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The sensitivity of river discharge to climate-system warming is highly uncertain, and the processes that govern river discharge are poorly understood, which impedes climate-change adaptation. A prominent exemplar is the Colorado River, where meteorological drought and warming are shrinking a water resource that supports more than 1 trillion dollars of economic activity per year. A Monte Carlo simulation with a radiation-aware hydrologic model resolves the longstanding, wide disparity in sensitivity estimates and reveals the controlling physical processes. We estimate that annual mean discharge has been decreasing by 9.3% per degree Celsius of warming because of increased evapotranspiration, mainly driven by snow loss and a consequent decrease in reflection of solar radiation. Projected precipitation increases likely will not suffice to fully counter the robust, thermodynamically induced drying. Thus, an increasing risk of severe water shortages is expected. Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.The origins and the early evolution of multicellular animals required the exploitation of holozoan genomic regulatory elements and the acquisition of new regulatory tools. Comparative studies of metazoans and their relatives now allow reconstruction of the evolution of the metazoan regulatory genome, but the deep conservation of many genes has led to varied hypotheses about the morphology of early animals and the extent of developmental co-option. In this Review, I assess the emerging view that the early diversification of animals involved small organisms with diverse cell types, but largely lacking complex developmental patterning, which evolved independently in different bilaterian clades during the Cambrian Explosion. © 2020. Published by The Company of Biologists Ltd.The paraoxonase (PON) family comprises three highly conserved members, PON1, PON2, and PON3. They are orthologs of Caenorhabditis elegans MEC-6, an endoplasmic reticulum resident chaperone that has a critical role in the proper assembly and surface expression of the touch-sensing degenerin channel in nematodes. We have recently shown that both MEC-6 and PON2 negatively regulate functional expression of the epithelial Na+ channel (ENaC), suggesting that the chaperone function is conserved within this family. We hypothesized that other PON family members also modulate ion channel expression. PON3 is specifically expressed in the aldosterone-sensitive distal tubules in the mouse kidney. We found here that knocking down endogenous PON3 in mouse cortical collecting duct cells enhanced Na+&nbsp;transport, which was associated with increased γENaC abundance. We further examined PON3 regulation of ENaC in two heterologous expression systems, Fisher rat thyroid (FRT) cells and Xenopus oocytes. [https://www.selleckchem.com/products/gdc6036.html selleck kinase inhibitor] PON3 co-immunoprecipitated with each of the three ENaC subunits in the FRT cells. As a result of this interaction, both the whole-cell and surface abundance of ENaC α and γ subunits were reduced by PON3. When expressed in oocytes, PON3 inhibited ENaC-mediated amiloride-sensitive Na+ currents, in part by reducing the surface expression of ENaC. In contrast, PON3 did not alter the response of ENaC to chymotrypsin-mediated proteolytic activation or [2- (trimethylammonium)ethyl]methanethiosulfonate (MTSET)-induced activation of αβS518Cγ, suggesting that PON3 does not affect channel open probability. Together, our results suggest that PON3 regulates ENaC expression by inhibiting its biogenesis and/or trafficking. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Tricellular tight junctions (tTJs) create paracellular barriers at tricellular contacts (TCs), where the vertices of three polygonal epithelial cells meet. tTJs are marked by the enrichment of two types of membrane proteins, tricellulin and angulin family proteins. However, how TC geometry is recognized for tTJ formation remains unknown. In the present study, we examined the molecular mechanism for the assembly of angulin-1 at the TCs. We found that clusters of cysteine residues in the juxtamembrane region within the cytoplasmic domain of angulin-1 are highly palmitoylated. Mutagenesis analyses of the cysteine residues in this region revealed that palmitoylation is essential for localization of angulin-1 at TCs. Consistently, suppression of Asp-His-His-Cys motif-containing palmitoyltransferases (DHHCs) expressed in EpH4 cells significantly impaired the TC localization of angulin-1. Cholesterol depletion from the plasma membrane of cultured epithelial cells hampered the localization of angulin-1 at TCs, suggesting the existence of a lipid membrane microdomain at TCs that attract highly palmitoylated angulin-1. Furthermore, the extracellular domain of angulin-1 was also required for its TC localization, irrespective of the intracellular palmitoylation. Taken together, our findings suggest that both angulin-1's extracellular domain and palmitoylation of its cytoplasmic region are required for its assembly at TCs. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Increasing hepatic mitochondrial activity through pyruvate dehydrogenase (PDH) and elevating enterohepatic bile acid recirculation are promising new approaches for metabolic disease therapy, but neither approach alone can completely ameliorate disease phenotype in high fat diet-fed mice.&nbsp; This study showed that diet-induced hepatosteatosis, hyperlipidemia, and insulin resistance can be completely prevented in mice with liver-specific HCLS1-associated protein X-1 (HAX-1) inactivation.&nbsp; Mechanistically, we showed that HAX-1 interacts with inositol 1,4,5-trisphosphate receptor-1 (InsP3R1) in the liver, and its absence reduces InsP3R1 levels thereby improving endoplasmic reticulum (ER)-mitochondria calcium homeostasis to prevent excess calcium overload and mitochondrial dysfunction.&nbsp; As a result, HAX-1 ablation activates PDH and increases mitochondria utilization of glucose and fatty acids to prevent hepatosteatosis, hyperlipidemia and insulin resistance.&nbsp; In contrast to the reduction of InsP3R1 levels, hepatic HAX-1 deficiency increases bile salt exporter protein (BSEP) levels thereby promoting enterohepatic bile acid recirculation, leading to activation of bile acid responsive genes in the intestinal ileum to augment insulin sensitivity, and cholesterol transport genes in the liver to suppress hyperlipidemia.