TREM2 promotes macrophage polarization from M1 to M2 and suppresses osteoarthritis through the NF-κB/CXCL3 axis.

Objective: Osteoarthritis (OA) is the most prominent chronic arthritic disease, affecting over 3 billion people globally. Synovial macrophages, as immune cells, play an essential role in cartilage damage in OA. Therefore, regulating macrophages is crucial for controlling the pathological changes in OA. Triggering receptor expressed on myeloid cells 2 (TREM2), as expressed on immune cell surfaces, such as macrophages and dendritic cells, has suppressed inflammation and regulated M2 macrophage polarization but demonstrated an unknown role in synovial macrophage polarization in OA. This study aimed to investigate TREM2 expression downregulation in OA mice macrophages. Furthermore, the expression trend of TREM2 was associated with polarization-related molecule expression in macrophages of OA mice. Results: We used TREM2 knockout (TREM2-KO) mice to observe that TREM2 deficiency significantly exacerbated the joint inflammation response in OA mice, thereby accelerating disease progression. Separating macrophages and chondrocytes from TREM2-KO mice and co-cultivating them significantly increased chondrocyte apoptosis and inhibited chondrocyte proliferation. Further, TREM2 deficiency also significantly enhanced phosphatidylinositol 3-kinase(PI3K)/AKT signaling pathway activation, increasing nuclear factor kappa light chain enhancer of activated B cells (NF-κB) signaling and C-X-C Motif Chemokine Ligand 3 (CXCL3) expression. Furthermore, NF-κB signaling pathway inhibition significantly suppressed arthritis inflammation in OA mice, thereby effectively alleviating TREM2 deficiency-related adverse effects on chondrocytes. Notably, knocking down CXCL3 of TREM2-KO mice macrophages significantly inhibits inflammatory response and promotes chondrocyte proliferation. Intravenous recombinant TREM2 protein (soluble TREM2, sTREM2) injection markedly promotes macrophage polarization from M1 to M2 and improves the joint tissue pathology and inflammatory response of OA. Conclusion: Our study reveals that TREM2 promotes macrophage polarization from M1 to M2 during OA by NF-κB/CXCL3 axis regulation, thereby improving the pathological state of OA.

CDKN1A regulation on chondrogenic differentiation of human chondrocytes in osteoarthritis through single-cell and bulk sequencing analysis.

Objective: Chondrocyte death is the hallmark of cartilage degeneration during osteoarthritis (OA). However, the specific pathogenesis of cell death in OA chondrocytes has not been elucidated. This study aims to validate the role of CDKN1A, a key programmed cell death (PCD)-related gene, in chondrogenic differentiation using a combination of single-cell and bulk sequencing approaches. Design: OA-related RNA-seq data (GSE114007, GSE55235, GSE152805) were downloaded from Gene Expression Omnibus database. PCD-related genes were obtained from GeneCards database. RNA-seq was performed to annotate the cell types in OA and control samples. Differentially expressed genes (DEGs) among those cell types (scRNA-DEGs) were screened. A nomogram of OA was constructed based on the featured genes, and potential drugs targeting the featured genes were predicted. The presence of key genes was confirmed using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR), Western blot (WB), and immunohistochemistry (IHC). Micromass culture and Alcian blue staining were used to determine the effect of CDKN1A on chondrogenesis. Results: Six cell types, namely HomC, HTC, RepC, preFC, FC, and RegC, were annotated in scRNA-seq data. Five featured genes (JUN, CDKN1A, HMGB2, DDIT3, and DDIT4) were screened by multiple biological information analysis methods. TAXOTERE had the highest ability to dock with DDIT3. Functional analysis indicated that CDKN1A was enriched in processes related to collagen catabolism and acts as a positive regulator of autophagy. Additionally, CDKN1A was found to be associated with several KEGG pathways, including those involved in acute myeloid leukemia and autoimmune thyroid disease. CDKN1A was confirmed down-regulated in the joint tissues of OA mouse model and OA model cell. Inhibiting the expression of CDKN1A can significantly suppress the differentiation of OA chondrocytes. Conclusion: Our findings highlight the critical role of CDKN1A in promoting cartilage formation in both in vivo and in vitro and suggest its potential as a therapeutic target for OA treatment.

Bidirectional Invisible Photoresponse Implemented in a Traps Matrix-Combination toward Fully Optical Artificial Synapses.

Fully optical artificial synapses are crucial hardware for neuromorphic computing, which is very promising to address the future large-scale computing capacity problem. The key characteristic required in a semiconductor device to emulate synaptic potentiation and depression in a fully optical artificial synapse is the bidirectional photoresponse. This work integrates wide-band-gap TiO2 polycrystals and narrow-band-gap PbS quantum dots into a graphene transistor simultaneously, providing the device with both near-ultraviolet and near-infrared photoresponses through the photogating effect. Moreover, the TiO2 serves as a hole-trapping matrix and the PbS as an electron-trapping matrix, which impose opposite effects to the device after photoexcitation, resulting in a photoresponse in the opposite polarity. As a result, the device demonstrates a wavelength-dependent bidirectional photoresponse, which enables it to be utilized as a fully optical artificial synapse. By using near-ultraviolet or near-infrared lights as stimuli, the device successfully mimics synaptic plasticity, including synaptic potentiation/depression, paired-pulse facilitation, and spike-rating-dependent plasticity, as well as the human brain-like transition of short-term memory and long-term memory and learning-experience behavior. This work validates the methodology of combining different trap matrices to achieve the bidirectional photoresponse, which can significantly inspire future research in fully optical artificial synapses.

Dynamic event-triggered adaptive finite-time consensus control for multi-agent systems with time-varying actuator faults.

In this study, the adaptive finite-time leader-following consensus control for multi-agent systems (MASs) subjected to unknown time-varying actuator faults is reported based on dynamic event-triggering mechanism (DETM). Neural networks (NNs) are used to approximate unknown nonlinear functions. Command filter and compensating signal mechanism are introduced to alleviate the computational burden. Unlike the existing methods, by combining adaptive backstepping method with DETM, a novel finite time control strategy is presented, which can compensate the actuator efficiency successfully, reduce the update frequency of the controller and save resources. At the same time, under the proposed strategy, it is guaranteed that all followers can track the trajectory of the leader in the sense that consensus errors converge to a neighborhood of the origin in finite time, and all signals in the closed-loop system are bounded. Finally, the availability of the designed strategy is validated by two simulation results.

Research on the Influence of the Allogeneic Bone Graft in Postoperative Recovery After MOWHTO: A Retrospective Study.

Purpose: To compare the effects of an allogeneic bone graft and a non-filled bone graft on the rate of osteotomy gap union in medial opening wedge high tibial osteotomy (MOWHTO) with an opening width less than 10 mm. Methods: A total of 65 patients undergoing MOWHTO between January 2018 and December 2020 were enrolled in this retrospective study. The patients were divided into two groups: the allograft group (MOWHTO with allogeneic bone grafting, 30 patients) and the non-filling group (MOWHTO without bone void fillers, 35 patients). The clinical outcomes, including the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC), Lysholm score, and post-operative complications, were compared. The radiographic evaluation included changes in hip-knee-ankle angle (HKA), medial proximal tibial angle (MPTA), femorotibial angle (FTA), and weight-bearing line ratio (WBLR) at pre-operation, at two-day post-operation, and the last follow-up. Radiographs were obtained at three, six and twelve months post-surgery, and at the time of the last follow-up to assess the fill area of the osteotomy gap. The union rate of the osteotomy gap was calculated and compared, and risk factors that may affect the rate of osteotomy gap union were also discussed. Results: The rate of osteotomy gap union at 3 and 6 months after the operation in the allograft group was significantly higher compared with the non-filling group (all P<0.05), while no significant difference was found after the 1-year post-operative and at the last follow-up. Also, the WOMAC and Lysholm scores of the allograft group were significantly higher than those of the non-filling group (all P<0.05), and there was no significant difference between the two groups at the last follow-up. Conclusion: Filling the gaps with the allograft bones may accelerate the union of osteotomy gap, improve clinical outcomes, and have important implications for patient rehabilitation in the early post-operative course. Bone grafting did not affect the final rate of osteotomy gap union and the clinical score of patients.

Sacubitril-Valsartan Ameliorates Heart Failure by Inhibiting Cardiac Remodeling Potentially via MAPK/ERK Signaling.

OBJECTIVE: Heart failure (HF) is a syndrome in which the heart pump function is impaired and cardiac output is insufficient to satisfy the basic metabolic need of the whole body. Recently, research has shown that Sacubitril-Valsartan improves cardiac function in cardiovascular diseases. However, the role of Sacubitril-Valsartan in HF deserves a further exploration. METHODS: We established a CHF animal model and an Ang-II-induced cell model. Echocardiography analysis was used to measure cardiac function. Masson's trichrome staining was conducted to analyze collagen deposition. Protein levels were determined by Western blot analysis. RESULTS: Functionally, Sacubitril-Valsartan treatment alleviated cardiac dysfunction, myocardial injury and collagen deposition in vivo. Moreover, Sacubitril-Valsartan treatment inhibited cell apoptosis and collagen production in vitro. Mechanistically, Sacubitril-Valsartan treatment inactivated the MAPK/ERK signaling by suppressing the phosphorylated p38 and ERK protein levels. The final rescue assays demonstrated that activation of MAPK/ERK signaling reversed the effect of Sacubitril-Valsartan on cell apoptosis and collagen deposition. CONCLUSIONS: Sacubitril-Valsartan ameliorated HF by inhibiting cardiac remodeling potentially via MAPK/ERK signaling.

Genetic Variation in VKORC1 and Risk for Osteoporosis.

BACKGROUND AND AIMS: The vitamin K epoxide reductase complex subunit 1 (VKORC1) plays an important role in bone development and bone metabolism by influencing the vitamin K cycle. The aim of this study was to investigate the association between VKORC1 gene polymorphisms and bone mineral density and the risk of osteoporosis. MATERIALS AND METHODS: We determined VKORC1 gene polymorphisms (rs9923231 and rs9934488) by using polymerase chain reaction-restriction and Sanger sequencing method in 606 postmenopausal women including 288 osteoporosis patients and 318 healthy controls. RESULTS: No significant differences were observed in the rs9934488 polymorphisms between the osteoporosis group and controls. Subgroup analyses also indicated no positive result. VKORC1 rs9923231 polymorphism increased the risk of osteoporosis in the homozygous and allelic models. A significant correlation was observed in a subgroup of the elderly (age ≥55 years). Additionally, the genotypes of the rs9923231 polymorphism were significantly associated with low body mass index, and T-score, but not with age, serum calcium, or phosphorus. CONCLUSIONS: In conclusion, VKORC1 rs9923231 polymorphism is a genetic contributor to osteoporosis risk and it should be confirmed in large well-designed studies.

Comparison of Antibacterial Effect of Cationic Peptide LL-37 and Cefalexin on Clinical Staphylococcus aureus-induced Infection after Femur Fracture Fixation.

OBJECTIVE: Antimicrobial peptides are widely present in nature, with many of the antimicrobial peptides having antimicrobial activity against Gram-positive and Gram-negative bacteria, fungi, parasites, and even coated viruses. Internal fixation of fractures is a reliable technique. However, the fracture is difficult to heal and internal fixation is not easy to maintain after infection. This study aims to verify the antibacterial effect of cationic peptide LL-37 on Staphylococcus aureus, explore the anti-biofilm effects of LL-37, and compare the effects of the cationic peptide LL-37 and Cefalexin in treatment of postoperative infection of femoral fracture in vivo. METHODS: The Staphylococcus aureus was clinically isolated from one patient with clinical infection after the fracture fixation at Wuxi 9th People's Hospital. The cationic peptide LL-37 was synthesized by Shanghai Apeptide Co. Ltd. To compare the effects of the cationic peptide LL-37 and Cefalexin in the treatment of postoperative infection of femoral fracture in vivo, 63 rabbits with internal fixation of femoral fractures were inoculated intravenously with clinically isolated pathogenic bacteria suspensions. Rabbits in the treatment groups were treated with peptide LL-37 and Cefalexin after surgery. Rabbits in the control groups were treated with physiological saline after surgery. The biofilms on internal fixtures were harvested from euthanized rabbits 1 h, 12 h, 1 day, 2 days, and 7 days after injection of LL-37, Cefalexin, or saline and calculated by colony count. The biofilms from treatment and control groups at 7 days were analyzed by fluorescence microscopy. Blood samples were collected at 1 h, 12 h, 1 day, 2 days, and 7 days following peptide LL-37 and Cefalexin injection. RESULTS: The results were compared statistically using Student's t-test or two-way analysis of variance (ANOVA). Cationic peptide LL-37 showed significant inhibitory effects on clinically isolated Staphylococcus aureus (P < 0.05) compared with Cefalexin and control group at 1 day (P = 0.021), 2 days (P = 0.019), and 7 days (P = 0.025). Fluorescent images of the biofilm reveal that the numbers of cells on biofilms are far less than those in the Cefalexin and control groups at 7 days. The levels of Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) reached a maximum at 2 days following the operation. After the injection of LL-37, there was an increase in the serum IL-6, TNF-α, and CRP contents in rabbits in both groups, however from 1 day postoperative the level of IL-6 (P = 0.034), TNF-α (P = 0.043), and CRP (P = 0.039) decreased significantly compared to the Cefalexin and control group. At 7 days postoperative, the level of IL-6 (P = 0.029), TNF-α (P = 0.033), and CRP (P = 0.027) had reverted to normal levels in LL-37 groups. CONCLUSIONS: Cationic peptide LL-37 may be a promising agent to control internal femoral fracture fixation infection in vivo.

A Tunneling Dielectric Layer Free Floating Gate Nonvolatile Memory Employing Type-I Core-Shell Quantum Dots as Discrete Charge-Trapping/Tunneling Centers.

A nonvolatile memory with a floating gate structure is fabricated using ZnSe@ZnS core-shell quantum dots as discrete charge-trapping/tunneling centers. Systematical investigation reveals that the spontaneous recovery of the trapped charges in the ZnSe core can be effectively avoided by the type-I energy band structure of the quantum dots. The surface oleic acid ligand surrounding the quantum dots can also play a role of energy barrier to prevent unintentional charge recovery. The device based on the quantum dots demonstrates a large memory window, stable retention, and good endurance. What is more, integrating charge-trapping and tunneling components into one quantum dot, which is solution synthesizable and processible, can largely simplify the processing of the floating gate nonvolatile memory. This research reveals the promising application potential of type-I core-shell nanoparticles as the discrete charge-trapping/tunneling centers in nonvolatile memory in terms of performance, cost, and flexibility.