Search

Abstract Background Tau protein serves a pro-inflammatory function in neuroinflammation. However, the role of tau in other inflammatory disorders such as rheumatoid arthritis (RA) is less explored. This study is to investigate the role of endogenous tau and the potential mechanisms in the pathogenesis of inflammatory arthritis. Methods We established collagen-induced arthritis (CIA) model in wild-type and Tau-/- mice to compare the clinical score and arthritis incidence. Micro-CT analysis was used to evaluate bone erosion of ankle joints. Histological analysis was performed to assess inflammatory cell infiltration, cartilage damage, and osteoclast activity in the ankle joints. Serum levels of pro-inflammatory cytokines were measured by ELISA. The expression levels of macrophage markers were determined by immunohistochemistry staining and quantitative real-time PCR. Results Tau expression was upregulated in joints under inflammatory condition. Tau deletion in mice exhibited milder inflammation and protected against the progression of CIA, evidenced by reduced serum levels of pro-inflammatory cytokines and attenuated bone loss, inflammatory cell infiltration, cartilage damage, and osteoclast activity in the ankle joints. Furthermore, tau deficiency led to the inhibition of classically activated type 1 (M1) macrophage polarization in the synovium. Conclusion Tau is a previously unrecognized critical regulator in the pathogenesis of RA and may provide a potential therapeutic target for autoimmune and inflammatory joint diseases.

We define a new kind of radially polarized twisted sinc-correlation Schell-model (RPTSCSM) source and establish the source parameter conditions necessary to produce a physical beam. With the help of the extended Huygens-Fresnel integral, Several typical numerical examples are provided to study the influence of the source parameter and turbulent parameter on the statistical properties of such beams on propagation. It is shown that the intensity profiles of such beams always exhibit rotation and self-splitting on propagation, which is caused by the twisted phase of the beams. Moreover, the light intensity splits into an array and maintains its array distribution in free space. While the array gradually evolves to a hollow distribution with a dark core in a turbulence medium, indicating that the light beam may automatically restore the radial polarized light intensity distribution in atmospheric turbulence after a certain distance of propagation. Compared with the intensity, the impact of the twisted factor on the degree of polarization is to produce noticeable distortion around its distribution centre. When propagating in a turbulent atmosphere, the degree of polarization of such beams exhibits well-turbulent resistance. The degree of coherence would also experience self-splitting and rotation caused by the twisted factor, and a turbulent atmosphere has an important influence on the degree of coherence. Our results will benefit multi-particle manipulation and free-space optical communication.

PurposePatients with non-muscle invasive bladder cancer (NMIBC) have a high possibility of recurrence after surgery. We aimed to assess the factors associated with tumor recurrence and to construct a nomogram model that can contribute to personalized treatment plans of each patient.Methods496 patients with primary bladder cancer (BC) from 2 centers were retrospectively analyzed. Preoperative neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and traditional clinical parameters were collected, then using univariate and multivariate Cox regression analysis to find out the independent risk factors associated with tumor recurrence among them, and then these independent factors were incorporated into the nomogram model. The internal calibration curves and the external calibration curves were used to verify their usefulness.ResultsIn the training cohort, 150 patients (43.1%) experienced recurrence. After Cox regression analysis, the independent risk factors affecting recurrence-free survival (RFS) were tumor grade, immediate postoperative instillation therapy (IPPIT), NLR, and SII. These factors were used to construct a model to predict RFS 1, 2, 3, and 5 years of NMIBC patients after surgery. And then, we found that the constructed model outperforms the conventional model in terms of accuracy and predictability, the results were verified by statistical tests.ConclusionPreoperative inflammatory response markers have a predictive value for postoperative recurrence in patients with NMIBC. The constructed nomogram model can be helpful in guiding personalized clinical evaluation and subsequent treatment.

A subtype of myeloid monocyte mediates the transition from autoimmunity to joint destruction in rheumatoid arthritis.

Objective This study aims to establish a nomogram model by combining traditional clinical parameters with immunohistochemical markers to predict the recurrence of non-muscle invasive bladder urothelial carcinoma (NMIBUC) after resection. Methods In total, 504 patients were included in this study. Of these patients, 353 underwent transurethral resection of bladder tumor (TURBT) in the Yongchuan Hospital of Chongqing Medical University and were identified as a training cohort. Univariate and multivariate Cox regression analyses were used to determine the risk factors associated with recurrence in the training cohort and to establish a nomogram model. A total of 151 patients who were hospitalized in the Second Affiliated Hospital of Chongqing Medical University (validation cohort) were used for further validation. The calibration curve was generated for internal and external model validation. The clinical practicability of this model was further verified by comparing the consistency index (C-index) among various models. Results The mean follow-up time of the training cohort was 45.6 months (range 4–90). In total, 146 patients relapsed in training cohort. After univariate analysis, multivariate analysis further confirmed tumor grade (p=.034), immediate postoperative instillation therapy (p=.025), Ki67 (p=.047), P53 (p=.038) and CK20 (p=.049) as independent risk factors for recurrence, and these factors were included in the nomogram model. The model more accurately predicted recurrence compared with other models based on the highest C-index of 0.82 (95% CI, 0.78–0.86) in the training cohort and 0.80 (95% CI, 0.77–0.83) in the validation cohort. Conclusions This proposed nomogram model based on traditional clinical parameters and immunohistochemical markers can more accurately predict postoperative recurrence in patients with NMIBUC.

To investigate the effects and mechanisms of irisin, a newly discovered myokine, in cartilage development, osteoarthritis (OA) pathophysiology and its therapeutic potential for treating OA we applied the following five strategical analyses using (1) murine joint tissues at different developmental stages; (2) human normal and OA pathological tissue samples; (3) experimental OA mouse model; (4) irisin gene knockout (KO) and knock in (KI) mouse lines and their cartilage cells; (5) in vitro mechanistic experiments. We found that Irisin was involved in all stages of cartilage development. Both human and mouse OA tissues showed a decreased expression of irisin. Intra-articular injection of irisin attenuated ACLT-induced OA progression. Irisin knockout mice developed severe OA while irisin overexpression in both irisin KI mice and intraarticular injection of irisin protein attenuated OA progression. Irisin inhibited inflammation and promoted anabolism in chondrogenic ADTC5 cells. Proliferative potential of primary chondrocytes from KI mice was found to be enhanced, while KO mice showed an inhibition under normal or inflammatory conditions. The primary chondrocytes from irisin KI mice showed reduced expression of inflammatory factors and the chondrocytes isolated from KO mice showed an opposite pattern. In conclusion, it is the first time to show that irisin is involved in cartilage development and OA pathogenesis. Irisin has the potential to ameliorate OA progression by decreasing cartilage degradation and inhibiting inflammation, which could lead to the development of a novel therapeutic target for treating bone and cartilage disorders including osteoarthritis.

p204, a murine member of an interferon-inducible p200 family, was reported to recognize intracellular viral and bacterial DNAs, however, its role in the innate immunity in vivo remains unknown due to the lack of p204-deficient animal models. In this study we first generated the p204−/− mice. Unexpectedly, p204 deficiency led to significant defect in extracellular LPS signaling in macrophages, as demonstrated by dramatic reductions of LPS-mediated IFN-β and pro-inflammatory cytokines. The serum levels of IFN-β and pro-inflammatory cytokines were also significantly reduced in p204−/− mice following LPS challenge. In addition, p204−/− mice were resistant to LPS-induced shock. LPS-activated NF-ĸB and IRF-3 pathways were all defective in p204-deficient macrophages. p204 binds to TLR4 through its Pyrin domain, and it is required for the dimerization of TLR4 following LPS-challenge. Collectively, p204 is a critical component of canonical LPS-TLR4 signaling pathway, and these studies also suggest that p204 could be a potential target to prevent and treat inflammatory and infectious diseases. Keywords: p204, LPS, TLR4, IFN-β, Inflammatory responses, Macrophages

We recently reported that progranulin (PGRN) is a novel regulator of glucocerebrosidase and its deficiency associates with Gaucher Diseases (GD) (Jian et al., 2016a; Jian et al., 2018). To isolate the relevant downstream molecules, we performed a whole genome microarray and mass spectrometry analysis, which led to the isolation of Chitinase-3-like-1 (CHI3L1) as one of the up-regulated genes in PGRN null mice. Elevated levels of CHI3L1 were confirmed by immunoblotting and immunohistochemistry. In contrast, treatment with recombinant Pcgin, a derivative of PGRN, as well as imigluerase, significantly reduced the expressions of CHI3L1 in both PGRN null GD model and the fibroblasts from GD patients. Serum levels of CHIT1, a clinical biomarker for GD, were significantly higher in GD patients than healthy controls (51.16 ± 2.824 ng/ml vs 35.07 ± 2.099 ng/ml, p

Abstract Background Atsttrin, an engineered protein composed of three tumor necrosis factor receptor (TNFR)-binding fragments of progranulin (PGRN), shows therapeutic effect in multiple murine models of inflammatory arthritis . Additionally, intra-articular delivery of PGRN protects against osteoarthritis (OA) progression. The purpose of this study is to determine whether Atsttrin also has therapeutic effects in OA and the molecular mechanisms involved. Methods Surgically induced and noninvasive rupture OA models were established in mouse and rat, respectively. Cartilage degradation and OA were evaluated using Safranin O staining, immunohistochemistry, and ELISA. Additionally, expressions of pain-related markers, degenerative factors, and anabolic and catabolic markers known to be involved in OA were analyzed. Furthermore, the anabolic and anti-catabolic effects and underlying mechanisms of Atsttrin were determined using in-vitro assays with primary chondrocytes. Results Herein, we found Atsttrin effectively prevented the accelerated OA phenotype associated with PGRN deficiency. Additionally, Atsttrin exhibited a preventative effect in OA by protecting articular cartilage and reducing OA-associated pain in both nonsurgically induced rat and surgically induced murine OA models. Mechanistic studies revealed that Atsttrin stimulated TNFR2-Akt-Erk1/2-dependent chondrocyte anabolism, while inhibiting TNFα/TNFR1-mediated inflammatory catabolism. Conclusions These findings not only provide new insights into the role of PGRN and its derived engineered protein Atsttrin in cartilage homeostasis as well as OA in vivo, but may also lead to new therapeutic alternatives for OA as well as other relative degenerative joint diseases.

To evaluate the influence of deployment strategy on the mechanical interaction between braided stent and parent artery of intracranial aneurysm (the elasticity of the arterial wall is considered), finite-element analyses are carried out by referring to computational models of flow-diverter device and arterial wall. Two implantation strategies are used to virtually implant the braided stent into the ideal intracranial aneurysm model. One is the noncompacted implantation method, and the other is the implantation method of using push-pull technique. During the process of the implantation, the changes of the arterial shape around the aneurysm and the changes of the wall pressure at the contact area between the braided stent and the inner wall of the artery are analyzed. The results indicate that the average contact pressure in the area of low porosity is 57 mmHg using the push-pull technique, and the average contact pressure of the parent artery is 10.45 mmHg using the non-push-pull technique. The diameter of the parent artery at the aneurismal orifice increased about 0.2 mm when using the push-pull technique, so the elasticity of the vessel should be considered in the mechanical analysis of interaction between stent and vessel.

The conventional dynamic programming-based track-before-detect (DP-TBD) methods are usually intractable in multi-target scenarios. The adjacent targets may interfere with each other, and the computational complexity is increased with the number of targets. In this paper, a DP-TBD method using parallel computing (PC-DP-TBD) is proposed to solve the above problems. The search region of the proposed PC-DP-TBD is divided into several parts according to the possible target movement direction. The energy integration is carried out independently and parallel in each part. This contributes to reducing the computational complexity in each part, since the divided search region is smaller than the whole one. In addition, the target energy can only be integrated adequately in the part in which the search direction matches the target movement. This is beneficial to improve the ability to detect the targets with various movement directions in different parts with different search directions. The solution to the problem of the adjacent targets interfering with each other is discussed. The procedure of the parallel computing in the proposed PC-DP-TBD is presented in detail. Simulations are conducted to verify the superiority of the proposed PC-DP-TBD in terms of detection probability and computational complexity.

Protein phosphatase 2A (PP2A) is a major protein phosphatase with important cell functions. Known and utilized as a potent inhibitor of PP2A, microcystin-LR (MCLR) targets PP2A as a core element that affects numerous cellular mechanisms. But apart from direct inhibition, the exact effect of MCLR on PP2A in cell is largely unknown, specifically with regard to cellular response and autoregulation. Here, we show that a low concentration of MCLR stimulates, rather than inhibits, PP2A activity in HEK293 cells. Immunoprecipitation and immunofluorescence assays reveal that the catalytic subunit and a regulatory subunit of PP2A, termed α4, dissociate from inactive complex upon MCLR exposure, suggesting that the released catalytic subunit regains activity and thereby compensates the activity loss. At high concentrations of MCLR, PP2A activity decreases along with dissociation of the core enzyme and altered post-translational modification of its catalytic subunit. In addition, the dissociation of α4 and PP2A may contribute to destabilization of HEK293 cells cytoskeleton architecture, detachment to extracellular matrix and further anoikis. Our data provide a novel PP2A upregulation mechanism and challenge the recognition of MCLR only as a PP2A inhibitor in cells.