1,668 research outputs found

    Suppression of hypoxia inducible factor-1α (HIF-1α) by YC-1 is dependent on murine double minute 2 (Mdm2)

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    Inhibition of HIF-1α activity provides an important strategy for the treatment of cancer. Recently, 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl indazole (YC-1) has been identified as an anti-HIF-1α drug in cancer therapy with unclear molecular mechanism. In the present study, we aimed to investigate the effect and mechanism of YC-1 on HIF-1α in a hepatocellular carcinoma cell line under hypoxic condition, which was generated by incubating cells with 0.1% O2. The phenotypic and molecular changes of cells were determined by cell proliferation assay, apoptosis assay, luciferase promoter assay, and Western blot analysis. YC-1 arrested tumor cell growth in a dose-dependent manner, whereas it did not induce cell apoptosis. Hypoxia-induced upregulation of HIF-1α was suppressed by YC-1 administration. YC-1 inhibited HIF-1α protein synthesis under normoxia and affected protein stability under hypoxia. YC-1 suppressed the expression of total and phosphorylated forms of murine double minute 2 (Mdm2), whereas this inhibitory effect was blocked by overexpression of Mdm2. In conclusion, YC-1 suppressed both protein synthesis and stability of HIF-1α in HCC cells, and its inhibitory effects on HIF-1α were dependent on Mdm2. © 2006 Elsevier Inc. All rights reserved.postprin

    Public access defibrillation in Hong Kong in 2017

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    Experimental and numerical study on soot formation in laminar diffusion flames of biodiesels and methyl esters

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    Biodiesel and blends with petroleum diesel are promising renewable alternative fuels for engines. In the present study, the soot concentration generated from four biodiesels, two pure methyl esters, and their blends with petroleum diesel are measured in a series of fully pre-vapourised co-flow diffusion flames. The experimental measurements are conducted using planar laser induced-incandescence (LII) and laser extinction optical methods. The results show that the maximum local soot volume fractions of neat biodiesels are 24.4% - 41.2% of pure diesel, whereas the mean soot volume fraction of neat biodiesel cases was measured as 11.3% - 21.3% of pure diesel. The addition of biodiesel to diesel not only reduces the number of inception particles, but also inhibits their surface growth. The discretised population balance modelling of a complete set of soot processes is employed to compute the 2D soot volume fraction and size distribution across the tested flames. The results show that the model also demonstrates a reduction of both soot volume fraction and primary particle size by adding biodiesel fuels. However, it is not possible to clearly determine which factors are responsible for the reduction from the comparison alone. Moreover, analysis of the discrepancies between numerical and experimental results for diesel and low-blending cases offers an insight for the refinement of soot formation modelling of combustion with large-molecule fuels.Bo Tian is supported by the fellowship provided by ZEPI. C. T. Chong is supported by the Newton Advanced Fellowship of the Royal Society (NA160115). Anxiong Liu gratefully acknowledges the financial support of the Chinese Scholarship Council (CSC) and the EPSRC grant No. EP/S012559/1

    MiR-200b/200c/429 subfamily negatively regulates Rho/ROCK signaling pathway to suppress hepatocellular carcinoma metastasis

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    MiR-200 family is an important regulator of epithelial-mesenchymal transition and has been implicated in human carcinogenesis. However, their expression and functions in human cancers remain controversial. In the work presented here, we showed that miR-200 family members were frequently down-regulated in hepatocellular carcinoma (HCC). Although all five members of miR-200 family inhibited ZEB1/2 expression in HCC cell lines, we showed that overexpression only of the miR-200b/200c/429 subfamily, but not the miR-200a/141 subfamily, resulted in impeded HCC cell migration. Further investigations led to the identification of RhoA and ROCK2 as specific down-stream targets of the miR-200b/200c/429 subfamily. We demonstrated that the miR-200b/200c/429 subfamily inhibited HCC cell migration through modulating Rho/ROCK mediated cell cytoskeletal reorganization and cell-substratum adhesion. Re-expression of miR-200b significantly suppressed lung metastasis of HCC cells in an orthotopic liver implantation model in vivo. In conclusion, our findings identified the miR-200b/200c/429 subfamily as metastasis suppressor microRNAs in human HCC and highlighted the functional discrepancy among miR-200 family members.published_or_final_versio

    (De)Constructing a Natural and Flavorful Supersymmetric Standard Model

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    Using the framework of deconstruction, we construct simple, weakly-coupled supersymmetric models that explain the Standard Model flavor hierarchy and produce a flavorful soft spectrum compatible with precision limits. Electroweak symmetry breaking is fully natural; the mu-term is dynamically generated with no B mu-problem and the Higgs mass is easily raised above LEP limits without reliance on large radiative corrections. These models possess the distinctive spectrum of superpartners characteristic of "effective supersymmetry": the third generation superpartners tend to be light, while the rest of the scalars are heavy.Comment: 36 pages, 4 figures ; v2: references added, expanded discussion of FCNC

    Where Does Mediator Bind In Vivo?

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    Background: The Mediator complex associates with RNA polymerase (Pol) II, and it is recruited to enhancer regions by activator proteins under appropriate environmental conditions. However, the issue of Mediator association in yeast cells is controversial. Under optimal growth conditions (YPD medium), we were unable to detect Mediator at essentially any S. cerevisiae promoter region, including those supporting very high levels of transcription. In contrast, whole genome microarray experiments in synthetic complete (SC) medium reported that Mediator associates with many genes at both promoter and coding regions. Principal Findings: As assayed by chromatin immunoprecipitation, we show that there are a small number of Mediator targets in SC medium that are not observed in YPD medium. However, most Mediator targets identified in the genome-wide analysis are false positives that arose for several interrelated reasons: the use of overly lenient cut-offs; artifactual differences in apparent IP efficiencies among different genomic regions in the untagged strain; low fold-enrichments making it difficult to distinguish true Mediator targets from false positives that occur in the absence of the tagged Mediator protein. Lastly, apparent Mediator association in highly active coding regions is due to a non-specific effect on accessibility due to the lack of nucleosomes, not to a specific association of Mediator. Conclusions: These results indicate that Mediator does not bind to numerous sites in the yeast genome, but rathe
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