Influence of Low Load Truncation Level on Crack Growth for Al 2324-T39 and Al 7050-T7451

AbstractTests with middle-crack tension (M(T)) specimens made of Al 2324-T39 and Al 7050-T7451 are conducted to investigate the influence of low load truncation level on fatigue crack growth. The six different truncated spectra are obtained by removing the small cycles of which amplitudes are less than the specified percentages of the maximum amplitude in the basic flight-by-flight loading spectrum and the remainder of the spectrum is untouched. The tests indicate that the mean level of fatigue crack growth life (FCGL) increases as the load truncation level is enhanced. Considering both the time saving and the influence on FCGL, there is an applicable choice (i.e. spectrum S2 or spectrum S3 in this investigation) for full scale fatigue test. The scatter of FCGL becomes much larger than that under the basic spectrum when the load truncation level is increased to a specified high level, mainly due to the occurrence of crack slanting and branching under the high level truncated loading spectra

Reciprocal Effects of MiR-122 on Expression of Heme Oxygenase-1 and Hepatitis C Virus Genes in Human Hepatocytes

Background & Aims Heme oxygenase-1 (HO-1) is an antioxidant defense and key cytoprotective enzyme, which is repressed by Bach1. MicroRNA-122 (miR-122) is specifically expressed and highly abundant in human liver and required for replication of hepatitis C virus (HCV) RNA. This study was to assess whether a specific miR-122 antagomir down-regulates HCV protein replication and up-regulates HO-1. Methods We transfected antagomir of miR-122, 2′-O-methyl-mimic miR-122, or non-specific-control antagomir (NSCA) into wild type Huh-7 cells or Huh-7 stably replicating HCV subgenomic core-NS3 (CNS3 replicon cells), or NS3-5B (9–13 replicon cells). Results Antagomir of miR-122 reduced the abundance of HCV-RNA by 64% in CNS3, and by 84% in 9–13 cells. In contrast, transfection with 2′-O-methlyl-mimic miR-122 increased HCV levels up to 2.5-fold; transfection with NSCA did not change the level of HCV. Antagomir of miR-122 also decreased Bach1 and increased HO-1 mRNA levels in CNS3, 9–13, and WT Huh-7 cells. Increasing HO-1 by silencing Bach1 with 50 nM Bach1-siRNA or by treatment with 5 μM cobalt protoporphyrin or heme (known inducers of HO-1) decreased HCV RNA and protein by 50% in HCV replicon cells. Conclusions Down-regulation of HCV replication using an antagomir targeted to miR-122 is effective, specific, and selective. Increasing HO-1, by silencing the Bach1 gene or by treatment with cobalt protoporphyrin or heme, decreases HCV replication. Thus, miR-122 plays an important role in the regulation of HCV replication and HO-1/Bach1 expression in hepatocytes. Down-regulation of miR-122 and up-regulation of HO-1 may be new strategies for anti-HCV intervention and cytoprotection

Joint Synthesis of Safety Certificate and Safe Control Policy using Constrained Reinforcement Learning

Safety is the major consideration in controlling complex dynamical systems using reinforcement learning (RL), where the safety certificate can provide provable safety guarantee. A valid safety certificate is an energy function indicating that safe states are with low energy, and there exists a corresponding safe control policy that allows the energy function to always dissipate. The safety certificate and the safe control policy are closely related to each other and both challenging to synthesize. Therefore, existing learning-based studies treat either of them as prior knowledge to learn the other, which limits their applicability with general unknown dynamics. This paper proposes a novel approach that simultaneously synthesizes the energy-function-based safety certificate and learns the safe control policy with CRL. We do not rely on prior knowledge about either an available model-based controller or a perfect safety certificate. In particular, we formulate a loss function to optimize the safety certificate parameters by minimizing the occurrence of energy increases. By adding this optimization procedure as an outer loop to the Lagrangian-based constrained reinforcement learning (CRL), we jointly update the policy and safety certificate parameters and prove that they will converge to their respective local optima, the optimal safe policy and a valid safety certificate. We evaluate our algorithms on multiple safety-critical benchmark environments. The results show that the proposed algorithm learns provably safe policies with no constraint violation. The validity or feasibility of synthesized safety certificate is also verified numerically.Comment: 24 pages, 8 figures, accepted for oral presentation at L4DC 202

Tissue-specific expression of ALA synthase-1 and heme oxygenase-1 and their expression in livers of rats chronically exposed to ethanol

Abstract5-Aminolevulinic acid synthase-1 (ALAS1) and heme oxygenase-1 (HO-1) are the rate-controlling enzymes for heme biosynthesis and degradation, respectively. Expression of these two genes showed tissue-specific expression pattern at both mRNA and protein levels in selected non-treated rat tissues. In the livers of rats receiving oral ethanol for 10 weeks, ALAS1 mRNA levels were increased by 65%, and the precursor and mature ALAS1 protein levels were increased by 1.8- and 2.3-fold, respectively, while no changes were observed in HO-1 mRNA and protein levels, compared with pair-fed controls. These results provide novel insights into the effects of chronic ethanol consumption on hepatic heme biosynthesis and porphyrias

Zinc Mesoporphyrin Induces Rapid Proteasomal Degradation of Hepatitis C Nonstructural 5A Protein in Human Hepatoma Cells

The nonstructural 5A (NS5A) protein of hepatitis C virus (HCV), plays a critical role in HCV replication and is an attractive target for the therapy of HCV infection. So far, little is known about the post-translational regulation of NS5A protein and its precise role in HCV RNA replication. Our objectives were to elucidate the down-regulation of NS5A protein and HCV RNA replication by zinc mesoporphyrin (ZnMP), and the mechanism by which this process occurs

MicroRNA-196 represses Bach1 protein and hepatitis C virus gene expression in human hepatoma cells expressing hepatitis C viral proteins

Hepatitis C virus (HCV) directly induces oxidative stress and liver injury. Bach1, a zipper (bZip) mammalian transcriptional repressor, negatively regulates heme oxygenase 1 (HMOX1), a key cytoprotective enzyme that has anti-oxidant and anti-inflammatory activities. microRNAs are small non-coding RNAs (~22 nt) that are important regulators of gene expression. Whether and how microRNAs regulate Bach1 or HCV are largely unknown. The aims of this study were to determine whether miR-196 regulates Bach1, HMOX1, and/or HCV gene expression. HCV replicon cell lines (Con1 and 9-13) of the Con1 isolate and J6/JFH1-based HCV cell culture system were used in this study. The effects of miR-196 mimic on Bach1, HMOX1 and HCV RNA and protein levels were measured by qRT-PCR and Western blots, respectively. The Dual Glo™ Luciferase Assay System was used to determine reporter activities. miR-196 mimic significantly down-regulated Bach1 and up-regulated HMOX1 gene expression, and inhibited HCV expression. Dual luciferase reporter assays demonstrated that transfection of miR-196 mimic resulted in a significant decrease in Bach1 3′-UTR-dependent luciferase activity but not in mutant Bach1 3′-UTR-dependent luciferase activity. Moreover, there was no detectable effect of mutant miR-196 on Bach1 3′-UTR-dependent luciferase activity

Inhibition of autophagy by 3-MA enhances IL-24-induced apoptosis in human oral squamous cell carcinoma cells

Abstract Background Interleukin-24(IL-24), also referred to as melanoma differentiation-associated gene-7(mda-7), is a unique member of the IL-10 gene family, which displays nearly ubiquitous cancer-specific toxicity. The most notable feature of IL-24 is selectively induced growth suppression and apoptosis in various cancer cells, with no harmful effects toward normal cells. Autophagy is a self-protective mechanism in many kinds of tumor cells that respond to anticancer treatment. It is reported that autophagy inhibition could enhance the effects of many kinds of anticancer treatments, including gene therapy. However, whether IL-24 is effective to treat oral squamous cell carcinomas (OSCC) and if autophagy inhibition could improve the anticancer effect of IL-24 towards OSCC is has not been detected. Methods MTT assays were carried out to determine the cell proliferation; Transfection was used to gene transfer; Western Blot was performed to detect the protein level of LC3II, P62, Beclin 1, Cleaved caspase-3, β-Tubulin and β-actin; Apoptosis rates and cell cycle alteration were analyzed using flow cytometry; Autophagy induction was confirmed by MDC staining, GFP-LC3 staining and transmission electron microscopy. Amount of IL-24 in the culture medium was quantified by ELISA. Apoptosis in vivo was analyzed by TUNEL assay. HE staining was used to observe the morphology of the samples. Results In the present study, we proved that IL-24 have a novel anticancer effect towards KB cells and that autophagy inhibition could improve the anticancer effect of IL-24. IL-24 treated cells showed autophagy characteristics and autophagy inhibition by 3-methyladenine (3-MA) significantly enhanced IL-24-induced apoptosis. Similar results were obtained in the KB cells xenograft tumor model. Conclusions These results suggest that the combination of autophagy inhibitors and IL-24 based on the AdLTR2EF1α-mediated gene transfer could be a promising way to cure OSCC.http://deepblue.lib.umich.edu/bitstream/2027.42/113230/1/13046_2015_Article_211.pd