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In cross-border logistics, mainline carriers (MCs) confronting demand uncertainty have to share their information with the overseas regional carrier (RC) via information system or electronic data interchange. However, does the RC or the incumbent MC have incentives to disclose the demand information to a new MC? The new MC competes with the incumbent MC but has no demand information, while the incumbent MC has accumulated big data and known demand uncertainty well. In this paper, we study the supply chain parties’ preferences over information leakage in a system consisting of an incumbent MC, a new MC and an overseas RC. Interestingly, we show that, when there is no information leakage, the new MC’s signal inference dramatically restricts the RC’s pricing flexibility. This induces the RC to disclose the incumbent MC’s information. We also show that, information leakage alters the MCs’ competition and their profits by balancing the RC’s service price and the MCs’ order sizes.

Branched-chain amino acid (BCAA; valine, leucine and isoleucine) supplementation is often beneficial to energy expenditure; however, increased circulating levels of BCAA are linked to obesity and diabetes. The mechanisms of this paradox remain unclear. Here we report that, on cold exposure, brown adipose tissue (BAT) actively utilizes BCAA in the mitochondria for thermogenesis and promotes systemic BCAA clearance in mice and humans. In turn, a BAT-specific defect in BCAA catabolism attenuates systemic BCAA clearance, BAT fuel oxidation and thermogenesis, leading to diet-induced obesity and glucose intolerance. Mechanistically, active BCAA catabolism in BAT is mediated by SLC25A44, which transports BCAAs into mitochondria. Our results suggest that BAT serves as a key metabolic filter that controls BCAA clearance via SLC25A44, thereby contributing to the improvement of metabolic health. The solute carrier transporter protein SLC25A44 regulates uptake of branched-chain amino acids in mitochondria of brown adipose tissue in which they are utilized for thermogenesis.

Lymphocyte activation gene 3 (LAG3) is a member of the immunoglobulin superfamily and has been implicated in the development, growth, and progression of several cancers. However, the biological role of LAG3 has not been investigated in pan-cancer datasets. We sought to perform a comprehensive bioinformatics analysis of pan-cancer datasets to determine the relationship of LAG3 with patient survival prognosis, tumor microenvironment, immunotherapy responsiveness, and mechanisms regulating tumorigenesis. We used TCGA, GTEx, TIMER2, GDSC, CTRP, and TISCH databases and online websites to extract data on LAG3 in a variety of cancers, and analyzed pan-cancer patient datasets to explore not only the correlation between LAG3 expression and clinical stage, diagnosis, and prognosis of cancers, but also the correlation between LAG3 expression, gene variants, methylation status, tumor stemness, and tumor immunity. The biological functions of LAG3 in osteosarcoma cells were determined by in vitro CCK-8, wound healing and transwell assays. Finally, through in vivo experiments, the study preliminarily explored the impact of LAG3 on osteosarcoma and its correlation with immune genes. Pan-cancer analysis showed that LAG3 expression was up-regulated in a variety of cancers, and the expression of LAG3 was closely related to the clinical stage, diagnosis and prognosis of cancers. GO and KEGG enrichment analyses showed that LAG3 was enriched in inflammatory, metabolic, and immune signaling pathways in a variety of cancers. Meanwhile, LAG3 expression not only has an impact on patient immunotherapy prognosis and immunotherapy response, but also has a significant effect on drug sensitivity. In vitro experiments have shown that LAG3 promotes the proliferation, migration and invasion of osteosarcoma cells. In vivo xenotransplantation experiments further confirmed that LAG3 promotes the growth of osteosarcoma, and the expression of LAG3 is positively correlated with CD8, CD19, and CD68. Our study suggests that LAG3 is a promising marker for cancer diagnosis, prognosis, and treatment.

The Wnt/β-catenin signaling pathway is associated with the pathogenesis of steroid-induced osteonecrosis. Our investigation studied whether aberrant CpG island hypermethylation of the FZD1 gene was present in patients with osteonecrosis of the femoral head (ONFH), which results in Wnt/β-catenin signaling inactivation and subsequent cell dysfunction. Bone marrow was collected from the proximal femurs of patients with steroid-associated ONFH ( n  = 21) and patients with new femoral neck fractures ( n  = 22), and then mesenchymal stem cells (MSCs) were isolated. We investigated cell viability, the transcription and translation levels of Wnt/β-catenin signaling-related genes, the extent of methylation at CpG islands of the FZD1 promoter, and the osteogenic and adipogenic differentiation abilities of MSCs from the control group and from the ONFH group treated with or without 5′-Aza-dC. According to the results, MSCs from the ONFH group showed a reduced proliferation ability, low transcription and translation levels of FZD1, inhibition of the Wnt/β-catenin signaling pathway, weakened osteogenesis and enhanced adipogenesis ability. Aberrant CpG island hypermethylation of FZD1 was observed in the ONFH group. Treatment with 5’-Aza-dC resulted in de novo FZD1 expression, reactivation of the Wnt/β-catenin signaling pathway and promotion of osteogenesis. Taken together, our study not only provides novel insights into the regulation of the Wnt/β-catenin signaling pathway in this disease but also reveals potential for the use of demethylating agents for the treatment of GC-associated ONFH. Bone disease: Signals from a modified gene Studies of genetic and molecular signaling processes in the bone disease osteonecrosis, when it is associated with steroid use, reveal insights into disease development and suggest new approaches for treatment. Steroid drugs increase the risk of osteonecrosis, in which bone tissue dies due to insufficient blood supply, but the mechanism of this effect is unclear. Researchers in China, led by Zhibo Sun at Wuhan University, investigated a link between the aberrant addition of methyl groups (CH 3 ) to the DNA of a specific gene and the onset of the disease. They identified an important molecular signaling pathway in cultured bone marrow cells from patients that is inhibited by the gene methylation. Treating these cells with a drug that inhibits methylation led to reactivation of the gene and the associated signalling pathway that promotes healthy bone formation.

MicroRNAs (miRNAs) have recently been recognized to have a role in human orthopedic disorders. The objective of our study was to explore the expression profile and biological function of miRNA-17-5p (miR-17-5p), which is well known to be related to cancer cell proliferation and invasion, in osteoblastic differentiation and in cell proliferation. The expression levels of miR-17-5p in the femoral head mesenchymal stem cells of 20 patients with non-traumatic osteonecrosis (ON) and 10 patients with osteoarthritis (OA) were examined by quantitative reverse transcription-PCR (qRT–PCR). Furthermore, the interaction between miR-17-5p and SMAD7 was observed. We found that in non-traumatic ON samples the level of mature miR-17-5p was significantly lower than that of OA samples ( P =0.0002). By targeting SMAD7 , miR-17-5p promoted nuclear translocation of β-catenin, enhanced expression of COL1A1 and finally facilitated the proliferation and differentiation of HMSC-bm cells. We also demonstrated that restoring expression of SMAD7 in HMSC-bm cells partially reversed the function of miR-17-5p. Together, our data suggested a theory that dysfunction of a network containing miR-17-5p, SMAD7 and β-catenin could contribute to ON pathogenesis. The present study prompts the potential clinical value of miR-17-5p in non-traumatic ON. Stem cells: Defects that derail bone growth Impaired stem cell proliferation and development may contribute to certain cases of bone degenerative disease. The blood vessel loss and resulting bone cell death associated with osteonecrosis (ON) can arise from trauma but in many cases the underlying pathology remains unknown. Researchers led by Weihua Xu and Shuhua Yang of the Huazhong University of Science and Technology in China showed that reduced expression of a particular regulatory RNA (miR-17-5p) may contribute to ON in some patients. The researchers examined mesenchymal stem cells (MSCs), which form diverse tissues including blood cells and bone. They observed reduced miR-17-5p levels in ON patients compared to osteoarthritis patients. This RNA has been shown to regulate cell growth and also appears to control bone formation by MSCs. Abnormalities in the miR-17-5p regulatory network may offer fruitful targets for treating ON.

Disuse osteoporosis is characterized by decreased bone mass caused by abnormal mechanical stimulation of bone. Piezo1 is a major mechanosensitive ion channel in bone homeostasis. However, whether intervening in the action of Piezo1 can rescue disuse osteoporosis remains unresolved. In this study, a commonly‐used hindlimb‐unloading model is employed to simulate microgravity. By single‐cell RNA sequencing, bone marrow‐derived mesenchymal stem cells (BMSCs) are the most downregulated cell cluster, and coincidentally, Piezo1 expression is mostly enriched in those cells, and is substantially downregulated by unloading. Importantly, activation of Piezo1 by systemically‐introducing yoda1 mimics the effects of mechanical stimulation and thus ameliorates bone loss under simulated microgravity. Mechanistically, Piezo1 activation promotes the proliferation and osteogenic differentiation of Gli1 + BMSCs by activating the β‐catenin and its target gene activating transcription factor 4 (ATF4). Inhibiting β‐catenin expression substantially attenuates the effect of yoda1 on bone loss, possibly due to inhibited proliferation and osteogenic differentiation capability of Gli1 + BMSCs mediated by ATF4. Lastly, Piezo1 activation also slightly alleviates the osteoporosis of OVX and aged mice. In conclusion, impaired function of Piezo1 in BMSCs leads to insufficient bone formation especially caused by abnormal mechanical stimuli, and is thus a potential therapeutic target for osteoporosis.

Objectives A role for the type II arginine methyltransferase PRMT5 in various human diseases has been identified. In this study, the potential mechanism underlying the involvement of PRMT5 in the pathological process leading to osteoarthritis (OA) was investigated. Methods PRMT5 expression in cartilage tissues from patients with OA and control individuals was assessed by immunohistochemical staining. The regulatory and functional roles of PRMT5 in the chondrocytes of patients with OA and control individuals were determined by western blotting and reverse transcription polymerase chain reaction. The effects of the PRMT5 inhibitor EPZ on interleukin-1β-induced inflammation were examined in the chondrocytes of patients with OA and in the destabilized medial meniscus (DMM) of a mouse model of OA. Results PRMT5 was specifically upregulated in the cartilage of patients with OA. Moreover, adenovirus-mediated overexpression of PRMT5 in human chondrocytes caused cartilage degeneration. This degeneration was induced by elevated expression levels of matrix-degrading enzymes (matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-13 (MMP-13)) in chondrocytes. The activation of the MAPK and nuclear factor κB signaling pathways was evidenced by elevated levels of p-p65, p-p38, and p-JNK. These effects were attenuated by inhibiting the expression of PRMT5. In the mouse model, EPZ inhibited PRMT5 expression, thus protecting mouse cartilage from DMM-induced OA. Conclusions Our results demonstrate that PRMT5 is a crucial regulator of OA pathogenesis, implying that EPZ has therapeutic value in the treatment of this cartilage-destroying disease.

Synovitis has recently been shown to be a critical early stage in development of osteoarthritis (OA), and inhibiting synovitis significantly alleviates OA symptoms. Denosumab, a monoclonal antibody targeting RANKL, previously developed for osteoporosis. Here, we report the effect of denosumab on fibroblast-like synoviocytes (FLSs), attenuating synovitis and consequently OA progression. We first demonstrate that RANKL is highly expressed in the knee synovium of OA mice, as well as in patients. Next, we show that denosumab, injected systemically, accumulates in the synovium and effectively reduces synovitis through RANK/TRAF6/FSTL1 signalling in post-traumatic, inflammatory, and aged OA murine models and a beagle dog OA model, delaying OA progression. Finally, a single-arm clinical trial with primary endpoints of VAS and OKS scores, and secondary endpoints of WOMAC score and adverse events rate, shows that denosumab alleviates synovitis and pain, improving joint function in knee OA patients. These findings provide a translational basis for using denosumab to treat knee OA in the clinic. Synovitis is a key early driver of osteoarthritis (OA), and RANKL contributes to cartilage degradation in OA. Here the authors show that denosumab, an anti-RNKL antibody, reduces synovitis and delays OA progression in animal models and patients.

Periprosthetic joint infection (PJI) is a severe complication following total joint arthroplasty, and the timeliness of its diagnosis and treatment is crucial for patient recovery. Although various biomarkers have been extensively evaluated and applied in clinical practice, the diagnosis of PJI remains challenging. Therefore, it is necessary to identify more precise biomarkers for the diagnosis of PJI. This study aims to investigate the value of ratio-based biomarkers using prealbumin (PA) for the diagnosis of PJI. This study compared the levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen (FIB), PA, CRP/PA (CPR), ESR/PA (EPR), FIB/PA (FPR), and the combined ratio of CPR+EPR+FPR(CEF) in 180 patients with PJI and 105 patients with aseptic loosening (AL) who presented at our department from January 2019 to December 2024. The diagnostic efficacy of these markers in PJI diagnosis was assessed using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Among these biomarkers, CPR has the highest AUC of 0.921 (95%CI 0.890-0.952), and it can distinguish PJI with a cut-off value of 0.0366, a sensitivity of 76.1%, and a specificity of 95.2%. In the diabetic subgroup, the combined biomarker CEF has an AUC of 0.951 for diagnosing PJI, with a sensitivity of 88.9% and a specificity of 94.4%. Ratio-based markers based on PA show promise as valuable new adjunctive diagnostic markers for PJI.