Enterovirus 71 (EV71) is an important pathogen causing death in children under 5 years old worldwide. However, the underlying pathogenesis remains unclear. This study reveals that EV71 infection in rhabdomyosarcoma (RD) and neuroblastoma (SK-N-SH) cells stimulated the autophagic process, which was demonstrated by an increase of punctate GFP-microtubule-associated protein 1 light chain 3 (GFP-LC3), the level of autophagosome-bound LC3-II protein and double-membrane autophagosome formation. EV71-induced autophagy benefited EV71 replication, which was confirmed by the autophagic inducer rapamycin and the inhibitor 3-methyladenine. Signaling pathway investigation revealed that the decreased expression of phosphorylated mTOR and phosphorylated p70S6K is involved in EV71-induced autophagy in a cell-specific manner. The expression of phosphorylated extracellular signal-regulated kinase (Erk) was suppressed consistently in EV71-infected cells. However it did not participate in the autophagic response of the cell. Other signaling pathway molecules, such as Erk, PI3K/Akt, Bcl-2, BNIP3, and Beclin-1 were not affected by infection with EV71. Electron microscopy showed co-localization of autophagosome-like vesicles with either EV71-VP1 or LC3 protein in neurons of the cervical spinal cord in ICR mice infected with EV71. In conclusion, EV71 infection triggered autophagic flux and induced autophagosome formation both in vitro and in vivo. Autophagy induced by EV71 is beneficial for viral replication. Understanding the role of autophagy induced by EV71 in vitro and the formation of autophagosome-like vesicle in vivo provide new insights into the pathogenesis of EV71 infection.

No abstract

No abstract

Supplemental Digital Content is available in the text

-Placement is an important step in the overall IC design process in DSM technologies, as it defines the on-chip interconnects, which have become the bottleneck in determining circuit performance. The rapidly increasing design complexity, combined with the demand for the capability of handling nearly flattened designs for physical hierarchy generation, poses significant challenges to existing placement algorithms. There are very few studies on understanding the optimality and scalability of placement algorithms, due to the limited sizes of existing benchmarks and limited knowledge of optimal solutions. The contribution of this paper includes two parts: 1) We implemented an algorithm for generating synthetic benchmarks that have known optimal wirelengths and can match any given net distribution vector. 2) Using benchmarks of 10K to 2M placeable modules with known optimal solutions, we studied the optimality and scalability of three state-of-the-art placers, Dragon [4], Capo [1], mPL [24] from academia, and one leading edge industrial placer, QPlace [5] from Cadence. For the first time our study reveals the gap between the results produced by these tools versus true optimal solutions. The wirelengths produced by these tools are 1.66 to 2.53 times the optimal in the worst cases, and are 1.46 to 2.38 times the optimal on the average. As for scalability, the average solution quality of each tool deteriorates by an additional 4% to 25% when the problem size increases by a factor of 10. These results indicate significant room for improvement in existing placement algorithms.

A novel series of 7-aroyl-aminoindoline-1-benzenesulfonamides showed excellent activity as inhibitors of tubulin polymerization through binding with the colchicine binding site of microtubules. Compound 15 and 16 display IC50 values of 1.1 and 1.2 microM, respectively. Compound 15 inhibited the human cancer cell growth of KB, MKN45, H460, HT29, and TSGH, as well as one human-resistant cancer line of KB-vin 10, with an IC50 of 9.6, 8.8, 9.4, 8.6, 10.8, and 8.9 nM, respectively.

Abstract-In this paper we study the large-scale mixed-size placement problem where there is a significant size variation between big and small placeable objects (the ratio can be as large as 10,000). We develop a multi-level optimization algorithm, MPG-MS, for this problem which can efficiently handle both large-scale designs and large size variations. Compared with the recently published work [1] on large-scale mixed macro and standard cell placement benchmarks for wirelength minimization, our method can achieve 13% wirelength reduction on average with comparable runtime.

Accumulating evidence has revealed that fucoidan exhibits anti-tumor activities by arresting cell cycle and inducing apoptosis in many types of cancer cells including hepatocellular carcinoma (HCC). Exploring its effect on microRNA expression, we found that fucoidan markedly upregulated miR-29b of human HCC cells. The induction of miR-29b was accompanied with suppression of its downstream target DNMT3B in a dose-dependent manner. The reduction of luciferase activity of DNMT3B 3′-UTR reporter by fucoidan was as markedly as that by miR-29b mimic, indicating that fucoidan induced miR-29b to suppress DNMT3B. Accordingly, the mRNA and protein levels of MTSS1 (metastasis suppressor 1), a target silenced by DNMT3B, were increased after fucoidan treatment. Furthermore, fucoidan also down-regulated TGF-β receptor and Smad signaling of HCC cells. All these effects leaded to the inhibition of EMT (increased E-cadherin and decreased N-cadherin) and prevention of extracellular matrix degradation (increased TIMP-1 and decreased MMP2, 9), by which the invasion activity of HCC cells was diminished. Our results demonstrate the profound effect of fucoidan not only on the regulation of miR-29b-DNMT3B-MTSS1 axis but also on the inhibition of TGF-β signaling in HCC cells, suggesting the potential of using fucoidan as integrative therapeutics against invasion and metastasis of HCC.