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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.

We present the twisted electromagnetic sinc-correlation Schell-model (EM TSSM) beam as an extension of the cylindrical sinc Schell-model beam and analyze the necessary source parameter conditions to generate a physically viable beam. Furthermore, we thoroughly investigate the propagation properties of the EM TSSM beam in atmospheric turbulence using the extended Huygens-Fresnel integral, explicitly focusing on spectral intensity, degree of polarization (DOP), and degree of coherence (DOC). It shows that the twisted phase has a noticeable impact on the intensity profiles of these beams, causing them to exhibit rotation and self-splitting while still maintaining their shape in free space. Moreover, during propagation through a turbulent atmosphere, it exhibits self-combining properties over a long range and recovers the plat-topped distribution. Compared with the sinc Schell-model beam without the twisted phase, the DOP distribution of such a beam can rotate around its distribution center. As these beams propagate through turbulent atmospheres, they can self-heal their DOP distribution within specific ranges affected by atmospheric turbulence. A twist factor causes non-unidirectional rotation of the DOC distribution in free space. The DOC gradually transforms from multi-strip profiles into a Gaussian-like distribution. Furthermore, the beam parameters play a crucial role in shaping the DOC. The results will be useful in optical trapping and optical communication. [ABSTRACT FROM AUTHOR]

We study a new class of partially coherent array beams with a non-uniform polarization, named radially polarized Gaussian Schell-model array (RPGSMA) beams and analyze the reliability conditions for the array beams based on the unified theory of coherence and polarization, Moreover, the statistical properties of such beam propagating in free space are investigated in detail. It is found that, the propagation properties of the RPGSMA beams are closely related to initial beam parameters. With an appropriate choice of the beam parameters, the average intensity will evolve into optical lattice patterns, and the degree of coherence (DOC) from the lattice distribution on the original plane evolves into a Gaussian profile in the far field, and the degree of polarization (DOP) appears a periodical grid-like distribution on propagation. These results may be beneficial to particle trapping and free-space optical communications. [ABSTRACT FROM AUTHOR]

Mutations in GBA1, encoding glucocerebrosidase (GCase), cause Gaucher disease (GD) and are also genetic risks in developing Parkinson's disease (PD). Currently, the approved therapies are only effective for directly treating visceral symptoms, but not for primary neuronopathic involvement in GD (nGD). Progranulin (PGRN), encoded by GRN, is a novel modifier of GCase, but the impact of PGRN in GBA1 mutation-associated pathologies in vivo remains unknown. Herein, Grn-/- mice crossed into Gba9v/9v mice, a Gba1 mutant line homozygous for the Gba1 D409V mutation, generating Grn-/-Gba9v/9v (PG9V) mice. PG9V mice exhibited neurobehavioral deficits, early onset, and more severe GD phenotypes compared to Grn-/- and Gba9v/9v mice. Moreover, PG9V mice also displayed PD-like phenotype. Mechanistic analysis revealed that PGRN deficiency caused severe neuroinflammation with microgliosis and astrogliosis, along with impaired autophagy associated with the Gba1 mutation. A PGRN-derived peptide, termed ND7, ameliorated the disease phenotype in GD patient fibroblasts ex vivo. Unexpectedly, ND7 penetrated the blood-brain barrier (BBB) and effectively ameliorated the nGD manifestations and PD pathology in Gba9v/null and PG9V mice. Collectively, this study not only provides the first line of in vivo but also ex vivo evidence demonstrating the crucial role of PGRN in GBA1/Gba1 mutation-related pathologies, as well as a clinically relevant mouse model for mechanistic and potential therapeutics studies for nGD and PD. Importantly, a BBB penetrant PGRN-derived biologic was developed that may provide treatment for rare lysosomal storage diseases and common neurodegenerative disorders, particularly nGD and PD. [ABSTRACT FROM AUTHOR]

The effect of anisotropic atmosphere turbulence on propagation characteristics of an electromagnetic twisted Gaussian Schell-model array (EM TGSMA) beam is investigated. An analytical expression for the cross-spectral density function of such beam propagating through anisotropic turbulent atmosphere is derived and used to explore the evolutionary behavior of the spectral intensity, degree of polarization (DOP) and degree of coherence (DOC). An example illustrates the fact that twisted strength and anisotropic turbulent factors have an important impact on the behavior of spectral density, DOC and DOP, in particular. The rotation angle of the array beams can also be controlled by adjusting twisted strength. Furthermore, strong anisotropic turbulence was also found to cause significant mergence of the array beams. Our results might be beneficial for free-space communications of the partially coherent beams endowed with twist. [ABSTRACT FROM AUTHOR]

Objectives: Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signalling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signalling in chondrocytes and OA.Methods: Biochemical copurification and proteomics screen were performed to isolate the intracellular cofactors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically modified mice with naturally occurring and surgically induced OA were performed to examine the importance of this pathway in chondrocytes and OA.Results: Signalling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN's therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signalled through activating extracellular signal-regulated kinase (ERK)-dependent Elk-1 while suppressing nuclear factor kappa B (NF-κB) in chondrocytes.Conclusions: This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously unrecognised TNFR2 pathway in the pathogenesis of OA. [ABSTRACT FROM AUTHOR]