Ligand recognition by A‐class Eph receptors: crystal structures of the EphA2 ligand‐binding domain and the EphA2/ephrin‐A1 complex

Ephrin (Eph) receptor tyrosine kinases fall into two subclasses (A and B) according to preferences for their ephrin ligands. All published structural studies of Eph receptor/ephrin complexes involve B‐class receptors. Here, we present the crystal structures of an A‐class complex between EphA2 and ephrin‐A1 and of unbound EphA2. Although these structures are similar overall to their B‐class counterparts, they reveal important differences that define subclass specificity. The structures suggest that the A‐class Eph receptor/ephrin interactions involve smaller rearrangements in the interacting partners, better described by a ‘lock‐and‐key’‐type binding mechanism, in contrast to the ‘induced fit’ mechanism defining the B‐class molecules. This model is supported by structure‐based mutagenesis and by differential requirements for ligand oligomerization by the two subclasses in cell‐based Eph receptor activation assays. Finally, the structure of the unligated receptor reveals a homodimer assembly that might represent EphA2‐specific homotypic cell adhesion interactions.     

Gender differences in adiponectin and low-grade inflammation among individuals with normal glucose tolerance,prediabetes, and type 2 diabetes

Background: Women with prediabetes and type 2 diabetes mellitus have a higher relative risk of cardiovascular disease than do men. The reason for this is unknown.Objective: We studied the gender differences in adiponectin and in low-grade inflammation, measured by high-sensitivity C-reactive protein (hs-CRP) and interleukin-1 receptor antagonist (IL-1RA), in individuals with normal glucose tolerance, prediabetes, and type 2 diabetes.Methods: In this population-based, cross-sectional study, all individuals born in 1942, 1947, 1952, 1957, and 1962 in Pieksämäki, East Finland, were recruited for participation. A 75-g oral glucose tolerance test and lipid panel were performed, and concentrations of adiponectin, hs-CRP, and IL-1RA were measured. The World Health Organization diagnostic criteria for diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) were used. Statistical comparisons between men and women were performed by a bootstrap-type ANCOVA.Results: The eligible population included 1294 middle-aged individuals, and of these, 904 (406 men and 498 women) had complete data and were included in the analyses. Absolute adiponectin concentrations were significantly higher in women at all levels of glucose tolerance (normal, prediabetes, and type 2 diabetes), but the gender ratio (women to men) for adiponectin concentrations decreased linearly (P = 0.011) from normal glucose tolerance (1.61; 95% CI, 1.48–1.75) to prediabetes (1.57; 95% CI, 1.36–1.83) and diabetes (1.16; 95% CI, 0.87–1.53). Among participants with normal glucose tolerance, no significant difference was found between the sexes in hs-CRP or IL-1RA. Among patients with prediabetes or diabetes, women had significantly higher concentrations than did men for hs-CRP (for prediabetes, 2.0 vs 1.5 mg/L; ratio, 1.39; 95% CI, 1.04–1.85) and IL-1RA (for prediabetes, 255 vs 178 pg/mL; ratio, 1.43; 95% CI, 1.121.83). The gender ratios (women to men) increased linearly from normal glucose tolerance to prediabetes and type 2 diabetes for both hs-CRP (P = 0.019) and IL-1RA (P = 0.013).Conclusions: Adiponectin concentrations in women decreased relatively more compared with men across individuals with normal glucose tolerance, prediabetes, and type 2 diabetes, whereas inflammatory markers increased relatively more in women. Higher inflammatory stress in women than in men with prediabetes and type 2 diabetes may explain their relatively higher cardiovascular disease risk.     

History vs. current demography: explaining the genetic population structure of the common frog (Rana temporaria)

The amount of genetic variability at neutral marker loci is expected to decrease, and the degree of genetic differentiation among populations to increase, as a negative function of effective population size. We assessed the patterns of genetic variability and differentiation at seven microsatellite loci in the common frog (Rana temporaria) in a hierarchical sampling scheme involving three regions (208-885 km apart), three subregions within regions and nine populations (5-20 km apart) within subregions, and related the variability and differentiation estimates to variation in local population size estimates. Genetic variability within local populations decreased significantly with increasing latitude, as well as with decreasing population size and regional site occupancy (proportion of censured localities occupied). The positive relationship between population size and genetic variability estimates was evident also when the effect of latitude (cf. colonization history) was accounted for. Significant genetic differentiation was found at all hierarchical levels, and the degree of population differentiation tended to increase with increasing latitude. Isolation by distance was evident especially at the regional sampling level, and its strength increased significantly towards the north in concordance with decreasing census and marker-based neighbourhood size estimates. These results are in line with the conjecture that the influence of current demographic factors can override the influence of historical factors on species population genetic structure. Further, the observed reductions in genetic variability and increased degree of population differentiation towards the north are in line with theoretical and empirical treatments suggesting that effective population sizes decline towards the periphery of a species' range.     

Predation-imposed selection on threespine stickleback (Gasterosteus aculeatus) morphology: a test of the refuge use hypothesis

The transition from marine to freshwater life in the threespine stickleback (Gasterosteus aculeatus) is accompanied by complex morphological changes-including reduction in bony armor and change in body shape-but experimental evidence for the selective agents behind these evolutionary transitions is sparse. We investigated whether selection by predatory fish affects threespine stickleback morphology differentially when refuge is absent (pelagic lifestyle-ancestral condition) or present (benthic lifestyle-derived condition). Our results show that selection favors low numbers of lateral plates in habitats with refuge, whereas fully plated individuals have a selective advantage in habitats without refuge. We also found that a decrease in the length of the caudal peduncle increased survival probability, irrespective of habitat. The effect of spine lengths on survival was evident only in a multivariate analysis of selection, implying that it is essential to account for phenotypic and genetic correlations between traits before drawing conclusions about the effects of selection on single traits. Apart from uncovering targets and patterns of predator-induced selection on threespine stickleback morphology, our results provide direct evidence to support the hypothesis that differences in antipredator strategies in pelagic versus benthic sticklebacks could play a role in the repeated, independent cases of plate number reduction following freshwater colonization in this species.     

Toxicological Profile of Ultrapure 2,2′,3,4,4′,5,5′-Heptachlorbiphenyl (PCB 180) in Adult Rats

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.     

Tie2 and Eph Receptor Tyrosine Kinase Activation and Signaling

The Eph and Tie cell surface receptors mediate a variety of signaling events during development and in the adult organism. As other receptor tyrosine kinases, they are activated on binding of extracellular ligands and their catalytic activity is tightly regulated on multiple levels. The Eph and Tie receptors display some unique characteristics, including the requirement of ligand-induced receptor clustering for efficient signaling. Interestingly, both Ephs and Ties can mediate different, even opposite, biological effects depending on the specific ligand eliciting the response and on the cellular context. Here we discuss the structural features of these receptors, their interactions with various ligands, as well as functional implications for downstream signaling initiation. The Eph/ephrin structures are already well reviewed and we only provide a brief overview on the initial binding events. We go into more detail discussing the Tie-angiopoietin structures and recognition.     

Associative clustering for exploring dependencies between functional genomics data sets

High-throughput genomic measurements, interpreted as cooccurring data samples from multiple sources, open up a fresh problem for machine learning: What is in common in the different data sets, that is, what kind of statistical dependencies are there between the paired samples from the different sets? We introduce a clustering algorithm for exploring the dependencies. Samples within each data set are grouped such that the dependencies between groups of different sets capture as much of pairwise dependencies between the samples as possible. We formalize this problem in a novel probabilistic way, as optimization of a Bayes factor. The method is applied to reveal commonalities and exceptions in gene expression between organisms and to suggest regulatory interactions in the form of dependencies between gene expression profiles and regulator binding patterns.     

Brain development and predation: plastic responses depend on evolutionary history

Although the brain is known to be a very plastic organ, the effects of common ecological interactions like predation or competition on brain development have remained largely unexplored. We reared nine-spined sticklebacks (Pungitius pungitius) from two coastal marine (predation-adapted) and two isolated pond (competition-adapted) populations in a factorial experiment, manipulating perceived predatory risk and food supply to see (i) if the treatments affected brain development and (ii) if there was population differentiation in the response to treatments. We detected differences in plasticity of the bulbus olfactorius (chemosensory centre) between habitats: marine fish were not plastic, whereas pond fish had larger bulbi olfactorii in the presence of perceived predation. Marine fish had larger bulbus olfactorius overall. Irrespective of population origin, the hypothalamus was smaller in the presence of perceived predatory risk. Our results demonstrate that perceived predation risk can influence brain development, and that the effect of an environmental factor on brain development may depend on the evolutionary history of a given population in respect to this environmental factor.