Structural heterogeneity of membrane receptors and GTP-binding proteins and its functional consequences for signal transduction.

Recent information obtained, mainly by recombinant cDNA technology, on structural heterogeneity of hormone and transmitter receptors, of GTP-binding proteins (G-proteins) and, especially, of G-protein-linked receptors is reviewed and the implications of structural heterogeneity for diversity of hormone and transmitter actions is discussed. For the future, three-dimensional structural analysis of membrane proteins participating in signal transmission and transduction pathways is needed in order to understand the molecular basis of allosteric regulatory mechanisms governing the interactions between these proteins including hysteretic properties and cell-cybernetic aspects.     

Systems Mapping for Hematopoietic Progenitor Cell Heterogeneity

Cells with the same genotype growing under the same conditions can show different phenotypes, which is known as “population heterogeneity”. The heterogeneity of hematopoietic progenitor cells has an effect on their differentiation potential and lineage choices. However, the genetic mechanisms governing population heterogeneity remain unclear. Here, we present a statistical model for mapping the quantitative trait locus (QTL) that affects hematopoietic cell heterogeneity. This strategy, termed systems mapping, integrates a system of differential equations into the framework for systems mapping, allowing hypotheses regarding the interplay between genetic actions and cell heterogeneity to be tested. A simulation approach based on cell heterogeneity dynamics has been designed to test the statistical properties of the model. This model not only considers the traditional QTLs, but also indicates the methylated QTLs that can illustrate non-genetic individual differences. It has significant implications for probing the molecular, genetic and epigenetic mechanisms of hematopoietic progenitor cell heterogeneity.     

Applications and extensions of Chao's moment estimator for the size of a closed population

This article revisits Chao's (1989, Biometrics45, 427-438) lower bound estimator for the size of a closed population in a mark-recapture experiment where the capture probabilities vary between animals (model M(h)). First, an extension of the lower bound to models featuring a time effect and heterogeneity in capture probabilities (M(th)) is proposed. The biases of these lower bounds are shown to be a function of the heterogeneity parameter for several loglinear models for M(th). Small-sample bias reduction techniques for Chao's lower bound estimator are also derived. The application of the loglinear model underlying Chao's estimator when heterogeneity has been detected in the primary periods of a robust design is then investigated. A test for the null hypothesis that Chao's loglinear model provides unbiased abundance estimators is provided. The strategy of systematically using Chao's loglinear model in the primary periods of a robust design where heterogeneity has been detected is investigated in a Monte Carlo experiment. Its impact on the estimation of the population sizes and of the survival rates is evaluated in a Monte Carlo experiment.     

Environmental heterogeneity as a universal driver of species richness across taxa,biomes and spatial scales

Environmental heterogeneity is regarded as one of the most important factors governing species richness gradients. An increase in available niche space, provision of refuges and opportunities for isolation and divergent adaptation are thought to enhance species coexistence, persistence and diversification. However, the extent and generality of positive heterogeneity–richness relationships are still debated. Apart from widespread evidence supporting positive relationships, negative and hump‐shaped relationships have also been reported. In a meta‐analysis of 1148 data points from 192 studies worldwide, we examine the strength and direction of the relationship between spatial environmental heterogeneity and species richness of terrestrial plants and animals. We find that separate effects of heterogeneity in land cover, vegetation, climate, soil and topography are significantly positive, with vegetation and topographic heterogeneity showing particularly strong associations with species richness. The use of equal‐area study units, spatial grain and spatial extent emerge as key factors influencing the strength of heterogeneity–richness relationships, highlighting the pervasive influence of spatial scale in heterogeneity–richness studies. We provide the first quantitative support for the generality of positive heterogeneity–richness relationships across heterogeneity components, habitat types, taxa and spatial scales from landscape to global extents, and identify specific needs for future comparative heterogeneity–richness research.     

Recognition pliability is coupled to structural heterogeneity: a calmodulin intrinsically disordered binding region complex

Protein interactions within regulatory networks should adapt in a spatiotemporal-dependent dynamic environment, in order to process and respond to diverse and versatile cellular signals. However, the principles governing recognition pliability in protein complexes are not well understood. We have investigated a region of the intrinsically disordered protein myelin basic protein (MBP(145-165)) that interacts with calmodulin, but that also promiscuously binds other biomolecules (membranes, modifying enzymes). To characterize this interaction, we implemented an NMR spectroscopic approach that calculates, for each conformation of the complex, the maximum occurrence based on recorded pseudocontact shifts and residual dipolar couplings. We found that the MBP(145-165)-calmodulin interaction is characterized by structural heterogeneity. Quantitative comparative analysis indicated that distinct conformational landscapes of structural heterogeneity are sampled for different calmodulin-target complexes. Such structural heterogeneity in protein complexes could potentially explain the way that transient and promiscuous protein interactions are optimized and tuned in complex regulatory networks.     

DIRECT ESTIMATION OF WITHIN-GROUP HETEROGENEITY IN PHOTO-IDENTIFICATION OF SPERM WHALES

Heterogeneity in photo-identification rates among individuals is a potentially serious problem in many studies of cetacean biology, especially the analysis of populations. However, this heterogeneity is usually difficult to identify or measure. Two instances in which closed groups of female and immature sperm whales ( Physeter macrocepbalus ) were tracked and identified using fluke photographs over periods of days off the Galápagos Islands allowed direct examination of heterogeneity in identification rates. A group of nine animals followed in 1999 provided almost no evidence for heterogeneity (permutation test for heterogeneity, P = 0.48), with an estimated coefficient of variation in identification rates of 0.03 (95% CI from 1,000 bootstrap replications: 0.00–0.10). In contrast, the identification rates of a group of 22 animals followed in 1995 seemed to show potentially important differences ( P = 0.058, CV = 0.20, 95% CI = 0.07–0.28). These differences were not related to the internal social structure of the group or to differences in numbers of markings on the flukes, but smaller whales had lower identification rates. Thus, young sperm whales may be underrepresented in photo-identification studies, but adults within groups seem to have similar identification rates. Situations in which animals are photo-identified from closed populations of known size are particularly useful for examining heterogeneity. They should be vigorously exploited by those who use photo-identification to examine population or behavioral biology.     

Semicontinuous affinity chromatography separations

The semicontinuous operation of affinity chromatography columns charged and eluted alternately is studied mathematically. A strongly nonlinear adsorption equilibrium relation is utilized to examine the periodic mode of adsorption and desorption. The governing differential equations are solved by the method of characteristics. The time interval between desorption and adsorption periods is estimated, and implications for separations are discussed to show the advantages of semicontinuous cyclic operation.     

Molecular heterogeneity of secretory IgA anti-DNP antibodies

Evidence is presented that demonstrates that the microscale sucrose isoelectric focusing technique can be used to assess the molecular heterogeneity of secretory IgA anti-DNP antibodies. The data indicate that substitution of the DNP group on the bacterial carrier, pneumococcus, can limit the structural complexity of secretory IgA anti-DNP antibodies. The data support the concept that factors governing secretory IgA antibody heterogeneity are analogous to those influencing the heterogeneity of serum IgG antibodies.     

Effects of memory on spatial heterogeneity in neutrally transmitted culture

We explore how cultural heterogeneity evolves without strong selection pressure or environmental differences between groups. Using a neutral transmission model with an isolation-by-distance spatiality, we test the effect of a simple representation of cultural ‘memory’ on the dynamics of heterogeneity. We find that memory magnifies the effect of affinity while decreasing the effect of individual learning on cultural heterogeneity. This indicates that, while the cost of individual learning governs the frequency of individual learning, memory is important in governing its effect.     

Cellular automaton simulation examining progenitor hierarchy structure effects on mammary ductal carcinoma in situ

A computer simulation is used to model ductal carcinoma in situ, a form of non-invasive breast cancer. The simulation uses known histological morphology, cell types, and stochastic cell proliferation to evolve tumorous growth within a duct. The ductal simulation is based on a hybrid cellular automaton design using genetic rules to determine each cell's behavior. The genetic rules are a mutable abstraction that demonstrate genetic heterogeneity in a population. Our goal was to examine the role (if any) that recently discovered mammary stem cell hierarchies play in genetic heterogeneity, DCIS initiation and aggressiveness. Results show that simpler progenitor hierarchies result in greater genetic heterogeneity and evolve DCIS significantly faster. However, the more complex progenitor hierarchy structure was able to sustain the rapid reproduction of a cancer cell population for longer periods of time.     

Mechanisms regulating the origins of the vertebrate vascular system

In order to sustain growth, differentiation, and organogenesis, vertebrate embryos must form a functional vascular system early in embryonic development. Intrinsic interest in this process as well as the promise of potential clinical applications has led to significant progress in understanding the mechanisms governing the formation of the vascular system, however the earliest stages of vascular development--the emergence of committed endothelial precursors from the mesoderm--remain unclear. A review of the current literature reveals an unexpected diversity and heterogeneity with respect to where vascular endothelial cells originate in the embryo, when they become committed and the mechanisms governing how endothelial cells acquire their identity. Spatially, a widespread region of the early mesoderm possesses the ability to give rise to vascular endothelial cells; temporally the process is not limited to a small window during embryogenesis, but rather, may continue throughout the lifespan of the organism. On the molecular level, recent findings point to several determinative pathways that regulate, modulate, and extend the scope of the Flk1/VEGF signaling system. An expanding array of novel gene products implicated in endothelial cell type determination appear to act synergistically, with different combinations of factors leading to diverse cellular responses, varying patterns of differentiation, and considerable heterogeneity of endothelial cell types during embryogenesis.     

How do pathogen evolution and host heterogeneity interact in disease emergence?

Heterogeneity in the parameters governing the spread of infectious diseases is a common feature of real-world epidemics. It has been suggested that for pathogens with basic reproductive number R(0)>1, increasing heterogeneity makes extinction of disease more likely during the early rounds of transmission. The basic reproductive number R(0) of the introduced pathogen may, however, be less than 1 after the introduction, and evolutionary changes are then required for R(0) to increase to above 1 and the pathogen to emerge. In this paper, we consider how host heterogeneity influences the emergence of both non-evolving pathogens and those that must undergo adaptive changes to spread in the host population. In contrast to previous results, we find that heterogeneity does not always make extinction more likely and that if adaptation is required for emergence, the effect of host heterogeneity is relatively small. We discuss the application of these ideas to vaccination strategies.     

Ghrelin – Defender of fat

With one quarter of the population of the Western world now considered obese, it is essential that we understand the factors giving rise to elevated fat deposition. This review summarizes the cellular and molecular mechanisms governing the volume of white adipose tissue (WAT), and outlines the physiological signals that regulate these processes. Particular attention is given to the role of the gastric hormone, ghrelin, describing its actions in general and presenting detailed evidence of its role in regulating adipocyte biology. Combining this evidence with an analysis of the factors governing ghrelin secretion, leads to the hypothesis that during periods of food deprivation ghrelin acts as an energy deficit signal, defending the fat stored in responsive WAT against the forces of utilization. This scenario has clear implications for programmes of sustainable weight loss.     

Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and lamm equation modeling

A new method for the size-distribution analysis of polymers by sedimentation velocity analytical ultracentrifugation is described. It exploits the ability of Lamm equation modeling to discriminate between the spreading of the sedimentation boundary arising from sample heterogeneity and from diffusion. Finite element solutions of the Lamm equation for a large number of discrete noninteracting species are combined with maximum entropy regularization to represent a continuous size-distribution. As in the program CONTIN, the parameter governing the regularization constraint is adjusted by variance analysis to a predefined confidence level. Estimates of the partial specific volume and the frictional ratio of the macromolecules are used to calculate the diffusion coefficients, resulting in relatively high-resolution sedimentation coefficient distributions c(s) or molar mass distributions c(M). It can be applied to interference optical data that exhibit systematic noise components, and it does not require solution or solvent plateaus to be established. More details on the size-distribution can be obtained than from van Holde-Weischet analysis. The sensitivity to the values of the regularization parameter and to the shape parameters is explored with the help of simulated sedimentation data of discrete and continuous model size distributions, and by applications to experimental data of continuous and discrete protein mixtures.     

SUCCESSION AND CURRENT DEMAND RELATIONSHIPS OF DIATOMS ON ARTIFICIAL SUBSTRATES IN PRATER'S CREEK,SOUTH CAROLINA1,2

A study concerning the colonization of glass slides by diatoms was conducted in Prater's Creek, Pickens County. S. C., to observe qualitatively and quantitatively the responses of the periphytic community to current velocities for varied lengths of time. Over short time periods (1, 2 and 4 weeks) diatoms seemed to adhere best at slow current velocities. Over longer periods (6 weeks) growth, of the initial colonizers seemed to be the density governing factor; consequently, the highest diatom densities developed at the higher current, velocities. The interaction of time and current resulted in a reversal of the diatom deposition phenomenon.     

Factors influencing the distribution of Azorean mountain vegetation: implications for nature conservation

In order to understand the main ecological factors that influence the distribution of mountain vegetation in Azores and to use it as a model for nature conservation, a study on Santa Bárbara Mountain on Terceira Island was performed. A multivariate analysis was done on vegetation data and the abiotic factors governing the vegetation pattern are discussed. The major factors contributing to the observed vegetation patterns are wind exposure, soil water saturation and historical human impacts. The vegetation analysis showed that Azorean Mountain habitats have a high variation of vegetation structure as a result of the habitat heterogeneity and the extreme ecological conditions. Using the co-dominant plants as indicator species, eco-zones are distinguished, characterized by the combination of different ecological–human factors which contribute to the distribution of specific types of natural vegetation communities. The studies of vegetation distribution give important information about the relation between vegetation and landscape that is essential for conservation, restoration proposals and landscape planning. Azores terrestrial Natura 2000 sites are largely dominated by mountain vegetation, therefore this work provides essential background data for the management plans of these sites.     

The role of heterogeneity in the persistence and prevalence of Sin Nombre virus in deer mice

Many diseases persist at a relatively low prevalence, seemingly close to extinction. For a chronic disease in a homogeneous population, reducing the transmission rate by a fraction proportional to the prevalence would be sufficient to eradicate the disease. This study examines how higher prevalence of the Sin Nombre virus in male deer mice (Peromyscus maniculatus) might contribute to disease persistence. Analyzing data from over 2,000 individual mice captured in 19 sites over 4 years, we found prevalences of 18.5% in males and 8.8% in females. By examining recaptures, we determined that males are more likely to contract the infection because of higher susceptibility or higher encounter rates. Comparing across 86 sampling periods, we found a higher proportion of males when population densities were low. A capture-recapture analysis indicates that males live longer than females. A mathematical model based on the measured parameters and population size trajectories suggests that the combined heterogeneity in encounters, susceptibility, and mortality may buffer the disease from extinction by concentrating disease in the subgroup most likely to transmit the disease. This buffering effect is not significantly stronger in a fluctuating population, indicating that these forms of heterogeneity might not be the key for disease persistence through host population bottlenecks.     

Assessing exposure-time treatment effect heterogeneity in stepped-wedge cluster randomized trials

A stepped-wedge cluster randomized trial (CRT) is a unidirectional crossover study in which timings of treatment initiation for clusters are randomized. Because the timing of treatment initiation is different for each cluster, an emerging question is whether the treatment effect depends on the exposure time, namely, the time duration since the initiation of treatment. Existing approaches for assessing exposure-time treatment effect heterogeneity either assume a parametric functional form of exposure time or model the exposure time as a categorical variable, in which case the number of parameters increases with the number of exposure-time periods, leading to a potential loss in efficiency. In this article, we propose a new model formulation for assessing treatment effect heterogeneity over exposure time. Rather than a categorical term for each level of exposure time, the proposed model includes a random effect to represent varying treatment effects by exposure time. This allows for pooling information across exposure-time periods and may result in more precise average and exposure-time-specific treatment effect estimates. In addition, we develop an accompanying permutation test for the variance component of the heterogeneous treatment effect parameters. We conduct simulation studies to compare the proposed model and permutation test to alternative methods to elucidate their finite-sample operating characteristics, and to generate practical guidance on model choices for assessing exposure-time treatment effect heterogeneity in stepped-wedge CRTs.