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PubMed1983

Studies of immune responses in mice prone to autoimmune disorders. I. Heterogeneity of the affinities of antihapten antibodies produced by NZB, NZW, and related strains of mice.

Mice of the NZB and NZW strains and their F1 hybrid produce antihapten plaque-forming cell (PFC) responses to T-dependent antigens (trinitrophenylated bovine gamma globulin and dansylated keyhole limpet hemocyanin) which are of unusually restricted heterogeneity of affinity, are relatively lacking in low-affinity PFC, and are of relatively high average affinity. Since some low-affinity PFC are present in NZB mice early after immunization, the results suggest a particularly marked down-regulation of low-affinity antibody production by these strains. The non-autoimmune-prone F1 hybrid (NZB X CBA) produces a typical heterogeneous response containing a high proportion of low-affinity PFC. Thus, the tendency to down-regulate low-affinity PFC is not inherited as a simple Mendelian dominant trait. The response of NZB mice to T-independent antigens does not show the same restricted heterogeneity of affinity. In fact, late after injections of trinitrophenylated Ficoll, NZB mice tend to have more heterogeneous responses than nonautoimmune-prone BALB/c mice in which a marked down-regulation of high-affinity antibody-producing PFC is seen. The possible relationship between these unusual features of the immune response of NZB and some related strains and their tendency to develop autoimmune disease is discussed.

Animals↗
PubMed1992

Behavior of the idiotypic network in conventional immune responses. II. Affinity and heterogeneity of idiotypic and anti-idiotypic antibodies following immunization with T-independent and T-dependent antigens.

The relative affinity and heterogeneity of affinity of idiotypic and anti-idiotypic antibodies in mice immunized with the T-independent antigen DNP-Ficoll and the T-dependent antigen DNP-HGG were measured by a plaque inhibition assay. Idiotypic plaque-forming cells (PFC) were detected by a conventional assay utilizing DNP-coated SRBC. Anti-idiotypic PFC were detected with SRBC coated with affinity-purified anti-DNP antibody of rabbit origin. It was found that both idiotypic and anti-idiotypic antibodies elicited by immunization with the T-independent antigen had lower affinity and were less heterogeneous than the corresponding antibodies originating in mice immunized with the T-dependent antigen. In addition, the affinity and heterogeneity values of the idiotypic antibodies were correlated with the affinity and heterogeneity values of the anti-idiotypic antibodies from the same mice. This finding indicates that idiotypic and anti-idiotypic antibodies mutually regulate each other, thus pointing to internal immunoregulatory effects of the idiotypic network with respect to these parameters.

Animals↗
PubMed1987

Heterogeneity of a human T-lymphoblastoid cell line.

A human T-lymphoblastoid cell line (Jurkat) was cloned, and four resulting sublines were characterized in a variety of ways with the objective of gaining information on heterogeneity in cell lines. Within a few weeks of cloning, distinct cellular morphologies and growth patterns became apparent in the four sublines. Growth rate measurements made over 3 months did not show any significant differences between the sublines. Surface protein profiles obtained by radioimmunoprecipitation using antisera in conjunction with extracts from [35S]Met and 125I-labeled cells revealed differences between the sublines. Analysis of total cell DNA showed that one of the sublines possessed only half the chromosome complement of the other sublines and the parental line. Karyotyping confirmed this result and, in addition, demonstrated that chromosome numbers fluctuated around a mean value for each subline. Karyotypic variability became apparent within 2 months of cloning and tended to increase with time in culture. G-banding analysis showed that the analyzed cell populations contained distinctive cytogenetic aberrations. Properties of the cloned sublines were monitored over a 9-month period. One of the sublines that had shown heterogeneous morphology even after 6 weeks maintained the heterogeneity throughout this time. Another subline underwent a marked change in morphology (round to irregular) and growth habit (single cells to large clumps) with increasing time in culture. Interestingly, several alterations to surface proteins accompanied these growth changes. A third subline had relatively stable morphology and chromosome number throughout the 9-month period. The modal chromosome number was hypotetraploid for three sublines and the parent line, but was diploid for another subline. However, it was interesting that progression toward tetraploidy in this subline was apparent after almost 2 years of culturing. The results showed that the original cell line consisted of a heterogeneous assemblage of cell types, some of which were quite unstable. Some implications for research using cultured cell lines are discussed.

Adolescent↗
PubMed1984

Conformational heterogeneity in polypeptide cardiac stimulants from sea anemones.

High-resolution 1H NMR spectra at 300 MHz of the polypeptide cardiac stimulants anthopleurin-A and Anemonia sulcata toxin II reveal conformational heterogeneity in both molecules. The two conformations, manifest in a number of split 1H resonances, are in slow exchange over a wide range of pH and temperature. Heterogeneity affects a region of these molecules containing the structurally and functionally important Asp residues. By comparison with a homologous polypeptide Anemonia sulcata toxin I, which does not show this type of heterogeneity, it is suggested that the heterogeneity may originate in cis-trans isomerism of the Gly-40 to Pro-41 peptide bond.

Amino Acid Sequence↗
PubMed1992

Characterization of the heterogeneity of polyethylene glycol-modified superoxide dismutase by chromatographic and electrophoretic techniques.

Covalent attachment of polyethylene glycol (PEG) chains to the enzyme Cu,Zn-superoxide dismutase (SOD) produces a heterogeneous mixture of modified protein species. The heterogeneity of the product (PEG-SOD) derives from a variable stoichiometric combination of PEG with individual SOD molecules in addition to the polydispersity of the PEG reagent. Characterization of PEG-SOD presents significant challenges due in part to this heterogeneity in addition to the hybrid nature of the modified enzyme. The application of classical methods of protein characterization is not always successful for these PEG-proteins requiring the development of alternative or modified procedures. A series of chromatographic techniques including reversed-phase, ion-exchange, size-exclusion, and hydrophobic interaction high-performance liquid chromatography along with electrophoretic techniques including isoelectric focusing, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and capillary zone electrophoresis have been developed for assessing the degree of heterogeneity of PEG-SOD samples which encompass a range of different stoichiometries. Examples will be given demonstrating the application of these techniques to characterize PEG-SOD samples of different composition produced during the course of the reaction between SOD and an activated PEG reagent.

Animals↗
PubMed1985

Molecular analysis of the heterogeneity region of the human ribosomal spacer.

The human ribosomal non-transcribed spacers are 30 X 10(3) base-pairs (or 30 kb) in length with a limited length heterogeneity localized in a specific region downstream from the 3' end of the transcribed region. Total DNA digested with EcoRI and BamHI and hybridized with a probe containing the 3' end of the 28 S ribosomal RNA coding region shows four major bands of 3.9 kb, 4.6 kb, 5.4 kb and 6.2 kb. The 5.4 kb band is the most abundant in every individual, followed by the 4.6 kb band. The longest and the shortest size classes are less well-represented and may even be absent. Every individual shows his own pattern of relative abundance of non-transcribed spacer length classes that can be followed through generations. We decided to investigate the molecular structure of the heterogeneity region, in order to cast light onto the mechanisms underlying the origin and maintenance of this length heterogeneity. Pertinent spacer regions of eight ribosomal clones from two human genomic libraries were subcloned and analyzed by restriction mapping and nucleotide sequencing. In the minimal length class, there is a sequence of 700 base-pairs that appears to be tandemly duplicated once, twice or three times in the other length classes. This repeated DNA module contains a region consisting of repetitions of simple pyrimidine groups like C-T, C-T-T-T or C-C-C-T. DNA module repeats may differ by the length of this pyrimidine-rich region. However, these length variations are not continuous, as revealed by Southern transfer analysis of several individuals and different cloned gene units: instead, the repeated modules fall into two discrete length classes of about 700 base-pairs and 800 base-pairs. An imperfect duplication of a short sequence of 86/89 base-pairs is present at the boundary between the heterogeneity region and the upstream flanking region, representing a very ancient duplication event.

Base Sequence↗
PubMed1996

Modeling nucleotide evolution: a heterogeneous rate analysis.

A new model of molecular evolution is introduced that allows for heterogeneous rates across the sequence positions. The development of this model was motivated by two issues: first, a number of studies have shown that the positions in a DNA sequence evolve at different rates, and second, it has been shown that not accounting for this heterogeneity can lead to biased estimates of evolutionary parameters. The authors generalize the Markovian model of molecular evolution to allow for heterogeneous rates and explore some of the consequences of such a model. In particular, they quantify the biases incurred by incorrectly assuming an equal-rate model and consider what can be learned about evolutionary parameters under a heterogeneous model.

Biological Evolution↗
PubMed1986

Evidence for kinetic heterogeneity among human low density lipoproteins.

The kinetics of low density lipoprotein apolipoprotein B (LDL apo B) metabolism are usually determined using turnover techniques in which radioiodinated LDL apo B is injected as a bolus into plasma, and serial plasma and urinary radioactivity samples are taken. The metabolic parameter of interest usually estimated from such data is the fractional catabolic rate (FCR). Two methods are normally employed to obtain an estimate of the FCR. One, the so-called Matthews' analysis, assumes plasma LDL apo B metabolism can be described by a single plasma pool while the other is determined by calculating the ratio of urinary radioactivity excreted to mean plasma radioactivity per day. Both of these methods assume LDL apo B is kinetically homogeneous, thus ignoring the evidence that LDL is biochemically heterogeneous in some individuals. If this biochemical heterogeneity manifests itself as kinetic heterogeneity, then the use of these data to estimate the FCR will not permit the resolution of the finer details of potential metabolic defects. This paper addresses the question of kinetic homogeneity and heterogeneity of LDL apo B within the context of several integrated kinetic models of increasing complexity. Each model fits reasonably the turnover data and hence cannot be rejected on the basis of failure to be compatible with the data. However, the models have strikingly different physiologic interpretations while providing essentially the same estimate for the FCR. Thus LDL apo B metabolism appears to be more complex than originally believed, and the models provide a framework within which to design new experiments to distinguish among them.

Adult↗
PubMed1991

Diffusion limitation of O2 supply to tissue in homogeneous and heterogeneous models.

The role of diffusion limitation in O2 supply was studied in cross-sectional elements of the Krogh cylinder model (with O2 supply from a central capillary) and of the solid cylinder model (with O2 supply from the outer surface). The effect of diffusion limitation was quantified in terms of the ratio O2 uptake/O2 requirement (= fraction of cross-sectional area supplied with O2), assuming local O2 requirement per unit volume to be constant and independent of PO2 at PO2 greater than 0. Calculations were performed for single cylinders of varied radius and O2 requirement (homogeneous models). Unequal distribution of diffusion conditions was represented by a model composed of three sorts of Krogh or solid cylinders, with radii in relation 3: square root of 3:1, but of equal cross-sectional area, i.e. number of cylinders of each sort in relation 1:3:9 (heterogeneous models). The results revealed the following main features. (1) At the same outer radius, diffusion limitation sets in at a smaller O2 requirement, and increases more steeply with increasing O2 requirement, in the homogeneous Krogh cylinder model compared with the homogeneous solid cylinder model. A similar behavior is observed when the radius of the cylinder section is increased at constant O2 requirement. (2) Diffusion limitation in the heterogeneous model sets in at a lower O2 requirement value, and increases more gradually with increasing O2 requirement, than in the corresponding homogeneous models with the same average cylinder diameter. This behavior is due to sequential onset, in the heterogeneous model, of anoxia in the cylinder sections of different radii. We conclude that diffusion heterogeneity has to be taken into account when the role of diffusion limitation in tissue O2 supply is investigated.

Animals↗
PubMed1989

Genetic heterogeneity of the RNA genome population of the plant virus U5-TMV.

The genetic heterogeneity in a population of the U5 strain of tobacco mosaic virus (U5-TMV) was studied. The T1 fingerprint characterizing a cloned population did not vary after a new cloning step in the local lesion host Nicotiana tabacum Xanthi-nc, nor during four series of 20 passages in the systemic host N. tabacum Samsum. No heterogeneity was observed among 10 clones derived from the cloned populations, while 1 of 18 clones derived from a 20-fold passaged population differed from the rest in 1 of 55 oligonucleotides. A higher heterogeneity was found in an uncloned field isolate in which 2 of 10 clones differed in type in 1 and 2 oligonucleotides, respectively. These data agree with those reported for bacterial and animal RNA viruses and are compatible with the quasi-species model for RNA populations. On the other hand, the intrapopulational heterogeneities found for U5-TMV are considerably smaller than those reported for other RNA viruses, our data showing a high genetic stability for U5-TMV.

Cloning, Molecular↗
PubMed1992

Rapid sequence evolution of street rabies glycoprotein is related to the highly heterogeneous nature of the viral population.

The sequence of the glycoprotein gene of a street rabies virus was determined directly using fragments of a rabid dog brain after PCR amplification. Compared with that of the prototype strain CVS, this sequence displayed 10% divergence in overall amino acid composition. However only 6% divergence was noted in the ectodomain suggesting that structural constraints are exerted on this portion of the glycoprotein. A human strain isolated on cell culture from the saliva of a patient with clinical rabies had only five amino acid differences with the canine isolate, an indication of their close relatedness. These differences could have originated during transmission from dog to dog, or from dog to man, or during isolation on cell culture; they are nonetheless indicative of a genetic evolution of street rabies virus. This evolution was further evidenced by the selection of cell-adapted variants which displayed new amino acid substitutions in the glycoprotein. One of them concerned antigenic site III where arginine at position 333 was replaced by glutamine. As expected this substitution conferred resistance to a site IIIa monoclonal antibody (MAb), but surprisingly did not abolish neurovirulence for adult mice. However, a decrease in the neurovirulence of the cell-adapted variant in the presence of a site IIIa specific MAb was noted, suggesting that neurovirulence was due to a subpopulation neutralizable by the MAb. Simultaneous presence of both the parental and variant sequences was indeed evidenced in the brain of a mouse inoculated with the cell-adapted variant; during multiplication in the mouse brain, the frequency of the parental sequence rose from less than 10% to nearly 50%, indicating the selective advantage conferred by arginine 333 in nervous tissue. Altogether these results were suggestive of an intrinsic heterogeneity of street rabies virus. This heterogeneity was further demonstrated by the sequencing of molecular clones of the glycoprotein gene, which revealed that only one-third of the viral genomes present in the brain of a rabid dog had the consensus sequence. Two-thirds of the clones analyzed displayed from one to three amino acid substitutions. Such heterogeneous populations have been referred to as quasispecies, a concept which implies heterogeneous populations kept together in a dynamic equilibrium. This equilibrium could be rapidly displaced, giving the virus the capacity to adapt easily to new environmental conditions.

Amino Acid Sequence↗
PubMed1985

Heterogeneity of human factor VIII/vWF in lipaemic plasma.

In order to determine the influence of plasma lipids on the apparent molecular size of human F VIII/vWF and on the relationship of the factor-related properties, namely F VIII:C, F VIIIR:Rcof, and F VIIIR:Ag to F VIII/vWF, the factor's elution pattern in the presence of lipids on Sephacryl 1000 was investigated. When fresh plasma of fasting donors was chromatographed on this gel, F VIII/vWF eluted in a single sharp peak with all three F VIII-related activities appearing in the separation range of the gel column. When fresh postprandial lipaemic plasma was chromatographed on this gel, F VIII/vWF showed distinct heterogeneity in the elution pattern with respect to molecular size and relationship to the F VIII-related properties. After incubation of lipaemic plasma with phospholipase C the elution pattern of F VIII/vWF changed from heterogeneity to homogeneity similar to those of plasma of fasting donors. After incubation of lipaemic plasma with triglycerid lipase the elution pattern of F VIII/vWF remained heterogenous. A similar heterogeneity in the elution pattern of F VIII/vWF was found when plasma of fasting donors was mixed with a preparation of very low density lipoproteins derived from human postprandial plasma or with a preparation of coagulant-active phospholipids.

Chemical Fractionation↗
PubMed1988

Immunovisualization of fibrinogen A alpha-chain heterogeneity in normal plasma and plasma from patients with DIC or on streptokinase therapy.

Purified fibrinogen as well as normal plasma, or plasma from patients with DIC or undergoing streptokinase(SK)-therapy was subjected to 1D- and 2D SDS-electrophoresis under reducing conditions. The pattern was revealed either by Coomassie-staining or immunostaining after Western-blotting and then compared. The use of polyclonal antibodies to fibrinogen as well as two monoclonal anti-bodies reacting with FPA and C-terminal part of the A alpha-chain confirmed immunologically the previously reported molecular weight heterogeneity of the A alpha-chain of the fibrinogen molecule as being a constituent of normal plasma, and lead to the following conclusions: 1. The MW-heterogeneity is observed in the fibrinogen pool of normal plasma as well as in DIC-plasma, SK-plasma and in purified fibrinogen, being the least noticeable in normal plasma and most advanced in SK-plasma. Patterns obtained using immunostaining with monoclonal anti-FPA confirm that the MW-heterogeneity of fibrinogen is mainly due to C-terminal degradation of the A alpha-chain. 2. Numerous A alpha-chain remnants (at least 9), with intact N-terminal ends, are found to be present in normal plasma, with a MW range from 66,200 to 36,000 Da, demonstrating that each of the "classical" HMW, LMW, LMW' subgroups consist of fibrinogen molecules which are very heterogeneous. 3. Two populations of A alpha-chains in purified fibrinogen and in fibrinogen in plasma react with the C-terminal specific Mab G-8. This is in contrast to the findings in plasma from streptokinase-treated patients, where several bands of lower molecular weights than the gamma-chain can be seen, suggesting the presence of free, circulating A-alpha chains split in the N-terminal half of the chain beyond the last inter-chain disulphide bond. 4. 2D electrophoresis disclosed substantial deviations in the patterns obtained with DIC-plasma, SK-plasma and with fibrinogen purified by beta-alanine-precipitation from that observed with normal plasma. The present technique allows selective characterization of fibrinogen independently of the other proteins present in plasma and offers extreme sensitivity.

Blotting, Western↗
PubMed1995

Antigenic heterogeneity of N2 neuraminidases of avian influenza viruses isolated in Israel.

Twenty one N2 neuraminidase (NA)-containing viruses isolated in Israel from different avian hosts during 1971-1984 were studied comparatively by means of the panel of 7 monoclonal antibodies (MAB) against A/Guiyang/57(H2N2) virus. Fifteen from the 21 viruses were studied in comprehensive cross reaction NA inhibition (NI) tests with the corresponding polyclonal antisera. The principal result of the studies is that all the isolates can be distributed into two main groups. The 1st group includes the majority of the isolates whose NA shows close relatedness to the "early" (1957 type) N2 NA by NI tests with polyclonal antisera, and demonstrates remarkable stability in the NI tests by reacting with the same 6 from 7 MABs of the panel. The 2nd group does not show any special kinship to either "early" or "late" (1968 type) N2 when analyzed with polyclonal antisera and demonstrates heterogeneity by the analysis with the MABs. A hypothetical explanation of the phenomenon of co-circulation in the local avian reservoir of viral strains displaying either remarkable stability or wide heterogeneity of their NAs is suggested. In accordance with it, the viruses with "stable" ("conservative") N2 NA did not leave the avian reservoir and, hence, did not drift because of very low antibody "selection pressure". Contrary to it, the viruses with heterogeneous N2 NA had been circulating in the human (mammalian) reservoir during various periods before their transfer into the avian reservoir; they drifted accordingly and, being then isolated from birds and designated as "avian" viruses, demonstrate heterogeneity of their NAs which is typical for human viruses.

Animals↗
PubMed1992

Sequence and length heterogeneity of alpha Fc gamma R transcripts in AKR mice.

The murine low-affinity receptors for IgG, Fc gamma RIII and Fc gamma RII, are encoded by the alpha and the beta Fc gamma R genes, respectively. By contrast to the sequence and the molecular polymorphism of human Fc gamma RIII, no heterogeneity of the murine Fc gamma RIII has been reported and a single alpha Fc gamma R transcript was observed. We describe here a double heterogeneity of alpha Fc gamma R transcripts. First, by S1 mapping of alpha transcripts and by cloning of cDNA coding for Fc gamma RIII, we found a strain-related sequence heterogeneity: four amino acids in the coding region and two stretches of nucleotides in the 3' untranslated sequences differ between alpha transcripts of AKR and BALB/c mice. Second, in AKR mice, we found a cell-dependent length heterogeneity: a short 0.9 kb alpha transcript was present in peritoneal thioglycolate-elicited cells (PEC) from AKR mice. This transcript was present neither in mast cells and NK cells from AKR and BALB/c mice nor in PEC from BALB/c mice. A short cDNA, with a deletion of all the 3' untranslated sequences, has been cloned from AKR PEC, and corresponds to the short alpha transcript. All the differences found in the 3' untranslated sequences of AKR alpha transcripts are located within the fifth exon of the mouse alpha Fc gamma R gene.

Amino Acid Sequence↗
PubMed1994

Karyotypic analysis of a heterogeneous human transitional cell carcinoma of the bladder.

The UCRU-BL-17 (BL-17) series of xenografts, tissue culture sublines, and cloned cell lines (Fig. 1) shows a range of heterogeneous growth characteristics both in vitro and in vivo (Table 1) and represents a model of human bladder cancer heterogeneity. Cytogenetic analysis was undertaken to determine if specific chromosome changes correlated with particular aspects of the heterogeneous phenotypes. The BL-17 sublines and cloned cell lines shared many common chromosome abnormalities. Indeed, the cloned cell lines showed nearly identical karyotypes despite their marked differences in growth characteristics. Karyotypic evolution with passage through the nude mice was apparent, however. This evolution occurred at the specific chromosome regions of 1p12, 3cen-3p21, and 6cen-6q21. Whether the heterogeneity of karyotype between the BL-17 cell lines resulted from the existence of multiple clones in the original patient tumor or from karyotypic instability through passage in nude mice is uncertain, but in either case the specificity of karyotypic evolution observed suggests that 1p12, 3cen-3p21, and 6cen-6q21 are hotspots for rearrangement in the BL-17 tumor. No specific correlations between chromosome abnormalities and biologic characteristics could be made, but several unique karyotypic features arose in the progression to two of the sublines, BL-17/23 alpha and BL-17/0/X2A, coinciding with a loss of anchorage-independent growth by BL-17/23 alpha and a change in growth in vivo from a solid tumor to a fluid-filled tumor by BL-17/0/X2A.

Aged↗
PubMed1995

Correlation of breast dose heterogeneity with breast size using 3D CT planning and dose-volume histograms.

The aim of this study was to evaluate the effect of breast size on dose heterogeneity. Twenty women underwent a planning CT scan of the thorax. A three-dimensional treatment plan was devised for each patient using a standard technique of isocentric medial and lateral wedged tangential fields. Three-dimensional dose distributions were derived using an equivalent path length (EPL) inhomogeneity correction and cumulative dose-volume histogram (DVH) data calculated for the breast. Analysis of the DVHs for each patient reveals that 0.2-23.8% of the breast received an absorbed dose outside the desired 95-105% of that prescribed at the isocentre. The degree of dose heterogeneity was most strongly correlated with breast volume (r = 0.70, 95% confidence interval (C.I.) 0.37-0.87). There was also a positive correlation for breast dose heterogeneity versus brassière (bra) cup size (Spearman rank correlation rho = 0.62), breast area (r = 0.39, 95% C.I. -0.06-0.71) and chest wall separation (r = 0.31, 95% C.I. -0.15-0.66). We conclude that breast size is an important determinant of dose heterogeneity within the breast.

Anthropometry↗
PubMed1991

The molecular basis of heterogeneity of hepatitis delta virus.

HDV-RNA displays genetic heterogeneity at several different levels. This heterogeneity is likely reflected in the biological properties, such as pathogenicity and evolution, of HDV. The variation and progression of the clinical picture of delta hepatitis is likely associated with the heterogeneity of the virus. The mechanism of the generation of the heterogeneity remains largely to be studied.

Antigens, Viral↗