Fatty acid binding protein 4 (FABP4) induces chondrocyte degeneration via activation of the NF-κb signaling pathway.

The pathogenesis of osteoarthritis (OA) is still unclear. Fatty acid binding protein 4 (FABP4), a novel adipokine, has been found to play a role in OA. This study aimed to explore the role of NF-κB in FABP4-induced OA. In the in vivo study, four pairs of 12-week-old male FABP4 knockout (KO) and wild-type (WT) mice were included. The activation of NF-κB was assessed. In parallel, 24 6-week-old male C57/Bl6 mice were fed a high-fat diet (HFD) and randomly allocated to four groups: daily oral gavage with (1) PBS solution; (2) QNZ (NF-κB-specific inhibitor, 1 mg/kg/d); (3) BMS309403 (FABP4-specific inhibitor, 30 mg/kg/d); and (4) BMS309403 (30 mg/kg/d) + QNZ (1 mg/kg/d). The diet and treatment were sustained for 4 months. The knee joints were obtained to assess cartilage degradation, NF-κB activation, and subchondral bone sclerosis. In the in vitro study, a mouse chondrogenic cell line (ATDC5) was cultured. FABP4 was supplemented to stimulate chondrocytes, and the activation of NF-κB was investigated. In parallel, QNZ and NF-κB-specific siRNA were used to inhibit NF-κB. In vivo, the FABP4 WT mice had more significant NF-κB activation than the KO mice. Dual inhibition of FABP4 and NF-κB alleviated knee OA in mice. FABP4 has no significant effect on the activation of the JNK signaling pathway. In vitro, FABP4 directly activated NF-κB in chondrocytes. The use of QNZ and NF-κB-siRNA significantly alleviated the expression of catabolic markers of chondrocytes induced by FABP4. FABP4 induces chondrocyte degeneration by activating the NF-κB pathway.

TRPV1+ neurons alter Staphylococcus aureus skin infection outcomes by affecting macrophage polarization and neutrophil recruitment.

BACKGROUND: The interaction between the nervous system and the immune system can affect the outcome of a bacterial infection. Staphylococcus aureus skin infection is a common infectious disease, and elucidating the relationship between the nervous system and immune system may help to improve treatment strategies. RESULTS: In this study, we found that the local release of calcitonin gene-related peptide (CGRP) increased during S. aureus skin infection, and S. aureus could promote the release of CGRP from transient receptor potential cation channel subfamily V member 1 (TRPV1+) neurons in vitro. The existence of TRPV1+ neurons inhibited the recruitment of neutrophils to the infected region and regulated the polarization of macrophages toward M2 while inhibiting polarization toward M1. This reduces the level of inflammation in the infected area, which aggravates the local infection. Furthermore, this study demonstrates that TRPV1 may be a target for the treatment of S. aureus skin infections and that botulinum neurotoxin A (BoNT/A) and BIBN4096 may reverse the inhibited inflammatory effect of CGRP, making them potential therapeutics for the treatment of skin infection in S. aureus. CONCLUSIONS: In S. aureus skin infection, TRPV1+ neurons inhibit neutrophil recruitment and regulate macrophage polarization by releasing CGRP. BoNT/A and BIBN4096 may be potential therapeutic agents for S. aureus skin infection.

Detection of rare microorganisms in bone and joint infections by metagenomic next-generation sequencing.

Aims: This aim of this study was to analyze the detection rate of rare pathogens in bone and joint infections (BJIs) using metagenomic next-generation sequencing (mNGS), and the impact of mNGS on clinical diagnosis and treatment. Methods: A retrospective analysis was conducted on 235 patients with BJIs who were treated at our hospital between January 2015 and December 2021. Patients were divided into the no-mNGS group (microbial culture only) and the mNGS group (mNGS testing and microbial culture) based on whether mNGS testing was used or not. Results: A total of 147 patients were included in the no-mNGS group and 88 in the mNGS group. The mNGS group had a higher detection rate of rare pathogens than the no-mNGS group (21.6% vs 10.2%, p = 0.016). However, the mNGS group had lower rates of antibiotic-related complications, shorter hospital stays, and higher infection control rates compared with the no-mNGS group (p = 0.017, p = 0.003, and p = 0.028, respectively), while there was no significant difference in the duration of antibiotic use (p = 0.957). In culture-negative cases, the mNGS group had lower rates of antibiotic-related complications, shorter hospital stays, and a higher infection control rate than the no-mNGS group (p = 0.036, p = 0.033, p = 0.022, respectively), while there was no significant difference in the duration of antibiotic use (p = 0.748). Conclusion: mNGS improves detection of rare pathogens in BJIs. mNGS testing reduces antibiotic-related complications, shortens hospital stay and antibiotic use duration, and improves treatment success rate, benefits which are particularly evident in culture-negative cases.

Wireless Optogenetic Targeting Nociceptors Helps Host Cells Win the Competitive Colonization in Implant-Associated Infections.

The role of nociceptive nerves in modulating immune responses to harmful stimuli via pain or itch induction remains controversial. Compared to conventional surgery, various implant surgeries are more prone to infections even with low bacterial loads. In this study, an optogenetic technique is introduced for selectively activating peripheral nociceptive nerves using a fully implantable, wirelessly rechargeable optogenetic device. By targeting nociceptors in the limbs of awake, freely moving mice, it is found that activation induces anticipatory immunity in the innervated territory and enhances the adhesion of various host cells to the implant surface. This effect mediates acute immune cell-mediated killing of Staphylococcus aureus on implants and enables the host to win "implant surface competition" against Staphylococcus aureus. This finding provides new strategies for preventing and treating implant-associated infections.

COVID-19 and Sinophobia: Detecting Warning Signs of Radicalization on Twitter and Reddit.

Hate crimes and hateful rhetoric targeting individuals of Asian descent have increased since the outbreak of COVID-19. These troubling trends have heightened concerns about the role of the Internet in facilitating radicalization. This article explores the existence of three warning signs of radicalization-fixation, group identification, and energy bursts-using data from Twitter and Reddit. Data were collected before and after the outbreak of COVID-19 to assess the role of the pandemic in affecting social media behavior. Using computational social science and Natural Language Processing techniques, we looked for signs of radicalization targeting China or Chinese individuals. Results show that fixation on the terms China and Chinese increased on Twitter and Reddit after the pandemic began. Moreover, tweets and posts containing either of these terms became more hateful, offensive, and negative after the outbreak. We also found evidence of individuals identifying more closely with a particular group, or adopting an "us vs. them" mentality, after the outbreak of COVID-19. These findings were especially prominent in subreddits catering to self-identified Republicans and Conservatives. Finally, we detected bursts of activity on Twitter and Reddit following the start of the pandemic. These warning signs suggest COVID-19 may have had a radicalizing effect on some social media users. This work is important because it not only shows the potential radicalizing effect of the pandemic, but also demonstrates the ability to detect warning signs of radicalization on social media. This is critical, as detecting warning signs of radicalization can potentially help curb hate-fueled violence.

No genetic causal association between Alzheimer's disease and osteoporosis: A bidirectional two-sample Mendelian randomization study.

Objective: Many observational studies have found an association between Alzheimer's disease (AD) and osteoporosis. However, it is unclear whether there is causal genetic between osteoporosis and AD. Methods: A two-sample Mendelian randomization (MR) study was used to investigate whether there is a causal relationship between osteoporosis and AD. Genes for osteoporosis and AD were obtained from published the genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) with significant genome-wide differences (p < 5 × 10-8) and independent (r 2 < 0.001) were selected, and SNPs with F ≥ 10 were further analyzed. Inverse variance weighted (IVW) was used to assess causality, and the results were reported as odds ratios (ORs). Subsequently, heterogeneity was tested using Cochran's Q test, pleiotropy was tested using the MR-Egger intercept, and leave-one-out sensitivity analysis was performed to assess the robustness of the results. Results: Using the IVW method, MR Egger method, and median-weighted method, we found that the results showed no significant causal effect of osteoporosis at different sites and at different ages on AD, regardless of the removal of potentially pleiotropic SNPs. The results were similar for the opposite direction of causality. These results were confirmed to be reliable and stable by sensitivity analysis. Conclusion: This study found that there is no bidirectional causal relationship between osteoporosis and AD. However, they share similar pathogenesis and pathways.

Investigating the causal relationship between ankylosing spondylitis and osteoporosis in the European population: a bidirectional Mendelian randomization study.

Background: Ankylosing Spondylitis (AS) is an inflammatory condition affecting the spine, which may lead to complications such as osteoporosis (OP). Many observational studies have demonstrated a close relationship with strong evidence between OP and AS. The combination of AS and OP is already an indisputable fact, but the exact mechanism of AS complicated with OP is unclear. To better prevent and treat OP in patients with AS, it is necessary to understand the specific mechanism of OP in these patients. In addition, there is a study showing that OP is a risk factor for AS, but the causal relationship between them is not yet clear. Therefore, we conducted a bidirectional Mendelian randomization (MR) analysis to determine whether there is a direct causal effect between AS and OP and to investigate the co-inherited genetic information between the two. Methods: Bone mineral density (BMD) was used as a phenotype for OP. The AS dataset was taken from the IGAS consortium and included people of European ancestry (9,069 cases and 13,578 controls). BMD datasets were obtained from the GEFOS consortium, a large GWAS meta-analysis study, and the UK Biobank and were categorized based on site (total body (TB): 56,284 cases; lumbar spine (LS): 28,498 cases; femoral neck (FN): 32,735 cases; forearm (FA): 8,143 cases; and heel: 265,627 cases) and age (0-15: 11,807 cases; 15-30: 4,180 cases; 30-45: 10,062 cases; 45-60: 18,062 cases; and over 60: 22,504 cases).To obtain the casual estimates, the inverse variant weighted (IVW) method was mainly used due to its good statistical power and robustness. The presence of heterogeneity was evaluated using Cochran's Q test. Pleiotropy was assessed utilizing MR-Egger regression and MR-pleiotropy residual sum and outlier (MR-PRESSO). Results: Generally, there were no significant causal associations between genetically predicted AS and decreased BMD levels. The results of MR-Egger regression, Weighted Median, and Weighted Mode methods were consistent with those of the IVW method. However, there was a sign of a connection between genetically elevated BMD levels and a decreased risk of AS (Heel-BMD: OR = 0.879, 95% CI: 0.795-0.971, P = 0.012; Total-BMD: OR = 0.948, 95% CI: 0.907-0.990, P = 0.017; LS-BMD: OR = 0.919, 95% CI: 0.861-0.980, P = 0.010). The results were confirmed to be reliable by sensitivity analysis. Conclusion: This MR study found that the causal association between genetic liability to AS and the risk of OP or lower BMD in the European population was not evident, which highlights the second effect (e.g., mechanical reasons such as limited movement) of AS on OP. However, genetically predicted decreased BMD/OP is a risk factor for AS with a causal relationship, implying that patients with OP should be aware of the potential risk of developing AS. Moreover, OP and AS share similar pathogenesis and pathways.

Motor neurons transplantation alleviates neurofibrogenesis during chronic degeneration by reversibly regulating Schwann cells epithelial-mesenchymal transition.

A novel understanding of peripheral nerve injury is epithelial-mesenchymal transition (EMT), which characterizes the process of dedifferentiation and transformation of Schwann cells after nerve injury. Despite being regarded as an important mechanism for healing nerve injuries, long-term EMT is the primary cause of fibrosis in other tissue organs. The potential mechanism promoting neurofibrosis in the process of chronic degeneration of nerve injury and the effects of motor neurons (MNs) transplantation on neurofibrosis and repair of nerve injury were studied by transcriptome sequencing and bioinformatics analysis, which were confirmed by in vivo and in vitro experiments. Even 3 months after nerve injury, the distal nerve maintained high levels of transforming growth factor ß-1 (TGFß-1) and Snail family transcriptional repressor 2 (Snai2). The microenvironment TGFß-1, Snai2 and endogenous TGFß-1 formed a positive feedback loop in vivo and in vitro, which may contribute to the sustained EMT state and neurofibrogenesis in the distal injured nerve. Inhibiting TGFß-1 and Snai2 expression and reversing EMT can be achieved by transferring MNs to distal nerves, and the removal of transplanted MNs is capable of reactivating EMT and promoting the growth of proximal axons. In conclusion, EMT persisting can be an explanation for distal neurofibrosis and a potential therapeutic target. By reversibly regulating EMT, MNs transplantation can alleviate neurofibrogenesis of distal nerve in chronic degeneration.

Diagnostic Role of mNGS in Polymicrobial Periprosthetic Joint Infection.

OBJECTIVES: The purpose of this study was to explore the clinical value of metagenomic next-generation sequencing (mNGS) in the diagnosis of polymicrobial periprosthetic joint infection (PJI). METHODS: Patients with complete data who underwent surgery at our hospital between July 2017 and January 2021 for suspected periprosthetic joint infection (PJI), according to the 2018 ICE diagnostic criteria, were enrolled, and all patients underwent microbial culture and mNGS detection, which were performed on the BGISEQ-500 platform. Microbial cultures were performed on two samples of synovial fluid, six samples of tissue, and two samples of prosthetic sonicate fluid for each patient. The mNGS was performed on 10 tissues, 64 synovial fluid samples, and 17 prosthetic sonicate fluid samples. The results of mNGS testing were based on the interpretation of mNGS results in the previous literature and the assertions of microbiologists and orthopedic surgeons. The diagnostic efficacy of mNGS in polymicrobial PJI was assessed by comparing the results of conventional microbial cultures and mNGS. RESULTS: A total of 91 patients were finally enrolled in this study. The sensitivity, specificity, and accuracy of conventional culture for the diagnosis of PJI were 71.0%, 95.4%, and 76.9%, respectively. The sensitivity, specificity, and accuracy of mNGS for the diagnosis of PJI were 91.3%, 86.3%, and 90.1%, respectively. The sensitivity, specificity, and accuracy of conventional culture for the diagnosis of polymicrobial PJI were 57.1%, 100%, and 91.3%, respectively. mNGS had a sensitivity, specificity, and accuracy of 85.7%, 60.0%, and 65.2%, respectively, for the diagnosis of polymicrobial PJI. CONCLUSIONS: mNGS can improve the diagnosis efficiency of polymicrobial PJI, and the combination of culture and mNGS is a promising method to diagnose polymicrobial PJI.

Dual-Level Knowledge Distillation via Knowledge Alignment and Correlation.

Knowledge distillation (KD) has become a widely used technique for model compression and knowledge transfer. We find that the standard KD method performs the knowledge alignment on an individual sample indirectly via class prototypes and neglects the structural knowledge between different samples, namely, knowledge correlation. Although recent contrastive learning-based distillation methods can be decomposed into knowledge alignment and correlation, their correlation objectives undesirably push apart representations of samples from the same class, leading to inferior distillation results. To improve the distillation performance, in this work, we propose a novel knowledge correlation objective and introduce the dual-level knowledge distillation (DLKD), which explicitly combines knowledge alignment and correlation together instead of using one single contrastive objective. We show that both knowledge alignment and correlation are necessary to improve the distillation performance. In particular, knowledge correlation can serve as an effective regularization to learn generalized representations. The proposed DLKD is task-agnostic and model-agnostic, and enables effective knowledge transfer from supervised or self-supervised pretrained teachers to students. Experiments show that DLKD outperforms other state-of-the-art methods on a large number of experimental settings including: 1) pretraining strategies; 2) network architectures; 3) datasets; and 4) tasks.

Reduction with Pre-Drilling Combined with a Finger Reduction Tool in Difficult-to-Reduce Intertrochanteric Fracture.

OBJECTIVE: To investigate the feasibility of pre-drilling combined with a finger reduction tool for the reduction of difficult-to-reduce intertrochanteric fractures. METHODS: Patients diagnosed with complicated intertrochanteric fractures during the period from July 2016 to May 2021 at the Affiliated Hospital of our College were enrolled in this study. All patients underwent reduction by pre-drilling combined with a finger reduction tool followed by fixing with proximal femoral nail antirotation. The outcome of reduction was evaluated by intraoperative fluoroscopy. The operation time, intraoperative fluoroscopy frequency, and incidence of postoperative complications (including infection in the incision area, coxa vara, nail withdrawal, nail breakage, blade cut-out, lower limb vein thrombosis, and pulmonary embolism) were recorded to evaluate the speed of the operation, the difficulty of the operation, and the prognosis of the patient, respectively. The Harris hip score at 9 months after surgery was used to evaluate the hip recovery. RESULTS: A total of 52 patients (17 men and 35 women), 61-88 (77.54 ± 7.40) years of age were included in the study. There were 14 patients with cardiovascular or cerebrovascular disease, ten patients with diabetes, three patients with Parkinson's disease, and three patients with respiratory diseases. The fractures included in the study were classified according to the Orthopedic Trauma Association 31 classification system as type A2.2 (n = 36) or type A2.3 (n = 16). The time from injury to surgery was 1-11 (3.35 ± 1.78) days, and the operation time ranged 31-101 (65.67 ± 14.17) min. The intraoperative blood loss ranged from 40 to 100 (67.69 ± 18.24) mL, and the number of intraoperative fluoroscopy images obtained was 12 to 32 (20.42 ± 5.27). The Harris hip score at 9 months after surgery ranged from 84 to 94 (90.06 ± 2.15). Patients were followed for 9-16 (10.63 ± 1.61) months. One patient died of acute myocardial infarction at 9 months after surgery. One patient suffered from nail withdrawal 5 months post-operation and thus underwent hemiarthroplasty. CONCLUSIONS: Satisfactory reduction can be achieved using a pre-drilling femoral trochanter combined with a finger reduction tool for the management of difficult-to-reduce complex intertrochanteric fractures. This technique does not increase surgical trauma and also reduces the dose of radiation administered to the patient.

Intraoperative method of femoral head central measurement to prevent leg length discrepancy following hemiarthroplasty.

Purpose: This study aimed to introduce and investigate the safety and efficiency of the intraoperative central measurement method of the femoral head (IM-CMFH) to prevent leg length discrepancies (LLD) after hemiarthroplasty. Methods: Overall, 79 patients aged 75 to 85 years with femoral neck fractures who underwent hemiarthroplasty were divided into two groups: the Control group (n = 46) and the IM-CMFH group (n = 33). The two groups were compared for postoperative LLD and the proportions of patients with greater than 10 mm, 6-10 mm, and within 5 mm, postoperative femoral offset (FO) difference and the proportions of patients within 5 mm, incremental greater than 5 mm and reduction greater than 5 mm. Next, the vertical distance from the center of the femoral head to the tip of the greater trochanter on the anatomical axis of the femur (VD-CFH-TGTAAF), leg length, and FO on the operative and non-operative sides within the IM-CMFH group. Finally, operative time, hemoglobin loss, Harris scores 3 months after surgery, and postoperative complications were analyzed. Results: Compared with the control group, the postoperative LLD and FO differences were significantly lower in the IM-CMFH group (P = 0.031; P = 0.012), and the proportion of patients with postoperative LLD greater than 10 mm decreased significantly (P = 0.041), while the proportion of patients with FO difference of within 5 mm increased (P = 0.009). In addition, there was no significant difference in the operative time, hemoglobin loss, and Harris score at 3 months postoperatively and postoperative complications between the two groups (P > 0.05). There was no significant difference in FO, leg-length, and VD-CFH-TGTAAF between the operative and non-operative sides within the IM-CMFH group (P > 0.05). Conclusion: Satisfactory results can be achieved by using the IM-CMFH to prevent LLD following hemiarthroplasty, and there is no increase in operative time, hemoglobin loss, or postoperative complications. This technique is efficient for hemiarthroplasties and is both simple and convenient.

The causal relationship between obesity and skin and soft tissue infections: A two-sample Mendelian randomization study.

Objective: Many observational studies have shown that obesity strongly affects skin and soft tissue infections (SSTIs). However, whether a causal genetic relationship exists between obesity and SSTIs is unclear. Methods: A two-sample Mendelian randomization (MR) study was used to explore whether obesity is causally associated with SSTIs using a publicly released genome-wide association study (GWAS). An inverse-variance weighted (IVW) analysis was used as the primary analysis, and the results are reported as the odds ratios (ORs). Heterogeneity was tested using Cochran's Q test and the I2 statistic, and horizontal pleiotropy was tested using the MR-Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO). Results: The results of the MR analysis showed a positive effect of BMI on SSTIs (OR 1.544, 95% CI 1.399-1.704, P= 5.86 × 10-18). After adjusting for the effect of type 2 diabetes (T2D) and peripheral vascular disease (PVD), the positive effect still existed. Then, we further assessed the effect of BMI on different types of SSTIs. The results showed that BMI caused an increased risk of impetigo, cutaneous abscess, furuncle and carbuncle, cellulitis, pilonidal cyst, and other local infections of skin and subcutaneous tissues, except for acute lymphadenitis. However, the associations disappeared after adjusting for the effect of T2D and PVD, and the associations between BMI and impetigo or cellulitis disappeared. Finally, we assessed the effects of several obesity-related characteristics on SSTIs. Waist circumference, hip circumference, body fat percentage, and whole-body fat mass, excluding waist-to-hip ratio, had a causal effect on an increased risk of SSTIs. However, the associations disappeared after adjusting for the effect of BMI. Conclusion: This study found that obesity had a positive causal effect on SSTIs. Reasonable weight control is a possible way to reduce the occurrence of SSTIs, especially in patients undergoing surgery.

Covalent Functionalization of Nanodiamonds with Natural Amino Acids and Ascorbic Acids.

Nanodiamonds have gained considerable attention nowadays owing to their excellent properties and various applications especially in biomedical field. Nevertheless, the tendency of agglomeration limits further wide applications of nanodiamonds. A biological method was conducted to graft natural amino acids and ascorbic acid on the surface of nanodiamonds. The results of Fourier transform infrared, Raman spectra, Thermogravimetric analysis and X-ray photoelectron spectroscopy indicate that the biomolecules were covalently boned on the nanodiamonds surface. Moreover, dynamic light scattering particle size analyzer and Transmission electron microscopic were conducted to investigate the particle size and morphology of surface modified nanodiamonds, which implies that nanodiamonds functionalized by biomolecules present smaller particle size, less aggregation and stable dispersion in organic solution and aqueous solution as well as phosphate buffer. This may enlarge the applications of nanodiamonds especially in biological area.

The expression and the functional roles of tissue factor and protease-activated receptor-2 on SW620 cells.

Tissue factor (TF) is believed to play an important role in tissue repair, inflammation, angiogenesis, and tumor metastasis. Protease-activated receptors (PARs) are widely expressed on various cells including tumor cells and associated with many pathological mechanisms. In the present study, the expression of TF and PAR1, PAR2 on human colon cancer cells (SW620 and SW480) was investigated and their functional roles on the behavior of tumor cells were evaluated. It was demonstrated that SW620 and SW480 cells expressed TF at antigen, activity and mRNA levels. However, the highly metastatic cell line SW620 showed slightly higher TF expression than the low metastatic cell line SW480. The PAR2 antigen was strongly expressed on the membrane of SW620 cells, but not on SW480 cells. The PAR1 antigen was not observed in SW620 or SW480 cells, while PAR1 and PAR2 mRNA was detected in SW620 and SW480 cells. The migratory potential of SW620 was stronger than that of SW480 seen in Boyden chambers. PAR2 agonist (SLIGKV-NH2) and factor VIIa significantly stimulated SW620 cell proliferation, migratory activity, and interleukin 8 (IL-8) secretion compared to control. The stimulating effects of factor VIIa could be inhibited by anti-TF and anti-PAR2 but not anti-PAR1 antibodies. In summary, this study demonstrates that TF and PAR2 are strongly expressed on highly metastatic colonic tumor cells and are closely associated with the proliferation and migration of the cells. TF may elucidate its roles in colonic cancer invasion and metastasis via PAR2 pathway.