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At least 829 records · Page 46Linked to original sources
PubMed2004

Ongoing development of two-dimensional polyacrylamide gel electrophoresis data standards.

We present an approach toward standardizing two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) data in support of developing a globally relevant proteomics consensus in order to provide more efficient database querying and data comparisons through the establishment of the necessary definitions and interdisciplinary reference fields for both the 2-D PAGE community, particularly in the proteomics area, and the clinical and experimental biological research communities, in general. This article covers the need for unifying the 2-D PAGE data through a common data repository, and its usefulness in data standards and data interoperability.

Databases, Protein↗
PubMed2004

Assessment of the sensitivity of the computational programs DEREK, TOPKAT, and MCASE in the prediction of the genotoxicity of pharmaceutical molecules.

Computational models are currently being used by regulatory agencies and within the pharmaceutical industry to predict the mutagenic potential of new chemical entities. These models rely heavily, although not exclusively, on bacterial mutagenicity data of nonpharmaceutical-type molecules as the primary knowledge base. To what extent, if any, this has limited the ability of these programs to predict genotoxicity of pharmaceuticals is not clear. In order to address this question, a panel of 394 marketed pharmaceuticals with Ames Salmonella reversion assay and other genetic toxicology findings was extracted from the 2000-2002 Physicians' Desk Reference and evaluated using MCASE, TOPKAT, and DEREK, the three most commonly used computational databases. These evaluations indicate a generally poor sensitivity of all systems for predicting Ames positivity (43.4-51.9% sensitivity) and even poorer sensitivity in prediction of other genotoxicities (e.g., in vitro cytogenetics positive; 21.3-31.9%). As might be expected, all three programs were more highly predictive for molecules containing carcinogenicity structural alerts (i.e., the so-called Ashby alerts; 61% +/- 14% sensitivity) than for those without such alerts (12% +/- 6% sensitivity). Taking all genotoxicity assay findings into consideration, there were 84 instances in which positive genotoxicity results could not be explained in terms of structural alerts, suggesting the possibility of alternative mechanisms of genotoxicity not relating to covalent drug-DNA interaction. These observations suggest that the current computational systems when applied in a traditional global sense do not provide sufficient predictivity of bacterial mutagenicity (and are even less accurate at predicting genotoxicity in tests other than the Salmonella reversion assay) to be of significant value in routine drug safety applications. This relative inability of all three programs to predict the genotoxicity of drugs not carrying obvious DNA-reactive moieties is discussed with respect to the nature of the drugs whose positive responses were not predicted and to expectations of improving the predictivity of these programs. Limitations are primarily a consequence of incomplete understanding of the fundamental genotoxic mechanisms of nonstructurally alerting drugs rather than inherent deficiencies in the computational programs. Irrespective of their predictive power, however, these programs are valuable repositories of structure-activity relationship mutagenicity data that can be useful in directing chemical synthesis in early drug discovery.

Computer Simulation↗
PubMed2006

A two-step procedure for constructing confidence intervals of trait loci with application to a rheumatoid arthritis dataset.

Preliminary genome screens are usually succeeded by fine mapping analyses focusing on the regions that signal linkage. It is advantageous to reduce the size of the regions where follow-up studies are performed, since this will help better tackle, among other things, the multiplicity adjustment issue associated with them. We describe a two-step approach that uses a confidence set inference procedure as a tool for intermediate mapping (between preliminary genome screening and fine mapping) to further localize disease loci. Apart from the usual Hardy-Weiberg and linkage equilibrium assumptions, the only other assumption of the proposed approach is that each region of interest houses at most one of the disease-contributing loci. Through a simulation study with several two-locus disease models, we demonstrate that our method can isolate the position of trait loci with high accuracy. Application of this two-step procedure to the data from the Arthritis Research Campaign National Repository also led to highly encouraging results. The method not only successfully localized a well-characterized trait contributing locus on chromosome 6, but also placed its position to narrower regions when compared to their LOD support interval counterparts based on the same data.

Arthritis, Rheumatoid↗
PubMed2006

A comparison of methods for intermediate fine mapping.

The arrival of highly dense genetic maps at low cost has geared the focus of linkage analysis studies toward developing methods for placing putative trait loci in narrow regions with high confidence. This shift has led to a new analytic scheme that expands the traditional two-stage protocol of preliminary genome scan followed by fine mapping through inserting a new stage in between the two. The goal of this new "intermediate" fine mapping stage is to isolate disease loci to narrow intervals with high confidence so that association studies can be more focused, efficient, and cost-effective. In this paper, we compared and contrasted five methods that can be used for performing this intermediate step. These methods are: the lod support approach, the generalized estimating equations (GEE) method, the confidence set inference (CSI) procedure, and two bootstrap methods. We compared these methods in terms of the coverage probability and precision of localization of the resulting intervals. Results from a simulation study considering several two-locus models demonstrated that the two bootstrap methods yield intervals with approximately correct coverage. On the other hand, the 1-lod support intervals, and those produced by the GEE method, tend to significantly undercover the trait locus, while the regions obtained by the CSI incline to overcover the gene position. When the observed coverage of the confidence intervals produced by all the methods was held to be the same, those obtained through the CSI procedure displayed a higher ability to localize loci, especially when these loci have a minor contribution to the trait and when the amount of data available for the analysis is relatively small. However, with very large sample sizes, lod support intervals emerged as a winner. Application of the methods to the data from the Arthritis Research Campaign National Repository led to intervals containing the position of a known trait locus for all methods, with the greatest precision achieved by the CSI.

Arthritis, Rheumatoid↗
PubMed2005

Factor XI deficiency database: an interactive web database of mutations, phenotypes, and structural analysis tools.

Factor XI (FXI) is the zymogen of a serine protease enzyme in the intrinsic pathway of blood coagulation and is an important factor in the creation of a stable fibrin clot. Deficiency of FXI leads to an injury-related bleeding disorder and is remarkable for the lack of correlation between bleeding symptoms and FXI coagulant activity (FXI:C). The FXI protein is composed of five domains: four tandem repeat domains of approximately 80 residues known as Apple (Ap) domains, and the catalytic serine protease (Sp) domain. A total of 65 mutations throughout the FXI gene (F11) have been reported in FXI deficient patients. An interactive web database of these mutations has been created (www.FactorXI.org) that integrates the phenotypic data with genetic data and structural homology models for the five FXI domains. The database provides a central repository for all reported genetic alterations within F11. With the use of recently developed visualization tools, each mutation can be highlighted on the structural models of the FXI domains together with an appropriate survey of patient data, such as FXI:C levels and FXI antigen levels. The database also enables new F11 mutations to be interpreted. The interactive design of this database will lead to a more comprehensive comparative understanding of the genetic factors that influence bleeding risk.

DNA Mutational Analysis↗
PubMed2006

The IMGT/HLA and IPD databases.

The IMGT/HLA database (www.ebi.ac.uk/imgt/hla) has provided a centralized repository for the sequences of the alleles named by the WHO Nomenclature Committee for Factors of the HLA System since 1998. Since its initial release, the database has rapidly grown in size and is recognized as the primary source of information for the study of sequences of the human major histocompatibility complex. The Immuno Polymorphism Database (IPD; www.ebi.ac.uk/ipd) is a set of specialist databases related to the study of polymorphic genes in the immune system. The IPD currently consists of four databases: IPD-KIR contains the allelic sequences of killer-cell immunoglobulin-like receptors; IPD-MHC is a database of sequences of the major histocompatibility complex of different species; IPD-HPA contains alloantigens expressed only on platelets (human platelet antigens or HPA); and IPD-ESTDAB provides access to the European Searchable Tumour Cell-Line Database, a cell bank of immunologically characterized melanoma cell lines.

Alleles↗
PubMed2007

The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models.

Atypical hemolytic uremic syndrome (aHUS) is a disease of hemolytic anemia, thrombocytopenia, and renal failure associated with defective alternative pathway (AP) complement control. Previously, we presented a database (www.FH-HUS.org) focusing on aHUS mutations in the Factor H gene (CFH). Here, new aHUS mutations are reported for the complement regulatory proteins Factor H (FH), Factor I (FI), and membrane cofactor protein (MCP). Additional mutations or polymorphisms within CFH have been associated with membranoproliferative glomerulonephritis (MPGN) and age-related macular degeneration (AMD). Accordingly, the database now includes substitutions that predispose to aHUS, MPGN, and AMD. For this, structural models for the domains in MCP and FI were developed using homology modeling. With this new database, patients with mutations in more than one gene can be displayed and interpreted in a coherent manner. The database also includes SNP polymorphisms in CFH, MCP, and IF. There are now a total of 167 genetic alterations, including 100 in CFH, 43 in MCP, and 24 in IF. The mutations characterize clinical outcomes that vary from several AMD-associated polymorphisms to those associated with aHUS, MPGN, or FI deficiency. A consensus short complement regulator (SCR) domain structure facilitated the interpretations of aHUS mutations. Specific locations within this consensus domain often correlate with the occurrence of clinical phenotypes. The AMD Tyr402His polymorphism is structurally located at a hotspot for several aHUS mutations. The database emphasizes the causative role of the alternative pathway of complement in disease and provides a repository of knowledge to assist future diagnosis and novel therapeutic approaches.

Amino Acid Sequence↗
PubMed1995

Extracellular matrix synthesized by clonal osteogenic cells is osteoinductive in vivo and in vitro: role of transforming growth factor-beta 1 in osteoblast cell-matrix interaction.

ROB-C26 (C26) is a multipotential, clonal cell line known to express several members of the TGF-beta superfamily and to become more osteoblastic (e.g., express higher levels of alkaline phosphatase) upon treatment with 10(-6)M retinoic acid (RA). We hypothesize that the expression of this more osteoblastic phenotype subsequent to RA exposure is the result of the treated cell's extracellular matrix (ECM) becoming a repository and active source of putative osteoinductive growth factors including, specifically, select members of the TGF-beta superfamily. To test this hypothesis, we isolated the ECM from RA-treated and untreated C26 cells and assessed them for their ability to promote osteogenic differentiation in vivo and in vitro. We then explored whether the latter activities could be attributed specifically to TGF-beta 1. We found that the ECM of treated cells isolated by cell lysis and extensive washing induced endochondral bone formation in vivo when implanted into the thigh muscles of athymic nude mice and stimulated alkaline phosphatase (ALP) activity in vitro in freshly plated C26 cells. This latter stimulation was comparable to levels observed with direct RA treatment. This latter in vitro activity was only very partially mimicked by the ECM prepared from untreated cells and not duplicated at all by RA-treated collagen or the ECM from another RA-treated multipotential cell line. Moreover, the in vivo osteoinductive effect of the treated C26 cell ECM was not duplicated by comparable ECM prepared from untreated cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed2004

Cystic fibrosis transmembrane conductance regulator in human and mouse red blood cell membranes and its interaction with ecto-apyrase.

Elevated blood ATP and increased red blood cell (RBC) ATP transport is associated with cystic fibrosis (CF). In this report, we demonstrate the presence of the wild-type and the DeltaF508 mutant form of the CF transmembrane conductance regulator protein in RBC membranes and its putative interaction with ecto-apyrase, an ATP hydrolyzing enzyme also present in the RBC membrane. RBC membranes of control and DeltaF508 individuals and of wild-type and CF transmembrane conductance regulator-knockout mice were examined by immunoblot using several antibodies directed against different epitopes of this protein. These experiments indicated that human RBC membranes contain comparable amounts of the wild-type CF transmembrane conductance regulator protein and the DeltaF508 mutant form of the protein, respectively. CF transmembrane conductance regulator protein was also detected in wild-type mouse RBC membranes but not in the gene knockout mouse RBC membranes. Antibodies directed against ecto-apyrase co-immunoprecipitated CF transmembrane conductance regulator protein of human RBC membranes indicating a physical interaction between these two membrane proteins consistent with ATP transport and extracellular hydrolysis. We conclude that RBCs are a significant repository of CF transmembrane conductance regulator protein and should provide a novel system for evaluating its expression and function.

Adenosine Triphosphate↗
PubMed1996

Cell line banks and their role in cancer research.

The utility of centralized cell banks in providing reference cultures for cancer research is reviewed. Procedures applied at The American Type Culture Collection in development, maintenance and expansion of such a resource are discussed for example, with emphasis on human tumor cell lines. The various categories of cell-line holdings are explained, and status with regard both to the numbers of lines available and distribution experienced are documented. The locations of other national cell repositories plus contact data are provided.

Adolescent↗
PubMed1985

Determination of human IgG and IgM class antibodies to West Nile virus by enzyme linked immunosorbent assay (ELISA).

An enzyme-linked immunosorbent assay (ELISA) was developed and used for the detection of IgG and IgM antibodies to West Nile virus in human sera. Thirteen paired sera of clinical cases and 24 control sera taken randomly from a blood bank repository were tested. The sera were reacted in microtiter plates coated with PEG-treated WNV antigen. IgG or IgM antibodies were quantitated by the use of alkaline-phosphatase-conjugated anti-human IgG or IgM antibodies. Of the 24 randomly collected serum samples, 7 were positive in the IgG-ELISA test. One positive by the IgM-ELISA was found to contain rheumatoid factor. In 12 of 13 paired sera of clinical cases, IgM as well as IgG antibodies were detected in the second serum sample taken about 3 wk after the onset of clinical signs. The IgM positive sera were screened for rheumatoid factor (RF) on IgG-coated plates. None of them contained RF. Antibody titers obtained by ELISA showed a good correlation with titers obtained by hemagglutination inhibition, complement fixation, and neutralization tests. The ELISA tests for detection of IgM and IgG antibodies to WNV therefore can replace the other serological methods for epidemiological surveillance and diagnostic purposes.

Antibodies, Viral↗
PubMed1986

Biochemistry and antigenicity of osteoarthritic and rheumatoid cartilage.

The purpose of this study was to test whether cartilage serves as the source or repository of antigenic components active in the stimulation of inflammation in rheumatoid arthritis through an analysis of peripheral blood lymphocyte proliferation. Articular cartilage samples were obtained from patients with osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis undergoing joint replacement surgery. Each sample was homogenized and characterized biochemically with respect to the content of proteoglycan, collagen, and immunoglobulin. Proteoglycan content of rheumatoid cartilage was reduced by 71% when compared to osteoarthritic cartilage; the proteoglycan content of ankylosing spondylitis cartilage was reduced by 40% when compared to osteoarthritic cartilage. Immunoglobulins were detectable in all cartilage samples when analyzed by ELISA or end-plate titration. Lymphocyte proliferation, quantified by uptake of 3H-thymidine, was unaltered by addition of cartilage fragments, low (saline) and high salt extracts (2.0 M CaCl2), or cartilage residues. Both autologous and heterologous lymphocytes were tested against the cartilage samples with no difference in reactivity. Purified bovine articular proteoglycans and Type II collagen were also inactive. Although tetanus toxoid and phytohemagglutinin were effective stimulants of proliferation, lymphocytes from arthritis patients were suppressed relative to those of normal individuals. Analysis of arthritic articular cartilage by these techniques failed to demonstrate the presence of antigen(s) stimulating proliferation of peripheral blood lymphocytes.

Adult↗
PubMed2001

Soluble tubulin complexes in oocytes of the common leopard frog, Rana pipiens, contain gamma-tubulin.

Oocytes of the leopard frog, Rana pipiens, contain soluble tubulin which was previously shown to exist predominantly in megadalton (MDa) fractions and that fails to readily assemble in vitro. In order to further characterize these tubulin complexes, DEAE Sepharose chromatography, Sephacryl S-300 size exclusion columns and specific immunoprecipitation were used. The results revealed the presence of alpha-, beta-, and gamma-tubulin associated with several other proteins in the soluble fraction of Rana pipiens ovarian oocytes. These Rana oocyte tubulin complexes appear to be analogous to those recently reported in Xenopus ovulated eggs as gamma-tubulin ring complexes. This seems true since both size (estimates, i.e. approximately 2MDa) and protein components are similar. Furthermore, both alpha- and gamma-tubulin antibodies immunoprecipitated identical protein bands from Rana oocyte soluble fraction. These putative Rana gamma-tubulin ring proteins include 107, 97, 95, 90 and 75 kDa components which are similar in size to those found in Xenopus and other species. Rana appears to belong to a select group in which gamma-tubulin complexes contain significant alpha- and beta-tubulin (i.e., Xenopus and sheep), while other species such as Drosophila, Aspergillus, Saccharomyces, human cells and many other mammalian cells tested lack the other tubulin components. The heterogeneity in both size and protein components of Rana oocyte gamma-tubulin ring complexes may reflect different states of tubulin complex assembly. The lower vertebrate oocyte is hypothesized to act as a repository and prestaging point for the assembly of gamma-tubulin ring complexes which will become the maternal contribution to the centrosomes of the embryo. While the gamma-tubulin ring complexes of vertebrate eggs have been described previously, this is the first report biochemically characterizing soluble gamma-tubulin complexes in vertebrate ovarian oocytes.

Animals↗
PubMed1995

McArdle's disease: molecular genetics and metabolic consequences of the phenotype.

McArdle's disease is defined as a lack of functional muscle glycogen phosphorylase. Analysis of the myophosphorylase gene has demonstrated substantial heterogeneity in the mutations that cause the disease, but in almost all individuals, the molecular phenotype is the absence of the protein in skeletal muscle. Muscle glycogen phosphorylase is a major repository of vitamin B6 in the body, accounting for at least 80% of the total body pool. In McArdle's patients, this pool is therefore missing, introducing the possibility that vitamin B6 metabolism might be altered in these individuals. Preliminary data have shown that McArdle's patients show signs of a subclinical vitamin B6 deficiency, and that oral vitamin B6 supplementation can improve vitamin B6 status and enhance fatigue resistance in muscle.

Base Sequence↗
PubMed2002

Epidermal stem cells.

The clinical implications of understanding epidermal stem cell biology abound. Thousands of burns victims across the world have benefited from early research into the proliferation of epidermal keratinocytes in vitro. Advances now indicate there are a number of stem cell repositories within the epidermis, two of which, the interfollicular epidermis and the bulge region of the hair follicle, may supply each other when damaged. This review details the progress made in the identification and characterisation of stem cells within the epidermis and discusses the molecules involved in the epidermal stem cell's choice of fate. Finally, the skin, like bone marrow, could be a readily accessible source of stem cells for therapeutic intervention and evidence of skin stem cell plasticity is highlighted.

Animals↗
PubMed2002

Prostatic stem cells.

Multipotent cells within the epithelial compartment, together with phenotypically 'plastic' mesenchyma cells (stromal stem cells), provide a repository of protected genetic information from which the structure, stability and functionality of the prostate gland can be maintained. However, mere preservation of cells in a non-dividing state is insufficient to provide the necessary reservoir of information from which the structure and function of the prostate gland can be retained or recreated. Rather, there is a constant dynamic interaction, at the level of information exchange, between stem cells (whether epithelial or mesenchymal) and their surrounding environment (both humoral and physical). Thus, with respect to epithelial stem cells, these reside within environmental 'niches' which allow their controlled and limited proliferation while preserving genomic integrity. Similar 'mesenchymal niches' are also predicted to occur, although not yet identified, thus providing the multipotent source from which the full spectrum of stromal phenotypes might be regenerated. Recent data from studies of the haematopoietic and hepato-biliary systems indicate that the potential scope of stem cells far exceeds the immediate phenotypic complement of those tissues within which they originate, being dependent upon their precise environment as well as their genomic integrity.

Cell Differentiation↗
PubMed2006

Population antibiotic susceptibility for Streptococcus pneumoniae and treatment outcomes in common respiratory tract infections.

PURPOSE: Antibiotic-resistant Streptococcus pneumoniae potentially threatens the successful treatment of common respiratory tract infections (RTIs); however, the relationship between antibiotic resistance and treatment outcomes remains unclear. We aimed to test the hypothesis that higher in vitro penicillin and erythromycin nonsusceptibility levels among clinical isolates of S. pneumoniae are associated with higher risk of treatment failure in suppurative acute otitis media (AOM), acute sinusitis, and acute exacerbation of chronic bronchitis (AECB). METHODS: We conducted a population-level analysis using treatment outcomes data from a national, managed-care claims database, and antibiotic susceptibility data from a national repository of antimicrobial susceptibility results between 1997 and 2000. Treatment outcomes in patients with suppurative AOM, acute sinusitis, or AECB receiving selected macrolides or beta-lactams were assessed. Associations between RTI-specific treatment outcomes and antibiotic nonsusceptibility were determined using Spearman correlation coefficients with condition-specific paired outcome and susceptibility data for each region and each year. RESULTS: There were 649 552 available RTI outcomes and 7252 susceptibility tests performed on S. pneumoniae isolates. There were no statistically significant trends across time for resolution proportions following treatment by either beta-lactams or macrolides among any of the RTIs. Correlation analyses found no statistically significant association between S. pneumoniae susceptibility and RTI treatment outcomes apart from a significant positive association between of erythromycin nonsusceptibility in ear isolates and macrolide treatment resolution for suppurative AOM. CONCLUSION: On the population level, in vitro S. pneumoniae nonsusceptibility to macrolide or beta-lactam antibiotics was not associated with treatment failure in conditions of probable S. pneumoniae etiology.

Acute Disease↗
PubMed2003

The proteomics standards initiative.

The Proteomics Standards Initiative (PSI) aims to define community standards for data representation in proteomics and to facilitate data comparison, exchange and verification. Progress has been made in the development of common standards for data exchange in the fields of both mass spectrometry and protein-protein interaction. A proteomics-specific extension is being created for the emerging American Society for Tests and Measurements mass spectrometry standard, which will be supported by manufacturers of both hardware and software. A data model for proteomics experimentation is under development and discussions on a public repository for published proteomics data are underway. The Protein-Protein Interactions group expects to publish the Level 1 PSI data exchange format for protein-protein interactions soon and discussions as to the content of Level 2 have been initiated.

Biochemistry↗