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Deformation tensor morphometry of semantic dementia with quantitative validation.

High-resolution structural MRI scans of 20 subjects diagnosed with semantic dementia were compared against scans of 20 cognitively normal control subjects using whole brain deformation tensor morphometry to study spatially consistent differences in local anatomical size. A fine lattice free-form volume registration algorithm was used to estimate a continuous mapping from a reference MRI to each individual subject MRI. The Jacobian of these transformations at each voxel were used to quantitatively map relative anatomical size in each individual brain. Intensity consistent filtering was applied to the determinant of these Jacobians. A careful validation using manually traced gyral anatomy was carried out and used to select an optimal deformation tensor filter scale at which to examine the anatomical size maps. General linear modeling at each voxel was used to decompose the influence of age and head size from the primary diagnosis. Maps of the T statistic of the diagnosis across the 40 subjects highlighted significant (P < 0.01 Bonferroni corrected) focal tissue contraction effects related to dementia diagnosis in the left temporal pole extending into the hippocampus, occipitotemporal gyrus and parahippocampal gyrus. Some evidence of greater focal contraction in gray over white matter was also apparent. Contraction effects were also seen, but with reduced significance in the right temporal anatomy, focused toward the temporal pole and hippocampal regions. Additional lower significance findings (P < 0.05 permutation corrected) were detected in the left superior frontal gyrus, left orbital gyrus and left parietal lobe.

Aged↗

Improvements in protein secondary structure prediction by an enhanced neural network.

Computational neural networks have recently been used to predict the mapping between protein sequence and secondary structure. They have proven adequate for determining the first-order dependence between these two sets, but have, until now, been unable to garner higher-order information that helps determine secondary structure. By adding neural network units that detect periodicities in the input sequence, we have modestly increased the secondary structure prediction accuracy. The use of tertiary structural class causes a marked increase in accuracy. The best case prediction was 79% for the class of all-alpha proteins. A scheme for employing neural networks to validate and refine structural hypotheses is proposed. The operational difficulties of applying a learning algorithm to a dataset where sequence heterogeneity is under-represented and where local and global effects are inadequately partitioned are discussed.

Artificial Intelligence↗

Identification and mapping of small-molecule binding sites in proteins: computational tools for structure-based drug design.

The number of protein structures is currently increasing at an impressive rate. The growing wealth of data calls for methods to efficiently exploit structural information for medicinal and pharmaceutical purposes. Given the three-dimensional (3D) structure of a validated protein target, the identification of functionally relevant binding sites and the analysis ('mapping') of these sites with respect to molecular recognition properties are important initial tasks in structure-based drug design. To address these tasks, a variety of computational tools have been developed. Approaches to identify binding pockets include geometric analyses of protein surfaces, comparisons of protein structures, similarity searches in databases of protein cavities, and docking scans to reveal areas of high ligand complementarity. In the context of binding-site analysis, powerful data mining tools help to retrieve experimental information about related protein-ligand complexes. To identify interaction hot spots, various potential functions and knowledge-based approaches are available for mapping binding regions. The results may subsequently be used to guide virtual screenings for new ligands via pharmacophore searches or docking simulations.

Artificial Intelligence↗

Accurate ionization potentials for UO and UO2: a rigorous test of relativistic quantum chemistry calculations.

Accurate ionization potential (IP) measurements provide essential thermodynamic information and benchmark data that can be used to evaluate the validity of electronic structure models. Calculations of the first IP of UO2 using relativistic methods consistently predict values that are approximately 0.7 eV higher than the accepted experimental value. The present measurements validate the theoretical calculations and show that the previous determinations corresponded to the ionization of thermally excited molecules. Similarly, new measurements of the IP for UO show that the currently accepted value is too low by 0.4 eV.

Journal Article↗

Conformational studies of antimetastatic laminin-1 derived peptides in different solvent systems, using solution NMR spectroscopy.

Due to its critical role in cancer progression, interactions between laminin-1 and the 67 kDa Laminin-Binding Protein (the 67 kDa LBP) have been the focus of a number of structural and biological studies. As laminin-1 is such a large and complex molecule, research interests have turned to the investigation of bioactive peptides derived from binding domains of laminin-1. Two peptides of interest, CDPGYIGSR (peptide 11) and YIGSR, both derived from the beta1 chain of laminin-1, have been shown to block invasion of basement membranes by tumor cells. Substituting the C-terminal arginine to lysine, a conservative substitution, results in a loss of peptide antimetastatic activity. This difference in bioactivity has been attributed, based on numerous modeling studies of free peptide conformations, to structural differences between YIGSR and YIGSK. Yet the nature of the 'active' free peptide backbone conformation has been a matter of debate and controversy. In order to test the validity of the structural modeling claims, we have undertaken detailed conformational studies of the two laminin-1 derived peptides YIGSR and CDPGYIGSR along with the biologically inactive YIGSK analog by two-dimensional solution 1H NMR spectroscopy in three different solvent systems. Herein we report that although both the active (YIGSR, CDPGYIGSR) and the inactive (YIGSK) peptides can adopt several closely related conformations in solution, the two peptides share similar conformational preferences, and there are no significant structural differences between the active and inactive peptides, contrary to previously reported modeling data. We conclude that the basis of the peptide biological activity, in contrast to published models, cannot be attributed to well-defined structural preferences of the free peptides. We infer that the difference in bioactivity observed between YIGSR and YIGSK originates primarily from the chemical nature of the arginine versus lysine sidechain substitution, rather than being due to a structural change in the free peptide conformations.

Amino Acid Sequence↗

Correlation between housestaff performance on the United States Medical Licensing Examination and standardized patient encounters.

BACKGROUND: There is interest in the use of "standardized patients" to assist in evaluating medical trainees' clinical skills, which may be difficult to evaluate with written exams alone. Previous studies of the validity of observed structured clinical exams have found low correlation with various written exams as well as with faculty evaluations. Since the United States Medical Licensing Examination (USMLE) results are often used by training programs in the selection of applicants, we assessed the correlation between performance on an observed structured clinical exam and the USMLE, steps 1 and 2, for internal medicine housestaff. METHODS: We collected scores on the USMLE, steps 1 and 2, and the overall score from a required standardized patient encounter for all PGY-1 trainees, in a single urban teaching hospital. Pearson coefficients were used to compare the USMLE and observed structured clinical exam performance. RESULTS: The two steps of the USMLE correlated with each other to a large extent (r=0.65, df=30, p=0.0001). However, both steps of the USMLE correlated poorly with the observed structured clinical exam (step 1 r=0.2, df=32, p=0.27; step 2 r=0.09, df=30, p=0.61). CONCLUSIONS: The low correlation between the USMLE and performance on a structured clinical exam suggests that either the written exam is a poor predictor of actual clinical performance, the small window of clinical skills measured by the structured clinical exam is inadequate, or the two methods evaluate different skill sets entirely. Our findings are consistent with previous work finding low correlations between structured clinical exams and accepted common means of evaluation, such as faculty evaluations, other written exams and program director assessments. The medical education community needs to develop an objective, valid method of measuring important, yet subjective, skill-sets such as interpersonal communication, empathy and efficient data collection.

Clinical Competence↗

[Use of frequency analysis for localization of functionally important regions of thermolysin].

A theoretical investigation of the functional topography of thermolysin molecule was carried out using frequency analysis of its primary and tertiary structures. The statistical validity of predictions was estimated for the enzyme active site, substrate-binding pocket, interdomain interface, and calcium-binding sites. It was shown that frequency analysis of primary structure could be employed to predict the localization of contiguous parts of the interdomain interface. Primary structure analysis cannot be used to search for the conformation-dependent enzyme active site and substrate-binding pocket. On the contrary, frequency analysis of interresidues contacts is not so effective for prediction of the interdomain interface as compared with active site, substrate-binding pocket, and calcium-binding sites. The set of original algorithms proposed could be used in searching for functional sites in various proteins.

Amino Acid Sequence↗

[Validation of the French translation and factorial structure of the Tiffany and Drobes Smoking Urge Questionnaire].

UNLABELLED: Over the past 10 years researches and clinicians have made substantial progress in understanding and treating nicotine dependence. To demonstrate the effectiveness of these treatments, reliable and sensitive measures of change and outcome must be used. In the nicotine dependence treatment literature numerous outcome have been used: frequencies drug use, problems associated with substance use, psychiatric comorbidity, withdrawal severity, and craving. The term craving reflects the subjective reports of addicts regarding their attempts to abstain from drug use and the state of their minds at the point at which they attempt to fail. Exposure to cues previously associated with nicotine play a role in precipitating relapse in eliciting a conditioned craving/withdrawal response and can be measures by the Questionnaire of Smoking Urge (QSU). OBJECTIVE OF THE STUDY: Validation in a French translated version of the QSU published in 1991 by Tiffany and Drobes. METHODOLOGY: 42 male and 62 female participated in the study with the translated questionnaire: mean age was 36.7 years, mean age at starting and mean duration of tobacco consumption was respectively 20.2 years old and 16.5 years, daily consumption was 16.6 cigarettes per day. The French translation of the QSU was administered to smokers instructed to abstain from smoking one hour and a half to three hours. RESULTS: The back translation has been accepted by Tiffany because more than 85% of the items are similar to the original questionnaire. We founded the same factor analysis with two factors, "desire to smoke" and "intention to smoke" accounting for 34% and 11% of the items variance, respectively. These two factors were the same than those of the original questionnaire. CONCLUSION: The validation of the French translation of the QSU gives the opportunity to use a sensitive instrument to assess craving.

Adolescent↗

Towards 3D structures of G protein-coupled receptors: a multidisciplinary approach.

Current strategies in pharmaceutical research comprise two methodologically different but complementary approaches for lead finding purposes, namely the random screening of compound libraries and the structure-based effort, commonly termed rational drug design. The structure-based approach is aimed to exploit 3D structure data of the molecular components involved in the molecular recognition event that underlies the attempt to therapeutically modulate the biological function of a macromolecular target with proven pathophysiological relevance for a disease state. In this context, G protein-coupled receptors (GPCRs) constitute the most prominent family of validated drug targets within biomedical research, since approximately 60 % of approved drugs elicit their therapeutic effects by selectively addressing members of that target family. From a 3D structure point of view, these transmembrane signal transduction systems represent the most challenging task for structure determination, which is due to the heterogeneous and fine-balanced environment conditions that are necessary for structural and functional integrity of the receptor protein. This contribution will address the different concepts to derive structurally relevant information on the transmemebrane seven-helix protein (7TM) domain of GPCRs with special emphasis laid on the multidisciplinarity of the applied methodologies. The current status of electron-cryo-microscopy on 2D crystals and even high-resolution x-ray crystallography on 7TM proteins will be introduced highlighting the transferability of the emerging structural principles onto the GPCR superfamily. Special techniques from bioinformatics and homology-related molecular modeling in combination with tailor-made protein simulation methodologies complement the experimentally derived data, in that they facilitate the 3D structure generation and structure validation process. This contribution summarises the most recent results of GPCR structure studies with the aim to underline the impact of structure data not only for the purpose of rationalising structure-activity data on low-molecular weight antagonists within the context of a protein binding pocket, but also for a better understanding of e.g. mutagenesis experiments, thus qualifying GPCR structure models as valid communication platforms establishing a functional link between molecular biology, biophysics, bioinformatics and organic chemistry in a highly efficient manner.

Amino Acid Sequence↗

Population genetic structure of Tomicus piniperda L. (Curculionidae: Scolytinae) on different pine species and validation of T. destruens (Woll.).

Genetic diversity and population structure of Tomicus piniperda was assessed using mitochondrial sequences on 16 populations sampled on 6 pine species in France. Amplifications of Internal transcribed space 1 (ITS1) were also performed. Our goals were to determine the taxonomic status of the Mediterranean ecotype T. piniperda destruens, and to test for host plant or geographical isolation effect on population genetic structure. We showed that T. piniperda clusters in two mtDNA haplotypic groups. Clade A corresponds to insects sampled in continental France on Pinus sylvestris, P. pinaster and P. uncinata, whereas clade B gathers the individuals sampled in Corsica on P. pinaster and P. radiata and in continental France on P. pinea and P. halepensis. Insects belonging to clade A and clade B also consistently differ in the length of ITS1. Individuals belonging to both clades were found once in sympatry on P. pinaster. Genetic distances between clades are similar to those measured between distinct species of Tomicus. We concluded that clade B actually corresponds to the destruens ecotype and forms a good species, T. destruens. Analyses of molecular variance ( amova ) were conducted separately on T. destruens and T. piniperda to test for an effect of either geographical isolation or host species. Interestingly, the effect of host plant was significant for T. piniperda only, while the effect of geographical isolation was not. Pine species therefore seems to act as a significant barrier to gene flow, even if host race formation is not observed. These results still need to be confirmed by nuclear markers.

Animals↗

Efficiency of diagnostic criteria for attention deficit disorder: toward an empirical approach to designing and validating diagnostic algorithms.

Using structured psychiatric interviews, 73 attention deficit disorder (ADD) patients, 26 psychiatric control patients, 26 normal controls, and all available first degree relatives of these index children were examined. ADD subgroups with and without comorbid psychiatric disorders did not differ on rates of specific ADD symptoms. The construct of ADD is internally consistent as measured by Cronbach's alpha. The diagnostic efficiency of individual items is presented. A receiver operating characteristic-based procedure is used to create an ADD diagnostic algorithm that is more efficient in discriminating ADD children from controls than the DSM-III-based clinical diagnosis. Cross-validation with family study data shows this procedure to be superior to the procedure used for the DSM-III-R diagnosis. The results show that proponents of conditional probability and receiver operating characteristic analyses are correct in asserting that the examination of symptom combinations may result in better diagnostic algorithms.

Algorithms↗

Examination of movement in patients with long-lasting musculoskeletal pain: reliability and validity.

BACKGROUND AND PURPOSE: An examination method based on psychosomatic physiotherapy, with 24 standardized tests related to general aspects of mobility, flexibility and the ability to relax, is used in some pain and rehabilitation clinics in Scandinavia in order to document where--and to what degree--patients have aberrations within the domain 'movement'. The measurement properties of the movement tests have, however, not been investigated in patients with long-lasting musculoskeletal pain. The aims of the present study were, therefore, to investigate inter-tester reliability and validity (construct, discriminative and concurrent validity) related to movement. METHOD: The study design was cross-sectional. Reliability was examined by three physiotherapists examining 19 people. Construct validity was studied by means of structural equation modelling (SEM). Discriminative validity was examined by comparing movement data from 247 patients with long-lasting musculoskeletal pain, and 104 healthy subjects. The patient sample was categorized according to localized or widespread pain, and movement scores compared between the groups. Most patients filled in a psychological screening questionnaire (MMPI-2), plus information about pain intensity and function, and concurrent validity of the movement measures were examined by correlation. RESULTS: SEM results indicated a modified movement scale, consisting of 16 items in four subscales. Both the original and modified versions showed good reliability, and scores differed significantly between healthy subjects and patients, and between patients with localized versus widespread pain. A relationship was found between the movement tests and psychological characteristics, but mainly in patients with widespread pain. Significant relationships were found between the ability to relax and pain, and between all aspects of movement and function. CONCLUSIONS: Movement may be reliably and validly assessed with composite scores from 4 x 4 items. The method may be useful as a global screening instrument in order to examine where, and to what extent, patients with long-lasting pain problems have movement aberrations; findings to be addressed in treatment.

Adult↗

Pain in pediatric oncology--children's and parents' perspectives.

There is a lack of valid epidemiological data on malignancy-associated pain in modern pediatric oncology. Pediatric oncology patients (self-assessment) and their parents from 28 hospitals were questioned using age-adapted, structured interviews and validated pain assessment tools. Pain intensity was measured by the NRS and Bieri faces scale. We conducted 363 interviews with patients and their parents, and 46 with the parents alone (if patients <2.5 years). Pain was reported at the time of the interview or within the last 24 h, 7 d, or 4 weeks in 15%, 28%, 50% and 58% of cases, respectively. The proportion of patients suffering severe to maximal pain (NRS>3; Bieri>2) increased significantly (p=0.001, chi2 test). The median pain intensity for the most severe pain episode within the last 4 weeks was 6.7 (NRS 0-10). Adverse effects of anti-tumor therapy were the most frequent cause of pain. Multivariate analyses depicted general physical condition either "severely reduced" (ASA status 3) (OR 4.0, 95% CI 1.1-14.7, p=0.037) or "moderately reduced" (ASA status 2) (OR 1.8, 95% CI 1.1-2.9, p=0.018), "in-patient status" (OR 1.8, 95% CI 1.2-2.9, p=0.010), and "co-morbidity present" (OR 3.5, 95% CI 1.1-10.7, p=0.030) as risk factors for severe to maximal pain. General anesthesia was the only factor significantly (OR 0.14, 95% CI 0.05-0.39, p<0.01) associated with a reduction in the proportion of patients suffering severe to maximal pain during bone marrow aspiration. Our data emphasize both the importance of in-house acute pain control and the need for general anesthesia during painful procedures in pediatric oncology.

Adolescent↗

The X-ray crystal structure of human beta-hexosaminidase B provides new insights into Sandhoff disease.

Human lysosomal beta-hexosaminidases are dimeric enzymes composed of alpha and beta-chains, encoded by the genes HEXA and HEXB. They occur in three isoforms, the homodimeric hexosaminidases B (betabeta) and S (alphaalpha), and the heterodimeric hexosaminidase A (alphabeta), where dimerization is required for catalytic activity. Allelic variations in the HEXA and HEXB genes cause the fatal inborn errors of metabolism Tay-Sachs disease and Sandhoff disease, respectively. Here, we present the crystal structure of a complex of human beta-hexosaminidase B with a transition state analogue inhibitor at 2.3A resolution (pdb 1o7a). On the basis of this structure and previous studies on related enzymes, a retaining double-displacement mechanism for glycosyl hydrolysis by beta-hexosaminidase B is proposed. In the dimer structure, which is derived from an analysis of crystal packing, most of the mutations causing late-onset Sandhoff disease reside near the dimer interface and are proposed to interfere with correct dimer formation. The structure reported here is a valid template also for the dimeric structures of beta-hexosaminidase A and S.

Acetylglucosamine↗

Enhanced recognition of protein transmembrane domains with prediction-based structural profiles.

MOTIVATION: Membrane domain prediction has recently been re-evaluated by several groups, suggesting that the accuracy of existing methods is still rather limited. In this work, we revisit this problem and propose novel methods for prediction of alpha-helical as well as beta-sheet transmembrane (TM) domains. The new approach is based on a compact representation of an amino acid residue and its environment, which consists of predicted solvent accessibility and secondary structure of each amino acid. A recently introduced method for solvent accessibility prediction trained on a set of soluble proteins is used here to indicate segments of residues that are predicted not to be accessible to water and, therefore, may be 'buried' in the membrane. While evolutionary profiles in the form of a multiple alignment are used to derive these simple 'structural profiles', they are not used explicitly for the membrane domain prediction and the overall number of parameters in the model is significantly reduced. This offers the possibility of a more reliable estimation of the free parameters in the model with a limited number of experimentally resolved membrane protein structures. RESULTS: Using cross-validated training on available sets of structurally resolved and non-redundant alpha and beta membrane proteins, we demonstrate that membrane domain prediction methods based on such a compact representation outperform approaches that utilize explicitly evolutionary profiles and multiple alignments. Moreover, using an external evaluation by the TMH Benchmark server we show that our final prediction protocol for the TM helix prediction is competitive with the state-of-the-art methods, achieving per-residue accuracy of approximately 89% and per-segment accuracy of approximately 80% on the set of high resolution structures used by the TMH Benchmark server. At the same time the observed rates of confusion with signal peptides and globular proteins are the lowest among the tested methods. The new method is available online at http://minnou.cchmc.org.

Algorithms↗

Automatic detection of molecular symmetry in the Cambridge Structural Database.

A method for the detection of approximate molecular symmetry in crystal structures has been developed. The point-group symmetry is assigned to each molecule and the relevant symmetry elements can be visualized, superimposed on the molecule. The method has been validated against reference structures with exact symmetry subjected to small random perturbation.

Journal Article↗

Cross-validation of the Temptation Coping Questionnaire: adolescent coping with temptations to use alcohol and illicit drugs.

OBJECTIVE: The present study had two primary objectives: (1) to examine differences in adolescent coping with temptations to use alcohol versus temptations for marijuana and/or other drug use and (2) to replicate and extend previous findings regarding the factor structure and psychometric validity of the Temptation Coping Questionnaire (TCQ). METHOD: This was a cross-sectional study of 1,273 high school students, 52% female and, on average, 16.6 years old. The TCQ was completed as part of a school-wide survey of cigarette, alcohol and other drug involvement. Responses to the TCQ were elicited in response to two hypothetical temptation situations, one involving offers of alcohol only and the other involving offers of marijuana and/or other drugs. RESULTS: The factor structure of the TCQ coping scale was confirmed for the original 11 items, both within and across situations representing temptations to use alcohol or marijuana and/or other drugs. In addition, the mean levels of perceived importance of abstaining and extent of coping efforts endorsed were higher for a marijuana and other drug than for an alcohol temptation situation. Finally, construct and criterion validity of the TCQ was replicated in the present sample. CONCLUSIONS: Present results suggest that similar coping strategies are employed regardless of the particular substance encountered in a temptation situation. However, situation appraisal and extent of coping efforts appeared to differ for distinct substance types. These findings corroborate previous evidence for the utility of the TCQ as a brief, reliable measure of adolescent temptation coping and provide convergent support for the temptation-coping construct.

Adaptation, Psychological↗

Theory into hospital practice: a pilot implementation.

Implementing the Adaptation Model required that the model's concepts be explicitly identified, defined, and understood. Guidelines, standards and tools had to be revised or developed. Effective nursing administration leadership and the personal and professional commitment of administrators, educators, and staff nurses to the goal were necessary ingredients. The abstract nature of theory often requires sheer determination and hard thinking if it is to be effectively applied to practice. A formal education process must also be dynamic and ongoing. Project members continue to gain greater insight into the model's structure, identify problems in its application, and seek ways to solve them. Their combined, concentrated efforts have proved a cost-effective way to close gap between education and practice. The project's initial outcomes, increased patient satisfaction and expanded professional nursing, support the application of the Adaptation Model in our hospital. Further validation of its structure and the value of its outcomes, however, needs additional study, and extended application in multiple practice settings. Validation of the Roy Adaptation Model or any of the evolving conceptual frameworks for nursing practice requires use, input, and evaluation by nurses in all settings. Opening the theoretical domain to hospital nurses needs the support and leadership of nursing and hospital administrators.

Adaptation, Psychological↗