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PubMed2004

Toward multiplexing the application of solvent accessibility probes for the investigation of RNA three-dimensional structures by electrospray ionization-Fourier transform mass spectrometry.

Multiple solvent accessibility probes can be applied simultaneously to investigate the three-dimensional structure of complex RNA substrates when electrospray ionization-Fourier transform mass spectrometry (ESI-FTMS) is employed in place of polyacrylamide gel electrophoresis (PAGE). We show that classic chemical probes, such as dimethylsulfate, kethoxal, and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, can be combined in probing mixtures designed to assess the full spectrum of base pairing and steric protection for the most abundant ribonucleotides included in RNA. After probe-independent hydrolysis of the alkylated substrate, the mixture of oligonucleotide products is mass mapped by ESI-FTMS analysis, which enables the unambiguous identification of probed bases from the unique mass signatures provided by the different chemical modifiers. In this bottom-up approach, any theoretical limit to the size of the possible target RNA will be determined by the effectiveness of the hydrolysis procedure rather than by the performance of the detection technique. Control experiments performed on the stem-loop 4 of human immunodeficiency virus type 1 have shown no adverse interactions between the reagents combined in the probing cocktails. No significant discrepancies between the alkylation patterns offered by the cocktails and the individual reagents could be detected, indicating that multiplexing the probe application does not necessarily lead to structural distortion but provides valid data on base accessibility and protection. To demonstrate the ruggedness of this approach, optimized cocktails were finally employed to assess the stability of the folded structure of mouse mammary tumor virus pseudoknot in the presence of different amounts of Mg2+. Multiplexing the probe application constitutes an essential step toward high-throughput applications, which will take advantage of a strategy that maximizes the information attainable from a single experiment, while minimizing time and sample consumption over PAGE-based methods.

Base Sequence↗
PubMed2001

Freeze-fracture studies on lipids and membranes.

Freeze-fracture electron microscopy is especially useful for investigation of lipid structures by the advantageous fracture course within hydrophobic zones. Freezing is, on the other hand, a restriction because the structures of lamellar and non-lamellar phase states with disordered acyl chains (L(alpha), H(II,) cubic) are difficult to preserve. An important aspect of this method is therefore the lipid structure of phase states with ordered acyl chains (crystal, gel), and with a different degree of hydration. Freeze-fracture of pure lipid systems creates a valid representation of the structure of non-lamellar phases and of the general structure of the "lamellar" lipid bilayer, and lamellar phases with characteristic deformations (ripples, curvatures, plane sectors) can be identified. Fracture through the hydrophobic bilayer centre of biological membranes reveals characteristic protein components, the intramembraneous particles (IMPs). The lateral distribution of the IMPs is a helpful marker for fluid and rigid phase states, also without deformation of the lamella. The overall history and the present state of knowledge concerning the different structures revealed by the freeze-fracture and freeze-etch techniques in lipid systems, and to a limited extent in biological membranes, is reviewed, taking into account studies from our own laboratory.

Animals↗
PubMed1996

The Abridged Dutch Metamemory in Adulthood (MIA) Questionnaire: structure and effects of age, sex, and education.

This study presents data on the factor structure, reliability, and discriminant validity of the Metamemory in Adulthood (MIA) questionnaire in a Dutch sample of 1,899 normal and healthy participants aged 24 to 86 years. The factor structure of the Dutch MIA corresponded with that of the original MIA. The Strategy scale could be divided into two subscales: External and Internal Memory Strategies. The number of items on the MIA could be reduced by 34% without loss of the factor structure or lowering of the internal consistency of the subscales. Data on the relation of the abridged MIA with age, sex, education, depression, anxiety, and subjective health are presented. The study supports the cross-national use of the MIA as a research and clinical instrument for the evaluation of subjective memory functioning.

Adult↗
PubMed2001

A literature network of human genes for high-throughput analysis of gene expression.

We have carried out automated extraction of explicit and implicit biomedical knowledge from publicly available gene and text databases to create a gene-to-gene co-citation network for 13,712 named human genes by automated analysis of titles and abstracts in over 10 million MEDLINE records. The associations between genes have been annotated by linking genes to terms from the medical subject heading (MeSH) index and terms from the gene ontology (GO) database. The extracted database and accompanying web tools for gene-expression analysis have collectively been named 'PubGene'. We validated the extracted networks by three large-scale experiments showing that co-occurrence reflects biologically meaningful relationships, thus providing an approach to extract and structure known biology. We validated the applicability of the tools by analyzing two publicly available microarray data sets.

Computer Communication Networks↗
PubMed1990

A CASE-SAR analysis of polycyclic aromatic hydrocarbon carcinogenicity.

A CASE SAR analysis was performed on a selected database of PAHs to investigate the possible use of the CASE method as an aid for preliminary assessment of carcinogenic potential of untested environmental PAHs. A data set, denoted LEARN, consisting of 78 PAHs and their experimental carcinogenicities was used to 'train' the CASE method and derive the CASE fragments. 8 activating fragments and 4 inactivating fragments were identified. These fragments predicted the activities of 94% of the LEARN set correctly. The biological significance of several of these fragments are rationalized in light of the current theories of PAH carcinogenesis. Using these fragments, the potential activities of a database of 106, mostly untested PAHs, denoted TEST, were predicted. These were compared to 'expert judgement' predictions based on mechanistic considerations in order to evaluate the extent of concordance between these two methods and their respective strengths and weaknesses. Initial poor agreement (64%) was attributed to limitations of the LEARN database involving inadequate representation of 2- and 3-ring PAH subclasses. When these subclasses were excluded from the TEST database, the concordance improved to 90%. The CASE fragments were also used to predict the activities of a database of 24 PAHs, denoted VALIDATE (not included in the LEARN set) for which carcinogenicity data were available. The total prediction accuracy of 75% (89% of the actives correctly identified), despite the structural diversity of the VALIDATE set, provided independent evidence of the utility of the present CASE results. A close examination of the CASE incorrect predictions was conducted to delineate inadequancies of these CASE results in order to provide cautionary guidance for future application of the method. Finally, the present results were compared to the results of a previous CASE analysis based on a more limited PAH data set, and were found to be of greater general utility. It is concluded that the CASE fragments derived in the current study should provide a useful tool for assisting and complementing 'expert judgement' in the preliminary screening of PAHs for carcinogenic activity.

Carcinogenicity Tests↗
PubMed1994

Development of a type 2 diabetes symptom checklist: a measure of symptom severity.

The aim of the present study was to develop a Type 2 diabetes symptom checklist for use in clinical and epidemiological research, which can measure differences in symptom severity between patients and detect changes over time within patients. Face and content validity of items and dimension structure were based on literature and experiences of diabetologists. Two Likert scales were used to measure symptom frequency and perceived burden. Reliability, responsiveness and validity were studied in 185 Type 2 diabetic patients. Factor-analysis confirmed the predesigned dimension structure with 34 items, distributed over 6 dimensions. The internal consistency with Cronbach alpha coefficients between 0.76 and 0.95 and test-retest reliability with Pearson product-moment correlation coefficients between 0.79 and 0.94 were satisfactory. The ability to detect change over time (responsiveness) was estimated in stable subjects, using sample size calculations. A minimal detectable mean change of 0.07-0.58 points in total score on the 10-point scale within a group of 100 subjects suggests an impressive responsiveness. Significant differences in symptom severity score were found between patients with different co-morbidity status and treatment modes, indicating satisfactory construct validity of the dimension structure. The Type 2 Diabetes Symptom Checklist was found to be a useful diabetes-specific symptom severity assessment method for clinical and epidemiological studies.

Aged↗
PubMed1996

Protein fold recognition by mapping predicted secondary structures.

A strategy is presented for protein fold recognition from secondary structure assignments (alpha-helix and beta-strand). The method can detect similarities between protein folds in the absence of sequence similarity. Secondary structure mapping first identifies all possible matches (maps) between a query string of secondary structures and the secondary structures of protein domains of known three-dimensional structure. The maps are then passed through a series of structural filters to remove those that do not obey simple rules of protein structure. The surviving maps are ranked by scores from the alignment of predicted and experimental accessibilities. Searches made with secondary structure assignments for a test set of 11 fold-families put the correct sequence-dissimilar fold in the first rank 8/11 times. With cross-validated predictions of secondary structure this drops to 4/11 which compares favourably with the widely used THREADER program (1/11). The structural class is correctly predicted 10/11 times by the method in contrast to 5/11 for THREADER. The new technique obtains comparable accuracy in the alignment of amino acid residues and secondary structure elements. Searches are also performed with published secondary structure predictions for the von-Willebrand factor type A domain, the proteasome 20 S alpha subunit and the phosphotyrosine interaction domain. These searches demonstrate how the method can find the correct fold for a protein from a carefully constructed secondary structure prediction, multiple sequence alignment and distant restraints. Scans with experimentally determined secondary structures and accessibility, recognise the correct fold with high alignment accuracy (86% on secondary structures). This suggests that the accuracy of mapping will improve alongside any improvements in the prediction of secondary structure or accessibility. Application to NMR structure determination is also discussed.

Algorithms↗
PubMed2001

Structure-based 3D QSAR and design of novel acetylcholinesterase inhibitors.

The paper describes the construction, validation and application of a structure-based 3D QSAR model of novel acetylcholinesterase (AChE) inhibitors. Initial use was made of four X-ray structures of AChE complexed with small, non-specific inhibitors to create a model of the binding of recently developed aminopyridazine derivatives. Combined automated and manual docking methods were applied to dock the co-crystallized inhibitors into the binding pocket. Validation of the modelling process was achieved by comparing the predicted enzyme-bound conformation with the known conformation in the X-ray structure. The successful prediction of the binding conformation of the known inhibitors gave confidence that we could use our model to evaluate the binding conformation of the aminopyridazine compounds. The alignment of 42 aminopyridazine compounds derived by the docking procedure was taken as the basis for a 3D QSAR analysis applying the GRID/GOLPE method. A model of high quality was obtained using the GRID water probe, as confirmed by the cross-validation method (q2LOO = 0.937, q2L50%O = 0.910). The validated model, together with the information obtained from the calculated AChE-inhibitor complexes, were considered for the design of novel compounds. Seven designed inhibitors which were synthesized and tested were shown to be highly active. After performing our modelling study the X-ray structure of AChE complexed with donepezil, an inhibitor structurally related to the developed aminopyirdazines, has been made available. The good agreement found between the predicted binding conformation of the aminopyridazines and the one observed for donepezil in the crystal structure further supports our developed model.

Acetylcholinesterase↗
PubMed1984

Revision of the self-monitoring scale.

Snyder's (1974) Self-Monitoring Scale exhibits a stable factor structure that does not correspond to the five-component theoretical structure he presents. Sets of face-valid items that better approximate the theoretical structure are described. Correlations between these sets of items and measures of other constructs reveal that four of the five components are positively related to social anxiety. Effective social interaction is supposedly the high self-monitor's forte, and social anxiety appears to be incompatible with this. The correlational results therefore question the entire theory and indicate the need for a narrower definition of the construct. Adopting such a definition from Snyder's review article (1979), we present a 13-item Revised Self-Monitoring scale which measures only sensitivity to the expressive behavior of others and ability to modify self-presentation. A 20-item Concern for Appropriateness scale is also described. This scale measures 2 variables that are directly associated with social anxiety--cross-situational variability and attention to social comparison information. Both scales have acceptable internal consistency, and both yield 2 subscale scores as well as a total score. Prospective users of either scale are advised to treat the 3 scores separately.

Adult↗
PubMed2005

Conformational changes in the ligand-binding domain of a functional ionotropic glutamate receptor.

Fluorescence resonance energy transfer was used to determine the structural changes in the extracellular ligand-binding segment in a functional glutamate receptor that contains the ligand-binding, transmembrane, and C-terminal segments. These studies indicate that the structural changes previously reported for the isolated ligand-binding domain due to the binding of partial and full agonists are also observed in this functional receptor, thus validating the detailed structure-function relationships that have been previously developed based on the structure of the isolated ligand-binding domain. Additionally, these studies provide the first evidence that there are no significant changes in the extent of cleft closure between the activated and desensitized states of the glutamate bound form of the receptor consistent with the previous functional investigations, which suggest that desensitization is mediated primarily by changes in the interactions between subunits composing the receptor.

Apoproteins↗
PubMed2000

Oxidation of iron: the relation between oxidation kinetics and oxide electronic structure

The test of the validity of the Fromhold-Cook theory of metal oxidation for the O2/Fe system in the tunnel regime is impeded by the growth of a passivating Fe2+/Fe3+ double layer at T</=150 degrees C. However, during an intermediate anneal step at 200 degrees C, the Fe3+ is reduced to Fe2+. The oxidation rate of this annealed layer is in agreement with the Fromhold-Cook theory. At room temperature, the ionic current is rate limiting. For T>150 degrees C, the thermionic emission of electrons is rate limiting for oxygen coverages larger than 13x10(15) atoms/cm(2).

Journal Article↗
PubMed1992

Structural and functional analysis of the visna virus Rev-response element.

The distantly related lentiviruses human immunodeficiency virus type 1 (HIV-1) and visna virus each encode a posttranscriptional regulatory protein, termed Rev, that is critical for expression of the viral structural proteins. We genetically mapped the cis-acting target sequence for visna virus Rev, the visna virus Rev-response element or RRE-V, to a complex 176-nucleotide RNA stem-loop structure that coincides with sequences encoding the N terminus of the transmembrane component of envelope. The computer-predicted structure of the RRE-V was validated by in vitro analysis of structure-specific RNase cleavage patterns. The visna virus Rev protein was shown to interact specifically with the genetically defined RRE-V in vitro but was unable to bind the HIV-1 RRE. Similarly, HIV-1 Rev was also unable to bind the RRE-V specifically. We therefore conclude that the HIV-1 and visna virus Rev proteins, while functionally analogous, nevertheless display distinct RNA sequence specificities. These findings provide a biochemical explanation for the observation that these two viral regulatory proteins are functional only in the homologous viral system.

Base Sequence↗
PubMed1994

Reliability and validity of a brief patient-report instrument for psychiatric outcome evaluation.

OBJECTIVE: The authors describe the Behavior and Symptom Identification Scale (BASIS-32), a brief patient-report measure for psychiatric outcome assessment, and present the measure's factor structure and reliability and validity data. METHODS: Using the BASIS-32, interviews were conducted with a total of 387 patients shortly after their admission to the adult inpatient services of a private not-for-profit psychiatric hospital. Six months after admission, they received a follow-up questionnaire version of the instrument. RESULTS: Factor analysis of the instrument yielded five factors, on which subscales were based: relation to self and others, daily living and role functioning, depression and anxiety, impulsive and addictive behavior, and psychosis. Internal consistency of the subscales ranged from .63 to .80. Internal consistency of the full 32-item scale was .89. Test-retest reliability ranged from .65 to .81 for the five subscales. Concurrent and discriminant validity analyses indicated that the BASIS-32 ratings successfully discriminated patients hospitalized six months after admission from those living in the community, patients working at follow-up from those not working, and patients with particular diagnoses. Follow-up ratings indicated that the BASIS-32 is sensitive to changes in symptomatology and functioning. CONCLUSIONS: The BASIS-32 provides a brief, standardized assessment of symptoms and problems from the patient's perspective. The instrument can be used for outcome assessment with most psychiatric inpatients.

Activities of Daily Living↗
PubMed1993

Dementia care creating a therapeutic milieu.

1. In dementia care, the full spectrum of interventions in a therapeutic milieu provides for safety, structure, support, involvement, and validation. 2. A safe environment accommodates wandering and compensates for physical and cognitive impairments. A therapeutic milieu provides for both physical and psychologic safety. 3. Two components of structure include the design of the physical environment and the schedule of activities. 4. The central element that defines quality in a therapeutic milieu is the dimension of interpersonal relationships.

Aged↗
PubMed2001

Estimating near-infrared leaf reflectance from leaf structural characteristics.

The relationship between near-infrared reflectance at 800 nm (NIRR) from leaves and characteristics of leaf structure known to affect photosynthesis was investigated in 48 species of alpine angiosperms. This wavelength was selected to discriminate the effects of leaf structure vs. chemical or water content on leaf reflectance. A quantitative model was first constructed correlating NIRR with leaf structural characteristics for six species, and then validated using all 48 species. Among the structural characteristics tested in the reflectance model were leaf trichome density, the presence or absence of both leaf bicoloration and a thick leaf cuticle (>1 μm), leaf thickness, the ratio of palisade mesophyll to spongy mesophyll thickness (PM/SM), the proportion of the mesophyll occupied by intercellular air spaces (%IAS), and the ratio of mesophyll cell surface area exposed to IAS (A(mes)) per unit leaf surface area (A), or A(mes)/A. Multiple regression analysis showed that measured NIRR was highly correlated with A(mes)/A, leaf bicoloration, and the presence of a thick leaf cuticle (r = 0.93). In contrast, correlations between NIRR and leaf trichome density, leaf thickness, the PM/SM ratio, or %IAS were relatively weak (r < 0.25). A model incorporating A(mes)/A, leaf bicoloration, and cuticle thickness predicted NIRR accurately for 48 species (r = 0.43; P < 0.01) and may be useful for linking remotely sensed data to plant structure and function.

Journal Article↗
PubMed2002

Evaluation of glucoiberin reference material from Iberis amara by spectroscopic fingerprinting.

Increasing worldwide regulations require increased efforts toward validation of analytical and pharmacological reference materials. A detailed survey of glucoiberin, a prototype lead constituent of therapeutic value, using 1D/2D NMR, MS, and X-ray spectroscopy provided precise phytochemical data for structure assignment. Quantitative reference validation was achieved by the recently proposed qNMR method.

Choline↗
PubMed2004

Predicting protein structure classes from function predictions.

MOTIVATION: We introduce a new approach to using the information contained in sequence-to-function prediction data in order to recognize protein template classes, a critical step in predicting protein structure. The data on which our method is based comprise probabilities of functional categories; for given query sequences these probabilities are obtained by a neural net that has previously been trained on a variety of functionally important features. On a training set of sequences we assess the relevance of individual functional categories for identifying a given structural family. Using a combination of the most relevant categories, the likelihood of a query sequence to belong to a specific family can be estimated. RESULTS: The performance of the method is evaluated using cross-validation. For a fixed structural family and for every sequence, a score is calculated that measures the evidence for family membership. Even for structural families of small size, family members receive significantly higher scores. For some examples, we show that the relevant functional features identified by this method are biologically meaningful. The proposed approach can be used to improve existing sequence-to-structure prediction methods. AVAILABILITY: Matlab code is available on request from the authors. The data are available at http://www.mpisb.mpg.de/~sommer/Fun2Struc/

Algorithms↗
PubMed2005

A cross-sectional evaluation of the factorial invariance of anxiety sensitivity in adolescents and young adults.

This study examined the cross-sectional factorial invariance of anxiety sensitivity in an ethnically diverse sample of adolescents (n = 173; mean age 15.5 years) and young adults (n = 291; mean age 20.1 years). Research in adult and youth samples suggests that anxiety sensitivity is best understood as a hierarchical construct with several lower-order factors. Factor models based on previous research using both adult and youth samples were compared and a hierarchical model with three lower-order factors provided the best fit to the data. Results supported the hypothesis that the factor structure of the Anxiety Sensitivity Index was invariant across age and gender. The factor scores also demonstrated differential correlations with symptoms of anxiety and depression. Results are discussed with regard to construct validation and understanding the structure of anxiety sensitivity in youth.

Adolescent↗