Beta‐Adrenoceptor Activation Reduces Both Dermal Microvascular Endothelial Cell Migration via a cAMP‐Dependent Mechanism and Wound Angiogenesis

Angiogenesis is an essential process during tissue regeneration; however, the amount of angiogenesis directly correlates with the level of wound scarring. Angiogenesis is lower in scar‐free foetal wounds while angiogenesis is raised and abnormal in pathophysiological scarring such as hypertrophic scars and keloids. Delineating the mechanisms that modulate angiogenesis and could reduce scarring would be clinically useful. Beta‐adrenoceptors (β‐AR) are G protein‐coupled receptors (GPCRs) expressed on all skin cell‐types. They play a role in wound repair but their specific role in angiogenesis is unknown. In this study, a range of in vitro assays (single cell migration, scratch wound healing, ELISAs for angiogenic growth factors and tubule formation) were performed with human dermal microvascular endothelial cells (HDMEC) to investigate and dissect mechanisms underpinning β‐AR‐mediated modulation of angiogenesis in chick chorioallantoic membranes (CAM) and murine excisional skin wounds. β‐AR activation reduced HDMEC migration via cyclic adenosine monophosphate (cAMP)‐dependent and protein kinase A (PKA)‐independent mechanisms as demonstrated through use of an EPAC agonist that auto‐inhibited the cAMP‐mediated β‐AR transduced reduction in HDMEC motility; a PKA inhibitor was, conversely, ineffective. ELISA studies demonstrated that β‐AR activation reduced pro‐angiogenic growth factor secretion from HDMECs (fibroblast growth factor 2) and keratinocytes (vascular endothelial growth factor A) revealing possible β‐AR‐mediated autocrine and paracrine anti‐angiogenic mechanisms. In more complex environments, β‐AR activation delayed HDMEC tubule formation and decreased angiogenesis both in the CAM assay and in murine excisional skin wounds in vivo. β‐AR activation reduced HDMEC function in vitro and angiogenesis in vivo; therefore, β‐AR agonists could be promising anti‐angiogenic modulators in skin. J. Cell. Physiol. 230: 356–365, 2015. © 2014 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.     

Is Female Visual Signaling to Male Song Socially Regulated in Brown‐headed Cowbirds?

This research focused on how adult female brown‐headed cowbirds, Molothrus ater, regulate social feedback on a group level to shape the development of male song. Specifically, females produce rapid wing movements in response to male song, termed ‘wing strokes,’ which have been shown to shape male song and predict song quality. These effects have been documented in captive dyads and triads, but not in more naturalistic flocks, where song development actually occurs. Here, we studied wing stroking in small seminatural flocks of differing female‐to‐male ratios. Despite differences in the number of females and their social selectivity, the same pattern of female feedback emerged in seven of eight flocks: One female produced the majority of wing strokes to male song, making her the primary wing stroker in her flock. Previous studies on large flocks have demonstrated females to facilitate male song improvisation and development if they exhibited higher social selectivity by approaching immature males less. Here, we found that primary wing strokers were indeed more socially selective than non‐primary wing strokers. This research is the first to document social stimulation being facilitated at the group level to ensure that more highly selective females deliver the most feedback.     

Climate change and dead zones

Estuaries and coastal seas provide valuable ecosystem services but are particularly vulnerable to the co‐occurring threats of climate change and oxygen‐depleted dead zones. We analyzed the severity of climate change predicted for existing dead zones, and found that 94% of dead zones are in regions that will experience at least a 2 °C temperature increase by the end of the century. We then reviewed how climate change will exacerbate hypoxic conditions through oceanographic, ecological, and physiological processes. We found evidence that suggests numerous climate variables including temperature, ocean acidification, sea‐level rise, precipitation, wind, and storm patterns will affect dead zones, and that each of those factors has the potential to act through multiple pathways on both oxygen availability and ecological responses to hypoxia. Given the variety and strength of the mechanisms by which climate change exacerbates hypoxia, and the rates at which climate is changing, we posit that climate change variables are contributing to the dead zone epidemic by acting synergistically with one another and with recognized anthropogenic triggers of hypoxia including eutrophication. This suggests that a multidisciplinary, integrated approach that considers the full range of climate variables is needed to track and potentially reverse the spread of dead zones.     

In situ adaptive response to climate and habitat quality variation: spatial and temporal variation in European badger (Meles meles) body weight

Variation in climatic and habitat conditions can affect populations through a variety of mechanisms, and these relationships can act at different temporal and spatial scales. Using post‐mortem badger body weight records from 15 878 individuals captured across the Republic of Ireland (7224 setts across ca. 15 000 km²; 2009–2012), we employed a hierarchical multilevel mixed model to evaluate the effects of climate (rainfall and temperature) and habitat quality (landscape suitability), while controlling for local abundance (unique badgers caught/sett/year). Body weight was affected strongly by temperature across a number of temporal scales (preceding month or season), with badgers being heavier if preceding temperatures (particularly during winter/spring) were warmer than the long‐term seasonal mean. There was less support for rainfall across different temporal scales, although badgers did exhibit heavier weights when greater rainfall occurred one or 2 months prior to capture. Badgers were also heavier in areas with higher landscape habitat quality, modulated by the number of individuals captured per sett, consistent with density‐dependent effects reducing weights. Overall, the mean badger body weight of culled individuals rose during the study period (2009–2012), more so for males than for females. With predicted increases in temperature, and rainfall, augmented by ongoing agricultural land conversion in this region, we project heavier individual badger body weights in the future. Increased body weight has been associated with higher fecundity, recruitment and survival rates in badgers, due to improved food availability and energetic budgets. We thus predict that climate change could increase the badger population across the Republic of Ireland. Nevertheless, we emphasize that, locally, populations could still be vulnerable to extreme weather variability coupled with detrimental agricultural practice, including population management.     

Diverse functional outcomes of Plasmodium falciparum ligation of EPCR: potential implications for malarial pathogenesis

Plasmodium falciparum‐infected erythrocytes (IRBC) expressing the domain cassettes (DC) 8 and 13 of the cytoadherent ligand P. falciparum erythrocyte membrane protein 1 adhere to the endothelial protein C receptor (EPCR). By interfering with EPCR anti‐coagulant and pro‐endothelial barrier functions, IRBC adhesion could promote coagulation and vascular permeability that contribute to the pathogenesis of cerebral malaria. In this study, we examined the adhesion of DC8‐ and DC13‐expressing parasite lines to endothelial cells from different microvasculature, and the consequences of EPCR engagement on endothelial cell function. We found that IRBC from IT4var19 (DC8) and IT4var07 (DC13) parasite lines adhered to human brain, lung and dermal endothelial cells under shear stress. However, the relative contribution of EPCR to parasite cytoadherence on different types of endothelial cell varied. We also observed divergent functional outcomes for DC8 cysteine‐rich interdomain region (CIDR)α1.1 and DC13 CIDRα1.4 domains. IT4var07 CIDRα1.4 inhibited generation of activated protein C (APC) on lung and dermal endothelial cells and blocked the APC–EPCR binding interaction on brain endothelial cells. IT4var19 CIDRα1.1 inhibited thrombin‐induced endothelial barrier dysfunction in lung endothelial cells, whereas IT4var07 CIDRα1.4 inhibited the protective effect of APC on thrombin‐induced permeability. Overall, these findings reveal a much greater complexity of how CIDRα1‐expressing parasites may modulate malaria pathogenesis through EPCR adhesion.     

Fullerene‐based inhibitors of HIV‐1 protease

A series of Fmoc‐Phe(4‐aza‐C₆₀)‐OH of fullerene amino acid derived peptides have been prepared by solid phase peptide synthesis, in which the terminal amino acid, Phe(4‐aza‐C₆₀)‐OH, is derived from the dipolar addition to C₆₀ of the Fmoc‐Nα‐protected azido amino acids derived from phenylalanine: Fmoc‐Phe(4‐aza‐C₆₀)‐Lys₃‐OH ( 1 ), Fmoc‐Phe(4‐aza‐C₆₀)‐Pro‐Hyp‐Lys‐OH ( 2 ), and Fmoc‐Phe(4‐aza‐C₆₀)‐Hyp‐Hyp‐Lys‐OH ( 3 ). The inhibition constant of our fullerene aspartic protease PRIs utilized FRET‐based assay to evaluate the enzyme kinetics of HIV‐1 PR at various concentrations of inhibitors. Simulation of the docking of the peptide Fmoc‐Phe‐Pro‐Hyp‐Lys‐OH overestimated the inhibition, while the amino acid PRIs were well estimated. The experimental results show that C₆₀‐based amino acids are a good base structure in the design of protease inhibitors and that their inhibition can be improved upon by the addition of designer peptide sequences. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.     

Investigating Devonian trees as geo‐engineers of past climates: linking palaeosols to palaeobotany and experimental geobiology

We present the rationale for a cross‐disciplinary investigation addressing the ‘Devonian plant hypothesis’ which proposes that the evolutionary appearance of trees with deep, complex rooting systems represents one of the major biotic feedbacks on geochemical carbon cycling during the Phanerozoic. According to this hypothesis, trees have dramatically enhanced mineral weathering driving an increased flux of Ca²⁺ to the oceans and, ultimately, a 90% decline in atmospheric CO₂ levels through the Palaeozoic. Furthermore, experimental studies indicate a key role for arbuscular mycorrhizal fungi in soil–plant processes and especially in unlocking the limiting nutrient phosphorus in soil via Ca‐phosphate dissolution mineral weathering. This suggests co‐evolution of roots and symbiotic fungi since the Early Devonian could well have triggered positive feedbacks on weathering rates whereby root–fungal P release supports higher biomass forested ecosystems. Long‐standing areas of uncertainty in this paradigm include the following: (1) limited fossil record documenting the origin and timeline of the evolution of tree‐sized plants through the Devonian; and (2) the effects of the evolutionary advance of trees and their in situ rooting structures on palaeosol geochemistry. We are addressing these issues by integrating palaeobotanical studies with geochemical and mineralogical analyses of palaeosol sequences at selected sites across eastern North America with a particular focus on drill cores from Middle Devonian forests in Greene County, New York State.