolaemia, hypertension, diabetes mellitus, obesity, septic conditions and in allergic and burnt patients, in alcoholics, in Alzheimer's disease and in schizophrenia. A short summary is given on red cell membrane fluidity changes in a Hungarian triosephosphate isomerase (TPI)-deficient family, reflecting how the very subtle changes in membrane fluidity can help to establish underlying biological differences between the clinical phenotypes of a severe enzyme (TPI) deficiency caused by the defect of a single gene in two brothers one with and one without neurological symptoms.

Anemia, Hemolytic, Congenital Nonspherocytic↗
PubMed2002

Differentiating anxious, aggressive, and socially competent preschool children: validation of the Social Competence and Behavior Evaluation-30 (parent version).

The present study examined the factor structure, internal consistency, and construct validity of the parent version of the Social Competence and Behavior Evaluation-30 for preschoolers (SCBE-30; LaFreniere, P. J. (1990). Social competence and behavior evaluation-30. Unpublished measure.), an adaptation of the validated teacher version of the same measure (LaFreniere & Dumas, Psychol. Asses. 8 (1996) 369). The parent version of the SCBE-30 is a 30-item Likert rating scale questionnaire designed to assess patterns of anxiety/withdrawal, anger/aggression, and social competence. Principal components analysis was used to identify the factor structure of the parent version of the SCBE-30 (N = 218 preschool children). To assess construct validity, a compliance task was utilized to determine whether children identified as high on anxiety/withdrawal, anger/aggression, or social competence with the parent version of the SCBE-30 (n = 20 for each group) could be distinguished behaviorally on several observational variables. Principal components analysis identified three factors accounting for 44% of the variance. Ten items positively loaded onto each factor and matched conceptual expectations. A between-subjects MANOVA demonstrated significant group differences in observed child behaviors including compliance, noncompliance, subtypes of noncompliance, and aversive behavior. Results of the current study suggested that the parent version of the SCBE-30 demonstrated both internal consistency and construct validity, and findings paralleled many of the results from LaFreniere and Dumas' validation of the teacher version of the SCBE-30.

Aggression↗
PubMed2006

Training at Washington University School of Medicine in Psychiatry in the late l950's, from the perspective of an affective disorder researcher.

In the late 1950s three men in the Department of Psychiatry at Washington University School of Medicine in St. Louis, MO, Drs. Eli Robins, Sam Guze and George Winokur, developed sets of criteria, based on published data and their own research, for the diagnosis and treatment of mental disorders. They also presented data on how to validate these diagnoses. They termed their endeavor, "The medical model for psychiatric disorders." Residents were taught how to use criteria to diagnose and treat psychiatric patients. Besides clinical interviewing, the emphasis was on published data, critical literature reading and research, either basic or clinical, always using structured interviews. All residents were required to do psychiatric research, supervised by one of the full-time staff. Besides the three above, there were many other faculty members who were actively engaged in teaching and research, but they all adhered to the above model. Repetition was the most important aspect of learning. It was an exciting time to be there and that enthusiasm led to many of the trainees continuing to be committed to academic careers and the others, to a very high standard of psychiatric care. In addition, it led to the development of DSMIII and beyond, a host of validated structured interviews, a method for testing new drugs, a method for validating psychiatric diagnoses, an emphasis on the importance of genetics to psychiatry, and many important clinical findings.

Education↗
PubMed2000

A general system for evaluating therapist adherence and competence in psychotherapy research in the addictions.

The Yale Adherence and Competence Scale (YACS) is a general system for rating therapist adherence and competence in delivering behavioral treatments for substance use disorders. The system includes three scales measuring 'general' aspects of drug abuse treatment (assessment, general support, goals of treatment), as well as three scales measuring critical elements of three treatments that are frequently implemented as control or comparison treatments in clinical research in the addictions (clinical management (CM), twelve step facilitation (TSF), and cognitive behavioral therapy (CBT)). Validation of the YACS using data from a randomized clinical trial indicated that the scales have excellent reliability, factor structure, concurrent and discriminant validity. Correlations between adherence and competence scores within scales were in the moderate range, indicating independence (and thus nonredundancy) of these dimensions. Strategies for using the YACS in both psychotherapy and pharmacotherapy research in the addictions are described.

Adult↗
PubMedDate not supplied

Comparative protein modeling of 1-deoxy-D-xylulose-5-phosphate reductoisomerase enzyme from Plasmodium falciparum: a potential target for antimalarial drug discovery.

Plasmodium falciparum 1-deoxy-D-xylulose-5-phosphate reductoisomerase (Pf-DXR) is a potential target for antimalarial chemotherapy. The three-dimensional model (3D) of this enzyme was determined by means of comparative modeling through multiple alignment followed by intensive optimization, minimization, and validation. The resulting model demonstrates a reasonable topology as gauged from the Ramachandran plot and acceptable three-dimensional structure compatibility as assessed by the Profiles-3D score. The modeled monomeric subunit consists of three domains: (1) N-terminal NADPH binding domain, (2) connective or linker domain (with most of the active site residues located in this domain), and (3) a C-terminal domain. This structure proved to be consistent with known DXR crystal structures from other species. The predicted active site compared favorably with those of the templates and appears to have an active site with a highly conserved architecture. Additionally, the model explains several site-directed mutagenesis data. Besides using several protein structure-checking programs to validate the model, a set of known inhibitors of DXR were also docked into the active site of the modeled Pf-DXR. The docked scores correlated reasonably well with experimental pIC50 values with a regression coefficient (R2) equal to 0.84. Results of the current study should prove useful in the early design and development of inhibitors by either de novo drug design or virtual screening of large small-molecule databases leading to development of new antimalarial agents.

Aldose-Ketose Isomerases↗
PubMed2006

Simultaneous determination of protein backbone structure and dynamics from residual dipolar couplings.

Determination of protein structure classically results in a single average configuration that takes no account of conformational fluctuation. Dynamics are, however, inherently linked to structure and crucial to our understanding of biological function. In this study we have used analytical descriptions of dynamic averaging of residual dipolar couplings (RDCs) to simultaneously determine the backbone structure and dynamics of protein GB3. RDCs alone are used to determine an ultrahigh-resolution structure that compares very closely with a refined X-ray structure (rmsd of 0.34 A overall backbone residues). Dynamic amplitudes reporting on motions up to the millisecond time scale reproduce the main characteristics of dynamics previously determined in conjunction with the crystal structure. The use of RDCs alone allows a bias-free comparison with a purely static approach to structure determination. Extensive cross validation clearly demonstrates that the dynamic description is superior to the static approximation. The demonstration that this level of structural resolution and dynamic detail can be extracted from RDCs supports previous indications that these parameters contain extremely precise information about biomolecular conformational sampling.

Models, Molecular↗
PubMed2004

Development of a high-performance boiling heat exchanger by improved liquid supply to narrow channels.

A two-phase flow loop is a promising method for application to thermal management systems for large-scale space platforms handling large amounts of energy. Boiling heat transfer reduces the size and weight of cold plates. The transportation of latent heat reduces the mass flow rate of working fluid and pump power. To develop compact heat exchangers for the removal of waste heat from electronic devices with high heat generation density, experiments on a method to increase the critical heat flux for a narrow heated channel between parallel heated and unheated plates were conducted. Fine grooves are machined on the heating surface in a transverse direction to the flow and liquid is supplied underneath flattened bubbles by the capillary pressure difference from auxiliary liquid channels separated by porous metal plates from the main heated channel. The critical heat flux values for the present heated channel structure are more than twice those for a flat surface at gap sizes 2 mm and 0.7 mm. The validity of the present structure with auxiliary liquid channels is confirmed by experiments in which the liquid supply to the grooves is interrupted. The increment in the critical heat flux compared to those for a flat surface takes a maximum value at a certain flow rate of liquid supply to the heated channel. The increment is expected to become larger when the length of the heated channel is increased and/or the gravity level is reduced.

Cold Temperature↗
PubMed2003

Bioinformatics methods to predict protein structure and function. A practical approach.

Protein structure prediction by using bioinformatics can involve sequence similarity searches, multiple sequence alignments, identification and characterization of domains, secondary structure prediction, solvent accessibility prediction, automatic protein fold recognition, constructing three-dimensional models to atomic detail, and model validation. Not all protein structure prediction projects involve the use of all these techniques. A central part of a typical protein structure prediction is the identification of a suitable structural target from which to extrapolate three-dimensional information for a query sequence. The way in which this is done defines three types of projects. The first involves the use of standard and well-understood techniques. If a structural template remains elusive, a second approach using nontrivial methods is required. If a target fold cannot be reliably identified because inconsistent results have been obtained from nontrivial data analyses, the project falls into the third type of project and will be virtually impossible to complete with any degree of reliability. In this article, a set of protocols to predict protein structure from sequence is presented and distinctions among the three types of project are given. These methods, if used appropriately, can provide valuable indicators of protein structure and function.

Algorithms↗
PubMed2004

Measurement structure of the Turkish translation of the Child Behavior Checklist using confirmatory factor analytic approaches to validation of syndromal constructs.

The new correlated 8-factor measurement structure of the Child Behavior Checklist for ages 6-18 (CBCL/6-18; T. M. Achenbach & L. A. Rescorla, 2001) derived from an American sample was used as a benchmark to evaluate its generalizability to Turkish general population (N = 5,195) and clinical (N = 963) samples. Item-level confirmatory factor analysis (CFA) was used to evaluate the adequacy of the correlated 8-factor model across 3 sample conditions (general population, clinical, and combined sample whose Total Problems scores were above the Turkish national median). The results supported the generalizability of the overall measurement structure of the CBCL to the Turkish population.

Child↗
PubMed1998

Oral health systems in Europe. Part II: The dental workforce.

OBJECTIVE: To describe and compare the practice of dentistry and the dental workforce in eighteen European countries. BASIC RESEARCH DESIGN: Semi-structured, in-depth validation interviews were carried out with key-informants from the main national dental associations of EU and associated countries. The interviews were structured around the responses to a previously completed questionnaire, whose topics and terminology had been agreed in advance with the collaborating associations. The resulting descriptions of dental practice and the dental workforce in each country were returned for further validation and correction by the collaborating associations. Ultimate editorial control over the review of each country's oral health system rested with the academic unit from which the associations jointly commissioned the study. RESULTS AND CONCLUSIONS: With the exception of Austria the primary training and registration of dentists is now more or less standard across Europe. However, wide international variation exists in the official recognition of dental specialists and auxiliaries. The Nordic countries of Sweden, Finland and Iceland recognise the broadest range of specialties. In contrast Spain, Portugal, Luxembourg and Belgium currently do not formally recognise any types of specialist practice. Fee-for-service is the dominant form of remuneration for dentists across Europe, but considerable variation exists in the level of fees, how they are decided and the proportion paid by the patient. When based upon standard questionnaires, semi-structured interviews with key informants are an effective method for capturing both the specifics of how an oral health system works, and the general similarities and differences between countries.

Delivery of Health Care↗
PubMed1998

Oral health systems in Europe. Part I: Finance and entitlement to care.

OBJECTIVE: To describe and compare the oral health systems in 18 European countries. BASIC RESEARCH DESIGN: Semi-structured, in-depth validation interviews were carried out with key informants from the main national dental associations of EU and associated countries. The interviews were structured around the responses to a previously completed questionnaire, the topics and terminology of which had been agreed in advance with the collaborating associations. The resulting descriptions of dental practice and the dental workforce in each country were returned for further validation and correction by the collaborating associations. Ultimate editorial control over the review of each country's oral health system rested with the authors. RESULTS AND CONCLUSIONS: Oral health care is mainly financed by government-regulated or compulsory social insurance in seven of the 18 countries examined here: Austria, Belgium, France, Germany, Luxembourg, The Netherlands and Switzerland. Providing universal or near-universal coverage by membership of insurance institutions, these systems provide oral health care for about 180 million people across Europe, and almost half of all EU citizens. In the Nordic countries and the UK entitlement to care is typically based upon residence or citizenship, and apart from in Norway and Iceland is provided within a tax-funded and government-organised health service. In southern Europe, Norway, Ireland and Iceland oral health care is largely financed directly by the patient, with occasional support through private insurance. Some publicly-funded and organised services do exist in these countries but generally only for specific population groups (e.g. children, unemployed), or in particular regions.

Child↗
PubMed1985

MR imaging of the aorta with three-dimensional vessel reconstruction: validation by angiography.

Longitudinal vascular structures are difficult to observe on the standard abdominal transaxial magnetic resonance (MR) image sections. To display the information in a three-dimensional reconstruction, an algorithm was written to identify blood flow in a series of transaxial MR sections and was applied to reconstructing images of the aorta and iliac arteries in 12 patients with aortic aneurysm, dissection, or aortoiliac atherosclerosis. Results were validated by angiography. In all patients, the outline of the flow channel in the reconstructed image followed closely the outline of the lumen on angiograms. In aortic dissection, the MR images showed the two lumens more completely than did the angiograms, and in atherosclerosis, sites of vascular stenosis were correctly identified on MR images. The technique is valuable in providing anatomic information as well as functional information on cross-sectional areas and relative flow velocities.

Aortic Dissection↗
PubMed1999

Confocal Scanning Laser Microscopy as a Tool for the Determination of 3D Floc Structure.

Several assumptions are made when confocal scanning laser microscopy is used for the determination of the fractal dimension of aggregates. The purpose of this study is to experimentally show that one of these assumptions, which concerns the relation existing between the structure of an aggregate and that of its sections, is valid. A comparison between the structures of sections and reconstructed 3D edifices of latex aggregates shows that they are both directly related even in the case of relatively small aggregates. Copyright 1999 Academic Press.

Journal Article↗
PubMed1994

Dosimetric characteristics, air-kerma strength calibration and verification of Monte Carlo simulation for a new Ytterbium-169 brachytherapy source.

PURPOSE: Ytterbium-169 (169Yb) is a promising new isotope for brachytherapy with a half life of 32 days and an average photon energy of 93 KeV. It has an Ir-192-equivalent dose distribution in water but a much smaller half-value layer in lead (0.2 mm), affording improved radiation protection and customized shielding of dose-limiting anatomic structures. The goals of this study are to: (a) experimentally validate Monte Carlo photon transport dose-rate calculations for this energy range, (b) to develop a secondary air-kerma strength standard for 169Yb, and (c) to present essential treatment planning data including the transverse-axis dose-rate distribution and dose correction factors for a number of local shielding materials. METHODS AND MATERIALS: Several interstitial 169Yb sources (type 6) and an experimental high dose-rate source were made available for this study. Monte-Carlo photon-transport (MCPT) simulations, based upon validated geometric models of source structure, were used to calculate dose rates in water. To verify MCPT predictions, the transverse-axis dose distribution in homogeneous water medium was measured using a silicon-diode detector. For use in designing shielded applicators, heterogeneity correction factors (HCF) arising from small cylindrical heterogeneities of lead, aluminum, titanium, steel and air were measured in a water medium. Finally, to provide a sound experimental basis for comparing experimental and theoretical dose-rate distributions, the air-kerma strength of the sources was measured using a calibrated ion chamber. To eliminate the influence of measurement artifacts on the comparison of theory and measurement, simulated detector readings were compared directly to measured diode readings. The final data are presented in the format endorsed by the Interstitial Collaborative Working Group. RESULTS: The in-air calibration revealed that the air-kerma strength per unit activity (mCi), as quoted by the vendor, varied from 1.30 to 1.57 cGy.cm2/mCi.h depending on seed design. The maximum difference between measured and MCPT-simulated absolute diode readings on the transverse axis was less than 2%, indicating that MCPT accurately predicts dose rate in medium for brachytherapy sources in this energy range. Comparison of measured and simulated HCFs for each of the 16 different cylindrical heterogeneities demonstrated 1-3% agreement. The HCFs vary by as much as 200% with respect to distance and by as much as 48% as a function of disk diameter, showing that HCF is strongly dependent on heterogeneity location and lateral dimensions as well as thickness. The dose-rate constant for water medium was found to be 1.225 cGy/h per kerma unit air-strength and 1.962 cGy/h per unit mCi as measured by the vendor. CONCLUSION: Monte Carlo simulation is an accurate and powerful tool for dosimetric characterization of brachytherapy sources in this energy range. Thin lead foils produce shielding factors comparable to standard shielded applicators for 137Cs. Meaningful theoretical absolute dose calculations in brachytherapy require accurately implemented air-kerma strength standards.

Brachytherapy↗