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Identifying causal relations or causal networks among molecules/genes, rather than just their correlations, is of great importance but challenging in biology and medical field, which is essential for unravelling molecular mechanisms of disease progression and developing effective therapies for disease treatment. However, there is still a lack of high-quality causal inference algorithms for any observed data in contrast to time series data. In this study, we developed a new causal concept for any observed data and its causal inference algorithm built on cross-validated predictability (CVP) can quantify the causal effects among molecules/genes in the whole system. The causality was extensively validated by combining a large variety of statistical simulation experiments and available benchmark data (simulated data and various real data). Combining the predicted causal network and the real benchmark network, the CVP algorithm demonstrates high accuracy and strong robustness in comparison with the mainstream algorithms. In particular, the CVP algorithm is robust in identifying reliable driver genes and network biomarkers from the perspective of network biology, with the prediction results outperforming the mainstream conventional methods for predicting driver genes. CRISPR-Cas9 knockdown experiments in the liver cancer have validated that the functional driver genes identified by the CVP algorithm effectively inhibit the growth and colony formation of liver cancer cells. By knockdown experiments, we demonstrated the accuracy and significance of the causality predicted by CVP and identified the novel regulatory targets of functional driver genes SNRNP200 and RALGAPB in the liver cancer. These inferred causal networks explain regulatory patterns in different biological contexts in a clear sense and provide biological insights into molecular mechanisms of disease progression from a causality perspective.

Background Currently, the reduction and support of comminuted medial cortex of humeral fracture remains a challenge, Therefore, a novel reduction and fixation technique that employs an anteromedial small locking plate was explored in this study, and its viability and the associated complications were assessed. Methods Fifteen cases of proximal humeral fractures with medial instability (five cases were classified as three-part and ten as four-part by Neer classification) were treated by the proposed reduction technique using an anteromedial small locking plate. Subsequently, the radiological and clinical outcomes were evaluated over an average follow-up period of 18.53 months. Results The average operation time was 108 min (range, 70–130 min), and the mean fracture union time in all patients was 12.13 weeks (range, 8–16 weeks). Complications such as infection and neurovascular injury were not observed. Postoperative X-ray showed avascular necrosis and screw penetration in one patient, while screw penetration, varus malunion, or significant reduction loss was not found in the other cases. The mean Constant score was 79.8 (range, 68–92) during the final visit. Conclusions The use of an anteromedial small locking plate improved the reduction efficiency, reconstructed the medial support, and alleviated the occurrence of complications in proximal humeral fractures with medial instability.

Dysfunction of bone marrow mesenchymal stem cells (BMSCs) is recognized critical in bone deteriorations of osteoporosis. However, the specific mechanisms that determine the fate of BMSCs remain elusive. MicroRNA-133a (miR-133a), a highly conserved microRNA, was investigated under both in vitro and in vivo conditions. In the in vitro study, cell proliferation, cell apoptosis, and osteoblast/adipocyte differentiation of BMSCs as a result of overexpression or knockdown of miR-133a was investigated. In the in vivo study, the ovariectomy (OVX) model was applied on mice, with further treatment of the models with BMSC-specific miR-133a antagomir through femur intramedullary injection. Microcomputed tomography scanning and histological analysis of the proximal and middle femur were performed to evaluate the morphological changes. The results revealed that overexpression of miR-133a suppressed cell proliferation, cell viability, and osteoblast differentiation of BMSCs, but increased adipocyte differentiation. We also found that FGFR1, an important upstream regulator of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signal pathway, was a major target of miR-133a. We also recorded that BMSC-specific knockdown of miR-133a attenuates bone loss in OVX mice. Our study suggested that miR-133a played an important role in maintaining the viability and balance between osteoblast and adipocyte differentiation of BMSCs through the MAPK/ERK signaling pathway by targeting FGFR1.

Increasing the fuel mixing performance substantially improves the overall performance of the scramjet engine for a long-distance flight. In this paper, the influence of coaxial injector arrays of hydrogen/air multi-jet on the mixing performance of the fuel in supersonic crossflow is fully investigated. Our main goal is to examine the impacts of air and fuel coaxial injector on fuel distribution and penetration downstream of injectors in different operating conditions. In this study, fuel and air are simultaneously injected through coaxial multi-jet at sonic condition while of free-stream Mach number is 4. Computational Fluid Dynamic is applied for simulation of the transverse coaxial jet at supersonic crossflow. The effect of jet diameter with the same mass flow rate of air and hydrogen on fuel mixing is also investigated. The mixing efficiency of different jet spaces and pressures is also examined to obtain an optimum jet arrangement in the combustor chamber. Our study shows that the injection of the coaxial air/hydrogen jet noticeably improves mixing downstream by augmentation of fuel interaction with an air jet. Our results also show that fuel jet space of 7 Dj offers maximum fuel mixing by the formation of multi vortices with uniform strength.

In this research study, a computational method is applied to examine the impacts of coaxial hybrid air and fuel jets on fuel mixing at the supersonic cross-flow of Mach = 4. This study examined the coaxial air and fuel jet effects on main parameters i. e. circulation, mixing efficiency, and fuel penetration. Computational Fluid Dynamic is employed for the modelling of the coaxial jet at cross supersonic flow. Reynolds Average Navier-Stocks equations with SST turbulence model for achieving hydrodynamic feature of the main model. Impacts of air-jet pressure and nozzle configurations on fuel distribution are also presented and the main effective factors for efficient fuel mixing condition are explained. Our results disclosed that injection of coaxial air and fuel jets at supersonic cross airflow significantly improves the fuel penetration and mixing inside the combustion chamber. Flow study analysis shows that the coaxial injector augments the spiral feature of the fuel jet, which surges fuel mixing downstream. Our circulation analysis confirms that circulation strength increases in far away from an injector by the injection of a coaxial air jet.

Background Dysfunction of mesenchymal stem cells (MSCs) is recognized as critical to the pathogenesis of glucocorticoid-induced osteoporosis (GIO), suggesting the potential of MSC-targeting interventions for this disorder. As the miR-133a has been shown to play an important role in bone metabolism, we hypothesized that miR-133a may also be involved in GIO. Methods In the in vitro study, we examined the effect of miR-133a antagomir on DEX-treated MSCs, including proliferation, apoptosis, osteoblast, and adipocyte differentiation, then, we explored the mechanism of these effects of miR-133a silencing through measuring the phosphorylation of ERK1/2 and its regulator FGFR1 via western blot and qRT-PCR. In the in vivo study, we developed a GIO rat model by injecting methylprednisolone and modulated the miR-133a expression in the femur by intramedullary injection of the miR-133a antagomir, and then micro-CT analyses and histological staining of the femurs were used to investigate the effect of miR-133a silencing on bone loss of the GIO rats. Results qRT-PCR analysis indicated that glucocorticoid induced high miR-133a expression in MSCs and animal models. The in vitro study showed that miR-133a antagomir significantly promoted cell proliferation, viability, and osteoblast differentiation and inhibited adipocyte differentiation in DEX-treated MSCs. Furthermore, the expression of p-ERK1/2 and FGFR1 in DEX-treated MSCs was also upregulated by miR-133a antagomir. Then we investigated the effect of miR-133a silencing on the bone architecture of GIO models, micro-CT analysis showed that miR-133a antagomir attenuated the loss of bone mass and improved the trabecular and cortical parameters induced by methylprednisolone. Histological study showed that miR-133a silencing simultaneously increased bone formation and decreased marrow fat accumulation in GIO rats. Conclusions Our findings suggested that miR-133a is strongly associated with GIO and similar disorders induced by glucocorticoids in MSCs. Silencing miR-133a resulted in positive effects on GC-treated MSCs and on bone loss in GIO animal models. Moreover, the FGFR1-MAPK/ERK signaling may be involved in the protective effect of miR-133a silencing.

Motivation Inferring gene regulatory networks (GRNs) from high-throughput data is an important and challenging problem in systems biology. Although numerous GRN methods have been developed, most have focused on the verification of the specific dataset. However, it is difficult to establish directed topological networks that are both suitable for time-series and non-time-series datasets due to the complexity and diversity of biological networks. Results Here, we proposed a novel method, GNIPLR (Gene networks inference based on projection and lagged regression) to infer GRNs from time-series or non-time-series gene expression data. GNIPLR projected gene data twice using the LASSO projection (LSP) algorithm and the linear projection (LP) approximation to produce a linear and monotonous pseudo-time series, and then determined the direction of regulation in combination with lagged regression analyses. The proposed algorithm was validated using simulated and real biological data. Moreover, we also applied the GNIPLR algorithm to the liver hepatocellular carcinoma (LIHC) and bladder urothelial carcinoma (BLCA) cancer expression datasets. These analyses revealed significantly higher accuracy and AUC values than other popular methods. Availabilityand implementation The GNIPLR tool is freely available at https://github.com/zyllluck/GNIPLR. Supplementary information Supplementary data are available at Bioinformatics online.

Steroid-induced avascular necrosis of the femoral head (SANFH) is a common orthopedic disease. Evidence has shown that microRNAs (miRNAs) played essential roles in the development of SANFH. Nevertheless, the role of miR-576-5p in SANFH remains unknown. The rabbit SANFH models were constructed by injection of horse serum and methylprednisolone. Bone mineral density (BMD) of the proximal femur (including the femoral head), pathological changes, bone cell apoptosis and expressions of OPG/RANK in femoral head bone tissue were assessed upon treatment of up-regulation of miR-576-5p or knockdown of ANXA2. Osteoblasts were extracted from SANFH rabbit femoral head and cultured. Proliferation, apoptosis and mineralization were tested upon treatment of up-regulation of miR-576-5p or knockdown of ANXA2. The targeting relationship between miR-576-5p and ANXA2 was verified. Up-regulated miR-576-5p or down-regulated ANXA2 inhibited the decrease of BMD, improved pathological changes, limited cell apoptosis and increased OPG/RANKL ratio in bone tissues of SANFH rabbits. Up-regulating miR-576-5p or down-regulating ANXA2 promoted proliferation and mineralization and inhibited apoptosis of osteoblasts from SANFH rabbits. In addition, ANXA2 was found to be a target gene of miR-576-5p. Furthermore, overexpression of ANXA2 abolished the protective role of elevated miR-576-5p against femoral head necrosis. Elevated miR-576-5p or reduced ANXA2 repressed the progression of SANFH. This study may provide novel biomarkers for SANFH diagnosis and treatment.

The relevance of circular RNAs (circRNAs) has been indicated in the progression of various diseases. Nevertheless, the precise function of circRNAs in osteoarthritis (OA) remains to be established. Therefore, we aimed to investigate changes in the expression of a specific circRNA, hsa_circ_0134111 (circ_PDE1C) and predict its functions in OA. A rat model of OA was constructed to detect circ_PDE1C expression in knee joint tissues. Subsequently, CHON-001 chondrocytes were treated with IL-1β to mimic OA in vitro. circ_PDE1C was significantly overexpressed in knee cartilage tissues from OA patients relative to amputation patients. Knockdown of circ_PDE1C inhibited extracellular matrix (ECM) degradation and chondrocyte apoptosis. Furthermore, circ_PDE1C could target miR-224-5p, and miR-224-5p expressed poorly in knee cartilage tissues from OA patients. Overexpression of miR-224-5p inhibited ECM degradation and apoptosis in chondrocytes. miR-224-5p also targeted CCL2, which activated the JAK2/STAT signaling pathway, thereby promoting cartilage degradation and exacerbating the symptoms of OA patients. In conclusion, our findings underscore a novel role of circ_PDE1C in OA pathogenesis and suggest that targeting circ_PDE1C/miR-224-5p/CCL2 axis might provide an attractive approach for OA therapy.

Gang Wang, Lecheng Zhang, Chao Yan, Fengbin Wang, Yuelei Zhang Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, 230000, People’s Republic of ChinaCorrespondence: Yuelei ZhangDepartment of Orthopedics, The First Affiliated Hospital of Anhui Medical University, 218 Jixi Road, Hefei, 230000, People’s Republic of ChinaTel/Fax +86-551-62922065Email yuelei.zhang2001@hotmail.comBackground: Postmenopausal osteoporosis is one of the most common types of osteoporosis that women suffer from. Studies involving molecular mechanisms for designing better therapeutic strategies for postmenopausal osteoporosis are still rare. The present study investigates the role of miR-125b in postmenopausal osteoporosis.Methods: Microarray analysis was done to screen the gene database. Tissue samples of postmenopausal women were collected to study the miRNA profiles. MC3T3-E1 cells were used and were submitted for transfection. CCK-8 assay was done to check the viability of cells, whereas toxicity was done by lactate dehydrogenase assay kit. TargetScan was done to target genes of miR-125b followed by confirmation by Luciferase reporter assay. For animal studies a rat model of ovariectomized rats was created. Bone mineral density and biomechanics were measured by densitometer. The mRNA levels were assessed by qRT-PCR and proteins by Western blot assay.Results: miR-125b was over-expressed in human osteoporosis samples. In vitro studies suggested that miR-125b suppressed the cell viability and promoted release of LDH, it also enhanced the RANKL/OPG ratio and suppressed levels of BMP2 and Runx2. Bioinformatics identified TRAF6 as a potential target of miR-125b, further confirmed by luciferase assay, also miR-125b negatively regulated the levels of TRAF6 gene in osteoporosis bones involving the JAK2/STAT3 cascade. In the rat model, miR-125b decreased the bone mineral density and biomechanical parameters in bones by altering the TRAF6 gene involving the JAK2/STAT3 pathway.Conclusion: The outcomes suggested that miR-125b was responsible for the development of postmenopausal osteoporosis and promoted its progression by the TRAF6 gene via the JAK2/STAT3 pathway.Keywords: miR‐125b, osteoporosis, TRAF6, JAK2/STAT3 pathway

To investigate the effectiveness of a modified anteromedial approach in the treatment of ulnar coronoid process fracture.Between February 2017 and July 2018, 15 patients with ulna coronoid process fracture were reviewed. There were 9 males and 6 females, with an average age of 42.3 years (range, 24-60 years). The causes of injury included falling in 10 cases and traffic accidents in 5 cases, all cases were closed injury. According to the O'Driscoll classification, there were 4 cases of type Ⅰ, 6 cases of type Ⅱ, and 5 cases of type Ⅲ. The time from injury to operation was 2-8 days (mean, 3.7 days). All fractures were treated via a modified anteromedial approach between the pronator teres and the flexor carpi radialis plus with partial incision of flexor tendon aponeurosis. The fracture healing, muscle strength of forearm, postoperative complications were observed. At last follow-up, the elbow mobility were measured, the function of elbow was evaluated by Mayo elbow performance score (MEPS).All cases were followed up 10-18 months (mean, 13.3 months). Fracture union was achieved in all patients with a mean time of 10 weeks (range, 8-14 weeks). No obvious decrease of hand grip strength, nerve injury, and infection occurred. One patient had slight heterotopic ossification without special treatment. At last follow-up, all patients had stable elbows with good flexion-extension and varus-valgus stability, the mean flexion was 123.3° (range, 100°-140°), mean extension loss compared with that before operation was 6.7° (range, 0°-20°), mean pronation was 76.0° (range, 60°-85°), and mean supination was 75.8° (range, 55°-90°). The MEPS score was 65-100 (mean, 90.3) with the result of excellent in 10 cases, good in 4 cases, and fair in 1 case.The treatment of ulnar coronoid process fracture via the modified anteromedial approach provides excellent exposure, minimal invasion, fewer complications, and satisfactory prognosis, which is conducive to elbow joint function recovery.探讨肘关节改良前内侧入路治疗尺骨冠状突骨折的临床效果。.2017 年 2 月—2018 年 7 月收治 15 例尺骨冠状突骨折患者。男 9 例，女 6 例；年龄 24～60 岁，平均 42.3 岁。致伤原因：摔伤 10 例，交通事故伤 5 例；均为闭合性损伤。尺骨冠状突骨折按 O’Driscoll 分型标准分型：Ⅰ型 4 例，Ⅱ型 6 例，Ⅲ型 5 例。受伤至手术时间 2～8 d，平均 3.7 d。采用经旋前圆肌和桡侧腕屈肌间隙显露，部分切断屈肌腱腱膜的改良前内侧入路治疗。观察骨折愈合情况以及术后前臂肌力变化、并发症发生情况，末次随访时测量肘关节活动度，采用 Mayo 肘关节评分（MEPS）评估肘关节功能。.15 例患者均获随访，随访时间 10～18 个月，平均 13.3 个月。患者冠状突骨折均愈合，愈合时间 8～14 周，平均 10 周。术后患者手部握力无明显减退，无神经损伤、切口感染等并发症发生。1 例患者出现轻度异位骨化，未作特殊处理。末次随访时，患者肘关节伸屈及内外翻稳定性良好，肘关节活动度为屈曲 100°～140°，平均 123.3°；与术前比较伸直丢失 0°～20°，平均 6.7°；旋前 60°～85°，平均 76.0°；旋后 55°～90°，平均 75.8°。患者 MEPS 评分为 65～100 分，平均 90.3 分；获优 10 例，良 4 例，中 1 例。.采用肘关节改良前内侧入路治疗尺骨冠状突骨折，具有显露充分、创伤小、并发症少等优点，有利于肘关节功能的恢复。.

Background: Tight sandstone reservoirs play an important role in the oil industry. The permeability of tight sandstone reservoir generally has stronger stress sensitivity than that of conventional reservoir because of the latter’s poor physical properties. However, the production analysis of tight sandstone reservoir did not fully considered the stress-sensitive permeability yet. Objective: This paper proposed a production analysis method considering the stress- sensitive permeability. Method: This paper firtstly investigated the stress sensitivity characteristics and the effect of stress-sensitive permeability on a tight reservoir. Decline-type curves that consider stress-sensitive permeability are then established, and a systematic analysis method was built for the production analysis to obtain the single-well controlled dynamic reserves and reservoir physical properties. Results: A field analysis was performed in combination with Block Yuan-284 of Changqing Oilfield. Results show that with the reduction of reservoir pressure, stress sensitivity leads to the decline in reservoir permeability and the increase in seepage resistance, thus reducing the actual single-well controlled reserve and radius. Conclusion: By utilizing the analysis method based on the decline curves, we can effectively predict the single-well controlled dynamic reserves of such reservoirs and evaluate the characteristic parameters of reservoirs.

Vitamin K2 has been demonstrated to promote the osteogenic differentiation of mesenchymal stem cells; however, the mechanisms underlying this effect remain unclear. As microRNA (miR)-133a has been identified as a negative regulator of osteogenic differentiation, the present study hypothesized that vitamin K2 promoted osteogenesis by inhibiting miR-133a. Using human bone marrow stromal cells (hBMSCs) overexpressing miR-133a, or a control, the expression levels of osteogenesis-associated proteins, including runt-related transcription factor 2, alkaline phosphatase and osteocalcin, were analyzed. miR-133a significantly suppressed the osteogenic differentiation of hBMSCs. To determine the effect of vitamin K2 on miR-133a expression and osteogenesis, hBMSCs were treated with vitamin K2. Vitamin K2 inhibited miR-133a expression, which was accompanied by enhanced osteogenic differentiation. Furthermore, the expression levels of vitamin K epoxide reductase complex subunit 1, the key protein in γ-carboxylation, were downregulated by miR-133a overexpression and upregulated by vitamin K2 treatment, indicating a positive feedback on γ-carboxylation. The results of the present study suggested that vitamin K2 targets miR-133a to regulate osteogenesis.

Alcohol is a leading risk factor for osteonecrosis of the femoral head (ONFH). We explored the molecular mechanisms underlying alcohol-induced ONFH and investigated the protective effect of the novel Akt activator SC-79 against this disease. We found that ethanol inhibited expression of the osteogenic genes RUNX2 and OCN, downregulated osteogenic differentiation, impaired the recruitment of Akt to the plasma membrane, and suppressed Akt phosphorylation at Ser473, thereby inhibiting the Akt/GSK3β/β-catenin signaling pathway in bone mesenchymal stem cells. To assess SC-79's ability to counteract the inhibitory effect of ethanol on Akt-Ser73 phosphorylation, we performed micro-computerized tomography and immunofluorescent staining of osteopontin, osteocalcin and collagen type 1 in a rat model of alcohol-induced ONFH. We found that SC-79 injections inhibited alcohol-induced osteonecrosis. These results show that alcohol-induced ONFH is associated with suppression of p-Akt-Ser473 in the Akt/GSK3β/β-catenin signaling pathway in bone mesenchymal stem cells. We propose that SC-79 treatment to rescue Akt activation could be tested in the clinic as a potential therapeutic approach to preventing the development of alcohol-induced ONFH.

Background This study purposed to compare the partial- threaded cannulated screws (PTCS) and the double-threaded cannulated screws (DTCS) in vertical shear femoral neck fractures both clinically and biomechanically. Methods Clinally, the radiographs of 81 patients with Pauwels Ⅲ femoral neck fractures, including 54 fractures fixed with PTCS and 27 fractures fixed with DTCS were analyzed. Complications consist of fixation failure (nail withdrawal, obvious fracture displacement, varus deformity or femoral neck shortening), bony nonunion and avascular necrosis (AVN) were determined. Biomechanically, twenty femur synthetic bones were equally divided and made to a vertical femoral neck fracture model, then fixed with three parallel PTCSs or DTCSs respectively. All specimens were tested for axial stiffness and a maximum load to failure with a loading rate of 2 mm/min. Results Clinically , 22 fractures in the PTCS group experienced fixation failure, including 19 nail withdrawal, 18 femoral neck shortening, 14 varus deformity and 8 obvious fracture displacement; while only 5 fractures showed up with fixation failure in the DTCS group, including 3 nail withdrawal, 4 femoral neck shortening, 4 varus deformity and 1 obvious fracture displacement. Additionally, 11 fractures in the PTCS group had nonunion while only 3 in the DTCS group and 9 fractures with AVN in the PTCS group while only 2 in the DTCS group. Biomechanically, The axial stiffness of DTCS was 152.89±22.74 N/mm, greater than PTCS (134.68±26.61), moreover, the failure load in DTCS was significantly greater than PTCS (1148.11±124.80 vs 795.88±162.50). Conclusion DTCS may exert more advantages than PTCS for vertical femoral neck fractures, including stronger fixation stability, lower rate of fixation failure and nonunion.

Background. The treatment of vertical femoral neck fractures in young patients remains a challenge. This study is aimed at comparing ordinary cannulated compression screw (OCCS) and double-head cannulated compression screw (DhCCS) fixation in vertical femoral neck fractures both clinically and biomechanically. Materials and Methods. Clinically, the radiographs of 81 patients with Pauwel’s III femoral neck fractures, including 54 fractures fixed with three parallel OCCSs and 27 fractures fixed with three parallel DhCCSs, were reviewed retrospectively. Complications consisting of fixation failure (screw loosening, obvious fracture displacement, varus deformity, or femoral neck shortening), bony nonunion, and avascular necrosis (AVN) were determined. Biomechanically, twenty synthetic femur models of vertical femoral fractures with an 80° Pauwel’s angle were divided into two groups and subsequently fixed with three parallel OCCSs or DhCCSs. All specimens were tested for axial stiffness, load to 5 mm displacement, and a maximum load to failure with a loading rate of 2 mm/min. Results. Clinically, 22 fractures in the OCCS group experienced fixation failure, including 19 screw loosening, 18 femoral neck shortening, 14 varus deformities, and 8 obvious fracture displacements, whereas only 4 fractures experienced fixation failure in the DhCCS group, including 3 screw loosening, 3 femoral neck shortening, 3 varus deformities, and 1 obvious fracture displacement. Additionally, 11 fractures in the OCCS group exhibited nonunion, whereas only 3 in the DhCCS group exhibited nonunion. Nine fractures with AVN were noted in the OCCS group, whereas only 1 was observed in the DhCCS group. Biomechanically, the axial stiffness of the DhCCS group was greater than that of the OCCS group ( 154.9 ± 6.81 vs. 128.1 ± 7.41 N/mm), and the load to 5 mm displacement was also significantly greater in the DhCCS group ( 646.1 ± 25.87 vs. 475.8 ± 21.46 N). Moreover, the maximum load to failure in the DhCCS group exhibited significant advantages compared with that of the OCCS group ( 1148 ± 39.47 vs. 795.9 ± 51.39 N). Conclusion. Our results suggested that using three DhCCSs improved the outcome of vertical femoral neck fractures compared to three OCCSs, offering a new choice for the treatment of femoral neck fracture.

OBJECTIVES: Osteoarthritis (OA) is the most common joint disease throughout the world. Exosomes derived from miR-140-5p-overexpressing synovial mesenchymal stem cells (SMSC-140s) may be effective in treating OA. We hypothesized that exosomes derived from SMSC-140 (SMSC-140-Exos) would enhance the proliferation and migration abilities of articular chondrocytes (ACs) without harming extracellular matrix (ECM) secretion. METHODS: SMSCs were transfected with or without miR-140-5p. Exosomes derived from SMSCs or SMSC-140s (SMSC-Exos or SMSC-140-Exos) were isolated and identified. Proliferation, migration and ECM secretion were measured in vitro and compared between groups. The mechanism involving alternative Wnt signalling and activation of Yes-associated protein (YAP) was investigated using lentivirus, oligonucleotides or chemical drugs. The preventative effect of exosomes in vivo was measured using Safranin-O and Fast green staining and immunohistochemical staining. RESULTS: Wnt5a and Wnt5b carried by exosomes activated YAP via the alternative Wnt signalling pathway and enhanced proliferation and migration of chondrocytes with the side-effect of significantly decreasing ECM secretion. Highly-expressed miR-140-5p blocked this side-effect via RalA. SMSC-140-Exos enhanced the proliferation and migration of ACs without damaging ECM secretion in vitro, while in vivo, SMSC-140-Exos successfully prevented OA in a rat model. CONCLUSIONS: These findings highlight the promising potential of SMSC-140-Exos in preventing OA. We first found a potential source of exosomes and studied their merits and shortcomings. Based on our understanding of the molecular mechanism, we overcame the shortcomings by modifying the exosomes. Such exosomes derived from modified cells hold potential as future therapeutic strategies.

Glucocorticoids (GCs) contribute to the increased incidence of secondary osteoporosis and osteonecrosis, and medications for the prevention and treatment of these complications have been investigated for many years. Vitamin K2 (VK2) has been proven to promote bone formation both in vitro and in vivo. In this study, we examined the effects of VK2 on dexamethasone (DEX)-treated MC3T3-E1 osteoblastic cells. We observed that VK2 promoted the proliferation and enhanced the survival of dexamethasone-treated MC3T3-E1 cells. In addition, VK2 upregulated the expression levels of osteogenic marker proteins, such as Runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP) and osteocalcin, which were significantly inhibited by dexamethasone. On the whole, our findings indicate that VK2 has the potential to antagonize the effects of GCs on MC3T3-E1 cells, and may thus prove to be a promising agent for the prevention and treatment of GC-induced osteoporosis and osteonecrosis.

The Large High Altitude Air Shower Observatory (LHAASO) is a hybrid detector array, which will be capable of surveying the north VHE gamma-ray sky from 100 GeV to 1 PeV. The muon detector is a kind of water Cherenkov detector; thus, its optical properties are crucial for construction and understanding of the detector. We designed a series of methods to measure the optical parameters of water and inner layer, and the results from different methods are consistent with each other, which proves the reliability of the measurement results and provides an improved understanding of the detector.