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PubMed2004

Partial tyrosinase-specific self tolerance by HLA-A*0201-restricted cytotoxic T lymphocytes in mice and man.

The human tyrosinase (hTyr) (369-377) cytotoxic T lymphocyte (CTL) epitope is presented by malignant melanoma and various nontransformed cells in association with human leukocyte antigen (HLA)-A*0201 (A2.1) and used for vaccination-based immunotherapy of melanoma patients. Its mouse homologue, mTyr (369-377), is naturally processed and bound by A2.1 with equivalent efficacy and thus enabled us to explore the effect of self tolerance on Tyr-specific T cells in different lines of A2.1 transgenic (Tg) mice and man. We found that self Tyr-reactive CTL in Tg mice and, importantly, in man were affected by partial tolerance resulting in only residual T lymphocytes of higher avidity for self Tyr along with low-avidity T cells to be present in the periphery. Immunizing mice with the xenogeneic nonself Tyr peptide facilitated the generation of self Tyr-reactive CTL. As compared to Tyr-reactive CTL induced by high amounts of the self Tyr epitope, however, the nonself antigen (Ag) had no effect on improving the avidity of self Tyr-specific mouse and human T cells. Depleting mice of CD25(+) T cells with and without CTL-associated Ag 4 (CTLA-4) blockade demonstrated that tolerance of Tyr-specific CTL was not regulated by CD4(+)CD25(+) T regulatory cells (Treg) or CTLA-4. Our studies have important implications for the design of anti-Tyr-based immunotherapeutics.

Animals↗
PubMed2004

Measurement of the sign and the magnitude of heteronuclear coupling constants from spin-state-edited J-cross-polarization NMR experiments.

New spin-state-selective (S3) NMR pulse sequences exclusively applying cross-polarization schemes to achieve optimum homonuclear and heteronuclear 1H-X coherence transfer are reported for the simple and accurate measurement of the magnitude and sign of heteronuclear coupling constants for samples at natural abundance. The proposed spin-edited HCP-TOCSY experiments are based on clean heteronuclear S3 excitation, generated by simultaneous co-addition of two independent in-phase and anti-phase components created during the mixing heteronuclear J-cross-polarization (HCP) step, which is finally transferred to other protons by a conventional homonuclear TOCSY mechanism. Selective 1D and non-selective 2D approaches for the easy determination of long-range proton-carbon and proton-nitrogen coupling constants on any protonated and non-protonated heteronuclei are presented and discussed for several organic molecules.

Carbon↗
PubMed2003

Assessment of homology-based predictions in CASP5.

This report describes the assessment of the homology-based predictions submitted to the fifth edition of the Critical Assessment of Methods for Protein Structure Prediction (CASP5) experiment. We assessed the ability of the methods to predict the overall fold, the portions of the structure that differ substantially between the target protein and its closest structural homologue and the conformation of the side-chains. We also compared the results with those obtained in previous editions of the experiment and derived some general conclusions about the state of the art of comparative modeling methods and their usefulness for experimentalists.

Computational Biology↗
PubMed1996

'External' proofreading of DNA replication errors and mammalian autonomous 3'-->5'exonucleases.

Mammalian nuclear DNA polymerases alpha and beta are known to be devoid of the editing 3'-->5' exonucleolytic activity. The base substitutions misinserted by these polymerases could be eliminated with two kinds of an 'external' proofreading carried out (1) by the 3'-->5' exonuclease function intrinsic to DNA polymerases delta and epsilon or/and (2) by the autonomous 3'-->5' exonucleases non-associated covalently with DNA polymerases. DNA polymerases delta and epsilon can be separated from autonomous 3'-->5' exonucleases by means of sedimentation. Ultracentrifugation of the nuclear extracts and cytosols from normal and regenerating rat liver as well as from total embryos has shown the bulk of the cellular 3'-->5' exonucleolytic activity is due to autonomous nucleases. Moreover, the level of such a specific activity correlates with the replicative status of the organs from adult animals: spleen > regenerating liver > normal liver > cardiac muscle > brain, maximum difference being an order of magnitude. In addition, autonomous exonucleases were shown to be the constituents of the multienzyme forms of DNA polymerases alpha and beta. Hence, autonomous 3'-->5' exonucleases seem to be the principal participants in an 'external' proofreading.

Animals↗
PubMed2005

Progress toward automated metabolic profiling of human serum: comparison of CPMG and gradient-filtered NMR analytical methods.

The investigation of drug delivery and metabolism requires the analysis of molecules in complicated biological matrices such as human serum. In NMR-based metabonomic analysis, T(2) relaxation editing with a CPMG filter is commonly used to suppress background signals from proteins and other endogenous components. Radio frequency pulse imperfections and incomplete irradiation across the spectral bandwidth can cause phase and baseline distortions in CPMG spectra. These distortions are exacerbated by water suppression techniques. Baseline correction methods included in commercially available data processing software packages may be incapable of producing artifact-free spectra. To increase the analytical precision of metabolic profiling, one NMR spectroscopist may be responsible for manually phasing and baseline correcting hundreds of spectra individually to remove operator-dependent variations, significantly reducing throughput. For metabonomic analysis of human serum, it was observed that the application of a pulsed field gradient filter produced (1)H NMR spectra well suited to automatic phasing routines. Superior baseline characteristics, an increased tolerance to radio frequency pulse imperfections, and improved water suppression were achieved. A concomitant reduction in signal intensity compared with the CPMG method was easily recovered by increasing the number of scans. Principal component analysis (PCA) of spectra, acquired under a variety of experimental conditions, revealed the improved reproducibility and robustness of (1)H NMR pulsed field gradient-filtered metabonomic analyses of serum compared to the CPMG method.

Female↗
PubMed2000

DNA polymerase of the T4-related bacteriophages.

The DNA polymerase of bacteriophage T4, product of phage gene 43 (gp43), has served as a model replicative DNA polymerase in nucleic acids research for nearly 40 years. The base-selection (polymerase, or Pol) and editing (3'-exonuclease, or Exo) functions of this multifunctional protein, which have counterparts in the replicative polymerases of other organisms, are primary determinants of the high fidelity of DNA synthesis in phage DNA replication. T4 gp43 is considered to be a member of the "B family" of DNA-dependent DNA polymerases (those resembling eukaryotic Pol alpha) because it exhibits striking similarities in primary structure to these enzymes. It has been extensively analyzed at the genetic, physiological, and biochemical levels; however, relationships between the in vivo properties of this enzyme and its physical structure have not always been easy to explain due to a paucity of structural data on the intact molecule. However, gp43 from phage RB69, a phylogenetic relative of T4, was crystallized and its structure solved in a complex with single-stranded DNA occupying the Exo site, as well as in the unliganded form. Analyses with these crystals, and crystals of a T4 gp43 proteolytic fragment harboring the Exo function, are opening new avenues to interpret existing biological and biochemical data on the intact T4 enzyme and are revealing new aspects of the microanatomy of gp43 that can now be explored further for functional significance. We summarize our current understanding of gp43 structure and review the physiological roles of this protein as an essential DNA-binding component of the multiprotein T4 DNA replication complex and as a nucleotide-sequence-specific RNA-binding translational repressor that controls its own biosynthesis and activity in vivo. We also contrast the properties of the T4 DNA replication complex to the functionally analogous complexes of other organisms, particularly Escherichia coli, and point out some of the unanswered questions about gp43 and T4 DNA replication.

Amino Acid Sequence↗
PubMed2000

Psychiatric disorders in juvenile patients with insulin-dependent diabetes mellitus.

The relationships of psychiatric characteristics to metabolic control and psychosocial functioning were examined in a group of 16 patients with insulin-dependent diabetes mellitus (IDDM) (mean age: 14.3+/-5.1 years, mean duration of follow-up: 5.0+/-2.3 years) and psychiatric disorders. The comparison is also made to 69 IDDM controls (mean age: 17.0+/-6.7 years) without psychiatric disorders. Metabolic control was evaluated in terms of glycosylated hemoglobin (HbA1c). Psychosocial functioning at both psychiatric treatment entry and discharge was assessed using the global assessment of functioning (GAF) scale. Subjects were divided into three subgroups - Somatoform Type (25%), Behavioral Type (50%) or Psychotic Type (25%) - according to the Diagnostic and Statistical Manual of Mental Disorders, third edition revised (DSM-III-R), based on semi-structured interviews. Four patients (25%) were diagnosed as having schizophrenia or schizoaffective disorder (Psychotic Type), which is rather rare. The mean HbA1c level in the Behavioral Type patients was significantly higher than in the other subgroups (P<0. 01). After psychiatric treatment a significant difference (P<0.0001) in the GAF Scale was observed in the Psychotic Type compared with the other subgroups. We conclude that the Behavioral Type is associated with poor metabolic control and that for the Psychotic Type, improved psychosocial functioning can be achieved through psychiatric treatment.

Adaptation, Psychological↗
PubMedDate not supplied

Frequency, comorbidity, and psychosocial impairment of anxiety disorders in German adolescents.

The frequency, comorbidity, and psychosocial impairment of anxiety disorders among German adolescents was estimated from a survey of 1,035 students aged 12-17 years. The adolescents were randomly selected from 36 schools in the province of Bremen, Germany. Anxiety disorders and other psychiatric disorders were coded based on criteria from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders, using the computerized Munich version of the Composite International Diagnostic Interview. Anxiety disorders occurred frequently in our sample of adolescents, with a rate of 18.6%. When considering the subtypes of anxiety disorders, phobia was the most common. Posttraumatic stress disorder and obsessive-compulsive disorder occurred less frequently with rates below 2%. Panic disorder and generalized anxiety disorder were the least common, with rates well below 1%. Anxiety disorders were significantly higher in girls than in boys, and that the rates increased with age. Comorbidity occurs quite frequently, both within the anxiety disorders and also with other psychiatric disorders. The most common pattern of comorbidity was that of anxiety and depressive disorders. Although a high number of anxiety cases were psychosocially impaired, at least during the worst episode of their disorders, only a few of them sought treatment for their problems. We conclude by discussing some research priorities in the area of anxiety disorders in children and adolescents.

Adaptation, Psychological↗
PubMed2002

Prognostic performance of the new classification of primary liver cancer of Japan (4th edition) for patients with hepatocellular carcinoma: a validation analysis.

The Japanese staging system that is generally used for hepatocellular carcinoma (HCC) (3rd edition) was considerably revised recently, especially T category. No study, however, has revealed how well the new classification (4th edition) works to stratify HCC patients at a pre-intervention stage. The purpose of this study is to assess the discriminatory value and predictive power of the 4th edition, and to compare its utility with the clinical utilities of the 3rd edition and the cancer of the liver Italian program (CLIP) score, as determined from 662 Japanese patients. We performed a retrospective analysis of the HCC diagnoses at four Japanese institutions from 1990 and 1998. Overall survival was the only end-point used in the analysis. The discriminatory ability and homogeneity of the 4th edition were compared to those of the 3rd edition and the CLIP score. As of January 1999, 440 patients (66.4%) had died. The overall median survival was 37.7 months. Liver function and tumor variables, which are already accounted for by the different scoring systems, were significantly associated with survival. Compared with the 3rd edition, the 4th editions' discriminatory ability (tested by the linear trend test) and homogeneity of survival within each category (tested by the likelihood ratio test) were enhanced in both the overall group of patients and the subgroups of patients receiving transcatheter arterial chemoembolizations and percutaneous ethanol injections. In patients receiving surgery, however, the 4th edition's abilities were the lowest among the indices. Multivariate analysis revealed that the CLIP score that includes liver function had additional explanatory power above that of the 4th edition. These findings indicate that the 4th edition has a higher stratification value than the 3rd edition. However, this benefit is due to the non-surgical patients, rather than to the surgical patients. If the 4th edition had an additional scoring system based on its original tumor staging and liver damage, it might be highly beneficial, although relative risk ratios of those should be analyzed.

Journal Article↗
PubMedDate not supplied

Report on a panel longitudinal study of college women's eating patterns and eating disorders: noncontinuum versus continuum measures.

The self-reported frequencies (prevalence and incidence) of eating patterns and disorders in a matched longitudinal sample of college women (N = 141) interviewed during their sophomore year (Time 1) and senior year (Time 2) were compared. The rate of eating disorders was assessed using a noncontinuum measure, the Eating Attitudes Test (Garner, Olmsted, Bohr, & Garfinkel, 1982), as well as continuum measures based on criteria in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1980). The noncontinuum measure revealed a prevalence rate of eating disorders per 2-year period comparable to that found in other studies of college student populations. The incidence rate per 2-year period was not of epidemic proportions. A sizable percentage of women appeared to get better from Time 1 to Time 2; a small percentage of women remained abnormal eaters. The continuum measurement uncovered a large group of women whose eating patterns were chronic but not severe enough to classify them as "abnormal" eaters. The implications of using different measures for defining and treating college women's eating disorders are discussed.

Feeding and Eating Disorders↗
PubMed2006

Twin gradients in APOBEC3 edited HIV-1 DNA reflect the dynamics of lentiviral replication.

The human immunodeficiency virus (HIV) Vif protein blocks incorporation of two host cell cytidine deaminases, APOBEC3F and 3G, into the budding virion. Not surprisingly, on a vif background nascent minus strand DNA can be extensively edited leaving multiple uracil residues. Editing occurs preferentially in the context of TC (GA on the plus strand) and CC (GG) depending on the enzyme. To explore the distribution of APOBEC3F and -3G editing across the genome, a product/substrate ratio (AA + AG)/(GA + GG) was computed for a series of 30 edited genomes present in the data bases. Two highly polarized gradients were noted each with maxima just 5' to the central polypurine tract (cPPT) and LTR proximal polypurine tract (3'PPT). The gradients are in remarkable agreement with the time the minus strand DNA remains single stranded. In vitro analyses of APOBEC3G deamination of nascent cDNA spanning the two PPTs showed no pronounced dependence on the PPT RNA:DNA heteroduplex ruling out the competing hypothesis of a PPT orientation effect. The degree of hypermutation varied smoothly among genomes indicating that the number of APOBEC3 molecules packaged varied considerably.

APOBEC Deaminases↗
PubMed2006

Using the Patient Health Questionnaire-9 to measure depression among racially and ethnically diverse primary care patients.

OBJECTIVE: The Patient Health Questionnaire depression scale (PHQ-9) is a well-validated, Diagnostic and Statistical Manual of Mental Disorders- Fourth Edition (DSM-IV) criterion-based measure for diagnosing depression, assessing severity and monitoring treatment response. The performance of most depression scales including the PHQ-9, however, has not been rigorously evaluated in different racial/ethnic populations. Therefore, we compared the factor structure of the PHQ-9 between different racial/ethnic groups as well as the rates of endorsement and differential item functioning (DIF) of the 9 items of the PHQ-9. The presence of DIF would indicate that responses to an individual item differ significantly between groups, controlling for the level of depression. MEASUREMENTS: A combined dataset from 2 separate studies of 5,053 primary care patients including non-Hispanic white (n=2,520), African American (n=598), Chinese American (n=941), and Latino (n=974) patients was used for our analysis. Exploratory principal components factor analysis was used to derive the factor structure of the PHQ-9 in each of the 4 racial/ethnic groups. A generalized Mantel-Haenszel statistic was used to test for DIF. RESULTS: One main factor that included all PHQ-9 items was found in each racial/ethnic group with alpha coefficients ranging from 0.79 to 0.89. Although endorsement rates of individual items were generally similar among the 4 groups, evidence of DIF was found for some items. CONCLUSIONS: Our analyses indicate that in African American, Chinese American, Latino, and non-Hispanic white patient groups the PHQ-9 measures a common concept of depression and can be effective for the detection and monitoring of depression in these diverse populations.

Adult↗
PubMed2005

maxdLoad2 and maxdBrowse: standards-compliant tools for microarray experimental annotation, data management and dissemination.

BACKGROUND: maxdLoad2 is a relational database schema and Java application for microarray experimental annotation and storage. It is compliant with all standards for microarray meta-data capture; including the specification of what data should be recorded, extensive use of standard ontologies and support for data exchange formats. The output from maxdLoad2 is of a form acceptable for submission to the ArrayExpress microarray repository at the European Bioinformatics Institute. maxdBrowse is a PHP web-application that makes contents of maxdLoad2 databases accessible via web-browser, the command-line and web-service environments. It thus acts as both a dissemination and data-mining tool. RESULTS: maxdLoad2 presents an easy-to-use interface to an underlying relational database and provides a full complement of facilities for browsing, searching and editing. There is a tree-based visualization of data connectivity and the ability to explore the links between any pair of data elements, irrespective of how many intermediate links lie between them. Its principle novel features are: the flexibility of the meta-data that can be captured, the tools provided for importing data from spreadsheets and other tabular representations, the tools provided for the automatic creation of structured documents, the ability to browse and access the data via web and web-services interfaces. Within maxdLoad2 it is very straightforward to customise the meta-data that is being captured or change the definitions of the meta-data. These meta-data definitions are stored within the database itself allowing client software to connect properly to a modified database without having to be specially configured. The meta-data definitions (configuration file) can also be centralized allowing changes made in response to revisions of standards or terminologies to be propagated to clients without user intervention.maxdBrowse is hosted on a web-server and presents multiple interfaces to the contents of maxd databases. maxdBrowse emulates many of the browse and search features available in the maxdLoad2 application via a web-browser. This allows users who are not familiar with maxdLoad2 to browse and export microarray data from the database for their own analysis. The same browse and search features are also available via command-line and SOAP server interfaces. This both enables scripting of data export for use embedded in data repositories and analysis environments, and allows access to the maxd databases via web-service architectures. CONCLUSION: maxdLoad2 http://www.bioinf.man.ac.uk/microarray/maxd/ and maxdBrowse http://dbk.ch.umist.ac.uk/maxdBrowse are portable and compatible with all common operating systems and major database servers. They provide a powerful, flexible package for annotation of microarray experiments and a convenient dissemination environment. They are available for download and open sourced under the Artistic License.

Data Interpretation, Statistical↗
PubMed2001

Validity of the CAGE questionnaire in an American Indian population.

OBJECTIVE: This study evaluated the performance of the CAGE questionnaire (a set of four questions about alcoholism) in an American Indian population. METHOD: We analyzed data from a cross-sectional study of 275 individuals (179 women) aged 21 years or older. Alcohol dependence was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Third Edition-Revised (DSM-III-R), based on a detailed psychiatric interview using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version. Accuracy of the CAGE questionnaire was quantified as sensitivity, specificity, likelihood ratios and the area under receiver operating characteristics (ROC) curves, using the DSM-III-R diagnosis as the reference. RESULTS: Of participants interviewed, 85% of men and 53% of women had a diagnosis of alcohol dependence by DSM-III-R. A CAGE score of > or = 2 had a sensitivity and specificity of 68% and 93%, respectively, in men and 62% and 79% in women, for the diagnosis of alcohol dependence. CAGE scores of 0, 1 and > or = 2 were associated with likelihood ratios of 0.3, 0.3 and 9.5, respectively, in men and 0.4, 0.7 and 1.5 in women. The area under the ROC curve was 81% for men and 75% for women. CONCLUSIONS: These findings suggest that the CAGE questionnaire is a valid screening method, in this population, for identifying people likely to have alcohol dependence.

Adult↗
PubMed1992

PHLIS: an electronic system for reporting public health data from remote sites.

Disease surveillance conducted by the Centers for Disease Control (CDC) in conjunction with state health departments provides databases of information to public health workers. These databases' utility is limited by the lag time from occurrence of disease events until records are available for analysis. We developed the Public Health Laboratory Information System (PHLIS), a PC-based electronic reporting system for entering, editing, and analyzing data locally and for transmitting data electronically to other state or federal offices. Advantages of PHLIS include reduction in paper handling, decrease in lag time between disease incident and availability of information for analysis, ability to rapidly examine data for clusters of disease, downloadable summary tables, data editing at site of input, data analysis capability, increased interaction among participants, and current data for responses to inquiries. PHLIS is available without cost and is transportable to other agencies, states, or countries.

Centers for Disease Control and Prevention, U.S.↗
PubMed1994

The AAMD Adaptive Behavior Scale--School Edition, Part Two: Test-retest reliability and parent-teacher agreement in a behavior disordered sample.

Test-retest reliability and parent-teacher agreement were estimated for Part Two of the AAMD Adaptive Behavior Scale--School Edition. Test-retest reliability was based on a subgroup of 20 students selected randomly from the total sample of 66; these were 7 students classified as Behavior Disordered, 7 students referred for behavior problems but not classified, and 6 students not referred or classified. Parent-teacher agreement was investigated for a subgroup of 25 students classified as Behavior Disordered. Test-retest reliability of .83 was significant, while parent-teacher agreement coefficients were nonsignificant. Such results are consistent with previous research using similar instruments. The implications are discussed and suggestions for research are presented.

Adaptation, Psychological↗
PubMed2004

Genetic relationship among gill-infecting Myxobolus species (Myxosporea) of cyprinids: molecular evidence of importance of tissue-specificity.

The importance of tissue-specificity was studied in Myxobolus spp. infecting the gills of 7 cyprinid species. The 18S rDNA of 10 Myxobolus species was amplified by optimised nested-PCR, resulting in approximately 1600 bp PCR products. Phylogenetic trees generated by distance matrix and parsimony analyses revealed 4 main groups. Muscle-infecting species all belonged to the same group, while members of 2 gill-infecting groups were clearly distinguishable on the basis of tissue-specificity, and were also recognisable by differences in spore morphology. On the basis of tissue tropism, phylogenetic relationships among the species examined indicate that genetic separation is a more ancient evolutionary feature than host-specificity.

Animals↗