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PubMed1967

Cellular heterogeneity in the production of an anti-hapten antibody.

Single lymph node cells from rats immunized with a conjugate of 3-iodo-4-hydroxy-5-nitrophenyl acetic acid chloride (NIP) and chicken globulin were tested against either NIP or NNP conjugated with bacteriophage. NNP is related to NIP but has a nitro group instead of iodine. The conjugated phages were still infective but easily inactivated by anti-hapten sera at a serum concentration of 10(-7). Phages carrying a related hapten were less sensitive to antibody than phages conjugated with the immunogenic hapten. When NIP-T2 and NNP-T4 conjugates were incubated in microdrops containing a single lymph node cell from an anti-NIP animal, strong inactivation of either or both phages occurred in some cases. For the reasons given in the text this inactivation was considered to be due to anti-NIP antibody produced by the cell in the microdrop. Inactivation of the two kinds of phages by the anti-NIP cells was highly nonrandom; some cells inactivated almost all of the 1700 or so NIP-T2 phages in the drop but left almost all NNP-T4 phages viable. Others had a very strong cross-reaction and inactivated equal proportions (up to 75%) of both phages. The remaining active cells exhibited an intermediate degree of cross-reaction. Control experiments indicated that there was a true cellular heterogeneity in the specificity of the anti-NIP produced by different cells. They suggested that the observed heterogeneity of specificities was limited to the structure of the hapten and was not influenced by the structure of the carrier. As all the cells studied were induced by a single hapten, the observed cellular heterogeneity was probably not caused by a heterogeneous antigen. It seems more likely that latent heterogeneity was present in the cells before they were stimulated by the NIP hapten.

Animals↗

PubMed2003

Fractal properties of perfusion heterogeneity in optimized arterial trees: a model study.

Regional blood flows in the heart muscle are remarkably heterogeneous. It is very likely that the most important factor for this heterogeneity is the metabolic need of the tissue rather than flow dispersion by the branching network of the coronary vasculature. To model the contribution of tissue needs to the observed flow heterogeneities we use arterial trees generated on the computer by constrained constructive optimization. This method allows to prescribe terminal flows as independent boundary conditions, rather than obtaining these flows by the dispersive effects of the tree structure. We study two specific cases: equal terminal flows (model 1) and terminal flows set proportional to the volumes of Voronoi polyhedra used as a model for blood supply regions of terminal segments (model 2). Model 1 predicts, depending on the number Nterm of end-points, fractal dimensions D of perfusion heterogeneities in the range 1.20 to 1.40 and positively correlated nearest-neighbor regional flows, in good agreement with experimental data of the normal heart. Although model 2 yields reasonable terminal flows well approximated by a lognormal distribution, it fails to predict D and nearest-neighbor correlation coefficients r1 of regional flows under normal physiologic conditions: model 2 gives D = 1.69 +/- 0.02 and r1 = -0.18 +/- 0.03 (n = 5), independent of Nterm and consistent with experimental data observed under coronary stenosis and under the reduction of coronary perfusion pressure. In conclusion, flow heterogeneity can be modeled by terminal positions compatible with an existing tree structure without resorting to the flow-dispersive effects of a specific branching tree model to assign terminal flows.

Animals↗

PubMed2000

Competition and the Effect of Spatial Resource Heterogeneity on Evolutionary Diversification.

A model is presented to explore how the form of selection arising from competition for resources is affected by spatial resource heterogeneity. The model consists of a single species occupying two patches connected by migration, where the two patches can differ in the type of resources that they contain. The main goal is to determine the conditions under which competition for resources results in disruptive selection (i.e., selection favoring a polymorphism) since it is this form of selection that will give rise to the evolutionary diversification of resource exploitation strategies. In particular, comparing the conditions giving rise to disruptive selection when the two patches are identical to the conditions when they contain different resources reveals the effect of spatial resource heterogeneity. Results show that when the patches are identical, the conditions giving rise to disruptive selection are identical to those that give rise to character displacement in previous models. When the patches are different, the conditions giving rise to disruptive selection can be either more or less stringent depending upon demographic parameters such as the intrinsic rate of increase and the migration rate. Surprisingly, spatial resource heterogeneity can actually make forms of evolutionary diversification such as character displacement less likely. It is also found that results are dependent on how the resource exploitation strategies and the spatial resource heterogeneity affect the population dynamics. One robust conclusion however, is that spatial resource heterogeneity always has a disruptive effect when the migration rate between patches is low.

Journal Article↗

PubMed2000

Competition and the Effect of Spatial Resource Heterogeneity on Evolutionary Diversification.

Lotka‐Volterra↗

PubMed2004

Effects of matrix heterogeneity on animal dispersal: from individual behavior to metapopulation-level parameters.

Mounting theoretical and empirical evidence shows that matrix heterogeneity may have contrasting effects on metapopulation dynamics by contributing to patch isolation in nontrivial ways. We analyze the movement properties during interpatch dispersal in a metapopulation of Iberian lynx (Lynx pardinus). On a daily temporal scale, lynx habitat selection defines two types of matrix habitats where individuals may move: open and dispersal habitats (avoided and used as available, respectively). There was a strong and complex impact of matrix heterogeneity on movement properties at several temporal scales (hourly and daily radiolocations and the entire dispersal event). We use the movement properties on the hourly temporal scale to build a simulation model to reconstruct individual dispersal events. The two most important parameters affecting model predictions at both the individual (daily) and metapopulation scales were related to the movement capacity (number of movement steps per day and autocorrelation in dispersal habitat) followed by the parameters representing the habitat selection in the matrix. The model adequately reproduced field estimates of population-level parameters (e.g., interpatch connectivity, maximum and final dispersal distances), and its performance was clearly improved when including the effect of matrix heterogeneity on movement properties. To assume there is a homogeneous matrix results in large errors in the estimate of interpatch connectivity, especially for close patches separated by open habitat or corridors of dispersal habitat, showing how important it is to consider matrix heterogeneity when it is present. Movement properties affect the interaction of dispersing individuals with the landscape and can be used as a mechanistic representation of dispersal at the metapopulation level. This is so when the effect of matrix heterogeneity on movement properties is evaluated under biologically meaningful spatial and temporal scales.

Animal Migration↗

PubMed1997

Assessment of hepatitis C virus quasispecies heterogeneity by gel shift analysis: correlation with response to interferon therapy.

Hepatitis C virus (HCV) quasispecies heterogeneity was assessed in pretreatment sera of 22 patients treated with interferon (IFN). Quasispecies heterogeneity was quantitated by analysis of 490 hypervariable region 1 (HVR1) clones using gel shift analysis (GSA), which allowed determination of two components of HCV quasispecies heterogeneity: genetic complexity (number of variants) and genetic diversity (mean genetic distance between variants). HCV genotype and pretreatment RNA titer were similar between responders (n = 12) and nonresponders (n = 10). GSA correlated well with nucleotide sequencing for estimating HCV genetic diversity (R = .952; P < .001). A positive correlation of .666 (P < .001) was observed between genetic diversity and complexity, suggesting that these components of quasispecies heterogeneity were related. However, while there were no significant differences in pretreatment complexity or genetic diversity among response groups, higher pretreatment genetic diversity was predictive of response failure (P = .041). Assessment of HVR1 heterogeneity by GSA revealed important relationships between quasispecies genetic diversity, complexity, and response to IFN therapy and suggested a need for analysis of other HCV genes.

Cloning, Molecular↗

PubMed1984

Compensating for heterogeneities in proton radiation therapy.

Our method for predicting, and compensating for, the effects of surface irregularities and tissue heterogeneities in proton radiation therapy was evaluated by comparing the predicted and measured dose distributions. Two heterogeneity configurations in a D-shaped water-filled phantom were handled in exactly the same way as patients. Target volumes were designated on thin-section CT scans, a single en face portal was defined, compensating boli were designed and made, and the dose distribution behind the phantom measured and compared with that intended. The compensation was accurate to within 1 mm for the phantom with a single air heterogeneity and to within 2.5 mm for the phantom with multiple bone and air heterogeneities. The bolus and phantom were misaligned by 3 mm and the dramatic change in the dose distribution demonstrated the need to address the problems of patient motion and imperfect immobilisation through compensator design. A philosophy of 'expanding' the bolus is described, and dose distributions measured with the 'expanded' boli indicate that target volume treatment can be assured within prespecified repositioning and motion uncertainties. The uncertainty in the alignment of bolus and heterogeneities leads to corresponding uncertainty in the penetration of the protons. Ranges within which they will stop are calculated and shown to encompass adequately the measured distributions in both the aligned and misaligned cases.

Humans↗

PubMed2006

The dosimetric effects of tissue heterogeneities in intensity-modulated radiation therapy (IMRT) of the head and neck.

The dosimetric effects of bone and air heterogeneities in head and neck IMRT treatments were quantified. An anthropomorphic RANDO phantom was CT-scanned with 16 thermoluminescent dosimeter (TLD) chips placed in and around the target volume. A standard IMRT plan generated with CORVUS was used to irradiate the phantom five times. On average, measured dose was 5.1% higher than calculated dose. Measurements were higher by 7.1% near the heterogeneities and by 2.6% in tissue. The dose difference between measurement and calculation was outside the 95% measurement confidence interval for six TLDs. Using CORVUS' heterogeneity correction algorithm, the average difference between measured and calculated doses decreased by 1.8% near the heterogeneities and by 0.7% in tissue. Furthermore, dose differences lying outside the 95% confidence interval were eliminated for five of the six TLDs. TLD doses recalculated by Pinnacle3's convolution/superposition algorithm were consistently higher than CORVUS doses, a trend that matched our measured results. These results indicate that the dosimetric effects of air cavities are larger than those of bone heterogeneities, thereby leading to a higher delivered dose compared to CORVUS calculations. More sophisticated algorithms such as convolution/superposition or Monte Carlo should be used for accurate tailoring of IMRT dose in head and neck tumours.

Air↗

PubMed1999

Transit time heterogeneity of bolus flow through the heart and lungs in patients with left-to-right intracardiac shunt.

Knowledge of the contributions of transit time heterogeneity to the cardiopulmonary system is important for understanding cardiopulmonary function in patients with intracardiac shunt. We determined the heterogeneity of blood transit times occurring between the right atrium and the left ventricle. Eighty two patients with suspected left-to right shunt were investigated with first-pass 99mTc-labelled red blood cell radiocardiography at supine rest. Forty two of them had a pulmonary-to-systemic flow ratio (Qp:Qs) of less than 1.2 and they served as a control group. The remaining study subjects had a Qp:Qs ratio of 1.7 +/- 0.3 (mean +/- SD). The patients with shunt had significantly greater (p < 0.001) heterogeneity of transit times (49 +/- 9%) than in the controls (39 +/- 7%). Overall heterogeneity of cardiopulmonary transit times in patients with shunt showed a curvature relationship; the highest values were centred in patients with moderate to severe shunt (1.5 < Qp:Qs < 2.5). The results suggest that the increased heterogeneity of transit times mainly occurs within the pulmonary capillary bed in patients with intracardiac shunt. This is probably due to the recruitment of the open capillaries without vessel distension.

Adolescent↗

PubMed2006

Dental follicle progenitor cell heterogeneity in the developing mouse periodontium.

As a developmental precursor for diverse periodontal tissues, the dental follicle (DF) harbors great promise for periodontal tissue regeneration. However, development of optimal therapy awaits the answer to a key question that impinges on many issues in development-Do adult progenitor tissues form a homogeneous cell population that differentiates into target tissues when they arrive at the site, or they contain heterogeneous cell populations that are committed to specific fates? To address the homogeneity/heterogeneity question, we analyzed differentiation pathways and markers in several cloned DF cell lines. Our studies revealed that each of our cloned DF lines featured remarkably unique characteristics, indicative of a separate and distinct lineage. One line, DF1, was high in proliferative activity but did not display any mineralization behavior, suggesting that it might be related to a periodontal ligament-type lineage. DF2 was similar to DF1, but featured remarkably high alkaline phosphatase activity indicative of a highly undifferentiated state. DF3 matched the mineralization characteristics of a same stage alveolar bone line AB1 in terms of gene expression and von Kossa staining, indicating that DF3 might be of cementoblastic or alveolar bone osteoblastic lineage. To verify the multilineage potential of the DF for purposes of tissue engineering, a series of differentiation induction experiments was conducted. For identification purposes, characteristics of these heterogeneous follicular progenitor cells were compared with follicle components in tissue sections of the postnatal developing periodontium. The presence of heterogeneous cell populations in the DF mirrors individual developmental pathways in the formation of the dental integument. The profound cellular heterogeneity of the DF as an adult progenitor for tissue regeneration also suggests that heterogeneous cellular constituents might play as much of a role in tissue regeneration as the inducible characteristics of individual lineages might do.

Adipogenesis↗

PubMed2005

Incorporation of tumor shape into an assessment of spatial heterogeneity for human sarcomas imaged with FDG-PET.

We have been exploring techniques for evaluation of fluoro-deoxyglucose (FDG) utilization characteristics in human sarcomas measured with positron emission tomography. In previous work, a measure of spatial heterogeneity based on evaluating the deviation of the FDG utilization distribution within the tumor region from a unimodal elliptically contoured spatial pattern was developed. This measure was shown to be a strong prognostic indicator of time to death. The present work explores a more general measure of heterogeneity which incorporates tumor boundary information. The approach relies on the use of a non-parametric representation for the tumor boundary surface. A set of 179 sarcoma patients with follow-up are evaluated with this technique. The results are analyzed to obtain empirical insight into the factors explaining elliptical heterogeneity. In terms of patient survival, the incorporation of the more sophisticated measure of spatial heterogeneity shows some potential improvement in the prediction risk. Further data will enable us to obtain a clearer empirical understanding of the role of the surface information in the measurement of tumor heterogeneity.

Data Interpretation, Statistical↗

PubMed1998

Heterogeneity in the accessory olfactory system.

The mammalian accessory olfactory bulb (AOB) is chemoarchitecturally heterogeneous in that it stains differentially with a number of markers; the receptor cells that project to the AOB are similarly heterogeneous. What is the significance of this heterogeneity? We have found that the AOB of the gray, short-tailed opossum, Monodelphis domestica, stains differentially with a number of 'markers': antibodies to olfactory marker protein (OMP) and the alpha subunit of the G protein Gi2, the lectin of Vicia villosa and NADPH-diaphorase. These markers stain the rostral AOB more strongly than the caudal AOB whereas, the G protein subunit G(o) alpha is located predominantly in the posterior subdivision of the AOB. This heterogeneity in the chemoarchitecture of the AOB may reflect a fundamental organizational dichotomy within the vomeronasal system that corresponds to a functional dichotomy. The vomeronasal sensory epithelium also exhibits a chemoarchitectural heterogeneity: receptor cells in the basal third are G(o) alpha-immunoreactive whereas the cells in the middle third are Gi2 alpha-immunoreactive. Tracing studies using WGA-HRP demonstrate that the neurons in the middle third of the vomeronasal sensory epithelium project their axons to the anterior AOB whereas those in the basal third appear to project to the posterior AOB.

Animals↗

PubMed2000

The evolution of recombination in a heterogeneous environment.

Most models describing the evolution of recombination have focused on the case of a single population, implicitly assuming that all individuals are equally likely to mate and that spatial heterogeneity in selection is absent. In these models, the evolution of recombination is driven by linkage disequilibria generated either by epistatic selection or drift. Models based on epistatic selection show that recombination can be favored if epistasis is negative and weak compared to directional selection and if the recombination modifier locus is tightly linked to the selected loci. In this article, we examine the joint effects of spatial heterogeneity in selection and epistasis on the evolution of recombination. In a model with two patches, each subject to different selection regimes, we consider the cases of mutation-selection and migration-selection balance as well as the spread of beneficial alleles. We find that including spatial heterogeneity extends the range of epistasis over which recombination can be favored. Indeed, recombination can be favored without epistasis, with negative and even with positive epistasis depending on environmental circumstances. The selection pressure acting on recombination-modifier loci is often much stronger with spatial heterogeneity, and even loosely linked modifiers and free linkage may evolve. In each case, predicting whether recombination is favored requires knowledge of both the type of environmental heterogeneity and epistasis, as none of these factors alone is sufficient to predict the outcome.

Alleles↗

PubMed1992

Structural heterogeneity in the Man8-13GlcNAc oligosaccharides from log-phase Saccharomyces yeast: a one- and two-dimensional 1H NMR spectroscopic study.

Previously, Man8-14GlcNAc oligosaccharides were isolated from highly purified Saccharomyces cerevisiae invertase and shown by one-dimensional 1H NMR spectroscopy and alpha 1,2-linkage-specific mannosidase digestion to constitute a homologous series of nearly homogeneous compounds, which appeared to define the intermediates in oligosaccharide core synthesis in yeast (Trimble, R.B. and Atkinson, P.H. (1986) J. Biol. Chem., 261, 9815-9824). To evaluate whether invertase oligosaccharides reflected global core processing of yeast glycans, the soluble glycoprotein pool of disrupted log-phase cells was digested with endo-beta-N-acetyl-glucosaminidase H and Man8-13GlcNAc were isolated by Bio-Gel P-4 chromatography. Although analysis of each size class by one-dimensional 400 MHz and two-dimensional 500 MHz phase-sensitive COSY 1H NMR spectroscopy revealed considerable structural heterogeneity in all but Man8GlcNAc, the major positional isomer in Man9-13GlcNAc (approximately 50%) was identical to that previously elucidated on invertase. The heterogeneity resided in four families of oligosaccharides: (i) Glc3Man9GlcNAc----Man8 GlcNAc trimming intermediates; (ii) alpha-mannosidase degradation products of the principal isomers; (iii) mannan elongation intermediates; (iv) core structures with the alpha 1,2-linked mannose usually removed by the processing alpha-mannosidase. The potential for the vacuolar alpha-mannosidase (AMS1 gene product) to generate heterogeneity in vitro was confirmed by isolating oligosaccharides from AMS1 and ams1 yeast strains in the presence of a Man13GlcNAc[3H]-ol marker (where GlcNAc[3H]-ol is N-acetylglucosamin [1-3H]itol). Degradation of the Man13GlcNAc[3H]-ol to Man9-12GlcNAc[3H]-ol occurred in the former, but not in the latter. A role for the vacuolar alpha-mannosidase in generating at least some heterogeneity in vivo was inferred from the 1H NMR spectrum of the AMS1 Man11GlcNAc pool, which showed more structural isomerism than seen in the spectrum of a comparable ams1 Man11GlcNAc preparation. Thus, the principal biosynthetic pathway of inner core mannan in Saccharomyces is defined by the Man8-13GlcNAc oligosaccharides found on external invertase, while structural heterogeneity in these size classes results from precursor processing in the endoplasmic reticulum, core extension in the Golgi and metabolic degradation in the vacuole.

Acetylglucosamine↗

PubMed1990

Heterogeneity in the familial aggregation of fasting plasma glucose in five North American populations: the Lipid Research Clinics Family Study.

Heterogeneity in the familial aggregation of plasma glucose in five samples of the Lipid Research Clinics Family Study (LRC) was investigated using path analysis. This study was deemed appropriate since recent investigations reported a wide range of estimates for genetic and cultural factors. The path model incorporated a measured index of the familial environment in order to separate the effects of genes and environments in the nuclear family design, genetic and environmental heritabilities, spouse resemblance, sibling environmental effects, and parental cultural transmission. The methodology was completely general in allowing sample-specific, as well as pooled-sample, estimation of all or any subset of the model parameters. Genetic heritability estimates were heterogeneous, ranging from zero to 33% across the clinics. Environmental heritability (7%), spouse resemblance, non-transmitted sibling environmental effects, and parental cultural transmission were homogeneous across samples. No support was found for specific maternal effects, nor for intergenerational differences in cultural or genetic heritability. We conclude that the genetic and environmental heritabilities for plasma glucose in the LRC are consistent with the diverse reports by earlier investigators. In addition, we were able to exclude methodological differences as a cause of this heterogeneity. Furthermore, formal hypothesis tests suggest that the aetiology of this heterogeneity is genetic (and not cultural), taking the form of two distinct homogeneous patterns (one for no genetic effect, and one for a moderate genetic effect). Only formal heterogeneity tests of the type described here can detect these effects, and allow pooling of separate studies in order to obtain more precise estimates of the parameters of interest.

Adult↗

PubMed1984

Spatial, temporal, and genetic heterogeneity in host populations and the design of immunization programmes.

The relevance of heterogeneity in infectious disease transmission to the design of immunization programmes is examined by the use of simple deterministic models of recurrent epidemic behaviour. In the context of spatial heterogeneity it is shown that an optimal vaccination programme, which concentrates on groups with relatively high density, can lead to eradication with overall coverage levels less than those estimated by a model which assumes homogeneity in host spatial distribution. Age-related heterogeneity in transmission can result in higher or lower coverage levels than those predicted by models which assume age-independent transmission, depending on the quantitative detail of how transmission changes with age. Genetic heterogeneity in host susceptibility to infection is shown to produce effects that are similar to those induced by age-related changes in transmission. It is concluded that much greater attention should be focused on transmission heterogeneity in future work on models of recurrent epidemic behaviour and the design of immunization programmes.

Biometry↗

PubMed1999

Heterogeneity of chemosensitivity of metastatic cutaneous melanoma.

Advanced melanoma has a poor prognosis and chemotherapy provides little benefit for most patients. This may be related to heterogeneity of chemosensitivity as well as frequent constitutive resistance to individual cytotoxic drugs. We have therefore examined the heterogeneity of chemosensitivity in metastatic cutaneous melanoma specimens using an ex vivo ATP-based chemosensitivity assay (ATP-TCA). Melanoma deposits (n=55) in skin or lymph node were tested using the ATP-TCA, performed in three separate laboratories. Analysis of the data collected (based on an arbitrary sensitivity index < 300) shows considerable heterogeneity of chemosensitivity. The most active single cytotoxic agents in the assay were identified as cisplatin, treosulfan, paclitaxel, vinblastine, gemcitabine and mitoxantrone. There was also a limited direct inhibition of melanoma cell growth by interferon-alpha2b, although this agent is known to have a number of indirect biological antitumor effects. Exposure of tumor cells to combinations of drugs at the concentrations tested as single agents showed the most active combinations to be treosulfan+gemcitabine, cisplatin+paclitaxel and vinblastine+paclitaxel. There was considerable heterogeneity of chemosensitivity: some tumors responded well to one agent or combination, while others showed no response to this and instead responded to one of the alternatives tested. Occasional highly resistant tumors showed no response to any of the single agents or combinations tested. The degree of heterogeneity observed suggests that the ATP-TCA could be used to select patients who might benefit from specific chemotherapeutic agents alone or in combination. This provides the rationale for future randomized controlled trials of ATP-TCA-directed chemotherapy versus physician's choice to determine whether assay-directed chemotherapy can improve patient response and survival.

Adenosine Triphosphate↗

PubMed1994

DNA content in cervical carcinoma: a flow cytometric assessment of DNA heterogeneity.

The degree of DNA heterogeneity varies between tumors arising in different body sites. Any substantial degree of variability within a given tumor can give rise to significant problems in the interpretation of DNA flow cytometric (FCM) studies. This study was undertaken to evaluate the degree of DNA heterogeneity in cervical carcinomas. A total of 100 3-mm punch biopsies were evaluated from single large cases in 10 sections of cervical carcinoma. Of the 10 tumors, 6 were squamous carcinoma, 1 was an adenocarcinoma, 1 was a mixed small cell and squamous carcinoma, 1 was an adenosquamous cancer, and 1 was a small cell carcinoma with a small area of adenocarcinoma. Adequate histograms were available for 95 (95%) of the samples. Of the 10 cases studied, 9 (90%) revealed homogeneity in the DNA pattern. A solitary case demonstrated heterogeneity in one histogram (nine samples DNA diploid and one sample DNA aneuploid). This case was predominantly small cell undifferentiated carcinoma with focal adenocarcinoma. The area of adenocarcinoma was probably the area that contributed to the heterogeneous FCM pattern. From this study we conclude that for most cervical carcinomas of a specific histologic type there is DNA homogeneity. However, for carcinomas with a mixed morphology, DNA heterogeneity is possible and this must be taken into account in any DNA ploidy studies that include mixed or combined tumors.

Adenocarcinoma↗