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In individuals afflicted with hemophilia, characterized by a deficiency of coagulation factor VIII (FVIII), the occurrence of spontaneous recurrent intra-articular hemorrhage precipitates the emergence of hemophilic arthropathy (HA). Although clotting factor replacement therapy reduces joint bleeding clinically, clotting factors need to be injected frequently due to the rapid diffusion of the drug. Hence, a novel drug delivery approach may be developed to improve the drug therapy. Platelet-derived extracellular vesicles (PEVs) are known to possess anti-inflammatory and hemostatic properties and could be used as a potential HA therapy. In this study, we constructed a PEV-LS@FVIII nanotherapeutic system by combining thioketal (TK), liposomes (LS), and FVIII to form the LS@FVIII complexes, and then hybridizing PEV with LS@FVIII. Our results demonstrated that PEV-LS@FVIII could efficiently facilitate FVIII delivery and specifically target the injured knee joint. Both in vitro and in vivo studies showed a reduction in the M1 phenotype of macrophages and an enhancement of the M2 phenotype, compared to FVIII free control. Furthermore, PEV-LS@FVIII appeared to alleviate HA-induced cartilage damage. In conclusion, our findings demonstrate that PEV-LS@FVIII could delay the progression of HA by targeting bleeding joints, modulating macrophage polarization to suppress inflammation, and mitigating cartilage damage.

Background Patients with mismatch repair-deficient (MMRd) endometrial cancer (EC) can derive great benefit from immune checkpoint inhibitors (ICI). However not all responses and predictors of primary resistance are lacking.Methods We compared the immune tumor microenvironment of MMRd EC ICI-responders (Rs) and ICI non-responders (NRs), using spatial multiplexed immune profiling and unsupervised hierarchical clustering analysis.Results Overall, NRs exhibited drastically lower CD8+, absent terminally differentiated T cells, lack of mature tertiary lymphoid structures and dendritic cells, as well as loss of human leukocyte antigen class I. However, no single marker could predict R versus NR with confidence. Clustering analysis identified a combination of four immune features that demonstrated that accurately predicted ICI response, with a discriminative power of 92%. Finally, 80% of NRs lacked programmed death-ligand 1, however, 60% exhibited another actionable immune checkpoint (T-cell immunoglobulin and mucin containing protein-3, indoleamine 2,3-dioxygenase 1, or lymphocyte activation gene 3).Conclusions These findings underscore the potential of immune tumor microenvironment features for identifying patients with MMRd EC and primary resistance to ICI who should be oriented towards trials testing novel immunotherapeutic combinations.

Abstract Purpose Previous studies have shown that DNA methyltransferase 3b (Dnmt3b) is the only Dnmt responsive to fracture repair and Dnmt3b ablation in Prx1-positive stem cells and chondrocyte cells both delayed fracture repair. Our study aims to explore the influence of Dnmt3b ablation in Gli1-positive stem cells in fracture healing mice and the underlying mechanism. Methods We generated Gli1-CreERT2; Dnmt3bflox/flox (Dnmt3b Gli1ER ) mice to operated tibia fracture. Fracture callus tissues of Dnmt3b Gli1ER mice and control mice were collected and analyzed by X-ray, micro-CT, biomechanical testing, histopathology and TUNEL assay. Results The cartilaginous callus significantly decrease in ablation of Dnmt3b in Gli1-positive stem cells during fracture repair. The chondrogenic and osteogenic indicators (Sox9 and Runx2) in the fracture healing tissues in Dnmt3b Gli1ER mice much less than control mice. Dnmt3b Gli1ER mice led to delayed bone callus remodeling and decreased biomechanical properties of the newly formed bone during fracture repair. Both the expressions of Caspase-3 and Caspase-8 were upregulated in Dnmt3b Gli1ER mice as well as the expressions of BCL-2. Conclusions Our study provides an evidence that Dnmt3b ablation Gli1-positive stem cells can affect fracture healing and lead to poor fracture healing by regulating apoptosis to decrease chondrocyte hypertrophic maturation.

Abstract Deep Learning (DL) can predict biomarkers from cancer histopathology. Several clinically approved applications use this technology. Most approaches, however, predict categorical labels, whereas biomarkers are often continuous measurements. We hypothesize that regression-based DL outperforms classification-based DL. Therefore, we develop and evaluate a self-supervised attention-based weakly supervised regression method that predicts continuous biomarkers directly from 11,671 images of patients across nine cancer types. We test our method for multiple clinically and biologically relevant biomarkers: homologous recombination deficiency score, a clinically used pan-cancer biomarker, as well as markers of key biological processes in the tumor microenvironment. Using regression significantly enhances the accuracy of biomarker prediction, while also improving the predictions’ correspondence to regions of known clinical relevance over classification. In a large cohort of colorectal cancer patients, regression-based prediction scores provide a higher prognostic value than classification-based scores. Our open-source regression approach offers a promising alternative for continuous biomarker analysis in computational pathology.

Abstract Low back pain (LBP) is a common orthopedic disease over the world. Lumbar intervertebral disc degeneration (IDD) is regarded as an important cause of LBP. Shensuitongzhi formula (SSTZF) is a drug used in clinical treatment for orthopedic diseases. It has been found that SSTZF can have a good treatment for IDD. But the exact mechanism has not been clarified. The results showed that SSTZF protects against LSI-induced degeneration of cartilage endplates and intervertebral discs. Meanwhile, SSTZF treatment dramatically reduces the expression of inflammatory factor as well as the expression of catabolism protein and upregulates the expression of anabolism protein in LSI-induced mice. In addition, SSTZF delayed the progression of LSI-induced IDD via downregulation the level of NF-κB signaling key gene RELA and phosphorylation of key protein P65 in endplate chondrocytes. Our study has illustrated the treatment as well as the latent mechanism of SSTZF in IDD.

Abstract Primary liver cancer arises either from hepatocytic or biliary lineage cells, giving rise to hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICCA). Combined hepatocellular- cholangiocarcinomas (cHCC-CCA) exhibit equivocal or mixed features of both, causing diagnostic uncertainty and difficulty in determining proper management. Here, we perform a comprehensive deep learning-based phenotyping of multiple cohorts of patients. We show that deep learning can reproduce the diagnosis of HCC vs. CCA with a high performance. We analyze a series of 405 cHCC-CCA patients and demonstrate that the model can reclassify the tumors as HCC or ICCA, and that the predictions are consistent with clinical outcomes, genetic alterations and in situ spatial gene expression profiling. This type of approach could improve treatment decisions and ultimately clinical outcome for patients with rare and biphenotypic cancers such as cHCC-CCA.

Recurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N=5) and osteoarthritis (OA) (N=5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss of Tnxb in F8-/- mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss. Tnxb knockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects following Tnxb knockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.

Postmenopausal Osteoporosis (PMOP) is the most prevalent primary osteoporosis, attributable to an imbalance in osteoblast and osteoclast activity. Modified You-Gui-Yin (MYGY), a traditional Chinese herbal formula, is able to effectively treat PMOP, while the critical components and pharmacological mechanisms of MYGY are still unclear. In this study, we aimed to investigate the therapeutic effects and underlying mechanisms of N-butanol extract of MYGY (MYGY-Nb) in ovariectomized (OVX)-induced osteoporosis mice. Histological staining and micro-computed tomography (μCT) analysis showed that MYGY-Nb was more effective in the suppression of OVX-induced bone loss than MYGY original formula. Subsequently, liquid chromatography and mass spectrometry analysis identified 16 critical compounds of MYGY-Nb and some of them are reported to affect osteoclast functions. Furthermore, in vivo and in vitro experiments demonstrated that MYGY-Nb significantly attenuated osteoclastogenesis by down-regulating RANKL-mediated NF-κB signaling. In conclusion, our study indicated that MYGY-Nb suppresses NF-κB signaling and osteoclast formation to mitigate bone loss in PMOP, implying that MYGY-Nb and its compounds are potential candidates for development of anti-PMOP drugs.

A three-dimensional stratum model stratum model is a useful auxiliary tool for geotechnical engineering and other exploration work. The existing methods for stratum model construction lack complete topological descriptions of entities, so it is difficult to apply them to 3D geological modeling with complex geometric structures and complex topological relationships between modules. To solve the above problem, in this paper, the boundary representation method is used to represent the arbitrarily-shaped geological entities, and the half winged-edge-face structure topological structure is proposed to describe the topological information of the stratum model for a complex entity. The topological structure can record the topological information of the solid stratum model completely, thereby providing the basis for operations with the model and the applications of various algorithms. Based on this topological structure, the construction process for a 3D solid stratum model is proposed. The reliability and effectiveness of the constructed 3D solid stratum model are verified by an engineering case. The solid stratum model not only solves the geological modeling problem with respect to complex geometric and topological relations, but also provides a new method and idea for 3D geological modeling.

Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by homogentisc acid (HGA) accumulation, the deposition of which in the joints usually causes ochronotic arthropathy. With no specific therapy for AKU currently, total joint arthroplasty in ochronotic arthropathy is applied to relieve the symptoms. A 63-year-old female patient came to our Orthopedic Surgery Department in 2019, complaining of severe limitation of movement and pain in the right hip for more than one year. A right total hip arthroplasy (THA) was performed due to the ineffective conservative therapy. At a follow-up of more than 15 months, the woman had full mobility with no complaining of pains. Since there is no relevant case reported about THA therapy for Chinese AKU patients, this report provides a feasible scheme, which makes clinical data more comprehensive.

Background: Shen-sui-tong-zhi formula (SSTZF) has been used to treat osteoporosis for decades and shows excellent clinical efficacy. This article aims to explore the optimal anti-osteoporotic ingredient and its precise mechanisms in mice models.Methods: In this study, we first screened the optimal anti-osteoporosis fraction of SSTZF extract in vivo, and then further explored the mechanism of its effects both in vivo and in vitro. Ten-week-old female C57BL/6J mice were administrated with each fraction of SSTZF. At 10 weeks after ovariectomy (OVX), femurs were collected for tissue analyses, including histology, micro-CT, biomechanical tests, and immunohistochemistry for ALP, FABP4, and β-catenin. Additionally, we also evaluated the mRNA expression level of ALP and FABP4 and the protein expression level of β-catenin after being treated with SSTZF extract in C3H10T1/2 cells. Moreover, we investigated the anti-osteoporosis effect of SSTZF extract on mice with β-catenin conditional knockout in growth plate chondrocytes (β-cateninGli1ER mice) through μCT, histology, and immunohistochemistry analyzes.Results: At 10 weeks after treatment, osteoporosis-like phenotype were significantly ameliorated in SSTZF n-butanol extract (SSTZF-NB) group mice, as indicated by increased trabecular bone area and ALP content, and decreased lipid droplet area and FABP4 content. No such improvements were observed after being treated with other extracts, demonstrating that SSTZF-NB is the optimal anti-osteoporosis fraction. Additionally, the elevated β-catenin was revealed in both OVX mice and C3H10T1/2 cells with SSTZF-NB administered. Furthermore, a significant osteoporosis-like phenotype was observed in β-cateninGli1ER mice as expected. However, SSTZF-NB failed to rescue the deterioration in β-cateninGli1ER mice, no significant re-upregulated ALP and downregulated FABP4 were observed after being treated with SSTZF-NB, demonstrating that SSTZF-NB prevents bone loss mainly via β-catenin signaling.Conclusion: SSTZF-NB enhances osteogenesis mainly via activation of β-catenin signaling in growth plate chondrocytes. SSTZF-NB is the optimal anti-osteoporosis fraction of SSTZF and it can be considered a salutary alternative therapeutic option for osteoporosis.

The mechanical performance analysis of the members is the primary basis for evaluating the hoisting quality and safety of the valve hall grid structure. Ordinarily, manual analysis of monitoring data and on-site experience inspection are employed to structural judgment, but it is challenging to evaluate the correlation of the various members and the overall safety of a valve hall. In this paper, an intelligent correlation real-time analysis method based on a BPNN (Back Propagation Neural Network) for the mechanical properties of members is proposed to intelligently control the safety of valve hall grid structure hoisting. The correlation between the mechanical properties of multi-points in the grid structure is used to model the target measuring points. In addition, an intelligent real-time analysis system is used to manage and apply the mechanical property correlation and abnormality of members in real-time. Then, the model is applied to a super-span valve hall in South China, and the application effect is good. The mechanical property correlation model can accurately reflect the mechanical state of the valve hall grid structure hoisting process. Simultaneously, it can effectively pinpoint hidden dangers and locate risk members. It provides a new reference for the normal operation and maintenance of a super-span valve hall grid.

Osteoarthritis (OA) is a common disease characterized by cartilage degeneration. In recent years much attention has been paid to Traditional Chinese Medicine (TCM) since its treatments have shown efficacy for ameliorating cartilage degradation with mild side effects. Osteoking is a TCM prescription that has long been used in OA treatment. However, the exact mechanism of Osteoking are not fully elucidated. In the current study, destabilization of the medial meniscus (DMM)-induced OA mice was introduced as a wild type animal model. After 8 weeks of administration of Osteoking, histomorphometry, OARSI scoring, gait analysis, micro-CT, and immunohistochemical staining for Col2, MMP-13, TGFβRII and pSmad-2 were conducted to evaluate the chondroprotective effects of Osteoking in vivo. Further in vitro experiments were then performed to detect the effect of Osteoking on chondrocytes. TGFβRIICol2ER transgenic mice were constructed and introduced in the current study to validate whether Osteoking exerts its anti-OA effects via the TGF-β signaling pathway. Results demonstrated that in wild type DMM mice, Osteoking ameliorated OA-phenotype including cartilage degradation, subchondral bone sclerosis, and gait abnormality. Col2, TGFβRII, and pSmad-2 expressions were also found to be up-regulated after Osteoking treatment, while MMP-13 was down-regulated. In vitro, the mRNA expression of MMP-13 and ADAMTS5 decreased and the mRNA expression of Aggrecan, COL2, and TGFβRII were up-regulated after the treatment of Osteoking in IL-1β treated chondrocytes. The additional treatment of SB505124 counteracted the positive impact of Osteoking on primary chondrocytes. In TGFβRIICol2ER mice, spontaneous OA-liked phenotype was observed and treatment of Osteoking failed to reverse the OA spontaneous progression. In conclusion, Osteoking ameliorates OA progression by decelerating cartilage degradation and alleviating subchondral bone sclerosis partly via the TGF-β signaling pathway.

Postmenopausal osteoporosis (PMOP) is a type of bone metabolism disease-related to estrogen deficiency with an increasing incidence. Traditional Chinese (TCM) has always been used and showed effectiveness in treating PMOP. In the current study, Bu-Yang herbs were considered to be the most frequently used and efficient TCM herbs in PMOP treatment. However, chemical and pharmacological profiles were not elucidated. Network pharmacology was conducted on representative Bu-Yang herbs (Yin-Yang-Huo. Du-Zhong, Bu-Gu-Zhi, Tu-Si-Zi) to investigate the mechanism of Bu-Yang herbs on PMOP. Chemical compounds, potential targets, and disease related genes were available from the corresponding database. Results showed that Bu-Yang herbs could interact with ESR1 and estrogen signaling pathways. For further validation, the Bu-Yang decoction (BYD), formula consisted of the above-mentioned 4 Bu-Yang herbs was presented for experimental validation. In vivo, BYD significantly reversed ovariectomy (OVX)-induced osteoporosis progress in a dose-dependent manner by up-regulation of bone mineral density and amelioration of bone microarchitecture. In vitro, BYD dramatically improved the proliferation and mineral nodules formation of osteoblasts. Both in vitro and in vivo results illustrated that the phenotype change induced by BYD is correlated with up-regulated of ESR1 and activation of the β-catenin pathway. Meanwhile, inhibition of ESR1 by ICI182, 780 blocked the osteogenic phenotype and β-catenin pathway activation induced by BYD. In conclusion, the current study suggested that Bu-Yang herbs are the most useful TCM herbs in treating PMOP. Furthermore, the integrated strategy of network pharmacology prediction with experimental validation suggested that BYD exerted its anti-PMOP via ESR1 and the downstream mechanism might be activation of the β-catenin signaling pathway.

Three-dimensional intelligent engineering management and control systems (EMCS) based on the browser/server (B/S) model are an important part of intelligent engineering development. These systems are used for solving the difficulties encountered in engineering management with frequent cross-specialties and are vital tools for data exchange and service sharing among multiple departments. Currently, most engineering management and control systems are based on service-oriented architectures (SOAs). The integration mechanism and high coupling of SOAs leads to the reduction in system expansibility, service quality and service safety of the engineering system, making it difficult for these architectures to serve the construction of long-span valve hall engineering. To address these concerns, the management and application technology of the multidisciplinary data of valve hall engineering based on a microservice architecture (MSA) is proposed to improve the management efficiency of engineering data. A 3D integration modeling method for valve hall engineering structures and geological environments is proposed to establish the topological association between engineering structures and geological environments, without increasing the amount of model data required. A 3D intelligent engineering management and control technology for the entire process of the construction of long-span valve hall engineering is proposed, which realizes the entire process simulation and control of engineering construction based on WebGL technology. Accordingly, a three-dimensional intelligent engineering management and control system for the entire construction process of a long-span valve hall project in Southeast China is established, which can effectively manage and apply the data, display and analyze the three-dimensional model, and control and make decisions regarding the construction schedule. This study provides support for the construction of "smart engineering", promotes information communication and transmission between different project units, and speeds up the transformation from traditional construction management relying on drawings to three-dimensional intelligent construction management based on cloud services.

In the process of using a long-span converter station steel structure, engineering disasters can easily occur. Structural monitoring is an important method to reduce hoisting risk. In previous engineering cases, the structural monitoring of long-span converter station steel structure hoisting is rare. Thus, no relevant hoisting experience can be referenced. Traditional monitoring methods have a small scope of application, making it difficult to coordinate monitoring and construction control. In the monitoring process, many problems arise, such as complicated installation processes, large-scale data processing, and large-scale installation errors. With a real-time structural monitoring system, the mechanical changes in the long-span converter station steel structure during the hoisting process can be monitored in real-time in order to achieve real-time warning of engineering disasters, timely identification of engineering issues, and allow for rapid decision-making, thus avoiding the occurrence of engineering disasters. Based on this concept, automatic monitoring and manual measurement of the mechanical changes in the longest long-span converter station steel structure in the world is carried out, and the monitoring results were compared with the corresponding numerical simulation results in order to develop a real-time structural monitoring system for the whole long-span converter station steel structure’s multi-point lifting process. This approach collects the monitoring data and outputs the deflection, stress, strain, wind force, and temperature of the long-span converter station steel structure in real-time, enabling real-time monitoring to ensure the safety of the lifting process. This research offers a new method and basis for the structural monitoring of the multi-point hoisting of a long-span converter station steel structure.