A Ca2+-dependent early functional heterogeneity in amoebae of Dictyostelium discoideum, revealed by flow cytometry

When freshly starved amoebae of Dictyostelium discoideum are loaded with the Ca2+-specific dye indo-1/AM and analyzed in a fluorescence-activated cell sorter, they exhibit a quasi-bimodal distribution of fluorescence. This permits a separation of the population into two classes: H, or ''high Ca2+-indo-1 fluorescence,'' and L, or ''low Ca2+-indo-1 fluorescence.'' Simultaneous monitoring of Ca2+-indo-1 and Ca2+-chlortetracycline fluorescence shows that by and large the same cells tend to have high (or low) levels of both cytoplasmic and sequestered Ca2+. Next we label H cells with tetramethylrhodamine isothiocyanate (TRITC) and mix them in a 1:4 ratio with L cells, In the slugs that result, TRITC fluorescence is confined mainly to the anterior prestalk region. This implies that amoebae with relatively high Ca2+ at the vegetative stage tend to develop into prestalk cells and those with low Ca2+ into prespores. Polysphondylium violaceum, a cellular slime mold that does not possess prestalk and prespore cells, also does not display a Ca2+-dependent heterogeneity at the vegetative stage or in slugs. Finally, confirming earlier findings with the fluorophore fura-2 (Azhar ef al., Curr. Sci. 68, 337-342 (1995)), a prestalk-prespore difference in cellular Ca2+ is present in the cells of the slug in vivo. These findings are discussed in light of the possible roles of Ca2+ for cell differentiation in D. discoideum.

Intermittent Dynamics, Stochastic Resonance and Dynamical Heterogeneity in Supercooled Liquid Water

Here we find through computer simulations and theoretical analysis that the low temperature thermodynamic anomalies of liquid water arises from the intermittent fluctuation between its high density and low density forms, consisting largely of 5-coordinated and 4-coordinated water molecules, respectively. The fluctuations exhibit strong dynamic heterogeneity (defined by the four point time correlation function), accompanied by a divergence like growth of the dynamic correlation length, of the type encountered in fragile supercooled liquids. The intermittency has been explained by invoking a two state model often employed to understand stochastic resonance, with the relevant periodic perturbation provided here by the fluctuation of the total volume of the system.

Genetic Heterogeneity in Autism Spectrum Disorders in a Population Isolate

Positional cloning has enabled hypothesis-free, genome-wide scans for genetic factors contributing to disorders or traits. Traditionally linkage analysis has been used to identify regions of interest, followed by meticulous fine mapping and candidate gene screening using association methods and finally sequencing of regions of interest. More recently, genome-wide association analysis has enabled a more direct approach to identify specific genetic variants explaining a part of the variance of the phenotype of interest. Autism spectrum disorders (ASDs) are a group of childhood onset neuropsychiatric disorders with shared core symptoms but varying severity. Although a strong genetic component has been established in ASDs, genetic susceptibility factors have largely eluded characterization. Here, we have utilized modern molecular genetic methods combined with the advantages provided by the special population structure in Finland to identify genetic risk factors for ASDs. The results of this study show that numerous genetic risk factors exist for ASDs even within a population isolate. Stratification based on clinical phenotype resulted in encouraging results, as previously identified linkage to 3p14-p24 was replicated in an independent family set of families with Asperger syndrome, but no other ASDs. Fine-mapping of the previously identified linkage peak for ASDs at 3q25-q27 revealed association between autism and a subunit of the 5-hydroxytryptamine receptor 3C (HTR3C). We also used dense, genome-wide single nucleotide polymorphism (SNP) data to characterize the population structure of Finns. We observed significant population substructure which correlates with the known history of multiple consecutive bottle-necks experienced by the Finnish population. We used this information to ascertain a genetically homogenous subset of autism families to identify possible rare, enriched risk variants using genome-wide SNP data. No rare enriched genetic risk factors were identified in this dataset, although a subset of families could be genealogically linked to form two extended pedigrees. The lack of founder mutations in this isolated population suggests that the majority of genetic risk factors are rare, de novo mutations unique to individual nuclear families. The results of this study are consistent with others in the field. The underlying genetic architecture for this group of disorders appears highly heterogeneous, with common variants accounting for only a subset of genetic risk. The majority of identified risk factors have turned out to be exceedingly rare, and only explain a subset of the genetic risk in the general population in spite of their high penetrance within individual families. The results of this study, together with other results obtained in this field, indicate that family specific linkage, homozygosity mapping and resequencing efforts are needed to identify these rare genetic risk factors.

A reanalysis of 409 European-Ancestry and African American schizophrenia pedigrees reveals significant linkage to 8p23.3 with evidence of locus heterogeneity

The detection and replication of schizophrenia risk loci can require substantial sample sizes, which has prompted various collaborative efforts for combining multiple samples. However, pooled samples may comprise sub-samples with substantial population genetic differences, including allele frequency differences. We investigated the impact of population differences via linkage reanalysis of Molecular Genetics of Schizophrenia 1 (MGS1) affected sibling-pair data, comprising two samples of distinct ancestral origin: European (EA: 263 pedigrees) and African-American (AA: 146 pedigrees). To exploit the linkage information contained within these distinct continental samples, we performed separate analyses of the individual samples, allowing for within-sample locus heterogeneity, and the pooled sample, allowing for both within-sample and between-sample heterogeneity. Significance levels, corrected for the multiple tests, were determined empirically. For all suggestive peaks, stronger linkage evidence was obtained in either the EA or AA sample than the combined sample, regardless of how heterogeneity was modeled for the latter. Notably, we report genomewide significant linkage of schizophrenia to 8p23.3 and evidence for a second, independent susceptibility locus, reaching suggestive linkage, 29 cM away on 8p21.3. We also detected suggestive linkage on chromosomes 5p13.3 and 7q36.2. Many regions showed pronounced differences in the extent of linkage between the EA and AA samples. This reanalysis highlights the potential impact of population differences upon linkage evidence in pooled data and demonstrates a useful approach for the analysis of samples drawn from distinct continental groups.

The importance of modelling heterogeneity in complex disease: application to NIMH Schizophrenia Genetics Initiative data

As for other complex diseases, linkage analyses of schizophrenia (SZ) have produced evidence for numerous chromosomal regions, with inconsistent results reported across studies. The presence of locus heterogeneity appears likely and may reduce the power of linkage analyses if homogeneity is assumed. In addition, when multiple heterogeneous datasets are pooled, inter-sample variation in the proportion of linked families (alpha) may diminish the power of the pooled sample to detect susceptibility loci, in spite of the larger sample size obtained. We compare the significance of linkage findings obtained using allele-sharing LOD scores (LOD(exp))-which assume homogeneity-and heterogeneity LOD scores (HLOD) in European American and African American NIMH SZ families. We also pool these two samples and evaluate the relative power of the LOD(exp) and two different heterogeneity statistics. One of these (HLOD-P) estimates the heterogeneity parameter alpha only in aggregate data, while the second (HLOD-S) determines alpha separately for each sample. In separate and combined data, we show consistently improved performance of HLOD scores over LOD(exp). Notably, genome-wide significant evidence for linkage is obtained at chromosome 10p in the European American sample using a recessive HLOD score. When the two samples are combined, linkage at the 10p locus also achieves genome-wide significance under HLOD-S, but not HLOD-P. Using HLOD-S, improved evidence for linkage was also obtained for a previously reported region on chromosome 15q. In linkage analyses of complex disease, power may be maximised by routinely modelling locus heterogeneity within individual datasets, even when multiple datasets are combined to form larger samples.

Understanding the heterogeneity of entrepreneurship education: going beyond Gartner

This paper seeks to draw attention to the importance of appreciating and using ever-present diversity to achieve increased legitimacy for entrepreneurship education. As such, it aims to draw the reader into a reflective process of discovery as to why entrepreneurship education is important and how such importance can be prolonged. Design/methodology/approach - The paper revisits Gartner's 1985 conceptual framework for understanding the complexity of entrepreneurship. The paper proposes an alternative framework based on the logic of Gartner's framework to advance the understanding of entrepreneurship education. The authors discuss the dimensions of the proposed framework and explain the nature of the dialogic relations contained within. Findings - It is argued that the proposed conceptual framework provides a new way to understand ever-present heterogeneity related to the development and delivery of entrepreneurship education. Practical implications - The paper extends an invitation to the reader to audit their own involvement and proximity to entrepreneurship education. It argues that increased awareness of the value that heterogeneity plays in student learning outcomes and programme branding is directly related to the presence of heterogeneity across the dimensions of the conceptual framework. Originality/value - The paper introduces a simple yet powerlu1 means of understanding what factors contribute to the success or otherwise of developing and delivering entrepreneurship education. The simplicity of the approach suggested provides all entrepreneurship educators with the means to audit all facets of their programme.

Farmland birds and habitat heterogeneity in intensively cultivated boreal agricultural landscapes

The biodiversity of farmland ecosystems has decreased remarkably during the latter half of the 20th century, and this development is due to intensive farming with its various environmental effects. In the countries of the EU the Common Agricultural Policy (CAP) is the main determinant affecting farmland biodiversity, since the agricultural policy defines guidelines of agricultural practices. In addition to policies promoting intensive farming, CAP also includes national agri-environment schemes (AES), in which a part of subsidies paid to farmers is directed to acts that are presumed to promote environmental protection and biodiversity. In order to shape AES into relevant and powerful tools for biodiversity protection, detailed studies on the effects of agriculture on species and species assemblages are needed. In my thesis I investigated the importance of habitat heterogeneity and effects of different habitat and landscape characteristics on farmland bird abundance and diversity in typical cereal cultivation-dominated southern Finnish agricultural environments. The extensive data used were collected by territory mapping. My two main study species were the drastically declined ortolan bunting (Emberiza hortulana) and the phenomenally increased tree sparrow (Passer montanus); in addition I studied assemblages of 20 species breeding in open arable and edge/bush habitats. In light of my results I discuss whether the Finnish AES take into account the habitat needs of farmland birds, and I provide suggestions for improvement of the future AES. My results show that heterogeneity of both uncultivated and cultivated habitats increases abundance and species richness among farmland birds, but in this respect the amount and diversity of uncultivated habitats are essential. Ditches in particular are a keystone structure for farmland birds in boreal landscapes. Ditches lined by trees or bushes increased ortolan bunting abundance. Loss of that kind of ditches (and clearance of forest and bush patches), reduced breeding ortolan buntings, mainly by decreasing availability of song-posts that are important for the breeding groups of the species. Heterogeneity of uncultivated habitats, most importantly open ditches and the habitat patch richness, increased densities and species richnesses of species assemblages of open arable and edge/bush habitats. Human impact (winter-feeding, nest-boxes) affected favourably the tree sparrow s rapid range expansion in southern Finland, but any habitat types had no significant effects. At the moment the Finnish agri-environmental policy does not conserve farmland ditches as a habitat type. Instead, sub-surface drainage is financially promoted. This is a fatal mistake as far as farmland biodiversity is concerned. In addition to the maintenance of ditches, at least the following aspects should be included more than is done previously in the measures of the future AES: 1) promotion of diverse crop rotation (especially by promoting animal husbandry), 2) maintenance of tree and bush vegetation in islets and along ditches, 3) promotion of organic farming.

Modelling heterogeneity of concrete using 2D lattice network for concrete fracture and comparison with AE study

In this paper, numerical modelling of fracture in concrete using two-dimensional lattice model is presented and also a few issues related to lattice modelling technique applicable to concrete fracture are reviewed. A comparison is made with acoustic emission (AE) events with the number of fractured elements. To implement the heterogeneity of the plain concrete, two methods namely, by generating grain structure of the concrete using Fuller's distribution and the concrete material properties are randomly distributed following Gaussian distribution are used. In the first method, the modelling of the concrete at meso level is carried out following the existing methods available in literature. The shape of the aggregates present in the concrete are assumed as perfect spheres and shape of the same in two-dimensional lattice network is circular. A three-point bend (TPB) specimen is tested in the experiment under crack mouth opening displacement (CMOD) control at a rate of 0.0004 mm/sec and the fracture process in the same TPB specimen is modelled using regular triangular 2D lattice network. Load versus crack mouth opening isplacement (CMOD) plots thus obtained by using both the methods are compared with experimental results. It was observed that the number of fractured elements increases near the peak load and beyond the peak load. That is once the crack starts to propagate. AE hits also increase rapidly beyond the peak load. It is compulsory here to mention that although the lattice modelling of concrete fracture used in this present study is very similar to those already available in literature, the present work brings out certain finer details which are not available explicitly in the earlier works.

DNA-induced conformational changes in RecA protein. Evidence for structural heterogeneity among nucleoprotein filaments and implications for homologous pairing

We have used circular dichroism as a probe to characterize the solution conformational changes in RecA protein upon binding to DNA. This approach revealed that RecA protein acquires significant amounts of alpha-helix upon interaction with DNA. These observations, consistent with the data from crystal structure (Story, R. M., Weber, I., and Steitz, T. (1992) Nature 355, 318-325), support the notion that some basic domains including the DNA binding motifs of RecA protein are unstructured and might contribute to the formation of alpha-helix. A comparison of nucleoprotein filaments comprised of RecA protein and a variety of DNA substrates revealed important structural heterogeneity. The most significant difference was observed with poly(dG). poly(dC) and related polymers, rich in GC sequences, which induced minimal amounts of alpha-helix in RecA protein. The magnitude of induction of alpha-helix in RecA protein, which occurred concomitant with the production of ternary complexes, was 2-fold higher with homologous than heterologous duplex DNA. Most importantly, the stimulation of ATP hydrolysis by high salt coincided with that of the induction of alpha-helix in RecA protein. These conformational differences provide a basis for thinking about the biochemical and structural transitions that RecA protein experiences during the formal steps of presynapsis, recognition, and alignment of homologous sequences.

Numerical Simulation of Groundwater Flow with Gradually Increasing Heterogeneity due to Clogging

Well injection replenishes depleting water levels in a well field. Observation well water levels some distance away from the injection well are the indicators of the success of a well injection program. Simulation of the observation well response, located a few tens of meters from the injection well, is likely to be affected by the effects of nonhomogeneous medium, inclined initial water table, and aquifer clogging. Existing algorithms, such as the U.S. Geological Survey groundwater flow software MODFLOW, are capable of handling the first two conditions, whereas time-dependent clogging effects are yet to be introduced in the groundwater flow models. Elsewhere, aquifer clogging is extensively researched in theory of filtration; scope for its application in a well field is a potential research problem. In the present paper, coupling of one such filtration theory to MODFLOW is introduced. Simulation of clogging effects during “Hansol” well recharge in the parts of western India is found to be encouraging.

Large latitudinal gradients and temporal heterogeneity in aerosol black carbon and its mass mixing ratio over southern and northern oceans observed during a trans-continental cruise experiment

Extensive, and collocated measurements of the mass concentrations (M-B) of aerosol black carbon (BC) and (M-T) of composite aerosols were made over the Arabian Sea, tropical Indian Ocean and the Southern Ocean during a trans-continental cruise experiment. Our investigations show that MB remains extremely low(<50 ng m(-3)) and remarkably steady (in space and time) in the Southern Ocean (20 degrees S to 56 degrees S). In contrast, large latitudinal gradients exist north of similar to 20 degrees S; M-B increasing exponentially to reach as high as 2000 ng m(-3) in the Arabian Sea (similar to 8 degrees N). Interestingly, the share of BC showed a distinctly different latitudinal variation, with a peak close to the equator and decreasing on either side. Large fluctuations were seen in M-T over Southern Ocean associated with enhanced production of sea-salt aerosols in response to sea-surface wind speed. These spatio-temporal changes in M-B and its mixing ratio have important implications to regional and global climate.

Analysis of Dynamic Heterogeneity in a Glass Former from the Spatial Correlations of Mobility

The growth of characteristic length scales associated with dynamic heterogeneity in glass-forming liquids is investigated in an extensive computational study of a four-point, time-dependent structure factor defined from spatial correlations of mobility, for a model liquid for system sizes extending up to 351 232 particles, in constant-energy and constant-temperature ensembles. Our estimates for dynamic correlation lengths and susceptibilities are consistent with previous results from finite size scaling. We find scaling exponents that are inconsistent with predictions from inhomogeneous mode coupling theory and a recent simulation confirmation of these predictions.

Genetic Heterogeneity in Wild Isolates of Cellular Slime Mold Social Groups

This study addresses the issues of spatial distribution, dispersal, and genetic heterogeneity in social groups of the cellular slime molds (CSMs). The CSMs are soil amoebae with an unusual life cycle that consists of alternating solitary and social phases. Because the social phase involves division of labor with what appears to be an extreme form of "altruism", the CSMs raise interesting evolutionary questions regarding the origin and maintenance of sociality. Knowledge of the genetic structure of social groups in the wild is necessary for answering these questions. We confirm that CSMs are widespread in undisturbed forest soil from South India. They are dispersed over long distances via the dung of a variety of large mammals. Consistent with this mode of dispersal, most social groups in the two species examined for detailed study, Dictyostelium giganteum and Dictyostelium purpureum, are multi-clonal.