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At least 1,333 records · Page 74Linked to original sources
PubMed1999

Molecular polymorphism of the syndecans. Identification of a hypo-glycanated murine syndecan-1 splice variant.

We have identified a cDNA that encodes a variant form of murine syndecan-1. The variant cDNA lacks the sequence corresponding to the first 132 nucleotides of the third exon of the syndecan-1 gene. The corresponding message is rare. The alternative splice respects the reading frame and deletes 44 amino acids from the protein, joining the S45GS47GT sequence to a variant immediate downstream context. This sequence context initiates with alanine instead of glycine as residue 50, reducing the number of SGXG sequence motifs in the protein from two to one. Expression of this variant syndecan-1 in Madin-Darby canine kidney or MOLT-4 cells yielded a recombinant proteoglycan with a reduced number and clustering of the heparan sulfate chains. Both the conversions of Ala50 and of Lys53 into glycine enhanced the heparan sulfate substitution of the variant protein. These findings support the concept that serine-glycine dipeptide signals for glycosaminoglycan/heparan sulfate synthesis depend on sequence context (Zhang, L., David, G., and Esko, J. D. (1995) J. Biol. Chem. 270, 27127-27135) and imply that alternative splicing mechanisms may in part control the molecular polymorphism of syndecan-1 and, therefore, the efficiency and versatility of this protein in its co-receptor functions.

Alternative Splicing↗
PubMed2001

The hairpin loop but not the bulged C of the iron responsive element is essential for high affinity binding to iron regulatory protein-1.

Vertebrates control intracellular iron concentration principally through the interaction of iron regulatory proteins with mRNAs that contain an iron responsive element, a small hairpin with a bulged C. The hairpin loop and bulged C have previously been assumed to be critical for binding and have been proposed to make direct contact with the iron regulatory proteins. However, we show here that a U or G can be substituted for the bulged C provided that specific nucleotides are also present within internal loops. The K(d), IC(50) and chemical modifications of the iron responsive element variants are similar to the wild-type. Results are more consistent with a role in which the C-bulge functions to orient the hairpin for optimal protein binding rather than to directly contact the protein. Characterization of these novel iron responsive element variants may facilitate the identification of additional mRNAs whose expression is controlled by iron regulatory proteins, as well as provide insight into the nature of a critical RNA-protein interaction.

Base Sequence↗
PubMed2006

Exploration, normalization, and genotype calls of high-density oligonucleotide SNP array data.

In most microarray technologies, a number of critical steps are required to convert raw intensity measurements into the data relied upon by data analysts, biologists, and clinicians. These data manipulations, referred to as preprocessing, can influence the quality of the ultimate measurements. In the last few years, the high-throughput measurement of gene expression is the most popular application of microarray technology. For this application, various groups have demonstrated that the use of modern statistical methodology can substantially improve accuracy and precision of the gene expression measurements, relative to ad hoc procedures introduced by designers and manufacturers of the technology. Currently, other applications of microarrays are becoming more and more popular. In this paper, we describe a preprocessing methodology for a technology designed for the identification of DNA sequence variants in specific genes or regions of the human genome that are associated with phenotypes of interest such as disease. In particular, we describe a methodology useful for preprocessing Affymetrix single-nucleotide polymorphism chips and obtaining genotype calls with the preprocessed data. We demonstrate how our procedure improves existing approaches using data from 3 relatively large studies including the one in which large numbers of independent calls are available. The proposed methods are implemented in the package oligo available from Bioconductor.

Algorithms↗
PubMed2003

"Do-it-yourself" dementia testing: issues regarding an Alzheimer's home screening test.

The Early Alert Alzheimer's Home Screening Test (AHST) is a variant of the Smell Identification Test (SIT) and the Cross-Cultural Smell Identification Test (CC-SIT), and recently became available for purchase by the general public. The validity and the practical utility of routine screening for individuals with asymptomatic cognitive impairment has not been established. There are considerable specific methodological concerns regarding the use of the AHST including the association of olfactory impairment with (a) age in the absence of cognitive impairment, (b) numerous acute and/or chronic medical conditions, and (c) lifestyle habits and social and/or demographic variables. General public misunderstanding of the difference between a screening and a diagnostic test, primary care physicians' frequent confusion about follow-up mechanisms for newly diagnosed patients with dementia, the possible lack of perceived counseling options for those self-diagnosed, and abuse of test findings create distinct possibilities for misuse of this test. The marketing of the AHST and its general use without appropriate public health educational safeguards is inappropriate and may be unethical.

Aged↗
PubMed2002

Angiotensin-1-converting enzyme (ACE) plasma concentration is influenced by multiple ACE-linked quantitative trait nucleotides.

Circulating angiotensin-1-converting enzyme (ACE) is a highly heritable trait, and a major component of the genetic variance maps to the region of the ACE gene. The strong effect of the locus, and the interest in ACE as a candidate gene for cardiovascular disorders, has led to extensive investigation of its relationship to the ACE phenotype, providing one of the most complete examples of quantitative trait locus (QTL) analysis in humans. Resequencing of ACE followed by haplotype analysis in families of British and French origin has shown that the genetic variants that are primarily associated with the ACE trait map to an 18 kb interval flanked by two intragenic, ancestral recombination breakpoints. This critical interval contains dozens of ACE-associated variants in Caucasians, but identification of which of these directly influence ACE concentration is ambiguous because of the almost complete linkage disequilibrium in European populations. In a complementary sequencing and genotyping study of individuals from West African families, we show that this population has much greater haplotype diversity across the gene. Through analysis of the contrasting relationships of the trait phenotype with haplotypes that carry different allelic combinations from those observed in Caucasians, we demonstrate that (at least) two major intragenic sites within the critical interval and (at least) one minor promoter site are associated with the ACE quantitative trait through additive effects. These results point to the importance of analysing diverse populations with different gene genealogies in gene-association studies.

Black People↗
PubMed2003

Advanced computational techniques for re-sequencing DNA with polymerase signaling assay arrays.

Re-sequencing, the identification of the specific variants in a sequence of interest compared with a known genomic sequence, is a ubiquitous task in today's biology. Universal arrays, which interrogate all possible oligonucleotides of a certain length in a target sequence, have been suggested for computationally determining a polynucleotide sequence from its oligonucleotide content. We present here new methods that use such arrays for re-sequencing. Our methods are applied to data obtained by the polymerase signaling assay, which arrays single-based primer extension reactions for either universal or partial arrays of pentanucleotides. The computational analysis uses the spectrum alignment algorithm, which is refined and enhanced here in order to overcome noise incurred by the use of such short primers. We present accurate re-sequencing results for both synthetic and amplified DNA molecules.

Algorithms↗
PubMed2003

Epidemiological, clinical and laboratory aspects of sandfly fever.

PURPOSE OF REVIEW: Sandfly fever viruses are still a significant health problem in many regions of the world, such as Africa, the Mediterranean basin, the Middle East, and Central Asia. This review provides an update on the advances in knowledge about epidemiological, clinical, and laboratory aspects of infections caused by Toscana, Sicilian and Naples viruses. RECENT FINDINGS: Diagnosis of Toscana virus infection has been facilitated by new molecular methods and by immunoenzymatic tests based on the recombinant nucleoprotein. Gene analysis has allowed identification of circulating Toscana variants possibly involved in the protean pathomorphism and extreme variability of the clinical picture. New attention has been addressed to the antigenic properties of the viral proteins (the nucleoprotein N and the surface glycoproteins G1 and G2), in order to understand their immunogenetic role. High genetic divergence within the serocomplexes belonging to each of the Sicilian and the Naples viruses has suggested that infection with one genotype may not completely immunize against infection with all other genotypes in a given serocomplex. These findings could serve as a basis for vaccine development and may account for reports of multiple episodes of sandfly fever in the same host. Recently, the performance of analysis models based on weather data and reported vector surveys has allowed the prediction of the risk of acquiring sandfly infection in the endemic geographic areas. SUMMARY: Recent developments include a better knowledge of the epidemiological, clinical, and laboratory aspects of sandfly infection, while the search for effective drugs and vaccines is still in progress.

Animals↗
PubMedDate not supplied

Coprocytobiology: on the nature of cellular elements from stools in the pathophysiology of colonic disease.

The gastrointestinal epithelium is known to undergo constant and rapid renewal resulting in millions of cells being shed into the fecal stream every day. The conventional wisdom was that these cells disintegrate upon exfoliation and will not survive the transit through the intestinal tract. In 1990, we (P.N.) made the discovery that a significant number of these cells remain intact and viable and that they can be isolated. The implications of this important discovery became apparent when we demonstrated that these cells are exclusively of colonic origin, are anatomically representative of the entire colon, and can be used for clinical investigations of disease processes. The term coprocytobiology (CCB) was coined to encompass the broad range of applications of this new technology. The somatic cell sampling and recovery (SCSR) process involves the isolation of exfoliated colonocytes from a small sample of stool ( approximately 1 g) collected and transported in a unique medium at ambient temperature, providing cells for the detection of a number of biomarkers of disease propensity. These exfoliated colonocytes express cytokeratins indicating epithelial lineage as well as colon-specific antigen. Over the years, the study of exfoliated colonocytes has provided striking new insights into the biology of colon cancer and inflammatory bowel disease, including detection of p53 gene mutations, reverse transcriptase polymerase chain reaction amplification, and identification of CD44 splice variants, neoplasia-associated specific binding of plant lectins, and expression of COX-2, the inducible form of cyclooxygenase. The functional diversity of cells isolated by SCSR is revealed by the demonstration of cell surface markers such as secretory component, IgA, and IgG on the one hand and the amplification and cloning of the human insulin receptor and the expression of the multidrug resistance gene mdr-1 on the other hand. This review portrays the immense potential of CCB as a powerful tool for investigating the pathophysiology of disease, identifying genetic variants in pharmacogenetics, assessment of mucosal immunity, and several other applications that use somatic cells.

Antigens, Neoplasm↗
PubMed2006

Identification of alternative amino acid substitutions in drug-resistant variants of the HIV-1 reverse transcriptase.

OBJECTIVE/DESIGN: To identify new drug-resistance-associated mutations in the HIV-1 reverse transcriptase (RT) protein, we screened the RT sequence database of our hospital for alternative amino acid substitutions at known RT drug-resistance positions. METHOD: The genotypic database used for this analysis contained 1322 RT sequences from 1015 patients. We analysed this RT database with a focus on alternative mutations at RT positions known to be involved in drug resistance. The patterns of drug resistance associated with these alternative mutations were investigated in a separate database containing genotype and drug-susceptibility results. RESULTS: We identified multiple alternative resistance-associated mutations at amino acid positions 44, 62, 67, 69, 70, 74, 75, 103, 181, 190, 210, and 219 in RT. Phenotypic analysis indicated that drug-resistance properties of the alternative Y181V and L74I mutants are similar, but not identical, to that of the well-known Y181C and L74V mutations. CONCLUSION: This initial survey indicates that many resistance-associated phenomena can be distilled from existing data. These findings endorse a more extensive analysis by computerized methods.

Anti-HIV Agents↗
PubMed2005

Understanding the genetic contribution to rheumatoid arthritis.

PURPOSE OF REVIEW: The identification of the genetic variants that mediate the risk for susceptibility and severity of rheumatoid arthritis will allow the development of new drug targets and also increase the ability to predict disease course. Technical and methodologic progress has fueled the advances in this field. RECENT FINDINGS: The second risk factor for rheumatoid arthritis, the PTPN22 polymorphism, has been identified. This genetic variant regulates the threshold of T cell activation. Intriguingly, this variant is a risk factor for diabetes as well. Moreover, it has been shown that multiple genetic variants in one pathway (both in a transcription factor, RUNX-1, as in the transcription factor binding site of RUNX1 in the SLC22A4 gene) can each confer very small risks but by gene-gene interactions can confer a ninefold risk for rheumatoid arthritis. These genetic risk factors have been found to confer risk for multiple autoimmune diseases. Phenotype-genotype interactions were described by the enhanced prevalence of a rheumatoid arthritis-specific autoantibody (anti-cyclic citrullinated peptide antibodies) in rheumatoid arthritis patients that harbor the rheumatoid arthritis-associated human leukocyte antigen class II genes, the shared epitope alleles. An environmental factor, smoking was demonstrated to confer risk for rheumatoid arthritis, especially in patients positive for both shared epitope and rheumatoid arthritis-specific anti-cyclic citrullinated peptide antibodies. SUMMARY: Two new pathways, T cell receptor signaling and a hematopoietic-specific signal transduction pathway, have been discovered that allow future pharmacologic interventions. The description of the new genetic risk factors and the interaction with environmental triggers as well as phenotypic features are gradually expanding the ability to predict disease susceptibility and course.

Arthritis, Rheumatoid↗
PubMed2005

Bilateral, persistent serous macular detachments with Waldenström's macroglobulinemia.

PURPOSE: Waldenström's macroglobulinemia is a rare, malignant lymphoplasmacytic disorder characterized by the monoclonal proliferation of immunoglobulin type M (IgM) producing B-lymphocytes. Ocular manifestations of Waldenström's macroglobulinemia have been described in association with the conjunctiva, cornea, uvea, retina, and periocular adnexa. Only rarely have macular findings, particularly serous macular detachments, been described in the presence of monoclonal hypergammaglobulinemias. The majority of reports to date have documented resolution of these serous macular detachments after treatment with blood plasmapheresis. This report presents a case of bilateral, persistent serous macular detachments in the presence of Waldenström's macroglobulinemia. CASE REPORT: A 53-year-old black man presented with gradual bilateral reduction in visual acuity over the last 2 months. He revealed having been diagnosed with Waldenström's macroglobulinemia approximately 1 month before presentation. He also reported having undergone multiple plasmapheresis treatments in conjunction with systemic chemotherapy over the same period. Funduscopic and fluorescein angiographic examination revealed bilateral, serous macular detachments in the presence of mild venous stasis retinopathy secondary to serum hyperviscosity. Subsequent funduscopic evaluations and serial optical coherence tomography readings confirmed the persistence of the serous detachments despite multiple plasmapheresis treatments. CONCLUSIONS: Although the funduscopic manifestations of excess serum immunoglobulins are typically the sequelae of circulatory stasis, the serum hyperviscosity induced in Waldenström's macroglobulinemia has been shown on rare occasions to induce serous macular detachments. Physical elimination of the excess macroglobulins through plasmapheresis is quite effective in resolving the neurosensory detachments induced by Waldenström's macroglobulinemia. Only a fraction of neurosensory detachments resulting from Waldenström's macroglobulinemia persist despite multiple plasmapheresis treatments. Novel angiographic evidence of retinal pigment epithelium atrophy beneath the area corresponding to the serous detachment provides a plausible explanation for unresponsive nature of this presentation. Identification of this rare variant of the classic angiographically silent macula known to occur with Waldenström's macroglobulinemia can aid the clinician in determining a patient's potential response to plasmapheresis and their final visual prognosis.

Fluorescein Angiography↗
PubMed2007

Single nucleotide polymorphism array analysis of cancer.

PURPOSE OF REVIEW: Classifying tumors and identifying therapeutic targets requires a description of the genetic changes underlying cancer. Single nucleotide polymorphism (SNP) arrays provide a high-resolution platform for describing several types of genetic changes simultaneously. With the resolution of these arrays increasing exponentially, they are becoming increasingly powerful tools for describing the genetic events underlying cancer. RECENT FINDINGS: The ability to map loss of heterozygosity (LOH) and overall copy number variations using SNP arrays is known. Techniques have recently been developed to map LOH at high resolution in the absence of paired normal data. Copy number variations described by SNP array studies are now reaching resolutions enabling the identification of novel oncogenes and tumor suppressor genes. The ability to determine allele-specific copy number changes has only recently been described. Moreover, SNP arrays offer a high-throughput platform for large-scale association studies that are likely to lead to the identification of multiple germline variants that predispose to cancer. SUMMARY: SNP arrays are an ideal platform for identifying both somatic and germline genetic variants that lead to cancer. They provide a basis for DNA-based cancer classification and help to define the genes being modulated, improving understanding of cancer genesis and potential therapeutic targets.

Chromosome Aberrations↗
PubMed2003

Heterologous expression of laccase cDNA from Ceriporiopsis subvermispora yields copper-activated apoprotein and complex isoform patterns.

Analysis of genomic clones encoding a putative laccase in homokaryon strains of Ceriporiopsis subvermispora led to the identification of an allelic variant of the previously described lcs-1 gene. A cDNA clone corresponding to this gene was expressed in Aspergillus nidulans and in Aspergillus niger. Enzyme assays and Western blots showed that both hosts secreted active laccase. Relative to the isozymic forms of the native C. subvermispora enzyme, the A. niger-produced laccase had a higher molecular mass and gave a single band on IEF gels. In contrast, A. nidulans transformants secreted several isoforms remarkably similar to those of the native system. Considered together with previously reported Southern blots and protein sequencing, expression in A. nidulans supports the view that C. subvermispora has a single laccase gene and that multiple isoforms result from post-translational processes. In addition, several lines of evidence strongly suggest that under copper limitation, A. nidulans secretes apoprotein which can be reconstituted by a short incubation with Cu(I) and to a lesser extent with Cu(II).

Apoproteins↗
PubMed2006

Accurate and reliable high-throughput detection of copy number variation in the human genome.

This study describes a new tool for accurate and reliable high-throughput detection of copy number variation in the human genome. We have constructed a large-insert clone DNA microarray covering the entire human genome in tiling path resolution that we have used to identify copy number variation in human populations. Crucial to this study has been the development of a robust array platform and analytic process for the automated identification of copy number variants (CNVs). The array consists of 26,574 clones covering 93.7% of euchromatic regions. Clones were selected primarily from the published "Golden Path," and mapping was confirmed by fingerprinting and BAC-end sequencing. Array performance was extensively tested by a series of validation assays. These included determining the hybridization characteristics of each individual clone on the array by chromosome-specific add-in experiments. Estimation of data reproducibility and false-positive/negative rates was carried out using self-self hybridizations, replicate experiments, and independent validations of CNVs. Based on these studies, we developed a variance-based automatic copy number detection analysis process (CNVfinder) and have demonstrated its robustness by comparison with the SW-ARRAY method.

Algorithms↗
PubMed2005

Proteomic identification of the involvement of the mitochondrial rieske protein in epilepsy.

PURPOSE: Kindled seizures are widely used to model epileptogenesis, but the molecular mechanisms underlying the attainment of kindling status are largely unknown. Recently we showed that achievement of kindling status in the Sprague-Dawley rat is associated with a critical developmental interval of 25 +/- 1 days; the identification of this long, well-defined developmental interval for inducing kindling status makes possible a dissection of the cellular and genetic events underlying this phenomenon and its relation to normal and pathologic brain function. METHODS: By using proteomics on cerebral tissue from our new rat kindling model, we undertook a global analysis of protein expression in kindled animals. Some of the identified proteins were further investigated by using immunohistochemistry. RESULTS: We report the identification of a modified variant of the Rieske iron-sulfur protein, a component of the mitochondrial cytochrome bc1 complex, whose isoelectric point is shifted toward more alkaline values in the hippocampus of kindled rats. By immunohistochemistry, the Rieske protein is well expressed in the hippocampus, except in the CA1 subfield, an area of selective vulnerability to seizures in humans and animal models. We also noted an asymmetric, selective expression of the Rieske protein in the subgranular neurons of the dorsal dentate gyrus, a region implicated in neurogenesis. CONCLUSIONS: These results indicate that the Rieske protein may play a role in the response of neurons to seizure activity and could give important new insights into the molecular pathogenesis of epilepsy.

Animals↗
PubMed1993

Multiple myeloma: 'early' plasma cell phenotype identifies patients with aggressive biological and clinical characteristics.

The immunological phenotype of bone marrow myeloma cells and peripheral blood lymphocytes was evaluated in 38 untreated myeloma patients. A striking increase of monotypic cells expressing the same light chain as the M component was observed in bone marrow from 18/38 (47%) patients. A two-colour analysis clarified that the majority of myeloma cells co-expressed plasma cell and B lymphocyte markers (cyIg, CD38, CD56 and sIg), and were regarded as early-plasma cells (early-PC). In the remaining patients, myeloma cells expressed plasma cell markers only (late-PC). Phenotype corresponded to a distinct morphological pattern: early-PC showed a lympho-plasmocytoid feature with significantly lower diameters than late-PC (12.1 v 14.8 microns, P < 0.007). Moreover, the plasma cell labelling index was significantly increased in early-PC patients (1.2 v 0.5%, P < 0.04). In peripheral blood from patients with early-PC, monotypic cells co-expressing sIg and CD38, CD56, but not CD19, were also detected. These data suggest a recirculation of early-PC. Myeloma cells maintained their phenotypic pattern during the course of the disease. This observation suggests that the degree of maturation is an intrinsic characteristic of the myeloma cell population in individual patients. The evaluation of prognostic factors, such as beta 2-microglobulin, C-reactive protein and neopterin, showed a statistically significant increase in the early-PC patients, suggesting a poor outcome. In conclusion, myeloma cell phenotype allows identification of a myeloma variant with aggressive biological and clinical characteristics.

Adult↗
PubMed1991

Breast carcinoma with osteoclast-like giant cells.

The cytological and histological findings of a case of breast carcinoma with osteoclast-like giant cells are presented. A fine needle aspiration specimen demonstrated the characteristic combination of malignant epithelium and reactive multinucleated cells and enabled identification of this rare variant of breast cancer. Immunocytochemical studies using the monoclonal antibody KP1[CD68] support a histiocytic origin for the osteoclast-like cells.

Aged↗
PubMed1983

Adrenomyeloneuropathy--clinical and biochemical diagnosis.

Adrenomyeloneuropathy (AMN) is an X-linked storage disease of very-long-chain fatty acids that presents as primary adrenocortical failure combined with spastic paraparesis and peripheral neuropathy. This disorder was diagnosed in three unrelated adult males. Definitive diagnosis was made by finding elevated very-long-chain fatty acids in plasma and skin biopsy samples. Biochemical characterisation of this disease has elucidated its genetics, clarified its relationship with adrenoleukodystrophy of children and other phenotypic variants, and allowed heterozygote identification, accurate genetic counselling and prenatal diagnosis.

Addison Disease↗