Inhibition of Autoimmune Diabetes in NOD Mice by miRNA Therapy

Autoimmune destruction of the pancreatic islets in Type 1 diabetes is mediated by both increased proinflammatory (Teff) and decreased regulatory (Treg) T lymphocytes resulting in a significant decrease in the Treg:Teff ratio. The non-obese diabetic (NOD) mouse is an excellent in vivo model for testing potential therapeutics for attenuating the decrease in the Treg:Teff ratio and inhibiting disease pathogenesis. Here we show for the first time that a bioreactor manufactured therapeutic consisting of a complex of miRNA species (denoted as TA1) can effectively reset the NOD immune system from a proinflammatory to a tolerogenic state thus preventing or delaying autoimmune diabetes. Treatment of NOD mice with TA1 resulted in a systemic broad-spectrum upregulation of tolerogenic T cell subsets with a parallel downregulation of Teff subsets yielding a dramatic increase in the Treg:Teff ratio. Moreover, the murine-derived TA1 was highly effective in the inhibition of allorecognition of HLA-disparate human PBMC. TA1 demonstrated dose-responsiveness and exhibited equivalent or better inhibition of allorecognition driven proliferation than etanercept (a soluble TNF receptor). These findings demonstrate that miRNA-based therapeutics can effectively attenuate or arrest autoimmune disease processes and may be of significant utility in a broad range of autoimmune diseases including Type 1 diabetes.     

Upslope development of a tidal marsh as a function of upland land use

To thrive in a time of rapid sea‐level rise, tidal marshes will need to migrate upslope into adjacent uplands. Yet little is known about the mechanics of this process, especially in urbanized estuaries, where the adjacent upland is likely to be a mowed lawn rather than a wooded natural area. We studied marsh migration in a Long Island Sound salt marsh using detailed hydrologic, edaphic, and biotic sampling along marsh‐to‐upland transects in both wooded and lawn environments. We found that the overall pace of marsh development was largely unaffected by whether the upland being invaded was lawn or wooded, but the marsh‐edge plant communities that developed in these two environments were quite different, and some indicators (soil salinity, foraminifera) appeared to migrate more easily into lawns. In addition, we found that different aspects of marsh structure and function migrated at different rates: Wetland vegetation appeared to be a leading indicator of marsh migration, while soil characteristics such as redox potential and surface salinity developed later in the process. We defined a ‘hydrologic migration zone’, consisting of elevations that experience tidal inundation with frequencies ranging from 20% to 0.5% of high tides. This hydrologically defined zone – which extended to an elevation higher than the highest astronomical tide datum – captured the biotic and edaphic marsh‐upland ecotone. Tidal inundation at the upper border of this migration zone is highly variable over time and may be rising more rapidly than mean sea level. Our results indicate that land management practices at the upland periphery of tidal marshes can facilitate or impede ecosystem migration in response to rising sea level. These findings are applicable to large areas of tidal marsh along the U.S. Atlantic coast and in other urbanized coastal settings.     

Does the house sparrow Passer domesticus represent a global model species for egg rejection behavior?

Conspecific brood parasitism (CP) is a facultative breeding tactic whereby females lay their eggs in the nests of conspecifics. In some species, potential hosts have evolved the ability to identify and reject foreign eggs from their nest. Previous studies suggest that the ubiquitous house sparrow Passer domesticus in Spain and South Africa employs both CP and egg rejection, while a population in China does not. Given the species’ invasive range expansions, the house sparrow represents a potentially excellent global model system for parasitic egg rejection across variable ecological conditions. We examined the responses of house sparrows to experimental parasitism at three geographically distinct locations (in Israel, North America, and New Zealand) to provide a robust test of how general the findings of the previous studies are. In all three geographic regions egg rejection rates were negligible and not statistically different from background rates of disappearance of control eggs, suggesting that the house sparrow is not a suitable model species for egg rejection experiments on a global scale.     

The role of lipid second messengers in aldosterone synthesis and secretion

Second messengers are small rapidly diffusing molecules or ions that relay signals between receptors and effector proteins to produce a physiological effect. Lipid messengers constitute one of the four major classes of second messengers. The hydrolysis of two main classes of lipids, glycerophospholipids and sphingolipids, generate parallel profiles of lipid second messengers: phosphatidic acid (PA), diacylglycerol (DAG), and lysophosphatidic acid versus ceramide, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate, respectively. In this review, we examine the mechanisms by which these lipid second messengers modulate aldosterone production at multiple levels. Aldosterone is a mineralocorticoid hormone responsible for maintaining fluid volume, electrolyte balance, and blood pressure homeostasis. Primary aldosteronism is a frequent endocrine cause of secondary hypertension. A thorough understanding of the signaling events regulating aldosterone biosynthesis may lead to the identification of novel therapeutic targets. The cumulative evidence in this literature emphasizes the critical roles of PA, DAG, and sphingolipid metabolites in aldosterone synthesis and secretion. However, it also highlights the gaps in our knowledge, such as the preference for phospholipase D-generated PA or DAG, as well as the need for further investigation to elucidate the precise mechanisms by which these lipid second messengers regulate optimal aldosterone production.