IgG4-related disease (IgG4-RD) has complex clinical manifestations ranging from fibrosis and inflammation to deregulated metabolism. The molecular mechanisms underpinning these phenotypes are ...unclear. In this study, by using IgG4-RD patient peripheral blood mononuclear cells (PBMCs), IgG4-RD cell lines and Usp25 knockout mice, we show that ubiquitin-specific protease 25 (USP25) engages in multiple pathways to regulate fibrotic and inflammatory pathways that are characteristic to IgG4-RD. Reduced USP25 expression in IgG4-RD leads to increased SMAD3 activation, which contributes to fibrosis and induces inflammation through the IL-1β inflammatory axis. Mechanistically, USP25 prevents ubiquitination of RAC1, thus, downregulation of USP25 leads to ubiquitination and degradation of RAC1. Decreased RAC1 levels result in reduced aldolase A release from the actin cytoskeleton, which then lowers glycolysis. The expression of LYN, a component of the B cell receptor signalosome is also reduced in USP25-deficient B cells, which might result in B cell activation deficiency. Altogether, our results indicate a potential anti-inflammatory and anti-fibrotic role for USP25 and make USP25 a promising diagnostic marker and potential therapeutic target in IgG4-RD.
Ginsenoside metabolite compound K (CK) is an active metabolite produced by ginsenosides
that has an anti-arthritic effect related to the glucocorticoid receptor (GR). However, the potential ...mechanisms of CK remain unclear.
This study explores the role and potential mechanisms of CK
and
.
Adjuvant arthritis (AA) model was induced in Sprague-Dawley (SD) rats; the rats were randomly divided into four groups (
= 10): normal, AA, CK (80 mg/kg), and dexamethasone (Dex) group (1 mg/kg). From day 15, rats were treated with CK (once a day, i.g.) and Dex (once every 3 days, i.p.) for 18 days. To further verify the mechanism of CK, fibroblast-like synoviocytes (FLS) were stimulated by tumour necrosis factor α (TNF-α) to establish an inflammatory model
.
CK (80 mg/kg) reduced paw swelling (52%) and arthritis global assessment (31%) compared to that in AA rats. In addition, CK (80 mg/kg) suppressed GLUT1 (38%), HK2 (50%), and PKM2 (56%) levels compared with those in AA FLS. However, the effects of CK (30 μM) on these events were weakened or enhanced after GR knockdown or overexpression in FLS stimulated by TNF-α (30 ng/mL). CK (80 mg/kg) also downregulated the expression of P65 (61%), p-IκB (92%), and HIF-1α (59%).
The inhibition of CK on glycolysis and the NF-κB/HIF-1α pathway is potentially mediated through activating GR. These findings provide experimental evidence for elucidating the molecular mechanism of CK in treating rheumatoid arthritis (RA).
Traditional autoregressive (AR) model-based damage identification methods construct structural damage sensitive features by trial and error, which are time-consuming, laborious and may lead to poor ...recognition effect. This study applies convolutional neural networks (CNNs) to quickly and automatically extract high-dimensional features of autoregressive model coefficients (ARMCs). In this research, AR model was utilized to fit the acceleration time series. The input matrices marked with damage location were produced by ARMCs, and then those matrices were sent to the proposed CNN for training. The trained CNN was employed for damage identification and localization. The effectiveness of the proposed method was verified by the damage identification and localization of a three-storied frame structure. The performance of the proposed CNN was compared with multilayer perception (MLP), random forest, and support vector machine (SVM). Meanwhile, the prediction results from different sample types were also discussed. Furthermore, parametric study in relation to the number of accelerometers and ARMCs used is conducted. These analyses demonstrate that the accuracy of CNN tests results reach 100%, 6.67%, 20%, and 25% higher than that of MLP, random forest, and SVM, respectively. Besides, other metrics calculated in this paper (e.g., precision, recall) further indicate that the proposed CNN performs well. The combination of AR and CNN does show excellent performance in damage identification and localization, which seems to be able to resist external excitation changes and accurately identify the multi-location damage and minor damage using limited accelerometers and ARMCs.
Studies concerning the mechanical properties of the human periodontal ligament under dynamic compression are rare. This study aimed to determine the viscoelastic properties of the human periodontal ...ligament under dynamic compressive loading. Ten human incisor specimens containing 5 maxillary central incisors and 5 maxillary lateral incisors were used in a dynamic mechanical analysis. Frequency sweep tests were performed under the selected frequencies between 0.05 Hz and 5 Hz with a compression amplitude that was 2% of the PDL's initial width. The compressive strain varied over a range of 4%-8% of the PDL's initial width. The storage modulus, ranging from 28.61 MPa to 250.21 MPa, increased with the increase in frequency. The loss modulus (from 6.00 MPa to 49.28 MPa) also increased with frequency from 0.05 Hz- 0.5 Hz but remained constant when the frequency was higher than 0.5 Hz. The tandelta showed a negative logarithmic correlation with frequency. The dynamic moduli and the loss tangent of the central incisor were higher than those of the lateral incisor. This study concluded that the human PDL exhibits viscoelastic behavior under compressive loadings within the range of the used frequency, 0.05 Hz- 5 Hz. The tooth position and testing frequency may have effects on the viscoelastic properties of PDL.
SMYD3, a member of the SET and MYND domain-containing (SMYD) family, is a histone methyltransferase (HMT) and transcription factor that plays an important role in transcriptional regulation in human ...carcinogenesis.
Using affinity purification and mass spectrometry assays to identify SMYD3-associated proteins in hepatocellular carcinoma (HCC) cells, we found several previously undiscovered SMYD3-interacting proteins, including the NuRD (MTA1/2) complex, the METTL family, and the CRL4B complex. Transcriptomic analysis of the consequences of knocking down SMYD3, MTA1, or MTA2 in HCC cells showed that SMYD3/NuRD complex targets a cohort of genes, some of which are critically involved in cell growth and migration. qChIP analyses showed that SMYD3 knockdown led to a significant reduction in the binding of MTA1 or MTA2 to the promoters of IGFBP4 and led to a significant decrease in H4K20me3 and a marked increase in H4Ac at the IGFBP4 promoter. In addition, we demonstrated that SMYD3 promotes cell proliferation, invasion, and tumorigenesis in vivo and in vitro and found that its expression is markedly upregulated in human liver cancer. Knockdown of MTA1 or MTA2 had the same effect as knockdown of SMYD3 on proliferation and invasion of hepatocellular carcinoma cells. Catalytic mutant SMYD3 could not rescue the phenotypic effects caused by knockdown of SMYD3. Inhibitors of SMYD3 effectively inhibited the proliferation and invasiveness of HCC cells.
These findings revealed that SMYD3 could transcriptionally repress a cohort of target genes expression by associating with the NuRD (MTA1/2) complex, thereby promoting the proliferation and invasiveness of HCC cells. Our results support the case for pursuing SMYD3 as a practical prognostic marker or therapeutic target against HCC.
The anti-foreign tissue (transplant rejection) response, mediated by the immune system, has been the biggest obstacle to successful organ transplantation. There are still many enigmas regarding this ...process and some aspects of the underlying mechanisms driving the immune response against foreign tissues remain poorly understood. Here, we found that a large number of neutrophils and macrophages were attached to the graft during skin transplantation. Furthermore, both types of cells could autonomously adhere to and damage neonatal rat cardiomyocyte mass (NRCM) in vitro. We have demonstrated that Complement C3 and the receptor CR3 participated in neutrophils/macrophages-mediated adhesion and damage this foreign tissue (NRCM or skin grafts). We have provided direct evidence that the damage to these tissues occurs by a process referred to as trogocytosis, a damage mode that has never previously been reported to directly destroy grafts. We further demonstrated that this process can be regulated by NFAT, in particular, NFATc3. This study not only enriches an understanding of host-donor interaction in transplant rejection, but also provides new avenues for exploring the development of novel immunosuppressive drugs which prevent rejection during transplant therapy.
Accumulating evidence indicates that circular RNAs have major roles in the progression of human cancers. Nevertheless, the molecular mechanism and effects of circFAM126A in oral squamous cell ...carcinoma (OSCC) remain unclear.
Quantitative real-time PCR (qRT-PCR) was used to detect expression levels of circFAM126A in OSCC tumor tissues and cell lines; the effects of circFAM126A small hairpin RNA (shRNA) on the proliferation, migration, and invasion of OSCC cells were detected by MTT, colony formation, and transwell assays; xenograft mouse models were used to determine the effects of circFAM126A shRNA on the growth of OSCC tumors
; the expression of miR-186 and RAB41 in OSCC tissues and cells was examined by qRT-PCR; the targeting relationship between circFAM126A and miR-186 was verified by dual-luciferase reporter and RNA pull-down assays; and the relationship between miR-186 and RAB41 was explored.
The expression of circFAM126A was significantly upregulated in OSCC tissues and cells. The transcription factor SP1 transcriptionally activated circFAM126A. However, knockdown of circFAM126A markedly suppressed the proliferation, migration, and invasion of OSCC cells
and inhibited tumor growth and distant metastasis
. Moreover, circFAM126A increased the expression of RAB41 and promoted its mRNA stability
binding to miR-186 and RNA-binding protein FUS. Overexpression of RAB41 antagonized the effects of circFAM126A knockdown and induced an aggressive phenotype of OSCC cells.
SP1 transcriptionally activated circFAM126A modulated the growth, epithelial-mesenchymal transition (EMT) of OSCC cells
targeting the miR-186/FUS/RAB41 axis, suggesting that circFAM126A is a potential biomarker for the treatment of OSCC.
The thermal error of CNC machine tools can be reduced by compensation, where a thermal error model is required to provide compensation values. The thermal error model adaptive update method can ...correct the thermal error model by supplementing new data, which fundamentally solves the problem of model robustness. Certain problems associated with this method in temperature-sensitive point (TSP) selection and model update algorithms are investigated in this study. It was found that when the TSPs were selected frequently, the selection results may be different, that is, there was a variability problem in TSPs. Further, it was found that the variability of TSPs is mainly due to some problems with the TSP selection method, (1) the conflict between the collinearity among TSPs and the correlation of TSPs with thermal error is ignored, (2) the stability of the correlation is not considered. Then, a stable TSP selection method that can choose more stable TSPs with less variability was proposed. For the model update algorithm, this study proposed a novel regression algorithm which could effectively combine the new data with the old model. It has advantages for a model update, (1) fewer data are needed for the model update, (2) the model accuracy is greatly improved. The effectiveness of the proposed method was verified by 20 batches of thermal error measurement experiments in the real cutting state of the machine tool.
As an important component of rotating machinery, the fault information of rolling element bearing is difficult to be recognized due to the background noise and harmonic frequency contained in the ...tested vibration signal. In order to accurately and completely extract the fault characteristic information from the vibration signal, a fault diagnosis research method (EAVGH-CSC-EES) based on the combination of enhanced top-hat morphological filtering (EAVGH) and cyclic spectrum coherence (CSC) is proposed. First of all, in view of the problem that the existing top-hat operators cannot fully extract the signal fault characteristics, this paper selects the optimal operator from the four enhanced morphology operators to construct the EAVGH. Since the reasonable selection of structural element (SE) scale has a great influence on the filtering result of morphological operators, then this paper applies feature energy factor (FEF) to select the optimal scale of SE. Subsequently, in order to further solve the influence of the non-linear modulation frequency components in the signal, while improving the filtering performance of EAVGH. This paper uses the cyclic spectrum coherence function (CSC) to further process the filtered signal. And then the enhanced envelope spectrum (EES) of the signal is obtained. Simulation and two sets of bearing fault experiments verify the rationality and effectiveness of the EAVGH-CSC method. The comparison results with other existing methods can further prove the superiority of the method proposed in this paper.
Immunogenic dying tumor cells hold promising prospects as cancer vaccines to activate systemic immunity against both primary and metastatic tumors. Especially, X-ray- induced dying tumor cells are ...rich in highly immunogenic tumor-associated antigens and self-generated dsDNA as potent adjuvants. However, we found that the X-ray induction process can result in the excessive exposure of phosphatidylserine in cancer vaccines, which can specifically bind with the MerTK receptor on macrophages, acting as a “checkpoint” to facilitate immune silence in the tumor microenvironment. Therefore, we developed a novel strategy combining X-ray-induced cancer vaccines with UNC2250, a macrophage MerTK “checkpoint inhibitor,” for treating peritoneal carcinomatosis in colon cancer. By incorporating UNC2250 into the treatment regimen, immunosuppressive efferocytosis of macrophages, which relies on MerTK-directed recognition of phosphatidylserine on vaccines, was effectively blocked. Consequently, the immune analysis revealed that this combination strategy promoted the maturation of dendritic cells and M1-like repolarization of macrophages, thereby simultaneously eliciting robust adaptive and innate immunity. This innovative approach utilizing X-ray-induced vaccines combined with a checkpoint inhibitor may provide valuable insights for developing effective cancer vaccines and immunotherapies targeting colon cancer.
Frozen dying tumor cells (FDT) combined with efferocytosis inhibitors can mobilize dendritc cells and macrophages simultaneously, thereby eliciting robust innate and adaptive immunity against peritoneal carcinomatosis in colon cancer. Display omitted
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