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PubMed2004

Characterization of macromolecular heterogeneity by equilibrium sedimentation techniques.

New graphical procedures have been developed to investigate the heterogeneity of protein preparations using sedimentation equilibrium. The heterogeneous systems that can be studied include self-associating systems contaminated by incompetent monomer, self-associating systems contaminated by non-dissociating oligomer and simple non-interacting monomer-oligmer disperse systems. The new procedures are based on the concentration dependence of the apparent association constants estimated by a non-linear least square fitting program (NONLIN), on the assumption of conservation of mass during sedimentation and on the applications of several standard techniques for statistical inferences of NONLIN estimations. The procedures outlined here can detect various types of heterogeneity, discriminate amongst different types of heterogeneity, estimate the amount of contaminant causing heterogeneity and determine the true equilibrium constant of the self-associating components. The procedures appear to be sensitive, accurate and easily applicable when tested using both protein samples and computer simulated data.

Attention↗

PubMed2006

Does gender contribute to heterogeneity in criteria for cannabis abuse and dependence? Results from the national epidemiological survey on alcohol and related conditions.

Previous research has noted that a unidimensional latent construct underlies criteria for cannabis abuse and dependence. However, no study to date has explored whether gender contributes to heterogeneity in the latent abuse and dependence construct and furthermore, whether after accounting for differences in the mean scores of abuse and dependence across genders, there is any evidence for heterogeneity in the individual abuse and dependence criteria. The present study utilizes data on criteria for cannabis abuse and dependence from a large, nationally representative sample (National Epidemiological Survey on Alcohol and Related Conditions) of 8172 lifetime cannabis users to investigate whether gender contributes to heterogeneity in the underlying construct of cannabis abuse and dependence, and in each individual criterion as well. Analyses, all of which were conducted in MPlus, included factor analysis, as well as MIMIC and multiple-group models for an examination of dimensionality and gender heterogeneity, respectively. Results favor a unidimensional construct for cannabis abuse/dependence, as seen in prior research. We also identify two abuse (legal and hazard) and two dependence (quit and problems) criteria, which show significant gender heterogeneity with the abuse criteria exhibiting higher thresholds in women and the dependence criteria in men. We conclude that the criteria that serve as indicators of DSM-IV cannabis abuse and dependence do not function identically in men and women and that certain criteria (e.g. hazardous use) require further refinement.

Adolescent↗

PubMed2005

Ion transfer across ion-exchange membranes with homogeneous and heterogeneous surfaces.

A homogeneous (AMX) and two heterogeneous (MA-40, MA-41) anion-exchange membranes, as well as a heterogeneous cation-exchange membrane (MK-40), are studied by electronic scanning microscopy, voltammetry, and chronopotentiometry. The presence of conducting and nonconducting regions on the surfaces of heterogeneous membranes is established by means of element analysis. The fraction of conducting regions is found by an image treatment. The surface of the AMX membrane was partially coated with microspots of a paint to make it heterogeneous (AMXheter). Voltammetric and chronopotentiometric measurements for AMX, AMXheter, and MA-41 membranes in NaCl solutions are carried out and the pH changes in the solution layers adjoining to these membranes are recorded. Analysis of obtained results shows that the concentration polarization of studied membranes characterized by the potential drop and the rate of water dissociation at the interface is mainly governed by the properties of their surfaces. It is found that the local limiting current density through conducting regions of a heterogeneous membrane is several times higher than the average limiting current through a homogeneous membrane.

Journal Article↗

PubMed2005

Transient electroosmotic flow induced by AC electric field in micro-channel with patchwise surface heterogeneities.

This paper investigates two-dimensional, time-dependent electroosmotic flow driven by an AC electric field via patchwise surface heterogeneities distributed along the micro-channel walls. The time-dependent flow fields through the micro-channel are simulated for various patchwise heterogeneous surface patterns using the backwards-Euler time stepping numerical method. Different heterogeneous surface patterns are found to create significantly different electrokinetic transport phenomena. The transient behavior characteristics of the generated electroosmotic flow are then discussed in terms of the influence of the patchwise surface heterogeneities, the direction of the applied AC electric field, and the velocity of the bulk flow. It is shown that the presence of oppositely charged surface heterogeneities on the micro-channel walls results in the formation of localized flow circulations within the bulk flow. These circulation regions grow and decay periodically in phase with the applied periodic AC electric field intensity. The location and rotational direction of the induced circulations are determined by the directions of the bulk flow velocity and the applied electric field.

Journal Article↗

PubMed2006

A novel and simple method for finding the heterogeneity of adsorbents on the basis of adsorption kinetic data.

The heterogeneity of adsorbent was characterized by a novel and simple method that uses adsorption kinetic data from solution. On the basis of different simulated adsorption kinetic data for heterogeneous adsorbents with two different adsorption sites, it was found that there is a deviation from linearity in pseudo-second-order adsorption kinetic models. The patterns of obtained diagrams (t/qt vs t) shows five main classes of adsorption. On the basis of this novel and simple method it is possible to show that the surface of adsorbents is homogeneous or heterogeneous, and in the case of heterogeneous surfaces it is possible to find the differences between adsorption sites. For finding kinetic constants of adsorption on heterogeneous surfaces with two different sites, a new equation was presented and called the two-site pseudo-second-order (TS-PSO) model. Finally, some experimental kinetic data of adsorption were analyzed by the new method.

Journal Article↗

PubMed2004

Heterogeneous response of cerebral blood flow to hypotension demonstrated by laser speckle imaging flowmetry in rats.

The response of cerebral blood flow (CBF) to mild hypotension shows great variability. CBF changes in different cortical regions at a mean arterial blood pressure (MABP) of 70 mmHg (near the lower limit of CBF-pressure autoregulation) were analyzed using laser speckle imaging flowmetry (LSIF). We hypothesize that variations in CBF autoregulation might be due to differences between regions within the cortex of each animal, regional heterogeneity, as opposed to differences between animals. Different responses of local CBF to hypotension in each rat were demonstrated as %CBF(70), the ratio of CBF at a MABP of 70 mmHg to CBF at a MABP of 100 mmHg. Regional heterogeneity ranged from 12 to 51%, expressed as the coefficient of variation of %CBF(70). At the same time LSIF revealed distinctly different patterns of CBF-pressure autoregulation between animals. Between-animal heterogeneity represents a continuous distribution, spread between animals with predominantly decreased CBF (%CBF(70) < 85%, rat #3) and animals with a high proportion of increased flow responses (%CBF(70) > 115%, rat #2). There are approximately equal contributions to the heterogeneity of %CBF(70) from within-animal (57 +/- 5%, percent variance +/- standard error) and between-animal (43 +/- 26%) variations. Within-animal variations could be due to heterogeneity of vascular anatomy, while the diversity of vascular control mechanisms might contribute to between-animal variations.

Animals↗

PubMed2006

Effect of scale of Cd heterogeneity and timing of exposure on the Cd uptake and shoot biomass, of plants with a contrasting root morphology.

A pot experiment was conducted to investigate the influence of spatial heterogeneity of Cd distribution in soil on shoot biomass, shoot metal concentration and total shoot Cd uptake by lettuce (Lactuca sativa, variety Tom Thumb) and Indian mustard (Brassica juncea). Five different soil treatments had similar overall concentration of Cd per pot, but different scales of heterogeneity and also timing of plant exposure during the growth cycle. The presence and scale of heterogeneity and timing of exposure were found to have significant effects on shoot biomass for both plants (with one exception). The mean values of Cd mass taken up were significantly affected by the presence of heterogeneity and timing only for lettuce. Only the scale of heterogeneity affected the uptake of Cd by Indian mustard, presumably because of its larger root system (approximately 18 cm, compared with approximately 5 cm for lettuce). These findings have important implications for phytoremediation, and for human health risk assessment where leafy vegetables are grown in situations with highly elevated Cd concentrations.

Analysis of Variance↗

PubMed2004

Relative character-state space, amount of potential phylogenetic information, and heterogeneity of nucleotide and amino acid characters.

We examined a broad selection of protein-coding loci from a diverse array of clades and genomes to quantify three factors that determine whether nucleotide or amino acid characters should be preferred for phylogenetic inference. First, we quantified the difference in observed character-state space between nucleotides and amino acids. Second, we quantified the loss of potential phylogenetic signal from silent substitutions when amino acids are used. Third, we used the disparity index to quantify the relative compositional heterogeneity of nucleotides and amino acids and then determined how commonly convergent (rather than unique) shifts in nucleotide and amino acid composition occur in a phylogenetic context. The greater potential phylogenetic signal for nucleotide characters was found to be enormous (on average 440% that of amino acids), whereas the greater observed character-state space for amino acids was less impressive (on average 150.4% that of nucleotides). While matrices of amino acid sequences had less compositional heterogeneity than their corresponding nucleotide sequences, heterogeneity in amino acid composition may be more homoplasious than heterogeneity in nucleotide composition. Given the ability of increased taxon sampling to better utilize the greater potential phylogenetic signal of nucleotide characters and decrease the potential for artifacts caused by heterogeneous nucleotide composition among taxa, we suggest that increased taxon sampling be performed whenever possible instead of restricting analyses to amino acid characters.

Amino Acids↗

PubMed2001

QT dispersion, T-wave projection, and heterogeneity of repolarization in patients with coronary artery disease.

The clinically useful prognostic value of precordial QT dispersion in patients with heart disease is generally attributed to its measurement of regional heterogeneity of ventricular repolarization. However, when repolarization is abnormal, differences in measured QT intervals might result simply from variation in projection of the T-wave loop. To provide insight into the mechanism of QT dispersion, we used an analog device to transform conventional 12-lead electrocardiograms (ECGs) of 78 patients to derived 12-lead ECGs based on the heart vector. Because the electrical activity of the heart is represented by a single dipole, all QT dispersion in the transformed ECGs results from variation in projection of the T-wave loop and cannot be due to local heterogeneity of repolarization. Measured as the difference between the longest and shortest precordial QT intervals, QT dispersion in the derived ECGs, with no local heterogeneity of repolarization, was 53 +/- 49 ms (mean +/- SD). QT dispersion in these derived ECGs was similar in magnitude to that measured from the original standard 12-lead ECGs in these patients (49 +/- 23 ms, p = NS). Therefore, the precordial QT dispersion measured from standard ECGs of patients with coronary artery disease can be explained by interlead variation in precordial projection of the T-wave loop. Although regional heterogeneity might still contribute to precordial repolarization findings and to prognosis, this is not required to explain the QT dispersion observed in patients with coronary artery disease. Therefore, QT interval dispersion is not equivalent to heterogeneity of repolarization.

Arrhythmias, Cardiac↗

PubMed1989

Charge heterogeneity of recombinant pro-urokinase and urinary urokinase, as revealed by isoelectric focusing in immobilized pH gradients.

When analysing homogeneous preparations of recombinant pro-urokinase and urinary urokinase by isoelectric focusing (IEF) in immobilized pH gradients, an extreme charge heterogeneity was detected (at least ten major and ten minor bands in the pH range 7-10). This extensive polydispersity was not caused by different degrees of glycosylation, or by IEF artefacts, such as binding to carrier ampholytes or carbamylation by urea. A great part of this heterogeneity could be traced back to the existence of a multitude of protein molecules containing Cys residues at different oxidation levels (-SH, -S-S-, even cysteic acid). Owing to the very large number of Cys residues in pro-urokinase (24 out of a total of 411 amino acids) and to the relatively high pI of its native forms (pI 9.5-9.8; the native form is believed to contain all Cys residues as -S-S- bridges), the presence of SH or cysteic acid residues would increase the negative surface charge, as even SH groups would be extensively ionized. In pro-urokinase, part of the heterogeneity was also due to spontaneous degradation to urokinase and possibly also to cleavage into lower-molecular-mass fragments. When all these causes of heterogeneity were removed, the pI spectrum was reduced to only four, about equally intense bands. The cause of this residual heterogeneity is unknown.

Electrophoresis, Polyacrylamide Gel↗

PubMed1976

Resolution in affinity chromatography. The effect of the heterogeneity of immobilized soybean trypsin inhibitor on the separation of pancreatic proteases.

By affinity chromatography, trypsins and chymotrypsins from mouse pancreas homogenates have been separated using soybean trypsin inhibitor immobilized on Sepharose. The effects of the functional heterogeneity of the adsorbent have been investigated in terms of the resolution obtained. Heterogeneity of the adsorbent have been investigated in terms of the resolution obtained. Heterogeneity has been found to originate from the following sources: heterogeneity of the ligand before immobilization; alteration of the ligand by immobilization; and modification of the ligand after immobilization by molecules to be fractionated. Only when the heterogeneity of the adsorbent was minimized could the resolution of closely related enzyme species be achieved. The elution conditions for different enzymes depended on the amount of enzyme applied, as no complete homogeneity could be obtained. In addition, it was found that the adsorbent was partly degraded by the pancreas extract, reducing its fractionating capacity.

Adsorption↗

PubMed1998

Non-linear elution effects in split-peak chromatography. II. Role of ligand heterogeneity in solute binding to columns with adsorption-limited kinetics.

The split-peak effect is a useful phenomenon in studying the kinetic behavior of chromatographic supports. This work examined the combined role of ligand heterogeneity and non-linear elution conditions (i.e., sample load dependence) on the solute free fractions that are measured during split-peak studies. Exact expressions were derived to describe the effects of ligand heterogeneity under linear elution conditions, and simulation models were developed to specifically examine the combined effects of ligand heterogeneity and non-linear elution in systems with adsorption-limited rates for solute binding. The simulations showed that ligand heterogeneity increased the amount of free solute seen at any flow-rate or sample size, with this being most noticeable when using low flow-rates or large samples. One application in which these increases were examined in detail concerned the use of the split-peak effect for association rate constant measurements. It was found that linear extrapolation methods developed for homogeneous systems (as a correction for non-linear elution conditions) could successfully be applied to columns containing heterogeneous ligands. Columns containing immobilized protein A and/or protein G were used as experimental models to test the validity of the simulations; the behavior of these columns showed good quantitative and qualitative agreement with the predicted theoretical results.

Adsorption↗

PubMed2000

An intuitive formulation for the reproductive number for the spread of diseases in heterogeneous populations.

The thresholds for mathematical epidemiology models specify the critical conditions for an epidemic to grow or die out. The reproductive number can provide significant insight into the transmission dynamics of a disease and can guide strategies to control its spread. We define the mean number of contacts, the mean duration of infection, and the mean transmission probability appropriately for certain epidemiological models, and construct a simplified formulation of the reproductive number as the product of these quantities. When the spread of the epidemic depends strongly upon the heterogeneity of the populations, the epidemiological models must account for this heterogeneity, and the expressions for the reproductive number become correspondingly more complex. We formulate several models with different heterogeneous structures and demonstrate how to define the mean quantities for an explicit expression for the reproductive number. In complex heterogeneous models, it seems necessary to define the reproductive number for each structured subgroup or cohort and then use the average of these reproductive numbers weighted by their heterogeneity to estimate the reproductive number for the total population.

Disease Outbreaks↗

PubMed2002

Detection of hormesis effect in longevity: simulation approach for heterogeneous population.

Manifestation of hormesis in longevity was modelled by modification of the mortality rate during and after the period of a stress factor action. In heterogeneous population this can lead to observation of unchanged mortality during action of the stress and decrease in mortality after stress period. Stochastic simulations were made to investigate the possibility of detecting the hormesis effect on the basis of the stress-control longitudinal data. The goal of the stochastic simulation was to investigate the role in the hormesis detection of control and stressed group size, of population heterogeneity variance value, of stress and hormesis attributable risks as well as the role of a prior information about the survival in the control group. It was demonstrated that if the attributable risks for stress and hormesis effects are approximately equal, then in both 'high' and 'low' heterogeneous populations the hormesis phenomenon is detected with probability higher than 75% even in relatively 'small' groups of 50 subjects. In case of 'weak' effect the hormesis phenomenon is not detected in a 'highly heterogeneous' population even in a group composed of 1000 subjects. In a 'low heterogeneous' population the hormesis phenomenon is detected with probability higher than 70% when the group size is not less than 200 subjects. Information about the survival in control group did not play a critical role in all experiments and exact survival curve may be replaced by the traditional Kaplan-Meier estimate.

Adaptation, Physiological↗

PubMed1990

Ultrastructural heterogeneity of lung carcinomas: representativity of samples for electron microscopy in tumor classification.

Histologic heterogeneity of tumors is a well-known phenomenon, which has been repeated studied at the light microscopic level. Electron microscopy has been advocated as an adjunct in classification of tumors which pose difficulties on light microscopic classification. However, in view of tumor heterogeneity, it might be anticipated that the problem of sample error could detract from the usefulness of electron microscopy in tumor typing. Ultrastructural heterogeneity of tumors has thus far not been systematically investigated. We performed an ultrastructural randomized and blinded study of superficial and deep samples of 44 resected lung carcinomas, tumors which are notorious for their histologic heterogeneity. Neuroendocrine and squamous differentiation, as well as adenodifferentiation, were assessed separately and semiquantitatively in each sample. Twenty-six tumors showed more than one type of differentiation in at least one sample. However, in only two cases did the main type of differentiation differ between the two samples. A further nine cases showed one predominant differentiation type in both samples, but a similarly pronounced second differentiation type in one of the samples. Thus, in terms of ultrastructural diagnosis, the two samples showed a major discrepancy in two of 44 cases, and a minor discrepancy in nine of 44 cases. We conclude that ultrastructural heterogeneity of lung tumors is a common occurrence, but that it only rarely leads to totally different ultrastructural diagnoses.

Carcinoma↗

PubMed1985

Lung cancer heterogeneity: a blinded and randomized study of 100 consecutive cases.

The heterogeneity of lung carcinomas was recognized in the past, but few previous studies attempted to quantitate this heterogeneity. In the present study 100 consecutive cases of lung carcinoma (65 surgical resections and 35 autopsies) were collected, and either the entire tumor or ten blocks were examined in a blinded and randomized fashion using the revised (1981) WHO classification. At least three of five panelists agreed on the major histologic type present for 94 per cent of the slides. Agreement for the diagnosis of small cell carcinomas (at least four of five observers) was 98 per cent, but only 72 per cent agreement was attained for the subtyping of small cell carcinomas (e.g., oat cell versus intermediate). Only 34 per cent of the cases were homogeneous according to the majority of the panelists. An additional 21 per cent of the cases showed minor (subtype) heterogeneity (e.g., mixtures of acinar and papillary patterns in adenocarcinoma). Forty-five per cent of the cases showed major heterogeneity, i.e., at least one slide from the case showed a major histologic type different from that of the remainder. Seven small cell carcinomas were homogeneous, whereas in eight cases mixtures of small cell and other cell types were seen. In all but one of the cases involving bronchioloalveolar cell patterns, other patterns of adenocarcinoma were present elsewhere in the tumor. In all six cases involving giant cell carcinoma patterns, adenocarcinoma patterns were also present in some sections. Heterogeneity was identified by extensive sampling of the entire tumor and was seldom recognized in biopsy specimens.

Adenocarcinoma↗

PubMedDate not supplied

Mechano-electric interactions in heterogeneous myocardium: development of fundamental experimental and theoretical models.

The heart is structurally and functionally a highly non-homogenous organ, yet its main function as a pump can only be achieved by the co-ordinated contraction of millions of ventricular cells. This apparent contradiction gives rise to the hypothesis that 'well-organised' inhomogeneity may be a pre-requisite for normal cardiac function. Here, we present a set of novel experimental and theoretical tools for the study of this concept. Heterogeneity, in its most condensed form, can be simulated using two individually controlled, mechanically interacting elements (duplex). We have developed and characterised three different types of duplexes: (i) biological duplex, consisting of two individually perfused biological samples (like thin papillary muscles or a trabeculae), (ii) virtual duplex, made-up of two interacting mathematical models of cardiac muscle, and (iii) hybrid duplex, containing a biological sample that interacts in real-time with a virtual muscle. In all three duplex types, in-series or in-parallel mechanical interaction of elements can be studied during externally isotonic, externally isometric, and auxotonic modes of contraction and relaxation. Duplex models, therefore, mimic (patho-)physiological mechano-electric interactions in heterogeneous myocardium at the multicellular level, and in an environment that allows one to control mechanical, electrical and pharmacological parameters. Results obtained using the duplex method show that: (i) contractile elements in heterogeneous myocardium are not 'independent' generators of tension/shortening, as their ino- and lusitropic characteristics change dynamically during mechanical interaction-potentially matching microscopic contractility to macroscopic demand, (ii) mechanical heterogeneity contributes differently to action potential duration (APD) changes, depending on whether mechanical coupling of elements is in-parallel or in-series, which may play a role in mechanical tuning of distant tissue regions, (iii) electro-mechanical activity of mechanically interacting contractile elements is affected by their activation sequence, which may optimise myocardial performance by smoothing intrinsic differences in APD. In conclusion, we present a novel set of tools for the experimental and theoretical investigation of cardiac mechano-electric interactions in healthy and/or diseased heterogeneous myocardium, which allows for the testing of previously inaccessible concepts.

Animals↗

PubMed1998

Programs for assessment of spatial heterogeneity of regional organ blood flow.

Regional organ blood flow (RBF) is spatially heterogeneous. Relative dispersion (standard deviation S.D./mean) is often used to assess heterogeneity of RBF. Relative dispersion is a global measure of heterogeneity and is strongly influenced by the tissue sample size making comparisons between research groups inappropriate. Spatial correlation (s.c.) of blood flow is, on the other hand, averaged local self similarity. Both parameters change oppositely secondary to interventions. Fractal dimension (D) is a scale-independent measure of spatial heterogeneity and thus facilitates comparison of data. Programs for calculation of s.c. and D have not been published. We present two portable computer programs written in C+2 for calculating s.c. and D. The programs were validated with six computer generated data sets of known heterogeneity. The results were in agreement with data from the literature: we conclude that the programs accurately calculate spatial correlation and fractal dimension of 1-, 2-, or 3-dimensional perfusion matrices.

Humans↗