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Results for “Heterogeneity Mapping”

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PubMed2006

A statistical investigation of normal regional intra-subject heterogeneity of brain metabolism and perfusion by F-18 FDG and O-15 H2O PET imaging.

BACKGROUND: The definite evaluation of the regional cerebral heterogeneity using perfusion and metabolism by a single modality of PET imaging has not been well addressed. Thus a statistical analysis of voxel variables from identical brain regions on metabolic and perfusion PET images was carried out to determine characteristics of the regional heterogeneity of F-18 FDG and O-15 H2O cerebral uptake in normal subjects. METHODS: Fourteen normal subjects with normal CT and/or MRI and physical examination including MMSE were scanned by both F-18 FDG and O-15 H2O PET within same day with head-holder and facemask. The images were co-registered and each individual voxel counts (Q) were normalized by the global maximal voxel counts (M) as R = Q/M. The voxel counts were also converted to z-score map by z = (Q - mean)/SD. Twelve pairs of ROIs (24 total) were systematically placed on the z-score map at cortical locations 15-degree apart and identically for metabolism and perfusion. Inter- and intra-subject correlation coefficients (r) were computed, both globally and hemispherically, from metabolism and perfusion: between regions for the same tracer and between tracers for the same region. Moments of means and histograms were computed globally along with asymmetric indices as their hemispherical differences. RESULTS: Statistical investigations verified with data showed that, for a given scan, correlation analyses are expectedly alike regardless of variables (Q, R, z) used. The varieties of correlation (r's) of normal subjects, showing symmetry, were mostly around 0.8 and with coefficient of variations near 10%. Analyses of histograms showed non-Gaussian behavior (skew = -0.3 and kurtosis = 0.4) of metabolism on average, in contrast to near Gaussian perfusion. CONCLUSION: The co-registered cerebral metabolism and perfusion z maps demonstrated regional heterogeneity but with attractively low coefficient of variations in the correlation markers.

Journal Article↗

PubMed1995

A novel transcriptional initiator activity of the GABP factor binding ets sequence repeat from the murine cytochrome c oxidase Vb gene.

The murine cytochrome c oxidase (COX) subunit Vb mRNA contains heterogeneous 5' ends mapping to +1, +6, +12, +17-22, +24-29, and +32-35 positions of the gene. We have previously shown that initiation of RNA at the +1 position of the promoter depends upon a YY-1 (NF-E1) binding initiator motif. In this article we show that the GABP factor binding duplicated ets motif, GTTCCCGGAAG, at +16 to +26 position functions as an independent initiator for transcription of RNAs mapping to the +18-19 and +23-26 regions. The initiation region ets sequence repeat (ets-ets sequence) can drive the transcription of the CAT reporter gene. The upstream ets site of the ets-ets sequence exhibits a low affinity for binding to purified GABP factors, whereas the downstream site exhibits high affinity. S1 analyses of RNA from transfected COS cells demonstrate that the initiation region ets-ets sequence can accurately initiate transcription at the +18-19 and +24-25 regions. Transcriptional initiation at these two positions, but not at +1, +12, and +31-32 positions, show a selective dependence for intact downstream ets site and GABP alpha and beta factors as tested in an in vitro reconstituted system. The activities of both COX IV and COX Vb single site ets initiators are induced in vivo by coexpression with GABP alpha and beta cDNAs. These results provide evidence that the 5' heterogeneity of the COX Vb mRNA is largely due to independent transcription initiators at multiple initiator motifs that bind to various transcription factors.

3T3 Cells↗

PubMed1998

Spatial structure, environmental heterogeneity, and population dynamics: analysis of the coupled logistic map.

Spatial extent can have two important consequences for population dynamics: It can generate spatial structure, in which individuals interact more intensely with neighbors than with more distant conspecifics, and it allows for environmental heterogeneity, in which habitat quality varies spatially. Studies of these features are difficult to interpret because the models are complex and sometimes idiosyncratic. Here we analyze one of the simplest possible spatial population models, to understand the mathematical basis for the observed patterns: two patches coupled by dispersal, with dynamics in each patch governed by the logistic map. With suitable choices of parameters, this model can represent spatial structure, environmental heterogeneity, or both in combination. We synthesize previous work and new analyses on this model, with two goals: to provide a comprehensive baseline to aid our understanding of more complex spatial models, and to generate predictions about the effects of spatial structure and environmental heterogeneity on population dynamics. Spatial structure alone can generate positive, negative, or zero spatial correlations between patches when dispersal rates are high, medium, or low relative to the complexity of the local dynamics. It can also lead to quasiperiodicity and hyperchaos, which are not present in the nonspatial model. With density-independent dispersal, spatial structure cannot destabilize equilibria or periodic orbits that would be stable in the absence of space. When densities in the two patches are uncorrelated, the probability that the population in a patch reaches extreme low densities is reduced relative to the same patch in isolation; this "rescue effect" would reduce the probability of metapopulation extinction beyond the simple effect of spreading of risk. Pure environmental heterogeneity always produces positive spatial correlations. The dynamics of the entire population is approximated by a nonspatial model with mean patch characteristics. This approximation worsens as the difference between the patches increases and the dispersal rate decreases: Under extreme conditions, destabilization of equilibria and periodic orbits occurs at mean parameter values lower than those predicted by the mean parameters. Apparent within-patch dynamics are distorted: The local population appears to have the wrong growth parameter and a constant number of immigrants (or emigrants) per generation. Adding environmental heterogeneity to spatial structure increases the occurrence of spatially correlated population dynamics, but the resulting temporal dynamics are more complex than would be predicted by the mean parameter values. The three classes of spatial pattern (positive, negative, and zero correlation), while still mathematically distinct, become increasingly similar phenomenologically.

Animals↗

PubMed2000

Chromosome mapping of the sweet potato little leaf phytoplasma reveals genome heterogeneity within the phytoplasmas.

To further understand the genomic diversity and genetic architecture of phytoplasmas, a physical and genetic map of the sweet potato little leaf (SPLL) strain V4 phytoplasma chromosome was determined. PFGE was used to determine the size of the SPLL-V4 genome, which was estimated to be 622 kb. A physical map was prepared by two-dimensional reciprocal digestions using the restriction endonucleases BssHII, Smal, Eagl and I-Ceul. Sixteen cleavage sites were located on the map. Southern hybridizations of digested SPLL-V4 chromosomal DNA were done using random clones and PCR-amplified genes as probes. This confirmed fragment positions and located the two rRNA operons and the linked fus/tuf genes encoding elongation factors G and Tu, respectively, on the physical map. An inversion of one of the rRNA operons was observed from hybridization data. Sequence analysis of one of the random clones identified a gid gene encoding a glucose-inhibited division protein. Digestions of the tomato big bud (TBB) phytoplasma chromosome with the same four enzymes revealed genome heterogeneity when compared to the closely related SPLL-V4, and a preliminary chromosome size for the TBB phytoplasma of 662 kb was estimated. This mapping information has revealed that significant genome diversity exists within the phytoplasmas.

Chromosome Mapping↗

PubMed1987

Sequence and S1 nuclease mapping of the 5' region of the dihydrofolate reductase-thymidylate synthase gene of Leishmania major.

The 5' structure of mRNA transcribed from the dihydrofolate reductase-thymidylate synthase (DHFR-TS) gene of the protozoan parasite Leishmania major has been characterized. S1 nuclease mapping identifies a heterogenous 5' structure which is not affected by growth phase or developmental stage. The DNA sequence of the 5' region of the DHFR-TS gene does not reveal homology with other trypanosomatid genes, eukaryotic consensus genetic elements, or the mammalian DHFR promoter element. This latter finding is especially significant as we show that the 5' region of the E. coli DHFR gene exhibits homology to the mammalian DHFR promoter element, despite their greater evolutionary distance.

Animals↗

PubMed2001

Benign familial infantile convulsions: mapping of a novel locus on chromosome 2q24 and evidence for genetic heterogeneity.

In 1997, a locus for benign familial infantile convulsions (BFIC) was mapped to chromosome 19q. Further data suggested that this locus is not involved in all families with BFIC. In the present report, we studied eight Italian families and mapped a novel BFIC locus within a 0.7-cM interval of chromosome 2q24, between markers D2S399 and D2S2330. A maximum multipoint HLOD score of 6.29 was obtained under the hypothesis of genetic heterogeneity. Furthermore, the clustering of chromosome 2q24-linked families in southern Italy may indicate a recent founder effect. In our series, 40% of the families are linked to neither chromosome 19q or 2q loci, suggesting that at least three loci are involved in BFIC. This finding is consistent with other autosomal dominant idiopathic epilepsies in which different genes were found to be implicated.

Chromosome Mapping↗

PubMed1987

An immunocytochemical and biochemical study of the microtubule-associated protein Tau during post-lesion afferent reorganization in the hippocampus of adult rats.

A monoclonal antibody against the microtubule-associated protein (MAP) Tau was used to examine the fate of this molecule during post-lesion afferent reorganization in the hippocampus of adult rats. An immunocytochemical analysis was carried out in the dentate gyrus after unilateral destruction of the entorhinal cortex (EC). In the non-denervated hippocampus, Tau immunoreactivity was detected in parallel axons and mossy fibers; no staining was present in neuronal cell bodies and dendrites. A significant decrease in Tau immunoreactivity was detected in the outer 2/3 of the ipsilateral dentate gyrus molecular layer (ML) 2 days after an EC lesion, whereas staining in the inner 1/3 of the same ML increased considerably. This was followed by a very rapid recovery of Tau immunoreactivity in the outer 2/3 of the denervated ML, which by 10 days post-lesion was almost identical to that of the contralateral non-denervated ML. A similar phenomenon was observed in other regions of the hippocampus denervated by the EC lesion. The modifications in Tau immunoreactivity in the denervated hippocampus were also accompanied by changes in the polypeptide composition of this heterogeneous group of MAPs, as revealed by immunoblot analysis of hippocampal extracts obtained at different post-lesion intervals; these changes involved a rapid and significant increase in low molecular weight migrating Tau-immunoreactive polypeptides. The present observations indicate that important modifications in Tau proteins occur in the deafferented hippocampus, a phenomenon that may well be related with the regulation of microtubule polymerization during post-lesion axonal growth.

Animals↗

PubMed2003

Genetic mapping of allelic loss on chromosome 6q within heterogeneous prostate carcinoma.

A number of genetic events have been reported in prostate carcinogenesis, including frequent loss of heterozygosity (LOH) on chromosomes 8q, 10q, 16q and 18q. In samples of heterogeneous, multifocal prostate carcinomas, we focused on chromosome 6q using PCR-based techniques with 15 microsatellite markers to identify the specific 6q deletion within tumors. LOH of one or more polymorphic markers was detected in 10 of 21 tumors (48%). Two of these 10 tumors demonstrated LOH in all cancerous foci at specific loci and 4 tumors showed deletion in one focus. Different deletion patterns were found in 3 tumors when different polymorphic markers were used. In 90% of tumors showing LOH in one or more foci, however, two common regions of LOH were identified; one at 1.81 cM on 6q15-16.3 between markers D6S1631 and D6S1056, and the other at 5.11 cM on 6q16-21 between markers D6S424 and D6S283. By RT-PCR analysis, the TAK1 gene located at these loci did not correlate with LOH status, indicating that TAK1 is not a target gene in prostate carcinoma. The 6q deletion occurs heterogeneously and LOH was more frequent in tumors of higher pathological stages, implying that this alteration is a late event in prostate carcinogenesis. Because prostate carcinomas are genetically multicentric and of multifocal origin, it remains unclear whether the foci containing 6q deletions specifically expand within tumors or to what extent they contribute to the histological heterogeneity characteristic of the disease.

Aged↗

PubMed2000

Direct observation of single-molecule generation at a solid-liquid interface

Direct observation of single-molecule generation from a chemical reaction was achieved at a solid-liquid interface. The reaction between fluorescamine and immobilized N'-(3-trimethoxysilylpropyl)diethylenetriamine (DETA) was studied at the single-molecule level. Time-lapse fluorescence images of single-molecule products, excited by the evanescent field generated at a quartz-liquid interface, were recorded to follow the chemical reaction to its completion. The reactions were restricted to the approximately 1 nm thick layer nearest to the interface. Analysis of the photoelectron intensity of the fluorescent product of the reaction and its distribution shows that the reaction kinetics goes through a transition from zeroth-order to first-order as the reaction proceeds. This approach offered a novel means to study single-molecule reactions at the solid-liquid interface. It also enabled the investigation of reaction kinetics and chemical mapping of surface heterogeneity at the single-molecule level.

Journal Article↗

PubMed2002

Parametric imaging of tumor perfusion using flow- and permeability-limited tracers.

PURPOSE: To quantitatively evaluate the spatial distribution of flow- and permeability-limited perfusion in MCF7 human breast cancer tumors orthotopically implanted in CD1-NU mice. MATERIALS AND METHODS: Flow-limited perfusion was derived from (2)H-MRI recorded before and after infusion of deuterated water. Permeability-limited perfusion was evaluated from GdDTPA-enhanced (1)H-MRI. RESULTS: The dominant processes in tumor perfusion, namely blood flow and capillary permeability, were mapped in orthotopically implanted MCF7 human breast cancer tumors. The dynamic data were processed according to physiological models, yielding parametric maps of intravascular volume fraction, water perfusion rate, GdDTPA permeability rate constant, and extracellular volume fraction accessible to GdDTPA. The maps exhibited the heterogeneous distribution of each perfusion parameter. Most of the tumor tissue (> or =95%) was perfused with HDO, while GdDTPA was perfused in only about 50% of it. In most loci the perfusion rate was limited by capillary permeability to GdDTPA. CONCLUSION: The results demonstrated the instructive value of tracers with different properties used in conjunction to achieve a deeper understanding of tumor perfusion capacity. This study offers tools for the accurate, noninvasive evaluation of drug delivery efficacy.

Animals↗

PubMed1990

Characterization of the Alu-rich 5'-flanking region of the human prothrombin-encoding gene: identification of a positive cis-acting element that regulates liver-specific expression.

The nt sequence of 6127 bp of sequence upstream of the human prothrombin-encoding gene (F2) has been determined. Since we previously characterized 417 bp of DNA immediately upstream from the transcription start point (tsp), 6544 bp of continuous flanking sequence are known. Eleven Alu repeat sequences present in this region comprise 45% of the sequence; other repetitive sequences were identified by searching GenBank. The tsp was found to be heterogeneous by exon mapping and primer extension analysis. To localize the cis-acting sequences responsible for the liver-specific expression of F2, hybrid cat genes were constructed with various lengths of F2 5'-flanking region cloned upstream from a promoterless cat gene. After transfection into HepG2 and HeLa cells, it was inferred that the region between nt -1101 and -798 was required for synthesis in HepG2 cells; no synthesis was observed using these constructs in HeLa cells. Two sequences for known liver-specific or regulatory cis-acting sequences were identified in this region.

Amino Acid Sequence↗

PubMed2004

Microanalysis by laser-induced plasma spectroscopy in the vacuum ultraviolet.

A new setup for microanalysis by laser-induced plasma spectroscopy in the VUV range is presented and described in detail. The system features an integrated ablation and detection module with a newly designed VUV echelle system. The echelle permits a full spectral coverage between 150 and 300 nm with a resolving power lambda/Deltalambda between 11,000 and 15,000. At present, the ablation module permits a microanalysis with a crater size of 25 microm and a nominal depth resolution with an ablation rate of 150 nm/pulse. The VUV performance was demonstrated for bulk analysis of steel; detection limits for sulfur, carbon, and phosphorus were in the lower milligram per kilogram range. The VUV scanning and mapping performance for heterogeneous matrixes was illustrated for mineral bottom ash samples from a waste incineration process.

Journal Article↗

PubMed1970

Isolation and characterization of structurally homogeneous antibodies from antipneumococcal sera.

Antibodies of sufficient homogeneity for sequence studies were readily obtained in high concentrations from rabbits immunized with pneumococcal vaccines. By taking advantage of slightly differing immunologic specificity for Type III and Type VIII capsular polysaccharides, an antibody with unique electrophoretic mobility could be isolated from serum containing several distinct antibody components by using appropriate cross-reacting immunoadsorbents. A unique sequence for the N-terminal 11 amino acid residues of the light chain of the antibody was found, in contrast to several sequences in the antibody mixture from which this component was isolated. The sequence of a nonimmune light chain pool demonstrates even greater heterogeneity. Chymotryptic peptide maps of the antibody light chain show two unique cysteine-containing variable region peptides not seen in maps of nonimmune light chain pool of the same allotypic specificity as that of the antibody light chain. The experimental approach described here may provide further insight into the structure-function relationship of several homogeneous antibodies of closely related specificity for the same polysaccharide antigen.

Acetates↗

PubMed1994

Deletion of the E4 region of the genome produces adenovirus DNA concatemers.

Two mutants containing large deletions in the E4 region of the adenovirus genome H5dl366 (91.9-98.3 map units) and H2dl808 (93.0-97.1 map units) were used to investigate the role of E4 genes in adenovirus DNA synthesis. Infection of KB human epidermoid carcinoma cells with either mutant resulted in production of large concatemers of viral DNA. Only monomer viral genome forms were produced, however, when mutants infected W162 cells, a monkey kidney cell line transformed with and expressing the E4 genes. Diffusible E4 gene products, therefore, complement the E4 mutant phenotype. The viral DNA concatemers produced in dl366- and dl808-infected KB cells did not have any specific orientation of monomer joining: the junctions consisted of head-to-head, head-to-tail, and tail-to-tail joints. The junctions were covalently linked molecules, but molecules were not precisely joined, and restriction enzyme maps revealed a heterogeneous size distribution of junction fragments. A series of mutants that disrupted single E4 open reading frames (ORFs) was also studied: none showed phenotypes similar to that of dl366 or dl808. Mutants containing defects in both ORF3 and ORF6, however, manifested the concatemer phenotype, indicating redundancy in genes preventing concatemer formation. These data suggest that the E4 ORFs 3 and 6 express functions critical for regulation of viral DNA replication and that concatemer intermediates may exist during adenovirus DNA synthesis.

Adenoviruses, Human↗

PubMed2003

Heterozygous mutations in BBS1, BBS2 and BBS6 have a potential epistatic effect on Bardet-Biedl patients with two mutations at a second BBS locus.

Bardet-Biedl syndrome (BBS) is a pleiotropic genetic disorder with substantial inter- and intrafamilial variability, that also exhibits remarkable genetic heterogeneity, with seven mapped BBS loci in the human genome. Recent data have demonstrated that BBS may be inherited either as a simple Mendelian recessive or as an oligogenic trait, since mutations at two loci are sometimes required for pathogenesis. This observation suggests that genetic interactions between the different BBS loci may modulate the phenotype, thus contributing to the clinical variability of BBS. We present three families with two mutations in either BBS1 or BBS2, in which some but not all patients carry a third mutation in BBS1, BBS2 or the putative chaperonin BBS6. In each example, the presence of three mutant alleles correlates with a more severe phenotype. For one of the missense alleles, we also demonstrate that the introduction of the mutation in mammalian cells causes a dramatic mislocalization of the protein compared with the wild-type. These data suggest that triallelic mutations are not always necessary for disease manifestation, but might potentiate a phenotype that is caused by two recessive mutations at an independent locus, thus introducing an additional layer of complexity on the genetic modeling of oligogenicity.

Bardet-Biedl Syndrome↗

PubMed1984

Structural analysis of the two tandemly repeated acid phosphatase genes in yeast.

We have sequenced the genetically linked genes for repressible (PHO5) and and constitutive (PHO3) acid phosphatase from S. cerevisiae. Both genes are located on a 3.91 Kb BamHI and HpaI fragment, in the order (5') PHO5, PHO3 (3'). The mRNA transcripts have been analysed by S1-nuclease mapping. They show heterogenous initiation sites. Each of the PHO5 and PHO3 genes codes for 467 amino acids as deduced from the DNA sequence. The coding regions of the two genes show homology both at the nucleotide (82%) and the amino acid (87%) level. In the coding sequences, long stretches of homologous regions are flanked by small non-homologous regions. The nucleotide homology (65%) extends to some length into the 5' and 3' non-coding flanking sequences. Further upstream sequences are unrelated. The comparison of the NH2-terminal amino acid sequence deduced from the nucleotide sequence, with that of purified repressible acid phosphatase revealed the presence of a putative signal peptide.

Acid Phosphatase↗

PubMed1991

Regulation of the multiple promoters of the human aldolase A gene: response of its two ubiquitous promoters to agents promoting cell proliferation.

The human aldolase A gene is transcribed from three distinct promoters, the two ubiquitous promoters PN and PH and the muscle specific promoter PM. In the present study, we investigate further aldolase A mRNA structure and expression. We demonstrate that the upstream N-type exon is, in fact, extremely heterogeneous. RNAse H mapping experiments permit quantification of relative abundance of N, M, and H type mRNAs and show that the level of transcripts containing the downstream H-type exon is at least 30 times higher than that of those containing N exon, in all tissues tested. Aldolase A level is up-regulated in proliferating cells. Here we show that both N and H type mRNAs, although barely detectable in normal liver, are highly expressed in human hepatomas biopsies. Furthermore, in human lymphocytes, N-type mRNA level is enhanced by serum treatment, while in cultured Hep G2 cells, both N-type and H-type mRNA levels are increased by serum and by the tumor promoting agent PMA. Using CAT constructs in transfection experiments, we demonstrate that the H exon plus its upstream region can function autonomously: the 420 base pairs upstream of the H exon are sufficient to confer to promoter PH an efficiency comparable that of the complete SV40 early promoter and enhancer in two cell lines.

Base Sequence↗

PubMed1996

Aetiology and pathogenesis of psoriasis.

The hereditary transmission of psoriasis is suggested by epidemiological data and familial association, but remains incompletely defined, not appearing to follow simple autosomal dominant or recessive patterns. The confusion may be due to a multifactorial inheritance, or to inheritance of only a 'predisposition' to disease which requires an environmental stimuli for expression. Recent advances in genetic mapping indicate genetic heterogeneity, and suggest that definition of psoriasis at the level of the gene may soon be possible. Two of the three major pathogenic features of psoriasis--abnormal keratinocyte differentiation and hyperproliferation of keratinocytes--are secondary to altered growth and maturation kinetics related to the normal wound healing process. The third major pathogenic feature--infiltration of inflammatory components into the skin--can be explained by keratinocyte release of a wide variety of cytokines, immune and inflammatory modulators. Three theories have been proposed for the relationship between epidermal keratinocyte and immunocyte activation. The first theory proposes direct activation of epidermal keratinocytes by physical, chemical, or ultraviolet injury, increasing the synthesis and release of cytokines, which trigger T-lymphocyte activation in an antigen-independent fashion. The other two theories propose persistent T-lymphocyte stimulation as a result of either antigen/superantigen presentation by antigen-presenting cells, or as a result of autoreactivity. One or more of these mechanisms may be operative in different patients, at different times, or in response to different environmental stimuli. Also, the genetic heterogeneity of psoriasis suggests that different mechanisms could be linked to different genetic loci. Advances in understanding the aetiology and pathogenesis of psoriasis suggest the possibility of innovative, targeted therapies.

Adolescent↗