Logic-Based Strategy for Spatiotemporal Release of Dual Extracellular Vesicles in Osteoarthritis Treatment.

To effectively treat osteoarthritis (OA), the existing inflammation must be reduced before the cartilage damage can be repaired; this cannot be achieved with a single type of extracellular vesicles (EVs). Here, a hydrogel complex with logic-gates function is proposed that can spatiotemporally controlled release two types of EVs: interleukin 10 (IL-10)+ EVs to promote M2 polarization of macrophage, and SRY-box transcription factor 9 (SOX9)+ EVs to increase cartilage matrix synthesis. Following dose-of-action screening, the dual EVs are loaded into a matrix metalloporoteinase 13 (MMP13)-sensitive self-assembled peptide hydrogel (KM13E) and polyethylene glycol diacrylate/gelatin methacryloyl-hydrogel microspheres (PGE), respectively. These materials are mixed to form a "microspheres-in-gel" KM13E@PGE system. In vitro, KM13E@PGE abruptly released IL-10+ EVs after 3 days and slowly released SOX9+ EVs for more than 30 days. In vivo, KM13E@PGE increased the CD206+ M2 macrophage proportion in the synovial tissue and decreased the tumor necrosis factor-α and IL-1ß levels. The aggrecan and SOX9 expressions in the cartilage tissues are significantly elevated following inflammation subsidence. This performance is not achieved using anti-inflammatory or cartilage repair therapy alone. The present study provides an injectable, integrated delivery system with spatiotemporal control release of dual EVs, and may inspire logic-gates strategies for OA treatment.

The optimal performance target of valuation adjustment mechanism agreement with real options perspective.

The valuation adjustment mechanism ('VAM') agreement has recently been widely adopted in venture capital investment in emerging markets. The VAM agreement endows venture capital institutions a contractual right to reevaluate invested startup contingent on preset performance targets, which is crucial for the effectiveness of the VAM agreement by deeply affecting the strategy and fate of the startup. Motivated by exploring a rational performance target setting, this paper: 1)Firstly, extracts a general structure of the VAM agreement by cases analysis;2) Secondly, adopts a real options methodology to derive the option value held by venture capital institutions and how the pre-determined performance target affect the payoff of venture capital institutions;3)Thirdly, derives the expected time to achieve the given performance target and the behavior choice of entrepreneurs of startups; 4)Finally, by maximizing the contractual value of venture capital institutions with the participation constraints of the entrepreneur, derives the optimal performance target setting. The result finds that the option value of the VAM agreement is positively related to the performance target. It may partially explain why venture capital institutions tend to dominate overly high targets from a real options perspective. We also confirm the incentive effect of the VAM agreement that entrepreneurs tend to exert their best effort. Furthermore, the derivation of the optimal performance target shows that it is an increased function of the agreement period and a subtractive function of project risk. This paper contributes to the literature on contingent payment mechanisms and provides practical implications for the VAM agreement design.

Multi-Function of the Ni Interlayer in the Design of a BiVO4-Based Photoanode for Photoelectrochemical Water Splitting.

BiVO4 with an appropriate band structure is considered to be an ideal candidate for photoanodes. However, slow water oxidation kinetics and low charge separation efficiency seriously restrict its application. To address these issues, an NF/N/BVO photoanode with a hierarchical network structure was successfully constructed by direct-current magnetron sputtering of Ni followed by electrochemical deposition of nickel-iron layered double hydroxide (NiFe-LDH) on BiVO4. A photocurrent density of 4.50 mA/cm2 was obtained for NF/N/BVO, which was 2.4 times that for pristine BiVO4. The introduction of the Ni layer contributed to the following growth of NiFe-LDH nanosheets with larger size, which acted as active sites and speeded up water oxidation kinetics. Furthermore, surface photovoltage microscopy revealed that Ni and NiFe-LDH acted as the electron collector and hole reservoir, respectively. The co-existence of the two components constituted a highly efficient surface charge separation structure, which was one of the important issues for the excellent water oxidation activity.

Osteoactivin inhibits dexamethasone-induced osteoporosis through up-regulating integrin ß1 and activate ERK pathway.

BACKGROUNDS: Dexamethasone (Dex) is widely used in autoimmune diseases and inflammation treatment. A sever side effect of prolonged exposure to Dex is increased risk of osteoporosis (OP) or even femoral head necrosis, which would cause much suffer to patients. To reveal the mechanism behind this phenomenon, provide therapeutic guidance and potential target, we analyzed the inhibitory mechanism of Dex on osteogenesis of rat-BMSC. METHODS: Rat BMSC were obtained and characterized with FACS analysis. Osteogenesis and adipogenesis abilities were detected with Oil-O-Red staining, Alizarin Red staining and ALP activity analysis. These BMSC were then treated with Dex in combination with recombinant OA or not and detected for osteogenesis related gene expression with qRT-PCR. Protein interaction and expression were detected by Co-Immunoprecipitation and western blot. RESULTS: Osteoactivin (OA) could promote integrin ß 1 expression and interact with this protein physically, leading to ERK activation and promoting osteogenesis related genes' expression including Runx2, Col1a and OCN in BMSC. Dex, however, could block expression of several upstream genes of OA and decrease OA mRNA and protein level, and eventually suppress integrin ß1-ERK activation and lead to decreased osteogenesis, which could finally develop into OP. CONCLUSION: Recombinant OA treated BMSC exerted better osteogenesis potency even with Dex administration. This is because additional OA in medium counter-acts with Dex's influence and rescued osteoblast differentiation via up-regulating integrin ß1 and activate ERK/MAPK pathway which promotes osteogenesis. Hence, OA/integrin ß1 could serve as potential therapeutic target for OP.