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PubMed1995

Polymorphism in the upstream regulatory region of DQA1 gene in the Italian population.

Polymorphism in the 5'-upstream regulatory region of the DQA1 gene has been recently described. Using PCR-SSO method and SSCP analysis we have investigated this polymorphism in a group of 111 Italian blood donors which had been oligotyped for DRB1, DQA1 and DQB1 genes. Eight allelic variants were detected. Looking at the relationships among QAP sequences and DQA1 and DRB1 genes, three alternative situations were found: 1. a one-to-one relation between QAP and DQA1 alleles, independently of the other class II genes; 2. the same QAP allele in association with different DQA1-DRB1 haplotypes; 3. the same DQA1 allele with different QAP sequences according to the DRB1 specificity. No unexpected associations with DQB1 gene were found. These results must be interpreted considering that DQA1 and DRB1 genes are transcribed in opposite directions so that the promoter region of DQA1 gene lies between DQA1 and DRB1, close to the former but several hundreds kb away from the latter.

Base Sequence↗
PubMed1976

The use of supplementary tests in the serological diagnosis of bovine brucellosis.

Comparative tests were carried out on serum samples using the Rose Bengal test (RBT), the complement fixation test (CFT), the antibovine globulin test (ABGT) by tube, plate and rapid variants, the mercaptoethanol test (MET) and the dithiothreitol test (DTT). Forty cows, from which Br. abortus had been recovered, gave strong reactions in all tests except for 2 cows in the SAT and 3 cows in the DTT Another group of 405 cows had not yielded Br. abortus on limited bacteriological examination. There was good correlation between the results of the CFT, RBT, tube ABGT, rapid ABGT and, to a lesser extent, the MET in cows with a CF titre greater than or equal to 16 or less than 4. In cows with CF titres of 8 the correlation was not as good while cows with a CF titre of 4 gave a wide range of reactions in these supplementary tests. A plate variant of the ABGT gave titres which were generally lower, by about 1 dilution, than those in the tube procedure. The results of the rapid ABGT correlated well with the results of the tube ABGT and the CFT in samples of high and low titre but not as well in samples of intermediate titre. The DTT gave titres which were usually lower than the corresponding MET titre. On the basis of the results obtained, tentative standards for the interpretation of the ABGT (tube) and MET were defined. It was concluded that these tests could be used to elucidate the status of a proportion of the cows which gave inconclusive results in the CFT.

Agglutination Tests↗
PubMed2003

An on-line assay for clinical detection of amyloidogenic transthyretin variants directly from serum.

We report here for the first time the on-line analysis of transthyretin genetic variants by mass spectral analysis. The use of mass spectrometry to analyze immunoprecipitated transthyretin has been previously described. However, the on-line analysis of TTR directly from serum reported here will allow for a fully automated high throughput analysis. Mutations in the plasma transport protein TTR are readily observed and distinguished from normal TTR. Free TTR as well as TTR-cysteine and TTR-cysteinylglycine adducts are clearly evident. The resulting assay from serum to final interpretation requires less than twenty minutes. The assay should be an effective first line discriminator of patients who are being considered to have Familial Amyloidotic Polyneuropathy (FAP) and an adjunct to definitive diagnosis by sequencing of the TTR gene or protein.

Amyloid Neuropathies, Familial↗
PubMed1999

Rapid appearance of M cells after microbial challenge is restricted at the periphery of the follicle-associated epithelium of Peyer's patch.

M cells within the follicle-associated epithelium (FAE) of the gut play a central role in the initiation of mucosal immune responses by transporting antigens to the intestinal lymphoid tissue. We have previously demonstrated that the instillation into the gut of a nonenteric microorganism, Streptococcus pneumoniae R36a, is an excellent experimental model to investigate the highly dynamic nature of the FAE in response to microbial challenge. In the present study, S. pneumoniae was introduced into rabbit ileal loops, each one containing a Peyer's patch (PP), and the number of M cells was assessed by morphological and functional characteristics in different areas of the FAE after a short time (1-3 hours). We report that a marked increase in the number of M cells was detected in the periphery, but not in the apical area, of the FAE as early as 1 hour after exposure to S. pneumoniae. Furthermore, a variant of this experiment enabled us to establish that the increased numbers of M cells led to an improved capability of the FAE to transport latex fluorescent microspheres (0.5 microm), highly specific to rabbit M cells, from the gut lumen to the intestinal lymphatic system. In these animals the cisterna chyli was cannulated, and the microparticles were introduced into the intestinal loops after stimulation with pneumococci. The microparticles reaching the lymph were then counted by flow cytometer. We interpreted these results as showing that only enterocytes located within the periphery of the FAE are converted to fully operational M cells by certain microbial interaction and the ability of enterocytes to undergo this conversion may depend on their stage of differentiation.

Animals↗
PubMed2005

The association of a distinctive allele of NAD(P)H:quinone oxidoreductase with pediatric acute lymphoblastic leukemias with MLL fusion genes in Japan.

BACKGROUND AND OBJECTIVES: The enzyme NAD(P)H:quinone oxidoreductase (NQO1) detoxifies chemicals with quinone rings including benzene metabolites and flavonoids. Previous studies in Caucasian populations have provided evidence that a loss of function allele at nt 609 (C609T, Pro187Ser) is associated with increased risk of infant acute lymphoblastic leukemia (ALL) with MLL-AF4 fusion genes. DESIGN AND METHODS: We genotyped 103 infants (<18 months) with ALL or acute myeloid leukemia (AML) in Japan and 185 controls for the frequency of allelic variation at nt 609 and 465 in NQO1 using standardized polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology. RESULTS: The C609T polymorphism is very common in Japan but we found no link with altered risk for infant ALL. However, a variant of another allele at nt 465 (C465T, Arg139Trp), also associated with diminished enzyme activity, was strongly associated (OR 6.36; CI 1.84-21.90; p=0.002) with infant ALL, especially in t(4;11)(q21;q23), MLL-AF4. No association was found between this allele and risk of infant AML with MLL gene fusions or infant ALL without MLL gene fusions. The same C465T allele has been linked recently, in an Oriental population, to sensitivity to benzene hematotoxicity. INTERPRETATION AND CONCLUSIONS: These data endorse the notion that infant ALL with MLL fusion genes have a unique etiology possibly involving transplacental exposure to chemicals.

Alleles↗
PubMed1985

Binding of horse-spleen ferritin to group A streptococci.

Receptors for horse-spleen ferritin were found on group A streptococci. Both electron microscopic and chemical investigation of Streptococcus cells treated with ferritin showed that M + variants of group A streptococci were able to bind substantially more ferritin than M - variants of the same serotypes. Ferritin receptors were located on the tops of filamentous protrusions of Streptococcus cell walls and only on the outer surface of isolated cell walls. Trypsin treatment destroyed the ferritin-binding capacity of streptococci completely, while mild pepsin treatment left the ferritin receptors undisturbed, or uncovered additional ones. The ferritin receptors were not identical with receptors for the Fc-portion of swine IgG. The finding of ferritin receptors on bacteria necessitates careful interpretation of results obtained by immunoferritin localization techniques.

Animals↗
PubMed1979

[A new technical variation of the latex agglutination test for the diagnosis of human hydatidosis].

A new variant of the latex agglutination test using latex particles of 0,81 mu diameter is described. Hidatid cyst fluid antigen standardized by immunoelectrophoretic analysis was used. Fifty-one human sera from surgically confirmed hydatidosis and ninety control sera from non-hydatid diseases and healthy donors were studied. The method showed a sensibility of 86,2% and a global inespecificity of 1,1%. A human case of teniasis by Taenia saginata was positive. General considerations about the interpretation of results in human hydatid disease serology are made.

Echinococcosis↗
PubMed1980

Typification and differentiation of medullary cells in the developing rat adrenal. A histochemical and electron microscopic study.

Various light and electron histochemical techniques were applied to the study of developing rat adrenal medulla. Adrenal glands or rudiments were examined at 14, 16, 18, 20 days of intrauterine life, at birth and at 1 week after birth. Material was processes for light microscopy as follows: (1) for the demonstration of cortical lipids by Sudan black B; (2) by immersion in Muller's formol-dichromate for the direct chromaffin reaction (CHR); (3) by sequential glutaraldehyde fixation and subsequent dichromate treatment for the indirect CHR. For electron microscopy, material from all developmental stages was fixed in glutaraldehyde and further processed in three ways: subsequent dichromate treatment (GD); sequential dichromate and osmium tetroxide (GDO); subsequent osmium tetroxide (GO). A positive direct CHR in the developing medullary; cells and discrete sudanophilic lipid droplets in the cortical cells were observed in 18-20 day embryos. Although the intensity of the direct CHR increased through the developmental stages, clear distinction between adrenaline (A) and noradrenaline (NA) cells was not observed until after birth by the indirect CHR. At an ultrastuctural level 'light' and 'dark' parenchymal cells were found in the sympathomedullary rudiment medial to the cortical anlage in the 14 day embryo: these 'light' cells, the phaeochromoblasts, together with nerve fibres, invade the cortex as from this stage. Phaeochromoblasts, the adrenomedullary precursor cells, were actively dividing and possessed a cytoplasmic content of numerous polyribosomes and a few (140 nm diameter) membrane-bounded inclusion granules. In embryos of 16-18 days, medullary cells were variously grouped as phaeochromoblasts, as the more differentiated phaeochromocytes and as intermediate forms. Phaeochromocytes contained a mixture of high and low density secretory granules (200 nm diameter) which in GD and GDO preparations were interpreted as NA and A granules. Cholinergic nerve terminals on medullary cells, the establishment of an endocrine-type relationship between regional capillaries and medullary cells and the presence of exocytotic profiles at the surface of these cells were all features of the 18 day and subsequent developmental stages. It was not possible to differentiate in GD and GDO preparations between A and NA cells on the basis of their granule typification until after birth. 'Light' and 'dark' variants of both A and NA cells observed at birth and thereafter were regarded as expressions of phase differences in the secretory cycles of these cells. The secretory granule population of medullary cells showed an overall increase during development and was especially high in the 'dark' variants of A and NA cells. Another developmental trend in the majority of medullary cells was an increase in the size of these granules (diameter range at 1 week, 160-330 nm); but in a few NA cells the mean granule diameter remained small (180 nm).

Adrenal Medulla↗
PubMed1995

Charge and size effects in the capillary zone electrophoresis of nuclease A and its variants.

The migration behavior of nuclease A from Staphylococcus aureus and 11 of its variants in capillary zone electrophoresis (CZE) was investigated in the light of their three-dimensional structure known from X-ray crystallography and nuclear magnetic resonance (NMR) measurements. Nuclease A (molecular mass 16.8 kDa, pKa 10.3) and the variants differ only in a single amino acid residue and have a very similar crystal structure. With the use of coated quartz capillaries and suitable buffers, the protein migration was investigated at pH from 2.8 to 9.5 without interference by wall adsorption. Although the selectivity of the electrophoretic system for the proteins was mainly determined by their charge differences, certain variants having the same net charge could also be readily separated under nondenaturing conditions. For instance, the mobility of variant K116A was sufficiently higher than that of K116G so that they could be separated by CZE. The structures of both variants are the same except for the solvent-exposed loop containing residue 116. For this reason, the difference in electrophoretic mobilities can be attributed to the fact that in K116G the backbone of the 112 to 117 amino acids protrudes slightly from the protein, with a concomitant increase in the hydrodynamic radius with respect to that of K116A. Consequently, K116G shows a smaller mobility than K116A due to its larger hydrodynamic radius despite its smaller molecular mass. The interpretation of the experimentally measured mobilities of such closely related proteins therefore requires not only consideration of their electrostatic charge but also the fine details of their molecular structures.

Amino Acid Sequence↗
PubMed2006

Detecting fluorescent protein expression and co-localisation on single secretory vesicles with linear spectral unmixing.

Many questions in cell biology and biophysics involve the quantitation of co-localisation and the interaction of proteins tagged with different fluorophores. However, the incomplete separation of the different colour channels due to the presence of autofluorescence, along with cross-excitation and emission "bleed-through" of one colour channel into the other, all combine to render the interpretation of multi-band images ambiguous. Here we introduce a new live-cell epifluorescence spectral imaging and linear unmixing technique for classifying resolution-limited point objects containing multiple fluorophores. We demonstrate the performance of our technique by detecting, at the single-vesicle level, the co-expression of the vesicle-associated membrane protein, VAMP-2 (also called synaptobrevin-2), linked to either enhanced green fluorescent protein (EGFP) or citrine [a less pH-sensitive variant of enhanced yellow fluorescent protein (EYFP)], in mouse cortical astrocytes. In contrast, the co-expression of VAMP-2-citrine and the lysosomal transporter sialine fused to EGFP resulted in little overlap. Spectral imaging and linear unmixing permit us to fingerprint the expression of spectrally overlapping fluorescent proteins on single secretory organelles in the presence of a spectrally broad autofluorescence. Our technique provides a robust alternative to error-prone dual- or triple colour co-localisation studies.

Animals↗
PubMed1990

Dynamic histone acetylation in alfalfa cells. Butyrate interference with acetate labeling.

Dynamic histone acetylation of alfalfa (Medicago sativa) was studied in suspension cultures by short-term labeling with radioactive acetate. The relative labeling rates for the acetylated histones were in order of decreasing incorporation; H3.2 greater than H3.1 greater than H4 greater than H2B.1 greater than H2A.3. Histone H3 showed at least seven sites of acetylation, histone H2B.1 had six sites and histone H4 had five sites. Low numbers of acetylation sites were observed for histone H2B.2 and all histone H2A variants. The mass ratio, steady state acetylation and dynamic acetylation between major variant H3.1 and minor variant H3.2 were approx. 2:1, 1:2 and 2:5, respectively. Treatment of alfalfa cells with 50 mM n-butyrate did not lead to histone hyperacetylation, but instead interfered with histone acetylation labeling by acetate. The extent of apparent inhibition increased with time and concentration of butyrate. It is likely that the conversion of butyrate to acetylCoA results in dilution of the specific radioactivity of [3H]acetate in the acetylCoA pool thereby inhibiting the labeling reaction. This interpretation is supported by 14C-labeling of alfalfa acetylated histones by [1-14C]butyrate.

Acetates↗
PubMed1995

Interaction between HLA-DR and HLA-DP, and between HLA and interleukin 1 alpha in juvenile rheumatoid arthritis indicates heterogeneity of pathogenic mechanisms of the disease.

EOP-JRA is an autoimmune disease that displays associations with DPB1*0201, DR8, DR5, and DR6, as well as an association with IL1A2 (a variant of IL1 alpha gene, not HLA linked). The purpose of this study was to analyze interactions between these genetic factors. We studied 103 EOP-JRA patients, 181 random controls, and 69 DR8-positive controls. We found a positive interaction between DPB1*0201 and the DRB1 alleles encoding DR3, DR5, or DR6, but not DR8. In addition, we found evidence for an interaction between IL1A2 and DR(3, 5, or 6) and DP2, but not DR8. We interpret the data to suggest heterogeneity in the HLA-associated pathogenic mechanisms of EOP-JRA.

Alleles↗
PubMed1997

Mucin-hypersecreting intraductal neoplasms of the pancreas: a precursor to cystic pancreatic malignancies.

BACKGROUND: Muncin-hypersecreting intraductal pancreatic neoplasms were first described in 1982 and have been observed in increasing numbers since. They are observed primarily by endoscopic retrograde cholangiopancreatography (ERCP) and are characterized by an intraductal papillary neoplasm that secretes thick mucin, causing pancreatic duct dilatation and obstructive pancreatitis. METHODS: Twenty patients are presented, 14 male and six female, with an average age of 59 +/- 11 years. All patients presented with abdominal pain, and most had nausea and vomiting, weight loss, and documented pancreatitis. Of the preoperative studies, ERCP was positive in all patients. Computed tomography scan, endoscopic ultrasonogram, and cytologic findings were less sensitive. Tumor markers were only positive in one patient. All 20 patients were treated surgically. Nine underwent Whipple procedure, one patient had a total pancreatectomy, and nine had distal pancreatic resections. The first patient in the series did not have a pancreatic resection, and his disease evolved into a lethal cystadenocarcinoma causing his death 99 months later. RESULTS: Histopathologic findings were interpreted as borderline malignant in 17 of the 20 patients, and three patients had evidence of invasive adenocarcinoma. Two of these three patients had nodal or distant metastases at the time of diagnosis, and all three died of adenocarcinoma. Seventeen of the patients are alive and well, although two of three with positive pancreatic margins have had recurrent symptoms and have been successfully reresected. CONCLUSIONS: The mucin-producing intraductal papillary tumor of the pancreas is a newly described variant of pancreatic cancer. It presents with symptoms of pancreatitis and has a progressive but more indolent course than the more lethal invasive ductal cancers. Patients with unexplained pancreatitis should undergo ERCP investigation, and aggressive surgical therapy should be carried out because the prognosis for this lesion, when appropriately treated, is more favorable than the usual pancreatic cancer.

Abdominal Pain↗
PubMed1996

Genetic interactions between naturally occurring alleles at quantitative trait loci and mutant alleles at candidate loci affecting bristle number in Drosophila melanogaster.

Previously, we mapped quantitative trait loci (QTL) affecting response to short-term selection for abdominal bristle number to seven suggestive regions that contain loci involved in bristle development and/or that have adult bristle number mutant phenotypes, and are thus candidates for bristle number QTL in natural populations. To test the hypothesis that the factors contributing to selection response genetically interact with these candidate loci, high and low chromosomes from selection lines were crossed to chromosomes containing wild-type or mutant alleles at the candidate loci, and the numbers of bristles were recorded in trans heterozygotes. Quantitative failure to complement, detected as a significant selection line*cross effect by analysis of variance, can be interpreted as evidence for allelism or epistasis between the factors on selected chromosomes and the candidate loci. Mutations at some candidate loci (bb, emc, h, Dl, Hairless) showed strong interactions with selected chromosomes, whereas others interacted weakly (ASC, abd, Scr) or not at all (N, mab, E(spl)). These results support the hypothesis that some candidate loci, initially identified through mutations of large effect on bristle number, either harbor or are close members in the same genetic pathway as variants that contribute to standing variation in bristle number.

Alleles↗
PubMed1995

Relationship of subunit 8 of yeast ATP synthase and the inner mitochondrial membrane. Subunit 8 variants containing multiple lysine residues in the central hydrophobic domain retain function.

A molecular genetic approach has been used to test the proposition that the central hydrophobic domain of yeast mitochondrial ATP synthase subunit 8 represents a transmembrane stem in contact with the lipid bilayer. The rationale for this approach is the general inability of membrane bilayers to accomodate unshielded charged residues of polypeptide chains. Non-polar residues at several positions within the central hydrophobic domain of subunit 8 were replaced with the positively charged amino acid lysine. This was done in an attempt to disrupt subunit 8 function, and thereby determine the boundaries of the putative transmembrane stem. Each subunit 8 variant was allotopically expressed in vivo as a mitochondrial import precursor encoded by a nuclear gene. It was found that all variants, which included proteins carrying two lysines at various positions in the hydrophobic domain, exhibited the ability to restore growth of subunit-8-deficient cells on the non-fermentable substrate ethanol. This indicated that the function of none of these subunit 8 variants was severely compromised. There was also no detectable change in the proteolipid characteristics of subunit 8, as defined by the chloroform/methanol solubility properties of variant proteins extracted from membranes following import into isolated mitochondria. These data suggest that subunit 8 is located in a hydrophobic niche in the mitochondrial ATP synthase, probably in contact with other protein subunits of the complex. We conclude that the function of subunit 8 does not necessarily require it to be integrated within the inner mitochondrial membrane, in contact with the lipid bilayer. Our findings also suggest that hydropathy plots, indicating hydrophobic domains within polypeptides, cannot reliably be interpreted as transmembrane helices in the absence of independent evidence.

Amino Acid Sequence↗
PubMed2003

Experimental examination of bacteriophage latent-period evolution as a response to bacterial availability.

For obligately lytic bacteriophage (phage) a trade-off exists between fecundity (burst size) and latent period (a component of generation time). This trade-off occurs because release of phage progeny from infected bacteria coincides with destruction of the machinery necessary to produce more phage progeny. Here we employ phage mutants to explore issues of phage latent-period evolution as a function of the density of phage-susceptible bacteria. Theory suggests that higher bacterial densities should select for shorter phage latent periods. Consistently, we have found that higher host densities (>/== approximately 10(7) bacteria/ml) can enrich stocks of phage RB69 for variants that display shorter latent periods than the wild type. One such variant, dubbed sta5, displays a latent period that is approximately 70 to 80% of that of the wild type-which is nearly as short as the RB69 eclipse period-and which has a corresponding burst size that is approximately 30% of that of the wild type. We show that at higher host densities (>/== approximately 10(7) bacteria/ml) the sta5 phage can outcompete the RB69 wild type, though only under conditions of direct (same-culture) competition. We interpret this advantage as corresponding to slightly faster sta5 population growth, resulting in multifold increases in mutant frequency during same-culture growth. The sta5 advantage is lost, however, given indirect (different-culture) competition between the wild type and mutant or given same-culture competition but at lower densities of phage-susceptible bacteria (</= approximately 10(6) bacteria/ml). From these observations we suggest that phage displaying very short latent periods may be viewed as specialists for propagation when bacteria within cultures are highly prevalent and transmission between cultures is easily accomplished.

Amino Acid Sequence↗
PubMed1993

A variant epithelial sub-population in normal thyroid with high proliferative capacity in vitro.

We describe the existence in normal human primary thyroid cultures of a hitherto unrecognised sub-population of epithelial cells. This variant phenotype is characterised by squamoid morphology, absence of thyroglobulin, and an altered profile of intermediate filament expression. We suggest that these cells are derived from scattered foci of squamous metaplasia present in the normal gland. Although they are initially present at a frequency of less than 10(-4), their very high proliferative capacity enables them to outgrow the 'classical' follicular cells and confers a much increased capacity for gene transduction. Recognition of these cells is therefore crucial in the interpretation of long-term thyroid culture experiments and those involving in vitro gene transfer.

Biomarkers↗
PubMed2000

MOC31 immunoreactivity in primary and metastatic carcinoma of the liver. Report of findings and review of other utilized markers.

Differentiating between primary tumors of the liver and metastatic lesions can, at times, be difficult. Various histochemical and immunohistochemical methods have been used in an effort to better delineate between hepatocellular carcinoma (HCC), especially the microglandular variant, primary cholangiocarcinoma, and metastatic adenocarcinoma; these ancillary studies can yield less than satisfactory results. Recently, anti-MOC31, a monoclonal antibody directed against a cell surface glycoprotein, has been shown to be helpful in distinguishing between adenocarcinoma and mesothelioma. This study addresses whether this antibody might be helpful in distinguishing between HCC, primary cholangiocarcinoma, and metastatic adenocarcinoma in the liver. Formalin-fixed, paraffin-embedded tissue sections from 15 HCC (including 10 microglandular variants), 14 primary cholangiocarcinomas, and 33 metastatic adenocarcinomas (7 colon, 1 lung, 8 breast, 4 GE jct/gastric, 9 pancreas, 2 small intestine, 1 renal, 1 ovary) were immunostained with anti-MOC 31 (1:40, Dako) after protease digestion and biotin block using a modified ABC technique. Positive staining was limited to membrane based reactivity; controls stained appropriately. Immunoreactivity for MOC31 was observed in 14 of 14 cholangiocarcinomas and 33 of 33 metastatic tumors. Staining was diffuse, intense, and readily interpretable, with rare exceptions. All 15 cases of HCC were negative. We conclude that cholangiocarcinoma and metastatic adenocarcinoma from a variety of sites express MOC31; HCC is uniformly negative for this marker. Anti-MOC31 may prove useful in the evaluation of liver neoplasms where primary hepatocellular and adenocarcinoma enter the differential diagnosis; it is not useful in separating primary cholangiocarcinoma from metastatic adenocarcinoma.

Adenocarcinoma↗