Supplementary Information 1.Theoretical model for microRNA-based chimeric circuits In microRNA-based chimeric (MBC) circuits, microRNA(miR) molecules bind to the 3' UTR of an mRNA of the target protein in order to form a miR-mRNA complex. As a result, miRs can

The epithelial-mesenchymal transition (EMT) often plays a critical role in cancer metastasis and chemoresistance, and decoding its dynamics is crucial to design effective therapeutics. EMT is regulated at multiple levels -transcriptional, translational, protein stability, and epigenetics; the mechanisms by which epigenetic regulation can alter the dynamics of EMT remain elusive. Here, to identify the possible effects of epigenetic regulation in EMT, we incorporate a feedback term in our previously proposed model of EMT regulation of the miR-200/ZEB/miR-34/SNAIL circuit. This epigenetic feedback that stabilizes long-term transcriptional activity can alter the relative stability and distribution of states in a given cell population, particularly when incorporated in the inhibitory effect on miR-200 from ZEB. This feedback can stabilize the mesenchymal state, thus making transitions out of that state difficult. Conversely, epigenetic regulation of the self-activation of ZEB has only minor effects. Our model predicts that this effect could be seen in experiments, when epithelial cells are treated with an external EMTinducing signal for a sufficiently long period of time and then allowed to recover. Our preliminary experimental data indeed shows that a prolonged TGF-β exposure gives rise to increasing difficult reversion back to the epithelial state. Thus, this integrated theoretical-

The outer membrane vesicle ( OMV ) derived from Porphyromonas gingivalis plays an essential role in causing inflammation which, in turn, plays an important part in the pathogenesis of cardiovascular diseases such as atherosclerosis and thromboembolism. However, the contribution of oral bacteria to vascular calcification is yet to be determined. Here, we evaluated the effect of OMV on vascular smooth muscle cell ( VSMC ) calcification both in vitro and ex vivo . We established a reproducible P. gingivalis OMV ‐induced differentiation and calcification model of VSMC s in vitro . The results indicate that OMV promotes VSMC calcification in a concentration‐dependent manner, modulating the expression of bone markers and SMC markers both on genes and proteins that are important for osteoblastic differentiation and mineralization of VSMC s. We also showed that the key osteogenic transcription factor, runt‐related transcription factor 2 (Runx2), which is affected by upstream extracellular‐regulated kinase ( ERK ) signaling, is a key regulator of OMV ‐induced VSMC differentiation and calcification. Taken together, our research demonstrates that Runx2 is a crucial component of OMV ‐induced calcification of VSMC s, and ERK signaling plays a vital role in mediating Runx2 up‐regulation and VSMC calcification.

Biodegradable polyetherester copolymer (PCL/PEG/PCL, PCEC) was synthesized by ring-opening polymerization of ε-caprolactone initiated by poly(ethylene glycol) (PEG). The PCEC nanoparticles were prepared by solvent diffusion method or w/o/w double emulsion method. The obtained particles' morphology was observed on scanning electron microscopy, and the particle size distribution was determined using Malvern laser particle sizer. Bovine serum albumin was used as the model water-soluble protein drug, which was successfully encapsulated in PCEC nanoparticles, the drug release behavior was studied in detail. The hydrolytic degradation behavior of the PCEC nanoparticles was also studied.