Recent studies have investigated the ability of extracellular vesicles (EVs) in regulating neighboring cells by transferring signaling molecules, such as microRNAs (miRs) in renal fibrosis. EVs released by bone marrow mesenchymal stem cells (BMSCs) contain miR-181d, which may represent a potential therapy for renal fibrosis. miR-181d has been speculated to regulate Krüppel-like factor 6 (KLF6), which activates the nuclear factor-kappa B (NF-κB) signaling pathway. Luciferase assays were performed to confirm the relationship between miR-181d and KLF6. Gain- and loss-of-function studies in vivo and in vitro were performed to assess the effect of BMSC-derived EVs (BMSC-EVs), which contained miR-181d, on KLF6, NF-κB, and renal fibrosis. Transforming growth factor-β (TGF-β)-induced renal tubular epithelial HK-2 cells were treated with EVs derived from BMSCs followed by evaluation of collagen type IV α1 (Col4α1), Collagen I and α-smooth muscle actin (α-SMA) as indicators of the extent of renal fibrosis. Renal fibrosis was induced in rats by unilateral ureteral obstruction (UUO) followed by the subsequent analysis of fibrotic markers. BMSC-EVs had higher miR-181d expression. Overexpression of miR-181d correlated with a decrease in KLF6 expression as well as the levels of IκBα phosphorylation, α-SMA, Col4α1, TGF-βR1 and collagen I in HK-2 cells. In vivo, treatment with miR-181d-containing BMSC-derived EVs was able to restrict the progression of fibrosis in UUO-induced rats. Together, BMSC-EVs suppress fibrosis in vitro and in vivo by delivering miR-181d to neighboring cells, where it targets KLF6 and inhibits the NF-κB signaling pathway.

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IP reuse methodology has been used extensively in SoC (system-on-chip) design. In this reuse methodology, while design and implementation costs are saved, manufacturing cost is not. To further reduce the cost, this reuse concept has been proposed at mask and die level in three-dimensional integrated circuits (3D-IC). In order to achieve manufacturing reuse, in this article, we propose a new methodology for designing a global clock tree in 3D-IC. The objective is to extend an existing clock tree in 2D IC to 3D IC, taking into consideration the wirelength, clock skew, and the number of TSVs. Compared with NNG-and 3D-MMMbased methods, our proposed method reduces the wirelength of the new die and the skew of the global 3D clock tree on average, 5.85% and 2.3%, and 76.92% and 48.7%, respectively. In more than two die design, the average improvements of the wirelength and clock skew of our method as compared with the 3D-MMM-based method are 4.23% and 46.84%, respectively.

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