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Aging-related osteoporosis (OP) is considered a serious public health concern. Approximately 30% of postmenopausal women suffer from OP; more than 40% of them risk fragility fractures. Multiple drugs have been prescribed to treat OP, but they are not ideal because of low cure rates and adverse side effects. miRNA-based gene therapy is a rapidly developing strategy in disease treatment that presents certain advantages, such as large-scale production capability, genetic safety, and rapid effects. miRNA drugs have been used primarily in cancer treatments; they have not yet been reported as candidates for osteoclast-targeted-OP treatment in primates. Their therapeutic efficacy has been limited by several shortcomings, such as low efficiency of selective delivery, insufficient expression levels in targeting cells, and unexpected side effects. Here, we identify miR-141 as a critical suppressor of osteoclastogenesis and bone resorption. The expression levels of miR-141 are positively correlated with BMD and negatively correlated with the aging of bones in both aged rhesus monkeys (Macaca mulatta) and osteoporotic patients. Selective delivery of miR-141 into the osteoclasts of aged rhesus monkeys via a nucleic acid delivery system allowed for a gradual increase in bone mass without significant effects on the health and function of primary organs. Furthermore, we found that the functional mechanism of miR-141 resides in its targeting of two osteoclast differentiation players, Calcr (calcitonin receptors) and EphA2 (ephrin type-A receptor 2 precursor). Our study suggests that miRNAs, such as miR-141, could play a crucial role in suppressing bone resorption in primates and provide reliable experimental evidence for the clinical application of miRNA in OP treatment. © 2018 American Society for Bone and Mineral Research.

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Type 1 diabetes mellitus (T1DM) is an autoimmune insulin-dependent disease associated with destructive bone homeostasis. Accumulating evidence has proven that miRNAs are widely involved in the regulation of bone homeostasis. However, whether miRNAs also regulate osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in T1DM mice is under exploration. In this study, miRNA microarray was utilized to screen the differentially expressed miRNAs, which uncovered that miR-214-3p potentially inhibited BMSCs osteogenic differentiation in T1DM mice. We found that high glucose suppressed BMSCs osteogenic differentiation with significant elevation of the miR-214-3p expression. Further study found that the osteogenic differentiation of BMSCs was inhibited by AgomiR-214-3p while enhanced by AntagomiR-214-3p in BMSCs supplemented with high glucose. Moreover, we found that miR-214-3p knockout T1DM mice were resistant to high-glucose-induced bone loss. These results provide a novel insight into an inhibitory role of high-glucose-induced miR-214-3p in BMSCs osteogenic differentiation both in vitro and in vivo. Molecular studies revealed that miR-214-3p inhibits BMSCs osteogenic differentiation by targeting the 3′-UTR of β-catenin, which was further corroborated in human bone specimens and BMSCs of T1DM patients. Taken together, our study discovered that miR-214-3p is a pivotal regulator of BMSCs osteogenic differentiation in T1DM mice. Our findings also suggest that miR-214-3p could be a potential target in the treatment of bone disorders in patients with T1DM.

This paper proposes a personalized output‐feedback path‐following control strategy for automated vehicles. A personalized path generation approach is created to obtain the expected paths of drivers with different driving styles. Historical driving data and road features are used to calculate the waypoints that characterize driving styles. Then, a robust H∞ output‐feedback controller is designed to follow the generated paths. A solution based on matrix partition is provided to compute the output‐feedback control gains without using the vehicle lateral velocity signal, which facilitates the practical implementation of the designed controller. The proposed driving strategy is validated in CarSim® simulations and scaled car experiments. The results show the personalized paths can match with drivers’ driving styles and can be tracked by the designed output‐feedback path‐following controller.

Many studies have indicated that the expression of interleukin-21 (IL-21) is associated with the pathogenesis of certain liver diseases. However, in alternative animal models of liver diseases, it remains unknown whether the tree shrew could be utilized to analyze the relationship between IL-21 and liver diseases. Here, the phylogenetic tree, sequence alignment and protein structure model of tree shrew and human IL-21 were analyzed using bioinformatics software. A pEGFP-N3/tsIL-21 eukaryotic expression vector of tree shrew IL-21 (tsIL-21) was constructed, and IL-21 expression by the vector-transfected Huh7 cells was evaluated using the newly established quantitative real-time PCR and immunologic protocols for assessing human IL-21. The cytokine profiles were also evaluated in tree shrew spleen lymphocytes induced by recombinant human IL-21 or concanavalin A. It was found that the coding sequence (CDS) of tsIL-21 amplified from spleen lymphocytes belonged to the predicted sequence. The tsIL-21 was closely clustered with primate IL-21 rather than rodent IL-21, and it had an alignment of 83.33% with the human IL-21 nucleotide sequence and 69.93% with the amino acid sequence. The profiles of secondary structure, hydrophobicity and surface charge of tsIL-21 were also similar with those of human IL-21. The tsIL-21 expressed by the vector-transfected Huh7 cells could be identified by their different sources of antibodies against human IL-21, which were all dose-dependent. Recombinant human IL-21 could induce the change of the cytokine profiles of tree shrew spleen lymphocytes, which showed a higher expression of IL-10 and IFN-γ rather than IL-2, IL-4, IL-17, TNF-a and IL-21 during the five-day stimulation. These results indicate that tsIL-21 has a high degree of homology, structural similarity and immunological cross-reactivity with human IL-21 and also confirm the accuracy of this predicted tsIL-21CDS. The protocols utilized in this study will lead to the experimental feasibility of further IL-21-related studies in vivo.

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This paper researches the authentication mechanism of Kerberos protocol under HDFS, and