The increasing impact of both climatic change and human activities on global river systems necessitates an increasing need to identify and quantify the various drivers and their impacts on fluvial water and sediment discharge. Here we show that mean Yangtze River water discharge of the first decade after the closing of the Three Gorges Dam (TGD) (2003–2012) was 67 km3/yr (7%) lower than that of the previous 50 years (1950–2002), and 126 km3/yr less compared to the relatively wet period of pre-TGD decade (1993–2002). Most (60–70%) of the decline can be attributed to decreased precipitation, the remainder resulting from construction of reservoirs, improved water-soil conservation and increased water consumption. Mean sediment flux decreased by 71% between 1950–1968 and the post-TGD decade, about half of which occurred prior to the pre-TGD decade. Approximately 30% of the total decline and 65% of the decline since 2003 can be attributed to the TGD, 5% and 14% of these declines to precipitation change, and the remaining to other dams and soil conservation within the drainage basin. These findings highlight the degree to which changes in riverine water and sediment discharge can be related with multiple environmental and anthropogenic factors.

FAM3A belongs to a novel cytokine-like gene family, and its physiological role remains largely unknown. In our study, we found a marked reduction of FAM3A expression in the livers of db/db and high-fat diet (HFD)-induced diabetic mice. Hepatic overexpression of FAM3A markedly attenuated hyperglycemia, insulin resistance, and fatty liver with increased Akt (pAkt) signaling and repressed gluconeogenesis and lipogenesis in the livers of those mice. In contrast, small interfering RNA (siRNA)-mediated knockdown of hepatic FAM3A resulted in hyperglycemia with reduced pAkt levels and increased gluconeogenesis and lipogenesis in the livers of C57BL/6 mice. In vitro study revealed that FAM3A was mainly localized in the mitochondria, where it increases adenosine triphosphate (ATP) production and secretion in cultured hepatocytes. FAM3A activated Akt through the p110a catalytic subunit of PI3K in an insulin-independent manner. Blockade of P2 ATP receptors or downstream phospholipase C (PLC) and IP3R and removal of medium calcium all significantly reduced FAM3A-induced increase in cytosolic free Ca 21 levels and attenuated FAM3A-mediated PI3K/Akt activation. Moreover, FAM3A-induced Akt activation was completely abolished by the inhibition of calmodulin (CaM). Conclusion: FAM3A plays crucial roles in the regulation of glucose and lipid metabolism in the liver, where it activates the PI3K-Akt signaling pathway by way of a Ca 21 /CaM-dependent mechanism. Up-regulating hepatic FAM3A expression may represent an attractive means for the treatment of insulin resistance, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). (HEPATOLOGY 2014;59:1779-1790 T ype 2 diabetes has become one of the most prevalent and debilitating chronic diseases, with a global prevalence 6.4%, affecting about 285 million adults in the year 2010.1 Hepatic insulin resistance and fatty liver play a crucial role in the development and progression of type 2 diabetes. Liver is the key tissue regulating release of glucose into circulation during the fasting state, and hepatic insulin resistance is a decisive factor causing fasting hyperglycemia and type 2 diabetes. The liver is also one of the major organs regulating triglyceride (TG) and cholesterol (CHO) metabolism.2 Hepatic insulin resistance is mainly described as the failure of insulin to repress the expression of gluconeogenic genes through the PI3K/ Akt signaling pathway and is closely associated with the dysregulation of glucose and lipid metabolism in the liver.2 Although the underlying mechanisms remain largely unknown, increasing evidence points to

Rationale Failing cardiomyocytes exhibit decreased efficiency of excitation-contraction (E-C) coupling. The down-regulation of junctophilin-2 (JP2), a protein anchoring the sarcoplasmic reticulum (SR) to T-tubules (TTs), has been identified as a major mechanism underlying the defective E-C coupling. However, the regulatory mechanism of JP2 remains unknown. Objective To determine whether microRNAs regulate JP2 expression. Methods and Results Bioinformatic analysis predicted two potential binding sites of miR-24 in the 3′-untranslated regions of JP2 mRNA. Luciferase assays confirmed that miR-24 suppressed JP2 expression by binding to either of these sites. In the aortic stenosis model, miR-24 was up-regulated in failing cardiomyocytes. Adenovirus-directed over-expression of miR-24 in cardiomyocytes decreased JP2 expression and reduced Ca2+ transient amplitude and E-C coupling gain. Conclusions MiR-24-mediated suppression of JP2 expression provides a novel molecular mechanism for E-C coupling regulation in heart cells, and suggests a new target against heart failure.

Rationale During the transition from compensated hypertrophy to heart failure, the signaling between L-type Ca2+ channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the sarcoplasmic reticulum (SR) becomes defective, partially due to the decreased expression of a TT-SR anchoring protein, junctophilin-2 (JP2). MiR-24, a JP2 suppressing microRNA, is up-regulated in hypertrophied and failing cardiomyocytes. Objective To test whether miR-24 suppression can protect the structural and functional integrity of LCC-RyR signaling in hypertrophied cardiomyocytes. Methods and Results In vivo silencing of miR-24 by a specific antagomir in an aorta-constricted mouse model effectively prevented the degradation of heart contraction but not ventricular hypertrophy. Electrophysiology and confocal imaging studies showed that antagomir treatment prevented the decreases in LCC-RyR signaling fidelity/efficiency and whole-cell Ca2+ transients. Further studies showed that antagomir treatment stabilized JP2 expression and protected the ultrastructure of TT-SR junctions from disruption. Conclusions MiR-24 suppression prevented the transition from compensated hypertrophy to decompensated hypertrophy, providing a potential strategy for early treatment against heart failure.

In the heart, glycosylation is involved in a variety of physiological and pathological processes. Cardiac glycosylation is dynamically regulated, which remains challenging to monitor in vivo. Here we describe a chemical approach for analyzing the dynamic cardiac glycome by metabolically labeling the cardiac glycans with azidosugars in living rats. The azides, serving as a chemical reporter, are chemoselectively conjugated with fluorophores using copper-free click chemistry for glycan imaging; derivatizing azides with affinity tags allows enrichment and proteomic identification of glycosylated cardiac proteins. We demonstrated this methodology by visualization of the cardiac sialylated glycans in intact hearts and identification of more than 200 cardiac proteins modified with sialic acids. We further applied this methodology to investigate the sialylation in hypertrophic hearts. The imaging results revealed an increase of sialic acid biosynthesis upon the induction of cardiac hypertrophy. Quantitative proteomic analysis identified multiple sialylated proteins including neural cell adhesion molecule 1, T-kininogens, and α2-macroglobulin that were upregulated during hypertrophy. The methodology may be further extended to other types of glycosylation, as exemplified by the mucin-type O-linked glycosylation. Our results highlight the applications of metabolic glycan labeling coupled with bioorthogonal chemistry in probing the biosynthesis and function of cardiac glycome during pathophysiological responses.