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Estrogen deficiency is considered the most important cause of postmenopausal osteoporosis. However, the underlying mechanism is still not completely understood. In this study, progranulin (PGRN) was isolated as a key regulator of bone mineral density in postmenopausal women through high throughput proteomics screening. In addition, PGRN-deficient mice exhibited significantly lower bone mass than their littermates in an ovariectomy-induced osteoporosis model. Furthermore, estrogen-mediated inhibition of osteoclastogenesis and bone resorption as well as its protection against ovariectomy-induced bone loss largely depended on PGRN. Mechanistic studies revealed the existence of a positive feedback regulatory loop between PGRN and estrogen signaling. In addition, loss of PGRN led to the reduction of estrogen receptor α, the important estrogen receptor involved in estrogen regulation of osteoporosis, through enhancing its degradation via K48-linked ubiquitination. These findings not only provide a previously unrecognized interplay between PGRN and estrogen signaling in regulating osteoclastogenesis and osteoporosis but may also present a new therapeutic approach for the prevention and treatment of postmenopausal osteoporosis by targeting PGRN/estrogen receptor α.

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]

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.

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]

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.

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.

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.

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]

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]

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]

In this paper, an analytical expression for describing propagation properties of twisted Gaussian Schell model array (TGSMA) beams through turbulent biological tissues is derived based on the extended Huygens Fresnel integral. With the help of the formulae, properties of the rotation and mergence for the TGSMA beams in turbulent biological tissues are researched in detail. It is found that the TGSMA beams go through the distinct mergence period in the far field besides phenomena of abruption and rotation in the near field, and turbulent biological tissues play a dominated role in mergence of the TGSMA beams. These novel results may be helpful in optical trapping. [ABSTRACT FROM AUTHOR]

TNFR1 and TNFR2 have received prominent attention because of their dominance in the pathogenesis of inflammation and autoimmunity. TNFR1 has been extensively studied and primarily mediates inflammation. TNFR2 remains far less studied, although emerging evidence demonstrates that TNFR2 plays an antiinflammatory and immunoregulatory role in various conditions and diseases. Herein, we report that TNFR2 regulates macrophage polarization, a highly dynamic process controlled by largely unidentified intracellular regulators. Using biochemical copurification and mass spectrometry approaches, we isolated the signaling molecule 14-3-3ε as a component of TNFR2 complexes in response to progranulin stimulation in macrophages. In addition, 14-3-3ε was essential for TNFR2 signaling-mediated regulation of macrophage polarization and switch. Both global and myeloid-specific deletion of 14-3-3ε resulted in exacerbated inflammatory arthritis and counteracted the protective effects of progranulin-mediated TNFR2 activation against inflammation and autoimmunity. TNFR2/14-3-3ε signaled through PI3K/Akt/mTOR to restrict NF-κB activation while simultaneously stimulating C/EBPβ activation, thereby instructing macrophage plasticity. Collectively, this study identifies 14-3-3ε as a previously unrecognized vital component of the TNFR2 receptor complex and provides new insights into the TNFR2 signaling, particularly its role in macrophage polarization with therapeutic implications for various inflammatory and autoimmune diseases with activation of the TNFR2/14-3-3ε antiinflammatory pathway. [ABSTRACT FROM AUTHOR]

Objective: Tumour necrosis factor alpha (TNF-α) signalling plays a central role in the pathogenesis of various autoimmune diseases, particularly inflammatory arthritis. This study aimed to repurpose clinically approved drugs as potential inhibitors of TNF-α signalling in treatment of inflammatory arthritis.Methods: In vitro and in vivo screening of an Food and Drug Administration (FDA)-approved drug library; in vitro and in vivo assays for examining the blockade of TNF actions by fexofenadine: assays for defining the anti-inflammatory activity of fexofenadine using TNF-α transgenic (TNF-tg) mice and collagen-induced arthritis in DBA/1 mice. Identification and characterisation of the binding of fexofenadine to cytosolic phospholipase A2 (cPLA2) using drug affinity responsive target stability assay, proteomics, cellular thermal shift assay, information field dynamics and molecular dynamics; various assays for examining fexofenadine inhibition of cPLA2 as well as the dependence of fexofenadine's anti-TNF activity on cPLA2.Results: Serial screenings of a library composed of FDA-approved drugs led to the identification of fexofenadine as an inhibitor of TNF-α signalling. Fexofenadine potently inhibited TNF/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-ĸB) signalling in vitro and in vivo, and ameliorated disease symptoms in inflammatory arthritis models. cPLA2 was isolated as a novel target of fexofenadine. Fexofenadine blocked TNF-stimulated cPLA2 activity and arachidonic acid production through binding to catalytic domain 2 of cPLA2 and inhibition of its phosphorylation on Ser-505. Further, deletion of cPLA2 abolished fexofenadine's anti-TNF activity.Conclusion: Collectively, these findings not only provide new insights into the understanding of fexofenadine action and underlying mechanisms but also provide new therapeutic interventions for various TNF-α and cPLA2-associated pathologies and conditions, particularly inflammatory rheumatic diseases. [ABSTRACT FROM AUTHOR]

The article discusses a study which aims to determine an effective inducer for dopaminerergic neuron differentiation. The study utilized cultured mesenchymal stem cells derived from bone marrow of rat which were induced into dopaminergic neurons. Results reveal that bone marrow-derived mesynchymal cells demonstrates typical neuronal morphological characteristics after induction.

The increased distribution of microcystins (MCs) has become a global issue. However, the MC response machinery has not been completely studied and elucidated until now. Our previous dose-related analysis has revealed that different concentrations of mirocystin-RR (MC-RR) can trigger comprehensive and various alterations in the protein expression profile using a proteomic approach. To further dissect the kinetics of cellular responses associated with MC-RR cytotoxic effects, the present study has set out to investigate the temporal protein expression pattern at three time points (3, 12, and 24 h after exposure). The relative intensity has changed significantly in MC-RR-treated FL cells, as compared with the control, in a total of 127 protein spots. One hundred and two proteins have been further identified with high confidence by peptide mass fingerprinting. These proteins can be categorized into diverse functional classes such as signal transduction, apoptosis, protein degradation, cell cycle, cell differentiation, transporter, and so forth. The wide range of different proteins involved suggests that MC-RR has profound effects on the biological response and toxic consequences of the affected cells. The identification of p53 and its potential targets confirms a known role for p53 in the MC-RR response. Moreover, it is noteworthy that MC-RR can up-regulate the expression of the PP2A A subunit and down-regulate the expression of a number of proteins implicated in the ubiquitin-proteasome pathway. Therefore, the present expression data provide a global view of dynamic changes in cell responses to MC-RR and, more importantly, generate novel hypotheses regarding MC-RR-responsive mechanisms. [ABSTRACT FROM AUTHOR]

This article discusses the 2023 Annual Meeting of the American Society for Bone and Mineral Research (ASBMR). The article presents a list of award recipients as well as all abstracts of all research presented at the meeting. Research topics include bone mineral density, osteoporosis and osteoclasts. [Extracted from the article]

Background: Peripheral blood inflammation indices, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), have become research hotspots in the diagnosis, treatment, and prognosis prediction of breast cancer, whereas existing research findings remain controversial.Methods: Data pertaining to 1808 breast cancer patients were collected retrospectively to analyze the predictive value of NLR/PLR/SII for breast cancer clinicopathological characteristics, chemotherapy response, and relapse. 1489, 258, and 53 eligible breast cancer patients entered into the three analyses, respectively. Logistic regression analyses were used to assess the correlation between these indices and poor response to chemotherapy. A predictive scoring model was established to predict chemotherapeutic responses based upon the odds ratio values of significant variables identified in logistic regression analyses.Results: Higher pretherapeutic NLR/PLR/SII values were significantly correlated with higher tumor stage, triple-negative breast cancer, premenopausal status, and younger age. Logistic regression analyses indicated that pretherapeutic high SII (as a continuous variable or with a cut-off value of 586.40) and HER2-negative status were independent predictors of poor response to neoadjuvant chemotherapy. A first-in-class SII-based predictive scoring model well distinguished patients who might not benefit from neoadjuvant chemotherapy, with an area under the curve of 0.751. In HR-positive cancers, SII was more strongly associated with clinicopathological features and chemotherapy response. In addition, a receiver operating characteristic curve analysis indicated that the specificity of follow-up SII in identifying cancer relapse was greater than 98.0% at a cut-off value of 900.Conclusion: As a predictor of breast cancer, especially in the HR-positive subtype, SII may eclipse NLR/PLR. SII-high patients are more likely to have a worse chemotherapy response and a higher risk of recurrence. [ABSTRACT FROM AUTHOR]

Purpose: The surgical treatment of bladder urothelial carcinoma depends on whether the tumor has invaded the bladder muscular layer. Normal ultrasound and contrast-enhanced magnetic resonance imaging (contrast-enhanced MRI) are widely used in patients bear bladder tumors; the latter is also widely used in estimating the muscularis invasion of bladder cancer (BC). However, contrast-enhanced ultrasound (CEUS) is rarely used in this aspect. As the gold standard in diagnosing muscularis invasion remains being pathological examination, this study was set to find out whether there are differences between CEUS and contrast-enhanced MRI in diagnosing bladder malignant tumors and in diagnosing the muscularis invasion of the bladder urothelial carcinoma under the guide of the pathological results. Methods: 160 patients from Yongchuan Hospital of Chongqing Medical University and The Second Affiliated Hospital of Chongqing Medical University were recruited from July 1st, 2021, to June 30th, 2022. Patients are arranged to undergo CEUS, contrast-enhanced MRI and then take a surgery. After surgery, we compare the results of CEUS, MRI and the pathological results, using software to run the statistical examinations. Results: The accuracies of CEUS and contrast-enhanced MRI in diagnosing malignant bladder tumors were 85.90 and 84.62%, and they had no differences (P > 0.05). While the accuracies of CEUS and contrast-enhanced MRI in diagnosing the muscularis invasion were 84.62 and 76.92%, in which CEUS had a better sensitivity (P < 0.05). Conclusions: We found that CEUS and contrast-enhanced MRI had no differences in diagnosing the different pathological types (benign or malignant) of BC, but CEUS holds a better sensitivity in diagnosing muscularis invasions of bladder urothelial carcinoma than the contrast-enhanced MRI. [ABSTRACT FROM AUTHOR]

We previously showed that kaempferol (KAE) could exert neuroprotective effects against PD. It has been demonstrated that abnormal autophagy plays a key role in the development of PD. Mitochondrial dysfunction, involved in the development of PD, can damage dopaminergic neurons. Whether the protective effects of KAE were exerted via regulating autophagy remains largely undefined, however. This study aimed to investigate whether KAE could protect dopaminergic neurons via autophagy and the underlying mechanisms using a MPTP/MPP+-stimulated PD model. Cell viability was detected by cell counting kit-8 (CCK-8) assay, and protein levels of autophagy mediators along with mTOR signaling pathway molecules were investigated by immunohistochemistry and Western blot analyses. The results showed that KAE could ameliorate the behavioral impairments of mice, reduce the loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta, and reduce α-synuclein (α-syn) levels. Furthermore, KAE upregulated levels of autophagy effector protein of Beclin-1 and autophagy microtubule associated protein of light chain 3 (LC3) in the substantia nigra (SN) while rescuing mitochondrial integrity, and downregulated levels of ubiquitin binding protein p62 and cleaved caspase-3, probably by decreasing the mammalian target of rapamycin (mTOR) signaling pathway. Further in vitro experiments demonstrated similar results. In conclusion, KAE exerts neuroprotective effects against PD potentially by promoting autophagy via inhibiting the mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Predicting the development of sporadic type B aortic dissection (TBAD) always remains a difficult issue. This study aimed to identify high-risk patients for development of TBAD based on morphological parameters. Methods: This propensity-score-matched case-control study collected and reconstructed the computed tomography angiography of acute TBAD patients and hospital-based control participants without aortic dissection from January 2013 to December 2016. Multivariate regression analysis was used to calculate the adjusted odds ratio (aOR) and 95% confidence interval (CI). Discriminant and reclassification abilities were compared between our model and a previously established model. Results: Our study included 76 acute TBAD patients and 79 control patients (48 cases and 48 controls after propensity-score matching). The degree of question mark (aOR 1.07, 95% CI 1.04-1.11), brachiocephalic trunk diameter (aOR 1.49, 95% CI 1.20-1.85), brachiocephalic trunk angle (aOR 0.97, 95% CI 0.94-0.99), aortic root diameter (aOR 1.31, 95% CI 1.15-1.48), and aortic width (aOR 1.12, 95% CI 1.07-1.17) were associated with a significantly increased risk of TBAD formation. Similar findings were observed in the propensity-score matching and sensitivity analysis only including hyperacute TBAD patients. A novel prediction model was established based on the aforementioned parameters. The new model showed significantly improved discriminant ability compared with the previously established model (c-index 0.78 [95% CI 0.71-0.85] vs. 0.67 [95% CI 0.58-0.75], p = .03), driven by increased reclassification ability in identifying TBAD patients (NRI for events 0.16, 95% CI 0.02-0.30, p = .02). Conclusion: Morphological predictors, including the degree of question mark, aortic width, aortic root diameter, brachiocephalic trunk angle, and brachiocephalic trunk diameter, may be used to identify patients at high risk of TBAD. [ABSTRACT FROM AUTHOR]

As a dense instance segmentation problem, rebar counting in a complex environment such as rebar yard and rebar transpotation has received significant attention in both academic and industrial contexts. Traditional counting approaches, such as manual counting and machine vision-based algorithms, are often inefficient or inaccurate since rebars with varied sizes and shapes are stacked overlapping, rebar image is not clear for complex light condition such as dawn, night and strong light, and other environmental noises exist in rebar image; thus, they no longer fulfil the requirements of modern automation. This paper proposes MaskID, an innovative counting method based on deep learning and heuristic strategies. First, an improved version of the Mask region-based convolutional neural network (Mask R-CNN) was designed to obtain the segmentation results through splitting and rescaling so as to capture more detail in a large-scale rebar image. Then, a series of intelligent denoising strategies corresponding to aspect ratio of recognized box, overlapping recognized objects, object distribution and environmental noise, were applied to improve the segmentation results. The performance of the proposed method was evaluated on open-competition and test-platform datasets. The F1-score was found to be over 0.99 on all datasets. The experimental results demonstrate that the proposed method is effective for dense rebar counting and significantly outperforms existing state-of-the-art methods. [ABSTRACT FROM AUTHOR]

Self‐healing polyurethane elastomers allow increasing the life cycle, adapting to the circular economy, thus reducing the generation of waste. In this work, ureido‐4[1H]‐pyrimidinone (UPy) compounds was used to construct on supramolecular polymer. The self‐healing polyurethane elastomers were successfully prepared by supramolecular polymer based on UPy via a simple blending way. The self‐healing performance of the polyurethane elastomers with UPy were investigated by the scratch test and the cut‐off test, respectively. The scratch of the self‐healing polyurethane elastomer (PU‐15UPy) was totally healed in 1 h at 35°C. The tensile strength and the elongation at break of PU‐15UPy were 0.81 MPa and 563.8%. After the cut‐off test, the healing efficiencies of tensile strength were 63.8% (0.51 MPa) and 85.2% (0.69 MPa) after healing for 10 h at 35 and 80°C, respectively. The healing efficiency of tensile strength reached the value of 90.1% (0.73 MPa) after healing for 24 h at 80°C. The chemical resistance of the self‐healing polyurethane elastomers was tested by immersion in water, NaCl solution (3%), HCl solution (5%), NaOH solution (5%), and diesel, respectively. The mass loss of self‐healing polyurethane elastomers were all less than 2% after immersed in these solutions for 1 month, indicating the excellent chemical resistance performance of PU‐15UPy. [ABSTRACT FROM AUTHOR]

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. 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. 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. This proposed nomogram model based on traditional clinical parameters and immunohistochemical markers can more accurately predict postoperative recurrence in patients with NMIBUC. [ABSTRACT FROM AUTHOR]

Progranulin (PGRN) is a key regulator of lysosomes, and its deficiency has been linked to various lysosomal storage diseases (LSDs), including Gaucher disease (GD), one of the most common LSD. Here, we report that PGRN plays a previously unrecognized role in autophagy within the context of GD. PGRN deficiency is associated with the accumulation of LC3-II and p62 in autophagosomes of GD animal model and patient fibroblasts, resulting from the impaired fusion of autophagosomes and lysosomes. PGRN physically interacted with Rab2, a critical molecule in autophagosome-lysosome fusion. Additionally, a fragment of PGRN containing the Grn E domain was required and sufficient for binding to Rab2. Furthermore, this fragment significantly ameliorated PGRN deficiency–associated impairment of autophagosome-lysosome fusion and autophagic flux. These findings not only demonstrate that PGRN is a crucial mediator of autophagosome-lysosome fusion but also provide new evidence indicating PGRN's candidacy as a molecular target for modulating autophagy in GD and other LSDs in general. Key messages: PGRN acts as a crucial factor involved in autophagosome-lysosome fusion in GD. PGRN physically interacts with Rab2, a molecule in autophagosome-lysosome fusion. A 15-kDa C-terminal fragment of PGRN is required and sufficient for binding to Rab2. This PGRN derivative ameliorates PGRN deficiency–associated impairment of autophagy. This study provides new insights into autophagy and may develop novel therapy for GD. [ABSTRACT FROM AUTHOR]

A long‐standing problem in biology is how to dissect traits for which no tractable model exists. Here, we screen for genes like the nude locus (Foxn1)—genes central to mammalian hair and thymus development—using animals that never evolved hair, thymi, or Foxn1. Fruit flies are morphologically disrupted by the FOXN1 transcription factor and rescued by weak reductions in fly gene function, revealing molecules that potently synergize with FOXN1 to effect dramatic, chaotic change. Strong synergy/effectivity in flies is expected to reflect strong selection/functionality (purpose) in mammals; the more disruptive a molecular interaction is in alien contexts (flies), the more beneficial it will be in its natural, formative contexts (mammals). The approach identifies Aff4 as the first nude‐like locus, as murine AFF4 and FOXN1 cooperatively induce similar cutaneous/thymic phenotypes, similar gene expression programs, and the same step of transcription, pre‐initiation complex formation. These AFF4 functions are unexpected, as AFF4 also serves as a scaffold in common transcriptional‐elongation complexes. Most likely, the approach works because an interaction's power to disrupt is the inevitable consequence of its selected‐for power to benefit. SYNOPSIS: This study reports a simple way to dissect the molecular basis of traits when the traits evolved in organisms difficult to study. The approach identifies selected‐for interactions, the molecular interactions shaped and preserved by positive selection during trait evolution, and here uncovers an essential transcriptional activator of a uniquely mammalian developmental mechanism. The selected‐for (most beneficial) interactions of mammalian molecules can be revealed via the molecules' most disruptive interactions in fruit flies, i.e., the interactions most synergistic and effective at inflicting harm.A genetic screen of flies for drivers of hair and thymus development in mammals identifies AFF4, a novel driver of hair and thymus development in mammals, providing proof of principle.The study's approach, flash‐forward genetics, turns tractable species into models for the evolutionary novelties of other lineages, in a sense inducing a "flash‐forward" along another evolutionary path. [ABSTRACT FROM AUTHOR]

Polyphenols from Toona sinensis seeds (PTSS) have demonstrated anti-inflammatory effects in various diseases, while the anti-neuroinflammatory effects still remain to be investigated. We aimed to investigate the effects of PTSS on Parkinson's disease and underlying mechanisms using a rat model. We employed 6-hydroxydopamine (6-OHDA) to male Sprague Dawley (SD) rats and PC12 cells to construct the in vivo and vitro models of PD and dopaminergic (DA) neuron injury, respectively. Cell viability was detected by cell counting kit-8 (CCK-8) assay and protein levels of inflammatory mediators and some p38 MAPK pathway molecules were investigated by immunohistochemistry and Western blot analyses. The results showed that 6-OHDA significantly increased protein levels of inflammatory mediators, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and tumor necrosis factor α (TNF-α), which could be reversed by PTSS through suppressing the p38 MAPK pathway. The anti-inflammatory effects of PTSS were significantly enhanced by the specific p38 inhibitor of SB203580 in vitro. The present work suggests that PTSS can exert anti-inflammatory effects on PD models, which may be attributed to the suppression of p38 MAPK signaling pathway. [ABSTRACT FROM AUTHOR]

2019 Annual Meeting of the American Society for Bone and Mineral Research Orange County Convention Center, Orlando, Florida, USA September 20-23, 2019. [Extracted from the article]

Computational fluid dynamics analyses were performed on three models which have a giant aneurysm with or without a stenosis. The first is a model with an aneurysm (no stenosis and no stent), the second is a model with a preaneurysm stenosis, and the third is a model with an aneurysm implanted with a stent. The increase in pressure in aneurismal sac caused by a 50% stenosis is about 10.3 mmHg at peak systole (comparison between the second model and the first model). It must pay attention to the increase of the pressure for the patient which has an aneurysm accompanied by a stenosis when making the treatment plan. Otherwise, it may cause the aneurysm rupture. [ABSTRACT FROM AUTHOR]

Purpose: Image-based computational fluid dynamics (CFD) is widely used to predict intracranial aneurysm wall shear stress (WSS), particularly with the goal of improving rupture risk assessment. Nevertheless, concern has been expressed over the variability of predicted WSS and inconsistent associations with rupture. Previous challenges, and studies from individual groups, have focused on individual aspects of the image-based CFD pipeline. The aim of this Challenge was to quantify the total variability of the whole pipeline.Methods: 3D rotational angiography image volumes of five middle cerebral artery aneurysms were provided to participants, who were free to choose their segmentation methods, boundary conditions, and CFD solver and settings. Participants were asked to fill out a questionnaire about their solution strategies and experience with aneurysm CFD, and provide surface distributions of WSS magnitude, from which we objectively derived a variety of hemodynamic parameters.Results: A total of 28 datasets were submitted, from 26 teams with varying levels of self-assessed experience. Wide variability of segmentations, CFD model extents, and inflow rates resulted in interquartile ranges of sac average WSS up to 56%, which reduced to < 30% after normalizing by parent artery WSS. Sac-maximum WSS and low shear area were more variable, while rank-ordering of cases by low or high shear showed only modest consensus among teams. Experience was not a significant predictor of variability.Conclusions: Wide variability exists in the prediction of intracranial aneurysm WSS. While segmentation and CFD solver techniques may be difficult to standardize across groups, our findings suggest that some of the variability in image-based CFD could be reduced by establishing guidelines for model extents, inflow rates, and blood properties, and by encouraging the reporting of normalized hemodynamic parameters. [ABSTRACT FROM AUTHOR]

Objective: It has been reported that ADAMTS‐12 is a susceptibility gene for rheumatoid arthritis (RA) development, and its level is significantly increased in RA patients. In addition, ADAMTS‐12 is reported to be required for inflammation in otherwise healthy subjects. This study was undertaken to determine the role of ADAMTS‐12 and the underlying mechanisms in the pathogenesis of inflammatory arthritis. Methods: The collagen‐induced arthritis (CIA) model was established in ADAMTS‐12–deficient mice and their control littermates to determine the role of ADAMTS‐12 in vivo. Micro–computed tomography scanning was used to demonstrate the destruction of the ankle joint; histologic analysis illustrated synovitis, pannus formation, and bone and cartilage destruction; enzyme‐linked immunosorbent assay was performed to measure serum levels of inflammatory cytokines; and protein–protein interaction assays were performed to detect the interactions of ADAMTS‐12 and its various deletion mutants with connective tissue growth factor (CTGF). Results: Deficiency of ADAMTS‐12 led to accelerated inflammatory arthritis in the CIA mouse model. Loss of ADAMTS‐12 caused enhanced osteoclastogenesis. In vitro and in vivo protein–protein interaction assays demonstrated that ADAMTS‐12 bound and processed CTGF, a previously unrecognized substrate of ADAMTS‐12. In addition, deletion of ADAMTS‐12 enhanced, while overexpression of ADMATS‐12 reduced, CTGF‐mediated inflammation. Furthermore, ADAMTS‐12 regulation of inflammation was largely lost in CTGF‐deficient macrophages. Importantly, blocking of CTGF attenuated elevated inflammatory arthritis seen in the ADAMTS‐12–deficient CIA mouse model. Conclusion: This study provides evidence that ADAMTS‐12 is a critical regulator of inflammatory arthritis and that this is mediated, at least in part, through control of CTGF turnover. [ABSTRACT FROM AUTHOR]