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PubMedDate not supplied

Preparation of monoclonal antibodies that differentiate between Histoplasma capsulatum variant capsulatum and H. capsulatum variant duboisii.

The immunosuppressive drug cyclophosphamide was used to facilitate the production of monoclonal antibodies (Mabs) which differentiated between the yeast phase of the two variants of the dimorphic fungus Histoplasma capsulatum by both enzyme-linked immunosorbent assay and Western blot. Two Mabs are described, identifying epitopes on a 70-75 kDa molecule, which are specific to H. capsulatum var. capsulatum and which do not identify epitopes of H. capsulatum var. duboisii. These Mabs have potential use in the epidemiology and serodiagnosis of histoplasmosis in areas where both classical and African forms of the disease occur.

Animals↗

PubMed2006

Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variant.

Although the follicular variant of papillary thyroid carcinoma (FVPTC) has been classified as a papillary cancer based on nuclear features, its follicular growth pattern and potential for hematogenous spread are more characteristic of follicular carcinoma. To gain insight into the biologic nature of FVPTC, we compared genetic alterations characteristic of papillary and follicular thyroid carcinomas in 24 FVPTCs and 26 classic PTC (CPTCs). In FVPTCs, we observed ras mutation in 6 of 24 cases (25%), BRAF mutation in 1 of 13 cases (7.6%), and ret rearrangement in 5 of 12 cases (41.7%). In CPTCs, we found ras mutation in no case, BRAF mutation in 3 of 10 cases (30%), and ret rearrangement in 5 of 11 cases (45%). One FVPTC exhibited simultaneous ras mutation and ret/PTC1 rearrangement, and one CPTC harbored simultaneous BRAF mutation and ret/PTC3 rearrangement. Based on these findings, we concluded that ras mutation correlates with follicular differentiation of thyroid tumors whereas ret activation is associated with papillary nuclei but not with papillary architecture. ret activation is not exclusive of ras or BRAF mutation, whereas ras and BRAF mutations are mutually exclusive. The implications of these results for follicular and papillary carcinogenesis are discussed.

Adenocarcinoma, Follicular↗

PubMed2000

Differential expression of estrogen receptor beta splice variants in rat brain: identification and characterization of a novel variant missing exon 4.

Estrogen receptor beta (ER-beta) mRNA is found in abundance in rat brain. The distribution of ER-beta mRNA in brain differs from that of ER-alpha suggesting they subserve different functions. ER-beta mRNA has been reported to be variably spliced, in contrast to ER-alpha, resulting in numerous isoforms that possess different functional properties. The present study was undertaken to determine whether the isoforms of ER-beta mRNA are differentially distributed in different brain regions. In order to assess the range of transcript forms expressed in various brain regions in the same assay, a micropunch dissection technique was combined with semiquantitative RT-PCR. The relative abundance of each ER-beta isoform (beta1>beta2>beta1delta3>beta2delta3) was similar in all ER-beta positive brain regions with the exception of the hippocampus, which contained low levels of most isoforms and a fifth ER-beta isoform, which we are calling ER-beta1delta4. Based on its sequence, ER-beta1delta4 encodes an ER-beta that is missing exon 4. Initial characterization studies of this showed that it did not bind estrogen, and that, unlike ER-beta1, it localized to the cytoplasm when expressed in cultured cells. The distribution of ER-beta1delta4 was different from that of the other isoforms in that it was expressed at high levels in the hippocampus, where the other isoforms were low, and that it was nearly undetectable in the brain regions that expressed the highest levels of the other ER-beta splice variants. These data suggest that a highly complex pattern of estrogen signaling can occur in a region specific manner in the rat brain.

Alternative Splicing↗

PubMed1995

Determination of the structure of two novel echistatin variants and comparison of the ability of echistatin variants to inhibit aggregation of platelets from different species.

Two new variants of short disintegrins were purified from the venom of Echis carinatus leakeyi and named echistatin beta and gamma. These proteins were found to be about 85% similar in amino acid sequence to echistatin alpha which has been well studied. The disulphide pattern of echistatin gamma appeared to be identical with that of echistatin alpha. They all contain the adhesive recognition sequence Arg-Gly-Asp (RGD) but inhibit the aggregation of platelets from human and other mammals with different potencies. Echistatin beta and alpha are far more effective on platelets from humans and guinea pigs than those from rabbits and rats whereas echistatin gamma is less discriminating of the platelets of the species tested. This species-dependent platelet sensitivity to echistatin beta and gamma could be attributed to the variations in residues 15, 21, 22 and 27, which are close to or within the RGD loop, rather than to the C-terminal variations after residue 46. Taking advantage of the presence of methionine residues flanking both sides of the ARGDDM motif in echistatin gamma, we deleted this hexapeptide by CNBr cleavage to produce des-(23-28)-echistatin gamma. The modified protein showed c.d. and fluorescent spectra grossly similar to the intact echistatin but its antiplatelet potency decreased more than 200-fold. We thus propose that a favourable conformation of the RGD region is responsible mainly for the high-affinity binding of echistatin to the platelet glycoprotein IIb-IIIa as shown previously for the binding of medium-size disintegrin.

Amino Acid Sequence↗

PubMedDate not supplied

Variant of type B blood in an El Salvador family. Expression of a variant B gene enhanced by the presence of an A2 gene.

A variant of type B blood was found in three members of a family from El Salvador. In two members, both genotype BO, the blood and saliva had the characteristics of the phenotype Be1 . In the third member, genotype A2B, the red cell B antigen was stronger than in his BO genotype relatives. Thus, in this family, the presence of the A2 gene appeared to enhance the expression of the B gene.

ABO Blood-Group System↗

PubMed2005

Multicentric contiguous variant of epithelioid angiosarcoma of the bone. A rare variant showing angiotropic spread.

Epithelioid angiosarcoma of the bone is a rare tumor and is a diagnostic challenge. Here we present an autopsy case of a 62-year-old man with multifocal osteolytic lesions in the extremities and the pelvis. The initial diagnosis of a tibial biopsy was poorly differentiated adenocarcinoma. On the occasion of autopsy, a fungating thrombotic nodule was found at the anterior wall of the right atrium, and small hemorrhagic infarcts with tumor thrombi were found in the lung. Histologically, the above lesions were identical to the former tibial biopsy and they showed large eosinophilic epithelioid cells with irregular ovoid nuclei and prominent eosinophilic nucleoli. Rare intracytoplasmic lumina were identified. Immunohistochemically, the tumor cells were positive for cytokeratins (CAM5.2 and AE1/AE3), CD31, factor VIII-related antigen, and vimentin. This case showed angiotropic spread of the tumor only to the right atrium and the lung, with no solid mass in other organs. Multicentric epithelioid angiosarcoma of the bone is a pitfall in pathological diagnoses, especially if a strong radiological impression of metastatic carcinoma is provided. Therefore, pathologists should be aware of this rare variant.

Adenocarcinoma↗

PubMed1972

Genetic variants of glucose 6-phosphate dehydrogenase from human erythrocytes: unique properties of the A - variant isolated from "deficient" cells.

The A(-) type of glucose 6-phosphate dehydrogenase (EC 1.1.1.49) has been isolated from human erythrocytes deficient in this enzyme. The specific activity of the purified protein is similar to that previously reported for the enzyme isolated from normal, nondeficient erythrocytes. During the purification procedure, a portion of the A(-) enzyme converts spontaneously, from the native "fraction I", to a "fraction II" having different kinetic and chromatographic properties. The conversion of fraction I to II can be reproduced freely by treatment with iodosobenzoate, and fraction II can be converted back to fraction I by treatment with dithioglycol. We suggest that fraction II is an enzyme species in which one or more sulfhydryl groups have been oxidized to disulfide(s). The tendency to oxidation appears to be a property specific to the A(-) variant and may represent the basis for its rapid rate of inactivation and consequent deficiency in vivo.

Blood Protein Electrophoresis↗

PubMed1998

Clinical forms of presentation and evolution of diffuse sclerosing variant of papillary carcinoma and insular variant of follicular carcinoma of the thyroid.

We investigated whether the diffuse sclerosing variant of papillary carcinoma (diffuse sclerosing PC) and insular carcinoma (IC), two different subforms of differentiated carcinoma of the thyroid gland, have different clinical behaviors and prognosis in order to select appropriate therapy. The characteristics of clinical presentation, and outcome after therapy were evaluated in a series of 113 patients (18 males and 95 females) with differentiated thyroid carcinoma treated with the same protocol, of which 7 had diffuse sclerosing PC and 6 had IC; within this series, patients with diffuse sclerosing PC and IC were compared with 76 cases of papillary carcinoma (PC) and 24 cases of follicular carcinoma (FC), respectively. Diffuse sclerosing PC patients were younger (23+/-9 vs. 38+/-16 years) and had a higher degree of lymphatic metastases at diagnosis (100%) than patients with PC (47%). Five of 7 patients with diffuse sclerosing PC were alive and without evidence of disease compared to 34 of 76 patients with PC at follow-up (6.4+/-5.1 and 7.9+/-7 years, respectively). No prognostic differences were found between them. IC showed a more advanced stage of disease at diagnosis and a more aggressive clinical course with a higher percent of metastases and mortality than patients with FC at follow-up (1 patient died and 5 were alive with persistent disease at 4.8+/-3.7 years for IC; 22 were alive, 13 of them with persistent disease; and 2 died at 8.4+/-5.3 years for FC). We conclude that patients with diffuse sclerosing PC do not require a different treatment than that given to PC patients, while in contrast, IC cases need a more aggressive therapeutic approach.

Adenocarcinoma, Follicular↗

PubMed2007

Plant Gene and Alternatively Spliced Variant Annotator. A plant genome annotation pipeline for rice gene and alternatively spliced variant identification with cross-species expressed sequence tag conservation from seven plant species.

The completion of the rice (Oryza sativa) genome draft has brought unprecedented opportunities for genomic studies of the world's most important food crop. Previous rice gene annotations have relied mainly on ab initio methods, which usually yield a high rate of false-positive predictions and give only limited information regarding alternative splicing in rice genes. Comparative approaches based on expressed sequence tags (ESTs) can compensate for the drawbacks of ab initio methods because they can simultaneously identify experimental data-supported genes and alternatively spliced transcripts. Furthermore, cross-species EST information can be used to not only offset the insufficiency of same-species ESTs but also derive evolutionary implications. In this study, we used ESTs from seven plant species, rice, wheat (Triticum aestivum), maize (Zea mays), barley (Hordeum vulgare), sorghum (Sorghum bicolor), soybean (Glycine max), and Arabidopsis (Arabidopsis thaliana), to annotate the rice genome. We developed a plant genome annotation pipeline, Plant Gene and Alternatively Spliced Variant Annotator (PGAA). Using this approach, we identified 852 genes (931 isoforms) not annotated in other widely used databases (i.e. the Institute for Genomic Research, National Center for Biotechnology Information, and Rice Annotation Project) and found 87% of them supported by both rice and nonrice EST evidence. PGAA also identified more than 44,000 alternatively spliced events, of which approximately 20% are not observed in the other three annotations. These novel annotations represent rich opportunities for rice genome research, because the functions of most of our annotated genes are currently unknown. Also, in the PGAA annotation, the isoforms with non-rice-EST-supported exons are significantly enriched in transporter activity but significantly underrepresented in transcription regulator activity. We have also identified potential lineage-specific and conserved isoforms, which are important markers in evolutionary studies. The data and the Web-based interface, RiceViewer, are available for public access at http://RiceViewer.genomics.sinica.edu.tw/.

Base Sequence↗

PubMed1978

Heterogeneity of hereditary methaemoglobinaemia: a study of 4 Cuban families with NADH-Methaemoglobin reductase deficiency including a new variant (Santiago de Cuba variant).

NADH-methaemoglobin reductase deficiency has been found in 4 Cuban families; 3 subjects carried the mild form of the deficiency while in 2 sibs of the fourth family the deficiency was associated with neurological involvement. The parents in this family were consanguinous and the sibs were shown to be homozygous for a new fast electrophoretic variant. It was named Diaphorase Santiago de Cuba.

Adolescent↗

PubMed2002

Human herpesvirus 6 variant A but not variant B induces fusion from without in a variety of human cells through a human herpesvirus 6 entry receptor, CD46.

Human herpesvirus 6 (HHV-6) is a lymphotropic betaherpesvirus that productively infects T cells and monocytes. HHV-6 isolates can be differentiated into two groups, variants A and B (HHV-6A and HHV-6B). Here, we show a functional difference between HHV-6A and -6B in that HHV-6A induced syncytium formation of diverse human cells but HHV-6B did not. The syncytium formation induced by HHV-6A was observed 2 h after infection; moreover, it was found in the presence of cycloheximide, indicating that HHV-6A induced fusion from without (FFWO) in the target cells. Furthermore, the fusion event was dependent on the expression of the HHV-6 entry receptor, CD46, on the target cell membrane. In addition, we determined that short consensus repeat 2 (SCR2), -3, and -4 of the CD46 ectodomain were essential for the formation of the virus-induced syncytia. Monoclonal antibodies against glycoproteins B and H of HHV-6A inhibited the fusion event, indicating that the syncytium formation induced by HHV-6A required glycoproteins H and B. These findings suggest that FFWO, which HHV-6A induced in a variety of cell lines, may play an important role in the pathogenesis of HHV-6A, not only in lymphocytes but also in various tissues, because CD46 is expressed ubiquitously in human tissues.

Animals↗

PubMed1982

Isolation and characterization of a variant of mouse plasmacytoma J558 synthesizing a 110,000-dalton immunoglobulin heavy chain and of secondary variants synthesizing either a 55,000-dalton or an 80,000-dalton immunoglobulin heavy chain: possible implications.

A mutant has been isolated from the J558 (immunoglobulin A, lambda, anti-alpha 1 leads to 3 dextran) cell line which synthesizes a heavy-chain immunoglobulin twice the size of normal heavy chain. Secondary variants that synthesized heavy chains either 1.5 times as large as wild type or the same size as wild type were identified. All mutants were serologically immunoglobulin continued to bind antigen, and retained the individual idiotype of the parent. Northern blot analysis and in vitro synthesis studies showed that the large heavy chains were primary synthetic products and not the consequence of abnormal covalent bonds. Cleavage of genomic DNA with restriction endonucleases and molecular hybridization studies showed new fragments in the 2 X and 1.5 X mutants which disappeared in the 1 X revertant. These data cannot easily be reconciled with the mutants arising either by unequal recombination or gene conversion. Further molecular characterization of these mutants should give additional insight into immunoglobulin gene evolution.

Animals↗

PubMed1989

Molecular basis for defective secretion of the Z variant of human alpha-1-proteinase inhibitor: secretion of variants having altered potential for salt bridge formation between amino acids 290 and 342.

Human alpha-1-proteinase inhibitor (A1PI) deficiency, associated with the Z-variant A1PI (A1PI/Z) gene, results from defective secretion of the inhibitor from the liver. The A1PI/Z gene exhibits two point mutations which specify amino acid substitutions, Val-213 to Ala and Glu-342 to Lys. The functional importance of these substitutions in A1PI deficiency was investigated by studying the secretion of A1PI synthesized in COS cells transfected with A1PI genes altered by site-directed mutagenesis. This model system correctly duplicates the secretion defect seen in individuals homozygous for the A1PI/Z allele and shows that the substitution of Lys for Glu-342 alone causes defective secretion of A1PI. The substitution of Lys for Glu-342 eliminates the possibility for a salt bridge between residues 342 and 290, which may decrease the conformational stability of the molecule and thus account for the secretion defect. However, when we removed the potential to form a salt bridge from the wild-type inhibitor by changing Lys-290 to Glu (A1PI/SB-290Glu), secretion was not reduced to the 19% of normal level seen for A1PI/Z-342Lys; in fact, 75% of normal secretion was observed. When the potential for salt bridge formation was returned to A1PI/Z-342Lys by changing Lys-290 to Glu, only 46% of normal secretion was seen. These data indicate that the amino acid substitution at position 342, rather than the potential to form the 290-342 salt bridge, is the critical alteration leading to the defect in A1PI secretion.

Amino Acid Sequence↗

PubMed2004

Expression of splice variants of the human ADAM15 gene and strong interaction between the cytoplasmic domain of one variant and Src family proteins Lck and Hck.

OBJECTIVE: The aim of the present study was to show variant species of ADAM15 and unique Src homology 3 (SH3)-binding motifs, which strongly bound Src family proteins compared with ADAM15. METHODS AND RESULTS: RT-PCR using primers for the cytoplasmic domain revealed the presence of different species, designated ADAM15v1 and ADAM15v2, which had characteristic SH3-binding class I and class II motifs. The mRNA of ADAM15v1 and ADAM15v2 was mainly found in peripheral blood mononuclear cells, T lymphocytes and monocytic cell lines. ADAM15v2 protein interacted more strongly with the Src family proteins Lck and Hck than did ADAM15 protein, as examined by pull-down analysis and immunoprecipitation followed by immunoblot analysis. The binding with Lck and Hck was enhanced by the phosphorylation of ADAM15v2 protein. CONCLUSIONS: These results suggest that the cytoplasmic domain of ADAM15v2 strongly interacts with Lck and Hck and regulates leukocyte function.

ADAM Proteins↗

PubMed1975

Hemoglobin Syracuse (alpha2beta2-143(H21)His leads to Pro), a new high-affinity variant detected by special electrophoretic methods. Observations on the auto-oxidation of normal and variant hemoglobins.

Family members from four generations were found to have polycythemia and increased whole blood O2 affinity (P50; 11 mm Hg; normal, 27 mm Hg). No abnormal hemoglobin bands were seen after electrophoresis on starch gel at pH 8.6 or agar gel at pH 6.0. Analysis of the oxygenated hemolysate by isoelectric focusing on polyacrylamide gel revealed two closely spaced bands. When deoxygenated hemolysate was analyzed in oxygen-free gels, the two components were more widely separated. About 40% of the patient's hemoglobin focused at a more acid pH than hemoglobin A, indicating a hemoglobin variant with impaired Bohr effect. Chromatography of globin in 8 M urea revealed two beta-chain peaks, the first of which was eluted at a lower buffer molarity than normal beta chain. Fingerprints of tryptic digests of the aminoethylated chains were done on silica gel thin-layer plates. Tp 14 from the abnormal beta chain had slower electrophoretic mobility and a greater Rf value. Amino acid analyses of this peptide gave values identical with those of betaTp 14, except that it contained one proline residue and no histidine. Since the one His in betaTp 14 is in position 143, hemoglobin Syracuse in alpha2beta2-143 His leads to Pro. Native Hb Syracuse could be separated from hemoglobin A on a carboxymethylcellulose column. The inclusion of 0.1 mM EDTA in the preparative buffers proved very useful in reducing the formation of methemoglobin. Oxygen equilibria of purified hemoglobin Syracuse showed high oxygen affinity (P50 value 12% that of hemoglobin A) and lack of cooperativity between subunits (Hill's n equals 1.1). The alkaline Bohr effect was about half that of hemoglobin A. The proline substitution at betaH21 disrupts the helical configuration and probably prevents the formation of salt bonds that are important in stabilizing the deoxy structure and contribute to the alkaline Bohr effect. Since beta143 His is a binding site for 2,3-diphosphoglycerate (2,3-DPG), it is not suprising that hemoglobin Syracuse had markedly impaired reactivity with 2,3-DPG. Hemoglobin Syracuse auto-oxidized more slowly than hemoglobin A, probably reflecting a slower rate of dissociation of oxygen from fully liganded hemoglobin.

Adult↗

PubMed2001

The Q allele variant (GLN121) of membrane glycoprotein PC-1 interacts with the insulin receptor and inhibits insulin signaling more effectively than the common K allele variant (LYS121).

When overexpressed, the membrane glycoprotein PC-1 may play a role in human insulin resistance through the inhibition of insulin receptor (IR) autophosphorylation. A PC-1 variant (K121Q, with lysine 121 replaced by glutamine) is also associated with whole-body insulin resistance when not overexpressed. To better understand the effects of the Q allele on IR function and downstream signaling, we transfected cultured cells with cDNAs for either the Q or the K alleles. In human MCF-7 cells, the Q allele was severalfold more effective (P < 0.05-0.01) than the K allele in reducing insulin stimulation of IR autophosphorylation, insulin receptor substrate-1 phosphorylation, phosphatidylinositol 3-kinase activity, glycogen synthesis, and cell proliferation. Similar data on IR autophosphorylation inhibition were also obtained in mouse R-/hIR and human HEK 293 cell lines. In transfected MCF-7 cells, 125I-labeled insulin binding and IR content were unchanged, and PC-1 overexpression did not influence IGF-1 stimulation of IGF-1 receptor autophosphorylation. Both the Q and K alleles directly interacted with the IR, as documented by coimmunoprecipitation assays. This interaction was greater for the Q allele than for the K allele (P < 0.01), suggesting that direct PC-1-IR interactions are important for the PC-1 inhibitory effect on insulin signaling. In conclusion, the Q allele has stronger inhibitory activity on IR function and insulin action than the more common K allele, and this is likely a consequence of the intrinsic characteristics of the molecule, which more strongly interacts with the IR.

Alleles↗

PubMed1977

Differences in affinity of variant beta chains for alpha chains: a possible explanation for the variation in the percentages of beta chain variants in heterozygotes.

The alpha and beta chains of the hemoglobins A, S, Leslie and N-Baltimore have been isolated as PMB derivates by CM-cellulose and DEAE-cellulose chromatography. The relative affinities of the betaA, betaS, betaLeslie and betaN-Baltimore chains for alpha chains were measured through quantitation by chromatography of the hemoglobins A and Leslie, A and S, and A and N-Baltimore that were formed when variable amounts of alpha chains were added to a mixture of equal amounts of the appropriate beta chains. The data indicate a greatly decreased affinity of betaLeslie chains for alpha chains; a similar preference of alpha chains for betaA chains was observed for mixtures involving alpha, betaA, and betaS chains, but the affinity of betaS chains for alpha chains was higher than that of betaLeslie chains. The betaN-Baltimore chains assembled with alpha chains at a similar rate as betaA chains. The data as interpreted indicate that the affinity of certain beta chains for alpha chains can be a major post-translational control mechanism which regulates the level of a beta chain variant in heterozygotes.

Chromatography, DEAE-Cellulose↗

PubMed1999

[The capacity of the mycelia of Streptomyces chrysomallus variants to bind exogenous actinomycin D and the synthesis by these variants of macrotetralides].

Streptomyces chrysomallus is known as an organism producing macrotetrolides (MTL) and actinomycin C. The dynamics of the MTL biosynthesis by some variants of S. chrysomallus in the process of their growth in liquid media was studied. In parallel the ability of the culture mycelium (washed or suspended in physiological solution) to bind exogenous actinomycin D (AMD) was estimated. An inverse correlation between the dynamics of MTL biosynthesis and the rate of the AMD binding by the washed mycelium during the whole period of the culture development was observed: a decrease in the culture ability to bind AMD corresponded to active biosynthesis of MTL and an increase in the culture ability to bind AMD corresponded to lower biosynthesis of MTL. It was suggested that the active biosynthesis of MTL correlated not only with a decrease in the ability of the suspended mycelium to bind AMD but also with a decrease in binding of actinomycin synthesized and excreted to the medium by the culture. A decrease in the reflux of the synthesized antibiotic to the cells was likely one of the components of the system of the S. chrysomallus insensitivity to its own antibiotic.

Anti-Bacterial Agents↗