Nanomedicines Promote Cartilage Regeneration in Osteoarthritis by Synergistically Enhancing Chondrogenesis of Mesenchymal Stem Cells and Regulating Inflammatory Environment.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of the articular cartilage and inflammation. Mesenchymal stem cells' (MSCs) transplantation in OA treatment is emerging, but its clinical application is still limited by the low efficiency in oriented differentiation. In our study, to improve the therapeutic efficiencies of MSCs in OA treatment by carbonic anhydrase IX (CA9) siRNA (siCA9)-based inflammation regulation and Kartogenin (KGN)-based chondrogenic differentiation, the combination strategy of MSCs and the nanomedicine codelivering KGN and siCA9 (AHK-CaP/siCA9 NPs) was used. In vitro results demonstrated that these NPs could improve the inflammatory microenvironment through repolarization of M1 macrophages to the M2 phenotype by downregulating the expression levels of CA9 mRNA. Meanwhile, these NPs could also enhance the chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating the pro-chondrogenic TGF-ß1, ACAN, and Col2α1 mRNA levels. Moreover, in an advanced OA mouse model, compared with BMSCs alone group, the lower synovitis score and OARSI score were found in the group of BMSCs plus AHK-CaP/siCA9 NPs, suggesting that this combination approach could effectively inhibit synovitis and promote cartilage regeneration in OA progression. Therefore, the synchronization of regulating the inflammatory microenvironment through macrophage reprogramming (CA9 gene silencing) and promoting MSCs oriented differentiation through a chondrogenic agent (KGN) may be a potential strategy to maximize the therapeutic efficiency of MSCs for OA treatment.

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis.

Osteoarthritis (OA) is a progressive joint disease characterized by inflammation and cartilage destruction, and its progression is closely related to imbalances in the M1/M2 synovial macrophages. A two-pronged strategy for the regulation of intracellular/extracellular nitric oxide (NO) and hydrogen protons for reprogramming M1/M2 synovial macrophages is proposed. The combination of carbonic anhydrase IX (CA9) siRNA and NO scavenger in "two-in-one" nanocarriers (NAHA-CaP/siRNA nanoparticles) is developed for progressive OA therapy by scavenging NO and inhibiting CA9 expression in synovial macrophages. In vitro experiments demonstrate that these NPs can significantly scavenge intracellular NO similar to the levels as those in the normal group and downregulate the expression levels of CA9 mRNA (≈90%), thereby repolarizing the M1 macrophages into the M2 phenotype and increasing the expression levels of pro-chondrogenic TGF-ß1 mRNA (≈1.3-fold), and inhibiting chondrocyte apoptosis. Furthermore, in vivo experiments show that the NPs have great anti-inflammation, cartilage protection and repair effects, thereby effectively alleviating OA progression in both monoiodoacetic acid-induced early and late OA mouse models and a surgical destabilization of medial meniscus-induced OA rat model. Therefore, the siCA9 and NO scavenger "two-in-one" delivery system is a potential and efficient strategy for progressive OA treatment.

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The convergent cross mapping (CCM) is a method to analyze causality of nonlinear time series variables. Different from the traditional linear system analysis method, CCM gets historical information based on their state space reconstruction. The presence of causality can be confirmed when the estimated values perform convergent with time series extension. Here, we introduced the develop-ment history of CCM and its advantages over the traditional Granger causality test, and elaborated the principle, algorithm process, and implementation approach. As a system analysis method aiming at the coupling relationship between variables from weak to moderate, CCM can effectively solve the complex causality among nonlinear multivariable in ecosystems. When it is applied to the causality analysis of multi-point time series variables with spatial information, the spatial autocorrelation among points should be fully considered and combined with the method that can remove the spatial correlation between variables and sequences, so as to ensure more accurate causality analysis using CCM and more convincing results.

Enhanced cancer therapeutic efficiency of NO combined with siRNA by caspase-3 responsive polymers.

The combination of nitric oxide (NO) and siRNA is highly desirable for cancer therapy. Here, the furoxans-grafted PEI polymer (FDP) with caspase-3 responsive cleavable DEVD linker was synthesized, and used to bind siRNAs via electrostatic interaction and self-assembled into FDP/siRNA nanoplexes by hydrophobic force. After cellular uptake and lysosomal escape, the FDP/siRNA nanoplexes could achieve GSH-triggered NO release, and then increase the activity of caspase-3. The activated caspase-3 could specifically cleave the DEVD peptide sequence and enhance cell apoptosis. With the cleavage of DEVD peptide sequence, the disassembly of FDP/siRNA nanoplexes was further promoted, thereby resulting in increased siRNAs of ~40% were released at 48 h compared with the caspase-3 non-responsive FDnP/siRNA nanoplexes. By this way, cell apoptosis promotion and cell proliferation inhibition was achieved by siRNA-based downregulation of EGFR protein and the upregulated activity of caspase-3, followed by the enhanced cascade release of NO from FDP/siRNA nanoplexes. Furthermore, in vivo results demonstrated the improved anti-cancer efficiency of FDP/siEGFR nanoplexes without any detectable side effects. Therefore, it is believed that the caspase-3 responsive cleavable furoxans-grafted PEI polymers could provide a potential and efficient enhancement for cancer therapeutic efficiency by the co-delivery of nitric oxide and siRNA.

Advances in joint species distribution models to reveal community structure and its environmental response.

Species distribution models are commonly used in basic and applied ecological research to examine the factors driving the distribution and abundance of organisms. They are employed to quantify species’ relationships with abiotic conditions, to predict species’ response to land-use and climatic change, and to identify potential conservation areas. Biotic interactions have been rarely included in traditional species distribution models, wherein joint species distribution models (JSDMs) emerge as a feasible approach to simultaneously incorporate environmental factors and interspecific interactions, making it a powerful tool for analyzing the structure and assembly of biotic communities. Generally, the JSDMs are based on species distribution models (SDMs), with the abundance or occurrence of multiple species as response variables and environmental factors, species associations and species traits being incorporated in the modeling framework. These models commonly use generalized linear regression methods (GLM) to relate multivariate response to environmental variables, and capture species associations in the form of random effects. The limitation has been overcome by the introduction of latent variable models (LVMs). Typically, the model parameters are estimated using maximum likelihood estimation or Bayesian methods implemented by Laplace Approximation and Markov Chain Monte Carlo (MCMC) simulations, respectively. In this review, the generation and theoretical basis of JSDMs were summarized. The characteristics of different types of JSDMs and their applications in modern ecology were emphatically introduced. The problems and prospects of JSDMs were discussed. With the in-depth study of the relationship between environmental factors and multi-species interactions, JSDMs would be the focus of future studies of species distribution model.

Improved Cell Transfection of siRNA by pH-Responsive Nanomicelles Self-Assembled with mPEG- b-PHis- b-PEI Copolymers.

Here, the novel pH-responsive nanomicelles self-assembled with amphipathic meo-poly(ethylene glycol)- b-poly(l-histidine)- b-polyethylenimine (mPEG- b-PHis- b-PEI, EHE) copolymers based on hydrophobic interaction of PHis with deprotonation of imidazoles were developed for siRNA transfection. The cationic nanomicelles could electrostatically compact siRNA into stable EHE/siRNA nanoplexes with a hydrodynamic diameter of ∼190 nm and present a low toxicity in normal physiological condition (pH ∼ 7.4). Different from pH-irresponsive ECE/siRNA nanoplexes based on mPEG- b-poly(ε-caprolactone)- b-PEI (ECE), the EHE/siRNA nanoplexes exhibited a higher cellular uptake along with an increased ζ-potential (from +18 to +32 mV) when the pH changed from 7.4 to 6.8 (extracellular acidic microenvironments). After cell internalization, the EHE/siRNA nanoplexes also exhibited an enhanced nanostructural disassembling and release of siRNA from lysosomal acidic microenvironments (pH ∼ 5.5). Furthermore, it was demonstrated that the EHE/siEGFR nanoplexes downregulated the expression levels of the corresponding mRNA and protein more efficiently than ECE/siEGFR in HeLa cells. The improved siRNA silencing effects of EHE/siEGFR nanoplexes resulted from the higher cellular uptake and enhanced endosomal/lysosomal escape, which is associated with the pH-responsive disassembly of nanostructure as well as the synergistic "proton sponge" effects of PHis and PEI in EHE copolymers. Therefore, the pH-responsive EHE nanomicelles would be promising and potential carriers for cell transfection of siRNA.

Species-abundance--seed-size patterns within a plant community affected by grazing disturbance.

Seed size has been advanced as a key factor that influences the dynamics of plant communities, but there are few empirical or theoretical predictions of how community dynamics progress based on seed size patterns. Information on the abundance of adults, seedlings, soil seed banks, seed rains, and the seed mass of 96 species was collected in alpine meadows of the Qinghai-Tibetan Plateau (China), which had different levels of grazing disturbance. The relationships between seed-mass-abundance patterns for adults, seedlings, the soil seed bank, and seed rain in the plant community were evaluated using regression models. Results showed that grazing levels affected the relationship between seed size and abundance properties of adult species, seedlings, and the soil seed bank, suggesting that there is a shift in seed-size--species-abundance relationships as a response to the grazing gradient. Grazing had no effect on the pattern of seed-size-seed-rain-abundance at four grazing levels. Grazing also had little effect on the pattern of seed-size--species-abundance and pattern of seed-size--soil-seed-bank-abundance in meadows with no grazing, light grazing, and moderate grazing), but there was a significant negative effect in meadows with heavy grazing. Grazing had little effect on the pattern of seed-size--seedling-abundance with no grazing, but had significant negative effects with light, moderate, and heavy grazing, and the |r| values increased with grazing levels. This indicated that increasing grazing pressure enhanced the advantage of smaller-seeded species in terms of the abundances of adult species, seedlings, and soil seed banks, whereas only the light grazing level promoted the seed rain abundance of larger-seeded species in the plant communities. This study suggests that grazing disturbances are favorable for increasing the species abundance for smaller-seeded species but not for the larger-seeded species in an alpine meadow community. Hence, there is a clear advantage of the smaller-seeded species over the larger-seeded species with increases in the grazing level.