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Ross River virus disease clusters and spatial relationship with mosquito biting exposure in Redland Shire, southern Queensland, Australia.

The spatial heterogeneity in the risk of Ross River virus (family Togaviridae, genus Alphavirus, RRV) disease, the most common mosquito-borne disease in Australia, was examined in Redland Shire in southern Queensland, Australia. Disease cases, complaints from residents of intense mosquito biting exposure, and human population data were mapped using a geographic information system. Surface maps of RRV disease age-sex standardized morbidity ratios and mosquito biting complaint morbidity ratios were created. To determine whether there was significant spatial variation in disease and complaint patterns, a spatial scan analysis method was used to test whether the number of cases and complaints was distributed according to underlying population at risk. Several noncontiguous areas in proximity to productive saline water habitats of Aedes vigilax (Skuse), a recognized vector of RRV, had higher than expected numbers of RRV disease cases and complaints. Disease rates in human populations in areas which had high numbers of adult Ae. vigilax in carbon dioxide- and octenol-baited light traps were up to 2.9 times those in areas that rarely had high numbers of mosquitoes. It was estimated that targeted control of adult Ae. vigilax in these high-risk areas could potentially reduce the RRV disease incidence by an average of 13.6%. Spatial correlation was found between RRV disease risk and complaints from residents of mosquito biting. Based on historical patterns of RRV transmission throughout Redland Shire and estimated future human population growth in areas with higher than average RRV disease incidence, it was estimated that RRV incidence rates will increase by 8% between 2001 and 2021. The use of arbitrary administrative areas that ranged in size from 4.6 to 318.3 km2 has the potential to mask any small scale heterogeneity in disease patterns. With the availability of georeferenced data sets and high-resolution imagery, it is becoming more feasible to undertake spatial analyses at relatively small scales.

Aedes↗

Regional hyperkalemia increases ventricular defibrillation energy requirements: role of electrical heterogeneity in defibrillation.

INTRODUCTION: Increased spatial electrical heterogeneity has been associated with impaired defibrillation efficacy. The current study investigated the relationship between electrical heterogeneity and defibrillation efficacy by manipulating spatial electrical heterogeneity. METHODS AND RESULTS: We increased spatial electrical heterogeneity by infusing potassium chloride (2 to 4 mEq/hour) or placebo in the left anterior descending artery in 13 pentobarbital anesthetized swine. Electrophysiologic measurements at five myocardial sites and defibrillation energy requirement (DER) values were determined at baseline and during regional hyperkalemia (n = 7) or placebo (n = 6). Regional potassium infusion was titrated to a 20% reduction in action potential duration in the perfused region. Regional hyperkalemia increased biphasic DER values by 87% (P = 0.02), whereas infusion of placebo did not alter defibrillation efficacy. Regional hyperkalemia decreased myocardial repolarization and refractoriness in the perfused region by 21% (P < 0.001) and 18% (P = 0.01), respectively. However, regional hyperkalemia increased ventricular fibrillation cycle length (VFCL) by 39% (P = 0.008). Consequently, dispersions of repolarization, refractoriness, and VFCL were significantly increased by 169%, 92%, and 200%, respectively. Regional hyperkalemia also increased ventricular conduction time to the perfused region by 54% (P = 0.006), indicating conduction velocity dispersion, while not affecting local pacing threshold or local voltage gradient. CONCLUSION: Regional hyperkalemia increased DER values. Regional hyperkalemia likely impairs defibrillation by increasing myocardial electrical heterogeneity, which supports the theory that electrical heterogeneity promotes nonuniform propagation of early postshock activations, thereby inhibiting defibrillation.

Animals↗

Oxygenation and metabolic status of KHT tumors as measured simultaneously by 19F magnetic resonance imaging and 31P magnetic resonance spectroscopy.

To evaluate the relationship between the partial pressure of oxygen (pO2) and the energy-related phosphorous metabolites in individual KHT murine sarcomas more clearly, the spatial distributions of pO2 were obtained simultaneously with 31P magnetic resonance spectra, and repeatedly as a function of growth. The pO2 maps, derived from serial images of the spin-lattice relaxation times of sequestered perfluorocarbon emulsions, were heterogeneous spatially, which is characteristic of solid tumors. Collectively, the median pO2 of the seven KHT tumors of mass varying from 0.2 to 1.8 g decreased from 60 to 0 mmHg, but it increased in one of five tumors which were followed in the growth study. The pHMRS and the high-energy ratio of phosphocreatine + nucleoside triphosphates to total observed phosphorous (TP) dropped on average as a function of tumor growth, while the low energy ratio of P(i) to TP increased. Also, for the tumors as a whole, the pH and high-energy ratio increased with increasing median pO2 while the low energy ratio decreased, but the 31P values of some tumors did not follow this general trend. These individual variations suggest the need for simultaneous and repeated measurements of phosphorous metabolites and oxygen tension for complete information regarding the tumor status in experimental studies and therapeutic procedures in humans.

Animals↗

Kinetics of adhesion molecule expression and spatial organization using targeted sampling fluorometry.

Cellular interactions with the vascular wall under flow conditions are controlled, in part, by the density of adhesion molecules on endothelial cells. The spatial arrangement and absolute levels of these molecules over the endothelium are therefore important determinants of cellular localization. Many biochemical and functional studies have characterized the interactions between leukocytes and endothelial monolayers, but no reliable method has been reported for quantifying the spatial expression of adhesion molecules on intact endothelial cell monolayers. We report the development of targeted sampling fluorometry (TSF), which uses standard immunostaining, fluorescence microscopy and digital image analysis techniques to analyze cell surface molecule expression on a cell-by-cell basis. This technique is performed on an intact monolayer and results in cellular intensity distributions that reflect spatial heterogeneity in adhesion molecule expression. We demonstrate the use of targeted sampling fluorometry in a study of the kinetics of tumor necrosis factor alpha-induced activation of human umbilical vein endothelial cell monolayers and show that the spatial patterns of adhesion molecule expression correlate with the locations of bound lymphocytes.

Cell Adhesion Molecules↗

A ratiometric imaging method for mapping ion flux densities.

A heterogeneous distribution of ion channels on the cell surface is a prerequisite for several cellular functions. Thus, there has been considerable interest in methods allowing the mapping of ion channel distributions. Here we report on a novel ratiometric imaging technique appropriate to measure spatially resolved ion flux signals by using ion sensitive dyes. However, given that certain relevant cell properties like the surface to volume ratio may exhibit significant spatial heterogeneities, the local influx signal cannot be interpreted as a measure of the local open channel concentration or flux density. To overcome this problem, we suggest an internal normalization procedure, which, in analogy to, but clearly distinct from, well-established ratioing techniques, eliminates effects which would otherwise obscure the desired result. Ratioing is performed on flux signals from a given cell, triggered by two different, subsequent stimuli. If the two stimuli address different ion channels, the flux density distribution caused by two channel types can be determined relative to each other. In cases where one of the stimuli triggers a spatially homogeneous flux signal, ratioing yields an ion flux density map for a given channel type. Thus distribution patterns of ion channels active during a given stimulus may be derived.

Animals↗

Shell shape of the land snail Cornu aspersum in North Africa: unexpected evidence of a phylogeographical splitting.

Anatomical and molecular characters used to differentiate populations of the land snail Cornu aspersum (Helix aspersa) exhibit, in the western Mediterranean, definite and concordant patterns of correlation with geography. Scenarios involving Pliocene geological changes and postglacial expansion during the Pleistocene were proposed in previous studies to account for the establishment of this geographical structure. In the present work, we have performed a spatial analysis of variation in shell morphometrics, after the partitioning of the overall variation into size and shape components by means of a principal component-based approach (Cadima and Jolliffe, 1996). In order to know if the same historical events have also structured shell variation, the analysis includes all the populations from North Africa which were investigated for anatomical and molecular surveys. Contrary to shell size, which shows a significant spatial heterogeneity essentially related to environmental pressures, variation in shell shape components splits the populations according to a geographical pattern reflective of hypotheses suggested for molecular markers and genital anatomy. This implies that the selective forces often invoked to explain spatial changes in shell shape are not the deciding factors in the present case. Moreover, within each of the two geographical clusters defined, Mantel correlograms show that the similarity between populations declines according to an isolation by distance model. Because of the different allometric relationships between shell size and genitalia measurements in Western and Eastern entities of North Africa, mechanical constraints, possibly leading to a precopulatory isolation in the contact zone, are involved.

Africa, Northern↗

Movement toward better environments and the evolution of rapid diffusion.

We study a reaction-diffusion-advection model for two ecologically equivalent competitors with different dispersal strategies inhabiting a spatially heterogeneous environment. The competitors represent different phenotypes of the same species. One is assumed to disperse by simple diffusion, the other by diffusion together with directed movement toward more favorable environments. We show that under suitable conditions on the underlying spatial domain, the competitor that moves toward more favorable environments may have a competitive advantage even if it diffuses more rapidly than the other competitor. This is in contrast with the case in which both competitors disperse by pure diffusion, where the competitor that diffuses more slowly always has the advantage. We determine competitive advantage by examining the invasibility, i.e. stability or instability, of steady states with only one competitor present. The mathematical approach is a perturbation analysis of principal eigenvalues.

Algorithms↗

Microspatial genetic structure in the land snail helix aspersa (Gastropoda: helicidae)

The microspatial genetic structure of allele frequencies at seven isozyme loci was examined for 15 populations of the land snail Helix aspersa sampled in a village from Brittany (north-western France). Spatial heterogeneity of allele frequencies was highly significant (P < 0.001). Fixation indices reflected nonrandom mating within neighbourhoods and a slight but consistent differentiation between colonies (FST=0.044; P < 0.01). Analyses of gene flow or genetic distances failed to reveal a significant relationship with geographical distance, probably because of the complexity of environmental heterogeneity. However, matrix comparisons between genetic distances and connectivity networks among adjacent colonies (Gabriel-connected graph) yielded a significant correlation in every case, indicating a 'step-by-step' relationship between neighbouring localities. Moreover, most of the allozymes were spatially structured and showed (i) a gradual isolation of colonies with increasing geographical distances, and (ii), for some correlogram profiles, a circular gradient illustrating a multidirectional colonization of the village. The probable existence of disperser individuals allowed us to suggest a metapopulation model which would explain the maintenance of such animals in fragmented habitats where anthropogenic disturbances and extinction/recolonization events are commonly observed.

Journal Article↗

Bifurcation asymmetry of the porcine coronary vasculature and its implications on coronary flow heterogeneity.

The branching pattern of the coronary arteries and veins is asymmetric, i.e., many small vessels branch off of a large trunk such that the two daughter vessels at a bifurcation are of unequal diameters and lengths. One important implication of the geometric vascular asymmetry is the dispersion of blood flow at a bifurcation, which leads to large spatial heterogeneity of myocardial blood flow. To document the asymmetric branching pattern of the coronary vessels, we computed an asymmetry ratio for the diameters and lengths of all vessels, defined as the ratio of the daughter diameters and lengths, respectively. Previous data from silicone elastomer cast of the entire coronary vasculature including arteries, arterioles, venules, and veins were analyzed. Data on smaller vessels were obtained from histological specimens by optical sectioning, whereas data on larger vessels were obtained from vascular casts. Asymmetry ratios for vascular areas, volumes, resistances, and flows of the various daughter vessels were computed from the asymmetry ratios of diameters and lengths for every order of mother vessel. The results show that the largest orders of arterial and venous vessels are most asymmetric and the degree of asymmetry decreases toward the smaller vessels. Furthermore, the diameter asymmetry at a bifurcation is significantly larger for the coronary veins (1.7-6.8 for sinus veins) than the corresponding arteries (1.5-5.8 for left anterior descending coronary artery) for orders 2-10, respectively. The reported diameter asymmetry at a bifurcation leads to significant heterogeneity of blood flow at a bifurcation. Hence, the present data quantify the dispersion of blood flow at a bifurcation and are essential for understanding flow heterogeneity in the coronary circulation.

Animals↗

Uncertainty in hydrogeological modelling.

Hydrogeological models are built to predict groundwater flow and the fate of contaminants in the subsurface. After the crucial step of building a conceptual model that includes the processes that should be accounted for, parameter values must be assigned to the components of the model. Measured values of these parameters are available only at a few locations, as is the case for transmissivity, hydraulic conductivity or porosity. Therefore, before making predictions about the movement of contaminants in the aquifer, it is necessary to predict the parameter values at unsampled locations. Given the spatial heterogeneity of the parameters involved, this prediction is always uncertain. Model parameter uncertainty propagates to flow-response variables and further to transport predictions. Parameter uncertainty can be modelled using stochastic methods. Stochastic simulation is used for the generation of alternative spatial realizations of the parameter values, which are then used as input to groundwater flow and mass transport models to obtain frequency distributions of the response variables, e.g. flow velocities, arrival times or concentration levels. These frequency distributions help in making risk-qualified decisions. In order to make these frequency distributions as precise and accurate as possible, it is necessary to incorporate all relevant information in the parameter uncertainty model, i.e. it is necessary to condition the parameter realizations to all direct and indirect information. With this aim, new techniques have recently been developed in hydrogeological modelling. One such technique, for the generation of conductivity realizations conditioned to conductivity, piezometric head and geophysical data, is the self-calibrated method.

Calibration↗

Folding stabilizes the evolution of catalysts.

Sequence folding is known to determine the spatial structure and catalytic function of proteins and nucleic acids. We show here that folding also plays a key role in enhancing the evolutionary stability of the intermolecular recognition necessary for the prevalent mode of catalytic action in replication, namely, in trans, one molecule catalyzing the replication of another copy, rather than itself. This points to a novel aspect of why molecular life is structured as it is, in the context of life as it could be: folding allows limited, structurally localized recognition to be strongly sensitive to global sequence changes, facilitating the evolution of cooperative interactions. RNA secondary structure folding, for example is shown to be able to stabilize the evolution of prolonged functional sequences, using only a part of this length extension for intermolecular recognition, beyond the limits of the (cooperative) error threshold. Such folding could facilitate the evolution of polymerases in spatially heterogeneous systems. This facilitation is, in fact, vital because physical limitations prevent complete sequence-dependent discrimination for any significant-size biopolymer substrate. The influence of partial sequence recognition between biopolymer catalysts and complex substrates is investigated within a stochastic, spatially resolved evolutionary model of trans catalysis. We use an analytically tractable nonlinear master equation formulation called PRESS (McCaskill et al., Biol. Chem. 382: 1343-1363), which makes use of an extrapolation of the spatial dynamics down from infinite dimensional space, and compare the results with Monte Carlo simulations.

Catalysis↗

How does resource supply affect evolutionary diversification?

The availability of different resources in the environment can affect the outcomes of evolutionary diversification. A unimodal distribution of diversity with resource supply has been widely observed and explained previously in the context of selection acting in a spatially heterogeneous environment. Here, we propose an alternative mechanism to explain the relationship between resource supply and diversification that is based on selection for exploitation of different resources. To test this mechanism, we conducted a selection experiment using the bacterium Pseudomonas fluorescens in spatially homogeneous environments over a wide range of resource supply rates. Our results show that niche diversification peaks at intermediate levels of resource availability. We suggest that this unimodal relationship is due to evolutionary diversification that is driven by competition for resources but constrained by the ecological opportunity represented by different resource types. These processes may underlie some general patterns of diversity, including latitudinal gradients in species richness and the effects of anthropogenic enrichment of the environment.

Adaptation, Biological↗

Forest gap dynamics and the Ising model.

The vegetation height in forest ecosystems is spatially heterogeneous. Canopy gaps (sites with low vegetation) are formed by treefalls, and they recover to canopy sites (with high vegetation) either by growth of small trees or by branch extension of surrounding trees. The dynamics of canopy gaps have been studied using a spatial Markov chain with nearest neighbor interaction. (1) If the canopy recovery rate is constant and if the gap formation rate for a site increases exponentially with the number of neighboring gap sites, the equilibrium distribution is the same as the one generated by the Ising model in statistical mechanics. Here, we extend the equivalence to the situation in which both the gap formation and canopy recovery depend on the neighborhood, as shown in recent forest data. (2) We develop a statistical test of whether a given spatial pattern is a random sample from the Ising model. The test is based on the conditional probability of configurations on a partial lattice. We apply the method to vegetation height data from the Ogawa forest reserve, Japan, measured on a 5x5 m grid in 1976, 1981, 1986, and 1991. The spatial pattern of the original forest data deviates significantly from the Ising model. We examine whether a larger sampling distance or the removal of the effects of the topography can reduce this deviation.

Ecosystem↗

Tissue electroporation: quantification and analysis of heterogeneous transport in multicellular environments.

Although electroporation is gaining increased attention as a technology to enhance clinical chemotherapy and gene therapy of tissues, direct measurements of electroporation-mediated transport in multicellular environments are lacking. In this study, we used multicellular tumor spheroids of DU145 prostate cancer cells as a model tissue to measure the levels and distribution of molecular uptake in a multicellular environment as a function of electrical and other parameters. These measurements, and subsequent analysis, were used to test the hypothesis that cells in a multicellular environment respond to electroporation in a heterogeneous manner that differs from isolated cells in suspension due to differences in cell state, local solute concentration, and local electric field. In support of the hypothesis, molecular uptake was consistently lower for cells within spheroids than cells in dilute suspension and was spatially heterogeneous, with progressively less uptake observed for cells located deeper within spheroid interiors. Reduced uptake and heterogeneity can be explained quantitatively by accounting for the effects of cell size on transmembrane voltage and cell volume, limited extracellular solute reservoir, heterogeneous field strength due to influence of neighboring cells, and diffusional lag times.

Biological Transport↗

Photothermal responses of individual cells.

Photothermal (PT) responses of individual intact cells are studied with a thermal lens dual-laser scheme. A multiparameter model for analysis of PT responses as a function of cell size, structure, and optical properties is suggested and verified experimentally for living cells, red blood cells, lymphocytes, tumor cells (K 562), hepatocytes, and miocytes, by applying pulsed laser radiation at 532 nm for 10-ns duration. PT responses for noninvasive and damaging modes of laser-cell interaction are investigated. It is shown theoretically and experimentally that specific optical and structural features of cells influence the polarity, shape, front, and tail lengths of their PT responses. Common for different cells, features of PT responses are evaluated. It is found that in cells with a highly heterogeneous light-absorbing structure, the PT response of a whole cell differs from that of the local absorbing area. The model suggested allows us to interpret PT responses from single cells and to compare cells in terms of their diameter, degree of spatial heterogeneity of light absorbance, and laser-induced damage thresholds.

Animals↗

Chromatin structure exhibits spatio-temporal heterogeneity within the cell nucleus.

Local chromatin compaction undergoes dynamic perturbations to regulate genetic processes. To address this, the direct measurement of the fluidity of chromatin structure is carried out in single live cells using steady-state anisotropy imaging and polarization modulation microscopy. Fluorescently tagged core and linker histones are used to probe different structural aspects of chromatin compaction. A graded spatial heterogeneity in compaction is observed for the chromatin besides the distinct positional ordering of core and linker histones. These spatio-temporal features are maintained by active processes and perturbed during death. With cell cycle, the distribution in compaction heterogeneity continually changes maximizing during M-G1 transition where it displays bimodal behavior. Such measurements of spatio-temporal chromatin fluidity could have broader implications in understanding chromatin remodeling within living cells.

Adenosine Triphosphate↗

A chemical signal possibly related to physiology in fossil cells detected by energy dispersive X-ray microanalysis.

Energy dispersive X-ray microanalysis (EDXMA) is a widely used tool employed to detect elemental composition and its spatial distribution in a sample without causing damage. Charcoalified cytoplasm is a new type of fossil material that came to people's attention only recently. In this paper, EDXMA is used for the first time to detect the spatial elemental distribution in charcoalified cytoplasm of two fossil plants that are more than 100 million years old. The results demonstrate certain elemental distribution patterns within charcoalified cytoplasm and the surrounding cell walls. Based on the results from cytological studies of extant material, the heterogeneous spatial elemental distribution within the charcoalified cytoplasm has the potential to be related to the maturation of cells, the presence of certain organelles, and the physiology of these organelles. This is the first chemical signal detected in cytoplasm residue that can possibly be related to plant physiology. This paves the way for further research on fossil cytoplasm, which will better our understanding on the physiology of fossil plants.

Carbon↗

Drug concentration heterogeneity facilitates the evolution of drug resistance.

Pathogenic microorganisms use Darwinian processes to circumvent attempts at their control through chemotherapy. In the case of HIV-1 infection, in which drug resistance is a continuing problem, we show that in one-compartment systems, there is a relatively narrow window of drug concentrations that allows evolution of resistant variants. When the system is enlarged to two spatially distinct compartments held at different drug concentrations with transport of virus between them, the range of average drug concentrations that allow evolution of resistance is significantly increased. For high average drug concentrations, resistance is very unlikely to arise without spatial heterogeneity. We argue that a quantitative understanding of the role played by heterogeneity in drug levels and pathogen transport is crucial for attempts to control re-emergent infectious disease.

Anti-HIV Agents↗