Gasdermin D maintains bone mass by rewiring the endo-lysosomal pathway of osteoclastic bone resorption.

Gasdermin D (GSDMD)-mediated pyroptosis induces immunogenic cell death and promotes inflammation. However, the functions of GSDMD in tissue homeostasis remain unclear. Here, we identify a physiological function of GSDMD in osteoclasts via a non-lytic p20-generated protein, which prevents bone loss to maintain bone homeostasis. In the late stage of RANKL-induced osteoclastogenesis, GSDMD underwent cleavage, which is dependent on RIPK1 and caspase-8/-3, to yield this p20 product. Gsdmd-deficient osteoclasts showed normal differentiation but enhanced bone resorption with excessive lysosomal activity. Mice with complete or myeloid-specific Gsdmd deletion exhibited increased trabecular bone loss and more severe aging/ovariectomy-induced osteoporosis. GSDMD p20 was preferentially localized to early endosomes and limited endo-lysosomal trafficking and maturation, relying on its oligomerization and control of phosphoinositide conversion by binding to phosphatidylinositol 3-phosphate (PI(3)P). We have thus identified an anti-osteoclastic function of GSDMD as a checkpoint for lysosomal maturation and secretion and linked this to bone homeostasis and endosome-lysosome biology.

Construction and Application of Farmers' Practical Teaching System in Vocational Education Based on Big Data Mining Technology.

With the establishment and perfection of social market economy, China has made changes to the disadvantages of farmers' vocational education system, such as singleness, backward educational means, and backward levels. Compared to traditional forms of farming, problems related to lack of farming expertise, poor scientific and technological awareness, and weak labor skills are analyzed by applying big data mining technology to retrieve key issues in order to establish a professional education system. Data mining can meet the needs of farming knowledge and rapidly develop into an automatic information farming model, which is an effective way to maximize and enhance professional knowledge. The establishment of a professional education system will train most scientific research members and further enhance diversified labor productivity. The experimental summary of this paper is as follows: (1) the relevant data need to be predicted before and after, the predicted experimental data will effectively improve students' grades, which is beneficial to the development of practical teaching, and the pretreatment stage plays a substantial role. (2) Among the three algorithms, the adaptive function of genetic clustering algorithm is obviously better than the other two algorithms, and the adaptive curve is relatively stable. (3) The comprehensive assessment of the course divides students into three categories: poor students, medium students, and excellent students, among which poor students account for 30%, medium students account for 50%, and excellent students account for 20%. (4) The standardization of the education system has brought users a good learning mechanism, in which the teaching resources have been strengthened, and users have very high satisfaction with the evaluation of the whole system.

Role of Education and Mentorship in Entrepreneurial Behavior: Mediating Role of Self-Efficacy.

Farmers have been very precious for societies for ages. Their active experiments, valuable knowledge about their surroundings, environment, and crops' requirements have been a vital part of society. However, the psychological perspectives have been a hole in the loop of farming. Hence, this study has investigated the antecedents of entrepreneurial behaviors of farmers with the mediating risk of their entrepreneurial self-efficacy (ESE). The population chosen for this study was the farming community of suburbs of China, and a sample size of 300 was selected for the data collection. This is a survey study, where a structured questionnaire was adapted on a five-point Likert scale. The data were collected from the farming community to know their psychological and behavioral preferences about their profession. This study has produced interesting results that education, training, and intrinsic motivation play a vital role in farmers' ESE, affecting their entrepreneurial behaviors. This study will add to the body of knowledge and provide an eminent path for emerging entrepreneurs to find more mentorship opportunities to overcome the limitations in upcoming endeavors influencing education and training.

Extracellular matrix scaffold crosslinked with vancomycin for multifunctional antibacterial bone infection therapy.

The treatment of acute and chronic bone infections remains a major clinical challenge. The various factors released by the bacteria, acidic environment, and bacterial colonies in the bone grooves and implanted synthetic materials collectively promote the formation of biofilms. Dormant bacteria and biofilms cause infections that are difficult to cure and that can develop chronically. Therefore, a new antibacterial material was synthesized in the present study for multifunctional bone infection therapy and consists of specific demineralized extracellular cancellous bone (SDECM) crosslinked with vancomycin (Van) by means of electrostatic interactions and chemical bonds. It was verified in vitro that the new material (Van-SDECM) not only has pH-sensitive release and biofilm inhibition properties, but also maintains sustained bactericidal ability accompanied by the degradation of the scaffold, which does not affect its favorable osteogenic performance. The infectious bone defect in vivo model further confirms the comprehensive anti-infective and osteogenic ability of the Van-SDECM. Further, these favorable properties are due to the pH-sensitive sustained release sterilization and scaffold contact antibacterial properties, accompanied by osteoclast activity inhibition, osteogenesis promotion and immunoregulation effects. This study provides a new drug-scaffold composite preparation method based on a native-derived extracellular matrix scaffold.

Smart Nanosacrificial Layer on the Bone Surface Prevents Osteoporosis through Acid-Base Neutralization Regulated Biocascade Effects.

Osteoporosis is a global chronic disease characterized by severe bone loss and high susceptibility to fragile fracture. It is widely accepted that the origin acidified microenvironment created by excessive osteoclasts causes irreversible bone mineral dissolution and organic degradation during osteoclastic resorption. However, current clinically available approaches are mainly developed from the perspective of osteoclast biology rather than the critical acidified niche. Here, we developed a smart "nanosacrificial layer" consisting of sodium bicarbonate (NaHCO3)-containing and tetracycline-functionalized nanoliposomes (NaHCO3-TNLs) that can target bone surfaces and respond to external secreted acidification from osteoclasts, preventing osteoporosis. In vitro and in vivo results prove that this nanosacrificial layer precisely inhibits the initial acidification of osteoclasts and initiates a chemically regulated biocascade to remodel the bone microenvironment and realize bone protection: extracellular acid-base neutralization first inhibits osteoclast function and also promotes its apoptosis, in which the apoptosis-derived extracellular vesicles containing RANK (receptor activator of nuclear factor-κ B) further consume RANKL (RANK ligand) in serum, achieving comprehensive osteoclast inhibition. Our therapeutic strategy for osteoporosis is based on original and precise acid-base neutralization, aiming to reestablish bone homeostasis by using a smart nanosacrificial layer that is able to induce chemically regulated biocascade effects. This study also provides a novel understanding of osteoporosis therapy in biomedicine and clinical treatments.

Periosteal matrix-derived hydrogel promotes bone repair through an early immune regulation coupled with enhanced angio- and osteogenesis.

Bone healing is a complex physiological process initiated by early regulation of the inflammatory immunity and entails multiple events including angiogenesis, osteogenic differentiation, and biomineralization. Here, we fabricated an injectable periosteal extracellular matrix (PEM) hydrogel that dynamically integrates multiple biological functions and, therefore, acts at different stages of the fracture healing process. PEM hydrogels were fully characterized compared with a collagen I hydrogel. The effects of PEM hydrogels on the different phases of the healing process were assessed in vitro. PEM hydrogels induced the recruitment and M2-polarization of macrophages, promoted the differentiation of MSCs into endothelial-like cells, HUVEC tube formation, osteogenic differentiation of primary calvarial osteoblasts and MSCs, and mineralization after being immersed in simulated body fluid. The dynamic and multiphase effects of the hydrogels were evaluated using a rat critical-sized calvarial defect model in vivo. During the early phase of repair, PEM hydrogels facilitated the M1-to-M2 transition of macrophages. As bone repair progressed, PEM hydrogels promoted blood vessel migration, the development of relative larger blood vessels, and functional vascularization. These effects were also verified in a subcutaneous embedding model. Eventually, PEM hydrogels promoted mature bone formation in large bone defects to a greater extent than collagen I hydrogels. These biological effects coordinated well with the natural process of bone regeneration. Thus, PEM hydrogels may serve as promising biomaterials in bone tissue engineering.

Arthroscopic Repair of Chronic Tears of the Anterior Horn of the Lateral Meniscus That Includes Covering the Lesion With an Infrapatellar Pedicle Fat Flap.

This study analyzed the efficacy and safety of arthroscopic outside-in repair of the anterior horn of the lateral meniscus that includes covering the lesion with an infrapatellar pedicle fat flap in patients with chronic tears. This retrospective study reviewed 87 patients with chronic tears of the anterior horn of the lateral meniscus who underwent arthroscopic outside-in repair, which included covering the lesion with an infrapatellar pedicle fat flap (group A, n=45) or not (group B, n=42). The 2 groups were similar in terms of age, sex, body mass index, and disease duration. Patient results were assessed with Tegner, Lysholm, and visual analog scale scores; healing criteria; magnetic resonance imaging; and complication rates. Mean follow-up was 38.2 months. Tegner and Lysholm scores improved postoperatively in both groups (all P<.01) and were similar for the 2 groups (all P>.05). Visual analog scale scores were reduced postoperatively in both groups (P<.01) and similar for the 2 groups (P>.05). Healing rates and complication rates did not differ between the 2 groups (all P>.05), but healing on magnetic resonance imaging was better in group A than group B (P<.05). The repair of chronic tears of the anterior horn of the lateral meniscus can lead to good clinical outcomes and a satisfactory success rate. Covering the repair site with an infrapatellar pedicle fat flap may improve meniscal healing and does not increase the complication rate. [Orthopedics. 2018; 41(3):e360-e364.].

[DIAGNOSIS AND TREATMENT OF ACETABULAR LABRUM INJURY IN PIPKIN FRACTURE].

OBJECTIVE: To observe the characteristics of acetabular labrum injury in Pipkin fractures and the effectiveness of repairing the labrum with suture anchor. METHODS: Between July 2010 and July 2013, 10 cases of Pipkin fractures accompanied by acetabular labrum injury were treated. There were 7 males and 3 females with an average age of 32.5 years (range, 24-56 years). The causes of injury included traffic accident in 8 cases and falling from height in 2 cases. According to the Pipkin classification criteria, there were 6 cases of type II, 2 cases of type III, and 2 cases of type IV. The average interval from injury to operation was 8 days (range, 6-14 days). All the patients underwent open reduction and internal fixation through transtrochanteric approach with trochanteric osteotomy, and repair the labrum with suture anchor. The effectiveness was evaluated according to the Thompson & Epstein scoring scales after operation. RESULTS: All incisions healed primarily without early complication of deep infection or deep vein thrombosis of lower limb. All the cases were followed up 22 months on average (range, 12-48 months). X-ray films showed that all osteotomies and acetabular fractures healed within 3-4 months, femoral head and femoral neck fracture healed within 6-11 months. MRI examinations showed that all repaired acetabular labrums well healed. One case had necrosis of the femoral head at 12 months after operation, and was treated by total hip arthroplasty. According to the Thompson & Epstein scoring scales at last follow-up, the results were excellent in 5 cases, good in 3 cases, fair in 1 case and poor in 1 case, with an excellent and good rate of 80%. CONCLUSION: The diagnosis of acetabular labrum injury can be easily missed during Pipkin fracture, preoperative diagnosis should be combined with hip MRI. Trochanteric osteotomy through transtrochanteric approach , and repairing the labrum with suture anchor can restore the hip function effectively.

[Inhibitory effect of baicalein on the proliferation and invasion of osteosarcoma cells and mechanism].

OBJECTIVE: To explore the effect of baicalein on the proliferation and invasion of osteosarcoma cells and its related mechanism. METHODS: Osteosarcoma MG-63 cells that were cultured in vitro were respectively treated with 20 µL culture medium (control group), dehydrated alcohol (0 µmol/L baicalein group), 100 and 200 µmol/L baicalein solution for 48 hours. Cell proliferation was analyzed by MTT assay. The cell invasion ability was detected using Transwell(TM) invasion assay. The expression of ezrin mRNA was examined by real-time quantitative PCR. The expressions of ezrin protein and p-ezrin protein were measured using Western blotting. Apoptosis index (AI) was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). RESULTS: The inhibitory rates of cell proliferation significantly increased in 100 and 200 µmol/L baicalein groups as compared with 0 µmol/L baicalein group. Moreover, that was higher in 200 µmol/L baicalein group than in 100 µmol/L baicalein group. In comparison with control and 0 µmol/L baicalein groups, the mean cell numbers of permeated membrane and levels of ezrin mRNA, ezrin protein and p-ezrin protein gradually decreased, but AI was gradually elevated with the increase of baicalein concentrations, whereas there was no significant difference in these indicators between 0 µmol/L baicalein group and control group. CONCLUSION: Baicalein can inhibit the proliferation and invasion of osteosarcoma MG-63 cells. The mechanism may be associated with the inhibited expression and activity of ezrin protein and the promoted tumor cell apoptosis.

Interleukin-17A in lipid metabolism and atherosclerosis.

Interleukin-17 (IL-17) A, the most important cytokine of the IL-17 family predominantly secreted by T helper 17 (Th17) cells, plays a critical role in the development of inflammatory diseases. Its receptor is an obligate heterodimer composed of IL-17 receptor (IL-17R) A and C, the main members of the IL-17R family. Binding of IL-17A to the IL-17RA/C complex can activate a variety of downstream signaling pathways such as nuclear factor kappa-B (NF-κB), activator protein 1 (AP1) and CCAAT/enhancer-binding protein (C/EBP) to induce the expression of proinflammatory cytokines and chemokines. IL-17A also promotes mRNA stability. Growing evidence shows that IL-17A is involved in lipid metabolism and the pathogenesis of atherosclerosis, a chronic inflammatory arterial disease driven by both innate and adaptive immune responses to modified lipoproteins. In the current review, we describe recent progress on regulation and signaling of IL-17A, and highlight its impacts on lipid metabolism and atherosclerosis.

Apelin and its receptor APJ in cardiovascular diseases.

Apelin is an adipokine that has been identified as an endogenous ligand for the orphan receptor APJ. Apelin and APJ are expressed in a diverse range of tissues with particular preponderance for the heart and vasculature. Apelin has powerful positive inotropic actions and causes endothelium- and nitric oxide-dependent vasodilatation. Growing evidence shows that apelin/APJ system functions as a critical mediator of cardiovascular homeostasis and is involved in the pathophysiology of cardiovascular diseases. Targeting apelin/APJ axis produces protection against cardiovascular diseases. In the current review we have summarized recent data concerning the role and therapeutic potential of apelin/APJ in several major cardiovascular diseases. An increased understanding of the cardiovascular actions of apelin/APJ system will help to develop novel therapeutic interventions for cardiovascular diseases.