Key Points Regional groundwater model for North China Plain integrating most available data Most comprehensive analyses to date of groundwater storage depletion in the NCP Groundwater sustainability under complex hydrologic and socioeconomic conditions

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Lysine crotonylation on histones is a recently identified post-translational modification that has been demonstrated to associate with active promoters and to directly stimulate transcription. Given that crotonyl-CoA is essential for the acyl transfer reaction and it is a metabolic intermediate widely localized within the cell, we postulate that lysine crotonylation on nonhistone proteins could also widely exist. Using specific antibody enrichment followed by high-resolution mass spectrometry analysis, we identified hundreds of crotonylated proteins and lysine residues. Bioinformatics analysis reveals that crotonylated proteins are particularly enriched for nuclear proteins involved in RNA processing, nucleic acid metabolism, chromosome organization, and gene expression. Furthermore, we demonstrate that crotonylation regulates HDAC1 activity, expels HP1α from heterochromatin, and inhibits cell cycle progression through S-phase. Our data thus indicate that lysine crotonylation could occur in a large number of proteins and could have important regulatory roles in multiple nuclei-related cellular processes.

Carbon dioxide reduction reaction (CO2RR) to useful fuels/chemicals such as methane, formic, and methanol, is an innovative way to address looming energy and environmental issues. Graphitic carbon nitride (g-C3N4), as...

Significant advances in regional groundwater flow modeling have been driven by the demand to predict regional impacts of human inferences on groundwater systems and associated environment. The wide availability of powerful computers, user friendly modeling systems and GIS stimulates an exponential growth of regional groundwater modeling. Large scale transient groundwater models have been built to analyze regional flow systems, to simulate water budget components changes, and to optimize groundwater development scenarios. This paper reviews the historical development of regional groundwater modeling. Examples of Death Valley and Great Artesian Basin transient groundwater models are introduced to show the application of large scale regional groundwater flow models. Specific methodologies for regional groundwater flow modeling are descried and special issues in regional groundwater flow modeling are discussed. ª 2011, China University of Geosciences (Beijing) and Peking University. Production and hosting by Elsevier B.V. All rights reserved.

T cells engineered to express CD19-specific chimeric antigen receptors (CARs) have shown breakthrough clinical successes in patients with B-cell lymphoid malignancies. However, similar therapeutic efficacy of CAR T cells in solid tumors is yet to be achieved. In this study we systematically evaluated a series of CAR constructs targeting glypican-3 (GPC3), which is selectively expressed on several solid tumors. We compared GPC3-specific CARs that encoded CD3ζ (Gz) alone or with costimulatory domains derived from CD28 (G28z), 4-1BB (GBBz), or CD28 and 4-1BB (G28BBz). All GPC3-CARs rendered T cells highly cytotoxic to GPC3-positive hepatocellular carcinoma, hepatoblastoma, and malignant rhabdoid tumor cell lines in vitro. GBBz induced the preferential production of Th1 cytokines (interferon γ/granulocyte macrophage colony-stimulating factor) while G28z preferentially induced Th2 cytokines (interleukin-4/interleukin-10). Inclusion of 4-1BB in G28BBz could only partially ameliorate the Th2-polarizing effect of CD28. 4-1BB induced superior expansion of CAR T cells in vitro and in vivo. T cells expressing GPC3-CARs incorporating CD28, 4-1BB, or both induced sustained tumor regressions in two xenogeneic tumor models. Thus, GBBz CAR endows T cells with superior proliferative potential, potent antitumor activity, and a Th1-biased cytokine profile, justifying further clinical development of GBBz CAR for immunotherapy of GPC3-positive solid tumors.

. Hydrogen sulfide reduces serum triglyceride by activating liver autophagy via the AMPK-mTOR pathway. Am J Physiol Endocrinol Metab 309: E925-E935, 2015. First published October 6, 2015; doi:10.1152/ajpendo.00294.2015.-Autophagy plays an important role in liver triglyceride (TG) metabolism. Inhibition of autophagy could reduce the clearance of TG in the liver. Hydrogen sulfide (H2S) is a potent stimulator of autophagic flux. Recent studies showed H2S is protective against hypertriglyceridemia (HTG) and noalcoholic fatty liver disease (NAFLD), while the mechanism remains to be explored. Here, we tested the hypothesis that H2S reduces serum TG level and ameliorates NAFLD by stimulating liver autophagic flux by the AMPK-mTOR pathway. The level of serum H2S in patients with HTG was lower than that of control subjects. Sodium hydrosulfide (NaHS, H2S donor) markedly reduced serum TG levels of male C57BL/6 mice fed a high-fat diet (HFD), which was abolished by coadministration of chloroquine (CQ), an inhibitor of autophagic flux. In HFD mice, administration of NaSH increased the LC3BII-to-LC3BI ratio and decreased the p62 protein level. Meanwhile, NaSH increased the phosphorylation of AMPK and thus reduced the phosphorylation of mTOR in a Western blot study. In cultured LO2 cells, high-fat treatment reduced the ratio of LC3BII to LC3BI and the phosphorylation of AMPK, which were reversed by the coadministration of NaSH. Knockdown of AMPK by siRNA in LO2 cells blocked the autophagic enhancing effects of NaSH. The same qualitative effect was observed in AMPK␣2 Ϫ/Ϫ mice. These results for the first time demonstrated that H2S could reduce serum TG level and ameliorate NAFLD by activating liver autophagy via the AMPKmTOR pathway. hydrogen sulfide; triglyceride; NAFLD; autophagy; AMPK HYPERTRIGLYCERIDEMIA (HTG) is the most common lipid metabolism disorder and is an important independent risk factor for cardiovascular and cerebrovascular diseases (2, 10, 29). The liver plays a cardinal role in lipid metabolism. Increased production and/or decreased clearance of triglyceride (TG) in the liver inevitably results in HTG (13, 30), while TG accumulation in the liver can lead to nonalcoholic fatty liver disease (NAFLD) (40). NAFLD is the most prevalent chronic liver disease in the developed world and is an important risk factor for the development of liver fibrosis and cirrhosis and predisposes to the development of hepatocellular carcinoma (1, 26).Recent research suggests that autophagy participates in the regulation of liver lipid metabolism (5, 33, 34). Autophagy modulates hepatocyte lipid metabolism through lipophagy, which involves sequestration of lipid drops in double-membrane autophagosomes, followed by fusion with lysosomes to form autolysosomes, and subsequent degradation of TG by lipases within the autolysosomes. Reduction of liver cell autophagic activity causes decreased lipolysis and provokes free fatty acid (FFA) ␤-oxidation, resulting in hepatic steatosis and often progresses to NAFLD and HTG (34).AMP-activated pro...

Obstructive sleep apnea (OSA) is closely related to atrial fibrillation (AF). However, the roles and mechanisms of chronic OSA in atrial remodeling are still unclear. Canine model of chronic OSA was simulated by stopping the ventilator and closing the airway for 4 h per day and lasting for 12 weeks. AF inducibility and duration was increased while atrial effective refractory period (AERP) was shortened after chronic apnea. Meanwhile, upregulation of proteins encoding inward rectifier K(+) current (IK1), delayed rectifier K(+) current (IKr and IKs), acetylcholine activated K(+) current (IKACh), transient outward K(+) current (Ito) and ultra-rapid delayed rectifier potassium current (IKur) as well as downregulation of protein encoding L-type Ca(2+) current (ICa,L) were found after chronic OSA. Besides abnormal electrical activity, chronic OSA induced apoptosis and interstitial fibrosis of atrial myocytes, which was partly mediated by caspase 9, phosphorylation of extracellular-regulated kinase 1/2, and α-smooth muscle actin. In addition, atrial sympathetic and parasympathetic hyperinnervation were found manifesting by enhanced growth-associated protein 43, tyrosine hydroxylase and elevated choline acetyltransferase. Moreover, protein expression of β1, β2, and M2 receptor were markedly increased by chronic OSA. In summary, we firstly demonstrated in canine model that chronic OSA could shorten AERP and lead to altered expression of important channel proteins, moreover, induce atrial structure remodeling by increased atrial apoptosis, fibrosis, and autonomic remodeling, eventually promoting the development of a substrate of AF. Our findings suggested that reversing atrial remodeling might be a potential therapeutic strategy for OSA-induced AF.