Polarized localization of phosphatidylserine in the endothelium regulates Kir2.1

Lipid regulation of ion channels is largely explored using in silico modeling with minimal experimentation in intact tissue; thus, the functional consequences of these predicted lipid-channel interactions within native cellular environments remain elusive. The goal of this study is to investigate how lipid regulation of endothelial Kir2.1 - an inwardly rectifying potassium channel that regulates membrane hyperpolarization - contributes to vasodilation in resistance arteries. First, we show that phosphatidylserine (PS) localizes to a specific subpopulation of myoendothelial junctions (MEJs), crucial signaling microdomains that regulate vasodilation in resistance arteries, and in silico data have implied that PS may compete with phosphatidylinositol 4,5-bisphosphate (PIP2) binding on Kir2.1. We found that Kir2.1-MEJs also contained PS, possibly indicating an interaction where PS regulates Kir2.1. Electrophysiology experiments on HEK cells demonstrate that PS blocks PIP2 activation of Kir2.1 and that addition of exogenous PS blocks PIP2-mediated Kir2.1 vasodilation in resistance arteries. Using a mouse model lacking canonical MEJs in resistance arteries (Elnfl/fl/Cdh5-Cre), PS localization in endothelium was disrupted and PIP2 activation of Kir2.1 was significantly increased. Taken together, our data suggest that PS enrichment to MEJs inhibits PIP2-mediated activation of Kir2.1 to tightly regulate changes in arterial diameter, and they demonstrate that the intracellular lipid localization within the endothelium is an important determinant of vascular function

The environmental setting of Epipalaeolithic aggregation site Kharaneh IV

The archaeological site of Kharaneh IV in Jordan's Azraq Basin, and its relatively near neighbour Jilat 6 show evidence of sustained occupation of substantial size through the Early to Middle Epipalaeolithic (c. 24,000 - 15,000 cal BP). Here we review the geomorphological evidence for the environmental setting in which Kharaneh IV was established. The on-site stratigraphy is clearly differentiated from surrounding sediments, marked visually as well as by higher magnetic susceptibility values. Dating and analysis of off-site sediments show that a significant wetland existed at the site prior to and during early site occupation (~ 23,000 - 19,000 BP). This may explain why such a substantial site existed at this location. This wetland dating to the Last Glacial Maximum also provides important information on the palaeoenvironments and potential palaeoclimatic scenarios for today's eastern Jordanian desert, from where such evidence is scarce

Living on a flammable planet: interdisciplinary, cross-scalar and varied cultural lessons, prospects and challenges: Table 1.

Living with fire is a challenge for human communities because they are influenced by socio-economic, political, ecological and climatic processes at various spatial and temporal scales. Over the course of 2 days, the authors discussed how communities could live with fire challenges at local, national and transnational scales. Exploiting our diverse, international and interdisciplinary expertise, we outline generalizable properties of fire-adaptive communities in varied settings where cultural knowledge of fire is rich and diverse. At the national scale, we discussed policy and management challenges for countries that have diminishing fire knowledge, but for whom global climate change will bring new fire problems. Finally, we assessed major fire challenges that transcend national political boundaries, including the health burden of smoke plumes and the climate consequences of wildfires. It is clear that to best address the broad range of fire problems, a holistic wildfire scholarship must develop common agreement in working terms and build across disciplines. We must also communicate our understanding of fire and its importance to the media, politicians and the general public. This article is part of the themed issue ‘The interaction of fire and mankind’

The biogeochemical impact of glacial meltwater from Southwest Greenland

Biogeochemical cycling in high-latitude regions has a disproportionate impact on global nutrient budgets. Here, we introduce a holistic, multi-disciplinary framework for elucidating the influence of glacial meltwaters, shelf currents, and biological production on biogeochemical cycling in high-latitude continental margins, with a focus on the silica cycle. Our findings highlight the impact of significant glacial discharge on nutrient supply to shelf and slope waters, as well as surface and benthic production in these regions, over a range of timescales from days to thousands of years. Whilst biological uptake in fjords and strong diatom activity in coastal waters maintains low dissolved silicon concentrations in surface waters, we find important but spatially heterogeneous additions of particulates into the system, which are transported rapidly away from the shore. We expect the glacially-derived particles – together with biogenic silica tests – to be cycled rapidly through shallow sediments, resulting in a strong benthic flux of dissolved silicon. Entrainment of this benthic silicon into boundary currents may supply an important source of this key nutrient into the Labrador Sea, and is also likely to recirculate back into the deep fjords inshore. This study illustrates how geochemical and oceanographic analyses can be used together to probe further into modern nutrient cycling in this region, as well as the palaeoclimatological approaches to investigating changes in glacial meltwater discharge through time, especially during periods of rapid climatic change in the Late Quaternary

Constitutive SRC-mediated phosphorylation of pannexin 1 at tyrosine 198 occurs at the plasma membrane

© 2019 DeLalio et al. Pannexin 1 (PANX1)-mediated ATP release in vascular smooth muscle coordinates α1-adrenergic receptor (α1-AR) vasoconstriction and blood pressure homeostasis. We recently identified amino acids 198-200 (YLK) on the PANX1 intracellular loop that are critical forα1-AR-mediated vasoconstriction and PANX1 channel function. We report herein that the YLK motif is contained within an SRC homology 2 domain and is directly phosphorylated by SRC proto-oncogene, nonreceptor tyrosine kinase (SRC) at Tyr198. We demonstrate that PANX1- mediated ATP release occurs independently of intracellular calcium but is sensitive to SRC family kinase (SFK) inhibition, suggestive of channel regulation by tyrosine phosphorylation. Using a PANX1 Tyr198-specific antibody, SFK inhibitors, SRC knockdown, temperature-dependent SRC cells, and kinase assays, we found that PANX1-mediated ATP release and vasoconstriction involves constitutive phosphorylation of PANX1 Tyr198 by SRC. We specifically detected SRC-mediated Tyr198 phosphorylation at the plasma membrane and observed that it is not enhanced or induced by α1-AR activation. Last, we show that PANX1 immunostaining is enriched in the smooth muscle layer of arteries from hypertensivehumansand that Tyr198 phosphorylation is detectable in these samples, indicative of a role for membrane-associated PANX1 in small arteries of hypertensive humans. Our discovery adds insight into the regulation of PANX1 by post-translational modifications and connects a significant purinergic vasoconstriction pathway with a previously identified, yet unexplored, tyrosine kinase-based α1-AR constriction mechanism. This work implicates SRC-mediated PANX1 function in normal vascular hemodynamics and suggests that Tyr198-phosphorylated PANX1 is involved in hypertensive vascular pathology