High hydrostatic pressure stimulates microbial nitrate reduction in hadal trench sediments under oxic conditions.

Hadal trenches are extreme environments situated over 6000 m below sea surface, where enormous hydrostatic pressure affects the biochemical cycling of elements. Recent studies have indicated that hadal trenches may represent a previously overlooked source of fixed nitrogen loss; however, the mechanisms and role of hydrostatic pressure in this process are still being debated. To this end, we investigate the effects of hydrostatic pressure (0.1 to 115 MPa) on the chemical profile, microbial community structure and functions of surface sediments from the Mariana Trench using a Deep Ocean Experimental Simulator supplied with nitrate and oxygen. We observe enhanced denitrification activity at high hydrostatic pressure under oxic conditions, while the anaerobic ammonium oxidation - a previously recognized dominant nitrogen loss pathway - is not detected. Additionally, we further confirm the simultaneous occurrence of nitrate reduction and aerobic respiration using a metatranscriptomic dataset from in situ RNA-fixed sediments in the Mariana Trench. Taken together, our findings demonstrate that hydrostatic pressure can influence microbial contributions to nitrogen cycling and that the hadal trenches are a potential nitrogen loss hotspot. Knowledge of the influence of hydrostatic pressure on anaerobic processes in oxygenated surface sediments can greatly broaden our understanding of element cycling in hadal trenches.

Discovery of a New CDK4/6 and PI3K/AKT Multiple Kinase Inhibitor Aminoquinol for the Treatment of Hepatocellular Carcinoma.

Background: Hepatocellular carcinoma (HCC) is a lethal malignancy lacking effective treatment. The Cyclin-dependent kinases 4/6 (CDK4/6) and PI3K/AKT signal pathways play pivotal roles in carcinogenesis and are promising therapeutic targets for HCC. Here we identified a new CDK4/6 and PI3K/AKT multi-kinase inhibitor for the treatment of HCC. Methods: Using a repurposing and ensemble docking methodology, we screened a library of worldwide approved drugs to identify candidate CDK4/6 inhibitors. By MTT, apoptosis, and flow cytometry analysis, we investigated the effects of candidate drug in reducing cell-viability,inducing apoptosis, and causing cell-cycle arrest. The drug combination and thermal proteomic profiling (TPP) method were used to investigate whether the candidate drug produced antagonistic effect. The in vivo anti-cancer effect was performed in BALB/C nude mice subcutaneously xenografted with Huh7 cells. Results: We demonstrated for the first time that the anti-plasmodium drug aminoquinol is a new CDK4/6 and PI3K/AKT inhibitor. Aminoquinol significantly decreased cell viability, induced apoptosis, increased the percentage of cells in G1 phase. Drug combination screening indicated that aminoquinol could produce antagonistic effect with the PI3K inhibitor LY294002. TPP analysis confirmed that aminoquinol significantly stabilized CDK4, CDK6, PI3K and AKT proteins. Finally, in vivo study in Huh7 cells xenografted nude mice demonstrated that aminoquinol exhibited strong anti-tumor activity, comparable to that of the leading cancer drug 5-fluorouracil with the combination treatment showed the highest therapeutic effect. Conclusion: The present study indicates for the first time the discovery of a new CDK4/6 and PI3K/AKT multi-kinase inhibitor aminoquinol. It could be used alone or as a combination therapeutic strategy for the treatment of HCC.

Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma.

BACKGROUND: Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC). METHODS: We used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC. RESULTS: We identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 µM for QGY7703and 4.04 µM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group. CONCLUSIONS: The present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.

Tsoong induces apoptosis and inhibits proliferation, migration and invasion of pancreatic ductal adenocarcinoma cells.

The roots of Codonopsis cordifolioidea (classified as campanulaceae cordifolioidea), locally known as Tsoong, have been used as a tonic food. The major components isolated from Tsoong have been demonstrated to present anti­human immunodeficiency virus­1 activities and cytotoxicity against various tumor cell lines. However, the possible effects of the novel compound isolated from Tsoong, cordifoliketones A, on pancreatic ductal adenocarcinoma (PDAC) cells, are still unknown. In the present study, cordifoliketones A extractions were prepared from Tsoong, and the possible effects on PDAC cell growth, apoptosis, migration and invasion in vitro and in vivo were exlored. The cytotoxicity assay, apoptosis assay, western blotting, migration and invasion assay, and a PDAC cell (AsPC­1, BxPC­3 and PANC­1) xenograft mice model were employed. The results demonstrated that treatment with cordifoliketones A: i) inhibited proliferation and promoted apoptosis of PDAC cells; ii) significantly induced apoptosis and altered expression of apoptosis­associated proteins in a dose­dependent manner; iii) suppressed migration and invasion of PDAC cells in a dose­dependent manner; and iv) restrained the growth of PDAC neoplasm in nude mice. Furthermore, cordifoliketones A demonstrated non­cytotoxic activity in a panel of normal human cells, including hTERT­HPNE, 293, hepatocyte HL­7702 and HL­1 cells. Therefore, these data indicated that cordifoliketones A may be a potential candidate compound for the prevention of PDAC cell proliferation and metastasis, presumably by induction apoptosis and inhibiting viability, invasion and migration of PDAC cells.

Testing the mantle plume hypothesis: an IODP effort to drill into the Kamchatka-Okhotsk Sea basement.

The great mantle plume debate (GPD) has been going on for ∼15years (Foulger and Natland, 2003; Anderson, 2004; Niu, 2005; Davies, 2005; Foulger, 2005; Campbell, 2005; Campbell and Davies, 2006), centered on whether mantle plumes exist as a result of Earth's cooling or whether their existence is purely required for convenience in explaining certain Earth phenomena (Niu, 2005). Despite the mounting evidence that many of the so-called plumes may be localized melting anomalies, the debate is likely to continue. We recognize that the slow progress of the debate results from communication difficulties. Many debaters may not truly appreciate (1) what the mantle plume hypothesis actually is, and (2) none of the petrological, geochemical and geophysical methods widely used can actually provide smoking-gun evidence for or against mantle plume hypothesis. In this short paper, we clarify these issues, and elaborate a geologically effective approach to test the hypothesis. According to the mantle plume hypothesis, a thermal mantle plume must originate from the thermal boundary layer at the core-mantle boundary (CMB), and a large mantle plume head is required to carry the material from the deep mantle to the surface. The plume head product in ocean basins is the oceanic plateau, which is a lithospheric terrane that is large (1000's km across), thick (>200km), shallow (2-4km high above the surrounding seafloors), buoyant (∼1% less dense than the surrounding lithosphere), and thus must be preserved in the surface geology (Niu et al., 2003). The Hawaiian volcanism has been considered as the surface expression of a type mantle plume, but it does not seem to have a (known) plume head product. If this is true, the Hawaiian mantle plume in particular and the mantle plume hypothesis in general must be questioned. Therefore, whether there is an oceanic plateau-like product for the Hawaiian volcanism is key to testing the mantle plume hypothesis, and the Kamchatka-Okhotsk Sea basement is the best candidate to find out if it is indeed the Hawaiian mantle plume head product or not (Niu et al., 2003; Niu, 2004).

Improved low temperature NH3-SCR performance of FeMnTiO(x) mixed oxide with CTAB-assisted synthesis.

FeMnTiOx mixed oxide is prepared by the CTAB-assisted co-precipitation method, and the transformation of anatase into rutile is inhibited by CTAB to some extent. The catalyst obtained in the present work shows nearly 100% NO conversion at 100-350 °C, more than 80% N2 selectivity at 75-200 °C, and excellent H2O durability for the selective catalytic reduction of NO by NH3 with a space velocity of 30,000 mL g(-1) h(-1).