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Frozen shoulder (FS) manifests as progressively worsening pain and a reduction in shoulder range of motion (ROM). Salvianolic acid B (SaB) is recently expected to be used in the treatment of fibrosis diseases including FS. We firstly demonstrate that SaB can effectively hinder the progression of oxidative stress, inflammation, and pathological fibrosis within the synovial tissue in FS, potentially leading to the reduction or reversal of capsule fibrosis and joint stiffness. For further clinical application, we design and synthesize a novel, superior, antioxidant and antibacterial CSMA-PBA/OD-DA (CPDA) hydrogel for the delivery of SaB. In vitro experiments demonstrate that the CPDA hydrogel exhibits excellent biocompatibility and rheological properties, rendering it suitable for intra-articular injections. Upon injection into the contracted joint cavity of FS model rat, the SaB-CPDA hydrogel accelerate the recovery of ROM and exhibit superior anti-fibrosis effect, presenting the promise for the treatment of FS in vivo.

Graph neural networks (GNNs) are extensively utilized to capture the spatial–temporal relationships among human body parts for skeleton-based action recognition. However, due to the inefficient information propagation caused by redundant sampling of video frames in the temporal domain, we focus on refining temporal graphs through key frame selection. To this end, we propose a multi-stage key frame selection (MSKFS) method, aiming to find the most representative frames as the graph nodes to learn compact temporal graph representations of human skeletons for action recognition. The MSKFS progressively selects key frames in two stages: (1) salient posture frame selection based on the global dynamics of body parts and (2) key frame refinement and alignment according to intra-frame correlations. The first stage captures the most salient information and aligns the corresponding information of skeleton sequences within the same category. The second stage enriches the subtle information for the integrity of the information derived by the salient frames. Moreover, variational inference is applied to differentiate the key frame refinement and alignment procedure, allowing the end-to-end optimization of arbitrary graph-based models to represent the obtained compact graph for skeleton-based action recognition. Our MSKFS method achieves state-of-the-art performances on two challenging action recognition datasets.

Abstract Objective Develop and evaluate an ensemble clinical machine learning–deep learning (CML-DL) model integrating deep visual features and clinical data to improve the prediction of supraspinatus/infraspinatus tendon complex (SITC) injuries. Methods Patients with suspected SITC injuries were retrospectively recruited from two hospitals, with clinical data and shoulder x-ray radiographs collected. An ensemble CML-DL model was developed for diagnosing normal or insignificant rotator cuff abnormality (NIRCA) and significant rotator cuff tear (SRCT). All patients suspected with SRCT were confirmed by arthroscopy examination. The model’s performance was evaluated using sensitivity, specificity, accuracy, and area under the curve (AUC) metrics, and a two-round assessment was conducted to authenticate its clinical applicability. Results A total of 974 patients were divided into three cohorts: the training cohort (n = 828), the internal validation cohort (n = 89), and the external validation cohort (n = 57). The CML-DL model, which integrates clinical and deep visual features, demonstrated superior performance compared to individual models of either type. The model’s sensitivity, specificity, accuracy, and area under curve (95% confidence interval) were 0.880, 0.812, 0.836, and 0.902 (0.858–0.947), respectively. The CML-DL model exhibited higher sensitivity and specificity compared to or on par with the physicians in all validation cohorts. Furthermore, the assistance of the ensemble CML-DL model resulted in a significant improvement in sensitivity for junior physicians in all validation cohorts, without any reduction in specificity. Conclusions The ensembled CML-DL model provides a solution to help physicians improve the diagnosis performance of SITC injury, especially for junior physicians with limited expertise. Critical relevance statement The ensembled clinical machine learning–deep learning (CML-DL) model integrating deep visual features and clinical data provides a superior performance in the diagnosis of supraspinatus/infraspinatus tendon complex (SITC) injuries, particularly for junior physicians with limited expertise. Key points 1. Integrating clinical and deep visual features improves diagnosing SITC injuries. 2. Ensemble CML-DL model validated for clinical use in two-round assessment. 3. Ensemble model boosts sensitivity in SITC injury diagnosis for junior physicians. Graphical Abstract

The development of deep learning techniques and support of big data computing power have revolutionized graph representation research by facilitating the implementation of the learning of different graph neural network structures. Existing methods, such as graph attention networks, mainly focus on global information propagation in graph neural networks, which have theoretically proven their strong representation capability. However, these general methods lack flexible representation mechanisms when facing graph data with local topology involving specific semantics, such as functional groups in the chemical reaction. Accordingly, it is of great importance to further exploit the local structure representations for graph-based tasks. Several existing methods either use domain expert knowledge or conduct subgraph isomorphism counting to learn local topology representations of graphs. However, there is no guarantee that these methods can easily be generalized to different domains without specific knowledge or complex substructure preprocessing. In this study, we propose a simple and automatic local topology inference method that uses variational convolutions to improve the local representation ability of graph attention networks. The proposed method not only considers the relationship reasoning and message passing on the global graph structure but also adaptively learns the graph’s local structure representations with the guidance of statistical priors that can be readily accessible. To be more specific, the variational inference is used to adaptively learn the convolutional template size, and the inference is conducted layer-by-layer with the guidance of the statistical priors to make the convolutional template size adaptable to multiple subgraphs with different structures in a self-supervised way. The variational convolution module is easily pluggable and can be concatenated with arbitrary hidden layers of any graph neural network. In contrast, due to the locality of the convolution operations, the relations between graph nodes can be further sparse to alleviate the over-squeezing problem in the global information propagation of the graph neural network. As a result, the proposed method can significantly improve the overall representation ability of the graph attention network using the variational inference of the convolutional operations for local topology representation. Experiments are conducted on three large-scale and publicly available datasets, i.e., the OGBG-MolHIV, USPTO, and Buchwald-Hartwig datasets. Experimental results show that exploiting various kinds of local topological information helps improve the performance of the graph attention network.

Abstract Background Lateral, All-Round and All-Inside (LARAI) portal is a viewing or working portal for observing and repairing the lesions of the lateral meniscus. However, there are safety concerns about popliteal artery (PA) injuries during the procedure. This study aimed to assess the safe distance between the trajectory of the LARAI portal and PA. Materials and methods Both three-dimensional computed tomography (3D-CT) and cadavers were used to simulate the LARAI portal trajectory. In the 3D-CT study, between January 2020 and September 2020, 45 participants who underwent computed tomography angiography were included in the study. The shortest distance from the PA to the simulated trajectory needle (PS) was measured using 3D-CT. Mean −3SD −2 was calculated to assess the safety of the LARAI portal trajectory. If this value was more than zero, the trajectory was considered “safe.” In the cadaveric study, lower limbs from seven fresh-frozen cadavers were used to establish the “safe” trajectories of the LARAI portal, and the PS was measured. Results In the 3D-CT study, the longest PS (P

Objective Patch technology has been the new technique in the treatment of partial thickness of the rotator cuff tear (PTRCTs) to address the limitation of traditional techniques. Compared with allogeneic patches and artificial materials, coracoacromial ligament is obviously closer to their own biology. The purpose of the study was to evaluate the functional and radiographic outcomes following arthroscopic autologous coracoacromial ligament augment technique for treatment of PTRCTs. Method This study included three female patients with PTRCTs who underwent arthroscopy operation in 2017 with an average age of 51 years (range from 50 to 52 years). The coracoacromial ligament implant was attached to the bursal side surface of the tendon. The clinical results were evaluated by American Shoulder and Elbow Surgeons (ASES) score, Simple Shoulder Test (SST), acromiohumeral distance (AHD) and muscle strength before and 12 months after operation. Magnetic resonance imaging (MRI) was performed 24 months after operation to assess the integrity of the anatomical structure of the original tear site. Result The average ASES score improved significantly from 57.3 preoperatively to 95.0 at 1‐year follow‐up. The strength improved significantly from grade 3 preoperatively to grade 5 at 1 year. Two of three patients underwent the MRI at 2‐year follow‐up. Radiographic released the complete healing of rotator cuff tear. No implant‐related serious adverse events were reported. Conclusion The new technique of using autogenous coracoacromial ligament patch augment provides good clinical results on patients with PTRCTs.

Objective Anteroposterior (AP) radiographs do not necessarily offer the optimal approach to measuring the critical shoulder angle (CSA) due to the malposition of the scapula. Three‐dimensional computed tomography (3D‐CT) may offer some advantages, including the ability to rotate the scapula for position alignment and pre‐operative planning for reducing CSA. This study aimed to investigate the accuracy and reliability of CSA measurement in 3D‐CT and to determine whether there is an association between CSA and rotator cuff tears (RCTs). Methods In this retrospective study we identified 200 patients who received shoulder arthroscopy from 2019 to 2021, including 142 patients (81 females, 61 males) with RCTs and 58 patients (14 females, 44 males) with non‐RCTs. For each participant, CSA was measured from standard shoulder AP radiographs and anterior views of 3D‐CT of the scapula by two independent assessors. Inter‐ and intra‐observer agreements were assessed by the intraclass correlation coefficient (ICC). The relationship between the two measurement methodologies was determined by Spearman's correlation coefficient and Bland–Altman plots. Discriminative capacity was calculated by using receiver operating curve (ROC) analyses in the whole cohort and age sub‐groups above and below 45 years. Results We found perfect inter‐observer (ICC >0.96) and intra‐observer (ICC >0.97) reliabilities for CSA measurements obtained from the standard AP radiographs and the 3D‐CT. There was a strong correlation between the two methods (r = 0.960, P

Graphical Abstract In this Editorial, our Chief Editor and members of our Advisory Editorial Board discuss recent breakthroughs, current challenges, and emerging opportunities in single‐cell biology and share their vision of “where the field is headed.”

Objective Strong tendon grasping is vital to the success of a tenodesis operation. The purpose of this study was to evaluate the initial tendon‐fixation strength of the Lark‐Loop technique in arthroscopic suprapectoral biceps tenodesis and compare it with others commonly used techniques. Methods Thirty‐three porcine superficial flexor digitorum tendons were harvested from a local slaughterhouse and randomly divided into three groups to perform three tendon fixation techniques (Lasso‐Loop stich group, Lark‐Loop stich group or Krackow stich group; 11 tendons each group) with a No. 2 suture, respectively. Each tendon was pre‐tensioned in 5°N for 2 min and then cyclically loaded 5 to 30°N for 500 cycles to assess displacement. After cyclic loading, the tendon was loaded to ultimate tendon‐suture configuration failure at the rate of 1 mm/s. Finally, the mode of failure and the construct stiffness of the tendon were recorded and calculated. Results After cyclical loading, the displacement of the Lark‐Loop group was equivalent to the Krakow group (P > 0.9999) but significantly smaller than the Lasso‐Loop group (P = 0.0009). The ultimate load to failure for the Lark‐Loop was equivalent to the Krakow technique group (P = 0.1463) but significantly greater than the Lasso‐Loop group (P

Arthroscopic rotator cuff repair is one of the most painful surgical procedures; patients complain of pain especially during the first 48 hours postoperatively. Pain management is an essential goal to reduce the demand for analgesic agents and patient discomfort. Various methods have been introduced for arthroscopic rotator cuff repair, including continuous arthroscopy-guided suprascapular nerve blocks (SSNB) and interscalene nerve blocks. However, the aforementioned procedures have shown disadvantages such as catheter mobilization, which may cause injury to the artery, a weak analgesic effect, and Horner syndrome, as well as phrenic nerve paralysis. A modification of the continuous arthroscopy-guided SSNB has been introduced at our hospital: the modified continuous arthroscopy-guided SSNB technique. The aim of this technique is to immobilize the catheter to reduce the chance of injury and minimize postsurgical analgesic needs and patient discomfort.

Abstract Objective The absence of patellar ligament will bring about a severe negative impact on daily life. Many reconstruction techniques have been described in adults. However, there is a lack of technical introduction regarding the reconstruction of the patellar ligament in children. The purpose of this study was to report a surgical technique for reconstructing the patellar ligament in children. Method A retrospective analysis of the clinical data on a patellar ligament (tendon sheath fibroma) patient with allogeneic tendon reconstruction. An 8‐year‐old child with postoperative recurrence of left patellar ligament tumor was enrolled in our study. Anterior tibialis tendon allograft was used to reconstruct the patellar ligament after complete resection of the patellar ligament for the tumor. The tunnels were constructed on the deep surface of the tibial tubercle and the root of the quadriceps tendon (to decrease the harmful impact on patella development), respectively. The allogeneic tendon was passed through the tunnels above in the shape of “8,” and the two ends of the tendon were attached to the bleeding bone bed at the inferior edge of the patella with suture anchors to achieve better bone‐tendon healing. During the follow‐up, the knee's range of motion and imaging manifestations were recorded. Result Postoperative pathology suggests chondromesenchymal hamartoma, a rare benign soft tissue tumor different from the previous operation (tendon sheath fibroma). During the 4‐year follow‐up, the patient's active range of motion of the knee achieved 0° to 120°; and the patient could walk normally without any external help. Physical examinations (the apprehension sign and J sign) showed no ligamentous instability or patellar ligament tenderness. Imaging analysis showed that the ratio length of the patellar ligament to the patella was almost normal. The integrity, continuity, and shape of the allogeneic ligament showed excellent results in MRI. Combined with clinical and imaging findings, allogeneic tendon patellar ligament reconstruction was deemed successful. Conclusion Allogeneic ligament reconstruction technique can provide a treatment option by reconstructing the extensor mechanism, minimizing the impact on patellar development, and augmenting biological healing for children with the absence of the patellar ligament.

Frozen shoulder (FS) is characterized by pain and limited range of motion (ROM). Inflammation and fibrosis are accepted as main pathologic processes associated with the development of FS. However, the intrinsic mechanisms underlying pathologic fibrosis remain unclear. We aimed to elucidate the key molecules involved in pathologic fibrosis and explore new therapeutic targets for FS. Synovial fibroblasts isolated from patient biopsies were identified using immunofluorescence. Western blotting, RT-qPCR, cell adhesion tests, and would-healing assays were used to evaluate the fibrosis-related functions of synovial fibroblasts. Elevated cluster of differentiation 36 (CD36) expression was detected in FS using Western blotting and immunohistochemistry. Salvianolic acid b (SaB) inhibited CD36, blocking synovial fibroblast-induced inflammation and fibrosis. Our RNA-seq data showed that knocking down CD36 dramatically impaired the capacity of synovial fibroblasts for cell adhesion and that the PI3K-Akt signaling pathway may be crucial to the fibrotic process of FS. By up-regulating CD36 and inhibiting the phosphorylation of Akt, we demonstrated that CD36 promotes pathologic fibrosis by activating the PI3k-Akt pathway. Finally, rats treated with SaB had improved ROM and less collagen fiber deposition than the FS model group.Conclusion: SaB attenuates inflammation and inhibited the CD36-mediated activation of the PI3K-Akt signaling pathway to block pathologic fibrosis of FS in vitro and in vivo models.

Abstract Background Butyrate is a major subgingival microbial metabolite that is closely related to periodontal disease. It affects the proliferation and differentiation of mesenchymal stem cells. However, the mechanisms by which butyrate affects the osteogenic differentiation of periodontal ligament stem cells (PDLSCs) remain unclear. Here, we investigated the effect of sodium butyrate (NaB) on the osteogenic differentiation of human PDLSCs. Methods PDLSCs were isolated from human periodontal ligaments and treated with various concentrations of NaB in vitro. The cell counting kit-8 assay and flow cytometric analysis were used to assess cell viability. The osteogenic differentiation capabilities of PDLSCs were evaluated using the alkaline phosphatase activity assay, alizarin red staining, RT-PCR, western blotting and in vivo transplantation. Results NaB decreased PDLSC proliferation and induced apoptosis in a dose- and time-depend manner. Additionally, 1 mM NaB reduced alkaline phosphatase activity, mineralization ability, and the expression of osteogenic differentiation-related genes and proteins. Treatment with a free fatty acids receptor 2 (FFAR2) antagonist and agonist indicated that NaB inhibited the osteogenic differentiation capacity of PDLSCs by affecting the expression of Smad1. Conclusion Our findings suggest that NaB inhibits the osteogenic differentiation of PDLSCs by activating FFAR2 and decreasing the expression of Smad1.

Abstract This case report describes a 21‐year‐old orthodontic patient experienced the external apical root resorption of maxillary central incisors with pulpitis during the orthodontic movement. The active cooperation of orthodontists and endodontists demonstrated the satisfactory treatment outcome and prevented further apical root resorption. The etiology of external apical root resorption is comprehensive, orthodontists should be armed with an adequate training and scientific knowledge, and keep the treatment mechanism simple and precise to guard against it. Besides, we should know the right timing of endodontic treatment and applying orthodontic force when external apical root resorption occurs.

Background: The regimens of immune checkpoint inhibitors (ICIs) alone or with chemotherapy are emerging as systemic therapy for patients with advanced and metastatic gastrointestinal cancers. However, the risk of treatment-related hematologic toxicity stays unclear.Methods: We enrolled in phase 3 randomized clinical trials (RCTs) comparing PD-1, PD-L1, and CTLA-4 inhibitors in advanced and metastatic gastrointestinal cancers. The incidences of overall treatment-related adverse events (TRAEs), discontinuation, leukopenia, neutropenia, thrombocytopenia, and anemia were extracted for the Bayesian network meta-analysis. Analyses with poor convergence or low incidence were reported as incidences with 95% CIs instead.Results: Sixteen phase 3 RCTs with 9732 patients who received systemic therapy were included. A total of 150 (1.54% [95% CI 1.31–1.80]) treatment-related death events were recorded, whereas 13 (0.13% [95% CI 0.08–0.22]) of them were hematologic. 0.24% (95% CI 0.12–0.48) patients received ICI plus chemotherapy were recorded for hematological deaths, 0.09% (95% CI 0.01–0.23) were for chemotherapy alone, and 0.05% were for ICI alone (95% CI 0.01–0.29). Febrile neutropenia was the most frequent cause of death in ICI with chemotherapy. For grade ≥3 TRAEs, we found nivolumab plus chemotherapy (OR 1.63 [95% CI 0.84–3.17]) had a higher risk than other treatments. Overall, ICI monotherapy led to fewer AEs than chemotherapy-based regimens in the analyses of leukopenia, neutropenia, thrombocytopenia, and anemia. Among the 11 treatments, toripalimab plus chemotherapy possessed the highest risk in any-grade leukopenia (OR 1.84 [95% CI 0.48, 6.82]) and neutropenia (OR 1.71 [95% CI 0.17, 17.40]) respectively. For grade ≥3 hematologic AEs, neutropenia (20.08% [95% CI 18.67–21.56]) related to ICI plus chemotherapy was the most dominant. ICI plus chemotherapy was likely to increase the incidence than dosing these drugs alone.Conclusion: Using ICI alone had a low incidence of causing hematologic mortality and AEs, while the combination with chemotherapy might magnify the side effects. Comprehensively, pembrolizumab plus chemotherapy and sintilimab plus chemotherapy were the safest regimens in terms of leukopenia and neutropenia respectively. This study will guide clinical practice for ICI-based chemotherapy.Systematic Review Registration: PROSPERO, identifier CRD42022380150

Objective To determine the functional outcomes after a novel method of H‐loop knotless double‐row technique in patients with rotator cuff tears. Method From June 2020 to September 2020, a total of six patients (five women, one man) with arthroscopic rotator cuff repair using the H‐loop knotless double‐row technique were enrolled in our study. The average age is 54 years (range: 50–61 years). The preoperative and final follow‐up clinical outcome were evaluated using the American Shoulder and Elbow Surgeons (ASES) score, visual analog scale (VAS), University of California Los Angeles (UCLA) score, and Constant–Murley score. The active shoulder range of motion (ROM) was also collected preoperatively and postoperatively at the final follow‐up (forward flexion and abduction). Accordingly, intraoperative and postoperative complications were observed as well. Result There were six patients that underwent arthroscopic rotator cuff repair using the H‐loop knotless double‐row technique. The average follow‐up period was 7.52 ± 0.70 months. The VAS, UCLA, ASES, and Constant–Murley scores improved from 5 ± 2.45, 15.67 ± 3.44, 47.67 ± 17.41 and 49.17 ± 8.98 preoperatively, to 0.83 ± 0.75, 36.27 ± 3.83, 91.67 ± 10.76 and 85.83 ± 4.31 at the final follow‐up, with statistical significances of P = 0.009, P

IntroductionSuprapectoral tenodesis is a common technique for the treatment of long head biceps tendon lesions. However, so far, there is no gold standard treatment in all-inside arthroscopy. The purpose of the present study was to introduce and evaluate the functional outcomes of an innovative, all-inside arthroscopic high resistance loop (H-loop, high resistance to tissue cutout and 360° grasping of the tendon) technique for long head of biceps (LHB) tenodesis.MethodFrom September 2020 to March 2022, a series of cases of 32 consecutive patients (28 rotator cuff tear with LHBT pathology and 4 superior labrum anterior-posterior (SLAP) tears which including 2 type II and 2 type IV) who received LHB tenodesis using all-inside arthroscopic high resistance loop technique were included in this study. The American Shoulder and Elbow Surgeon Score (ASES), Visual Analog Scale (VAS), Simple Shoulder Test Score (SST), Constant–Murley scores, and University of California at Los Angeles Scoring System (UCLA) were used to evaluate the clinical outcomes of patients in preoperative and final follow-up. Meanwhile, postoperative complications were also observed.Result32 patients (14 women and 18 men, average age was 55.7 years) underwent all-inside arthroscopic knotless suprapectoral biceps tenodesis using the H-Loop stitch technique. The mean time of follow-up was 16.2 ± 2.6 months. The ASES, VAS, Constant–Murley, SST, and UCLA scores improved from 51.5 ± 15.8, 5.5 ± 1.6, 57.8 ± 14.7, 5.0 ± 2.8, and 16.1 ± 3.8 preoperatively, to 89.1 ± 7.5, 1.0 ± 0.8, 87.3 ± 5.5, 10.4 ± 1.5, and 31.3 ± 2.6 in the last follow-up, respectively (p

Objective To investigate the Young's modulus value of infraspinatus tendons using shear wave elastography (SWE) technique in normal adults, and to analyze the influence of gender, postures, exercise, and dominant side on Young's modulus of infraspinatus tendons. Methods This is a prospective cross‐sectional study. From January 2019 to July 2020, 14 healthy subjects were identified, including seven males and seven females aged between 24 to 34, with a mean age of 27.67 ± 3.08 years. The Young's modulus of their infraspinatus tendons was measured by two operators using SWE in neutral and maximum external rotation positions of both sides before exercise and the dominant side after exercise. The Young's modulus values in different sexes, different postures, before vs after exercise, and dominant vs non‐dominant side were statistically analyzed. Results All 14 subjects completed the data collection process. The mean Young's modulus values of infraspinatus tendon for dominant sides in neutral position were 33.04 ± 3.01 kPa for males and 28.76 ± 3.09 kPa for females. And for non‐dominant sides in the neutral position, the values were 33.02 ± 2.38 kPa for males and 28.86 ± 2.47 kPa for females. In the maximum external rotation position, the values for dominant sides were 50.19 ± 4.86 kPa for males and 42.79 ± 4.44 kPa for females, and for non‐dominant sides were 50.95 ± 3.24 kPa for males and 42.42 ± 3.66 kPa for females. After exercise, the mean Young's modulus values of infraspinatus tendon for dominant sides in neutral position were 54.56 ± 3.76 kPa for males and 46.66 ± 5.99 kPa for females. And for the maximum external rotation position, the values were 59.13 ± 3.78 kPa for males and 54.49 ± 5.67 kPa for females. The Young's modulus of infraspinatus tendon in the neutral and maximum external rotation positions showed statistically significant differences in males and females, as well as before and after exercise (P 0.05). Intergroup reliability between both operators was excellent (ICC > 0.85). Conclusion There are gender‐related differences and post‐exercise increase in Young's modulus, yet such a difference cannot be witnessed between the dominant and non‐dominant sides.

Abstract Inflammation is a key factor in the development and complications of various diseases because it has a complex pathogenesis. Andrographis paniculate (Burm. f.) Nees (Chuan Xinlian) is a well-known form of Traditional Chinese Medicine (TCM) applied in clearing heat and detoxification. Also, it is rich in bioactive lactones, with various anti-inflammatory activities. Here, network pharmacology combined with molecular biology experimental approach was used to predict and verify the potential molecular mechanism of Chuan Xinlian in treating inflammation. The bioactive ingredients of Chuan Xinlian were obtained from the TCMSP database and literature. Besides, the targets of Chuan Xinlian and inflammation were collected based on the multi-source databases and used to generate the PPI network. Network topology analysis and functional enrichment analysis were used to screen hub genes and their mechanisms. Molecular docking simulation was performed to evaluate the binding activity between the predicted hub genes and the bioactive ingredients. Additionally, LPS-induced NO production in RAW264.7 cell inflammatory response, RT-PCR and Western blot were used to validate the efficacy of the Chuan Xinlian in the treatment of inflammation. Network analysis outcomes indicated that five targets (IL-6, VEGFA, PTGST2, TNF-α, and MMP-9) were identified as the key targets of Chuan Xinlian in the treatment of inflammation. Further, molecular docking findings revealed that the majority of the bioactive ingredients exhibited a strong binding efficacy towards the predicted hub genes. Functional analysis results showed that the potential mechanisms were primarily concentrated in key pathways including cancer, immunology, and inflammation process. Moreover, RT-PCR and Western blot analysis indicated that Chuan Xinlian extract suppressed the production of inflammatory mediators with anti-inflammatory effects. Our study shows that Chuan Xinlian potentially exerts an anti-inflammatory effect via key pathways including cancer, immunology, and inflammation process. This suggests that Chuan Xinlian has a potential anti-inflammatory action, thereby providing a scientific reference for clinical studies.

Graphical Abstract EMM Scientific Editors and Editor‐in‐Chief announce that the scope of articles considered will expand, with the goal to enhance our commitment to precision medicine. The scope expansion will cover three major areas: environmental health, clinical studies and case reports, and biomedical technologies

This paper aims to propose an explainable and generalized chemical reaction representation method for accelerating the evaluation of the chemical processes in production. To this end, we designed an explainable coarse-fine level representation model that incorporates a small amount of easily available expert knowledge (i.e., coarse-level annotations) into the deep learning method to effectively improve the performances on reaction representation related tasks. We also developed a new probabilistic data augmentation strategy with contrastive learning to improve the generalization of our model. We conducted experiments on the Schneider 50k and the USPTO 1k TPL datasets for chemical reaction classification, as well as the USPTO yield dataset for yield prediction. The experimental results showed that our method outperforms the state of the art by just using a small-scale dataset annotated with both coarse-level and fine-level labels to pretrain the model.

Abstract Inflammation, a protective response against infection and injury, involves a variety of biological processes. Sophorae Flavescentis (Kushen) is a promising Traditional Chinese Medicine (TCM) for treating inflammation, but the pharmacological mechanism of Kushen’s anti-inflammatory effect has not been fully elucidated. The bioactive compounds, predicted targets, and inflammation-related targets of Kushen were obtained from open source databases. The “Component-Target” network and protein–protein interaction (PPI) network were constructed, and hub genes were screened out by topological analysis. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on genes in the PPI network. Furthermore, nitric oxide (NO) production analysis, RT-PCR, and western blot were performed to detect the mRNA and protein expression of hub genes in LPS-induced RAW264.7 cells. An immunofluorescence assay found that NF-κB p65 is translocated. A total of 24 bioactive compounds, 465 predicted targets, and 433 inflammation-related targets were identified and used to construct “Component-Targets” and PPI networks. Then, the five hub genes with the highest values-IL-6, IL-1β, VEGFA, TNF-α, and PTGS2 (COX-2)- were screened out. Enrichment analysis results suggested mainly involved in the NF-κB signaling pathway. Moreover, experiments were performed to verify the predicted results. Kushen may mediate inflammation mainly through the IL-6, IL-1β, VEGFA, TNF-α, and PTGS2 (COX-2), and the NF-κB signaling pathways. This finding will provide clinical guidance for further research on the use of Kushen to treat inflammation.

Abstract Background Sarcomas, cancers originating from mesenchymal cells, are comprehensive tumors with poor prognoses, yet their tumorigenic mechanisms are largely unknown. In this study, we characterize infiltrating immune cells and analyze immune scores to identify the molecular mechanism of immunologic response to sarcomas. Method The “CIBERSORT” algorithm was used to calculate the amount of L22 immune cell infiltration in sarcomas. Then, the “ESTIMATE” algorithm was used to assess the “Estimate,” “Immune,” and “Stromal” scores. Weighted gene co-expression network analysis (WGCNA) was utilized to identify the significant module related to the immune therapeutic target. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed using the “clusterProfiler” package in R for annotation and visualization. Results Macrophages were the most common immune cells infiltrating sarcomas. The number of CD8 T cells was negatively associated with that of M0 and M2 macrophages, and positively associated with M macrophages in sarcomas samples. The clinical parameters (disease type, gender) significantly increased with higher Estimate, Immune, and Stromal scores, and with a better prognosis. The blue module was significantly associated with CD8 T cells. Functional enrichment analysis showed that the blue module was mainly involved in chemokine signaling and the PI3K-Akt signaling pathway. CD48, P2RY10 and RASAL3 were identified and validated at the protein level. Conclusion Based on the immune cell infiltration and immune microenvironment, three key genes were identified, thus presenting novel molecular mechanisms of sarcoma metastasis.

Abstract Background The critical shoulder angle (CSA), which helps to predict patients who are at risk of rotator cuff tears (RCTs) with large degree and who are susceptible to osteoarthritis with low angle, has been identified as one of the most vital acromial parameters; anterolateral and lateral acromioplasties have been proven to be valid ways to reduce CSA. However, no study has compared the effect of different acromioplasties on the reduction of the large CSA (≥33°) clinically. Additionally, either anterolateral or lateral acromioplasty could not precisely correct large CSAs to a favorable range (30–33°) in each patient. Thus, we will propose a novel precise acromioplasty technique for the purpose of reducing CSA accurately and effectively, and compare the effectiveness of different acromioplasties on the reduction of the CSA. Methods A total of 60 RCT patients who have indications for arthroscopic rotator cuff repair and with pre-operative CSA ≥33° will be recruited in outpatient center of Sun Yat-sen Memorial Hospital. Eligible participants will be randomly allocated to Group A (anterolateral acromioplasty), Group B (lateral acromioplasty) or Group C (precise acromioplasty) via a random, computer-generated number system. Three surgical plans will be made for each participant respectively by one professional surgeon according to the results of randomization allocation. The post-operative CSA will be measured 2 days post-operation. Follow-up will be maintained at 3, 6, and 12 months after surgery including the visual analog scale score, the University of California at Los Angeles score, the Constant Shoulder Score and the American Shoulder and Elbow Surgeon Shoulder Assessment Form. Finally, all outcomes will be assessed by two researchers who are blinded to the recruitment and allocation. Discussion This is the first clinical trial to evaluate the impact of different acromioplasties on the reduction of the CSA. Additionally, this study will provide a new precise acromioplasty technique, which is a novel precision and individualized treatment to prevent degenerative RCTs by reducing the CSA. Trial registration ChiCTR2000032343 . Registered on April 26th, 2020.

Abstract Background Osteosarcoma (OS) is a common malignant bone tumor originating in the interstitial tissues and occurring mostly in adolescents and young adults. Energy metabolism is a prerequisite for cancer cell growth, proliferation, invasion, and metastasis. However, the gene signatures associated with energy metabolism and their underlying molecular mechanisms that drive them are unknown. Methods Energy metabolism-related genes were obtained from the TARGET database. We applied the “NFM” algorithm to classify putative signature gene into subtypes based on energy metabolism. Key genes related to progression were identified by weighted co-expression network analysis (WGCNA). Based on least absolute shrinkage and selection operator (LASSO) Cox proportional regression hazards model analyses, a gene signature for the predication of OS progression and prognosis was established. Robustness and estimation evaluations and comparison against other models were used to evaluate the prognostic performance of our model. Results Two subtypes associated with energy metabolism was determined using the “NFM” algorithm, and significant modules related to energy metabolism were identified by WGCNA. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) suggested that the genes in the significant modules were enriched in kinase, immune metabolism processes, and metabolism-related pathways. We constructed a seven-gene signature consisting of SLC18B1, RBMXL1, DOK3, HS3ST2, ATP6V0D1, CCAR1, and C1QTNF1 to be used for OS progression and prognosis. Upregulation of CCAR1, and C1QTNF1 was associated with augmented OS risk, whereas, increases in the expression SCL18B1, RBMXL1, DOK3, HS3ST2, and ATP6VOD1 was correlated with a diminished risk of OS. We confirmed that the seven-gene signature was robust, and was superior to the earlier models evaluated; therefore, it may be used for timely OS diagnosis, treatment, and prognosis. Conclusions The seven-gene signature related to OS energy metabolism developed here could be used in the early diagnosis, treatment, and prognosis of OS.

Objective. The mechanism of Panax notoginseng in treating myocardial fibrosis (MF) was investigated using network pharmacology. Methods. Effective ingredients and potential targets of Panax notoginseng were screened in relevant databases to construct a compound-target network. Targets of MF were then screened to select common targets and construct a protein-protein interaction network. This was followed by Gene Ontology and pathway enrichment analyses. Molecular docking then verified the results of network analysis. Results. A total of 14 effective ingredients and 119 potential targets for MF were predicted. Quercetin, beta-sitosterol, and gossypetin were speculated to be the main active ingredients. The mechanism of action may be related to AGE-RAGE, proteoglycans, and IL-17 signaling pathways. Five key targets (IL6, ALB, AKT1, TNF, and VEGFA) may be involved in the treatment of MF using Panax notoginseng. Conclusions. This study embodies the complex network relationship of multicomponents, multitargets, and multipathways of Panax notoginseng in treating MF and provides a novel method for further research on this herb’s mechanism.

Avian influenza A virus (IAV) strains replicate poorly in mammalian hosts, but mechanisms underlying species restriction are incompletely understood. Here, Bogdanow et al. show that avian and mammalian adapted IAV strains have evolved different RNA structure features for regulation of M segment RNA splicing.

It is challenging to characterize diverse transcript isoforms by short-read sequencing. Here the authors report full-length transcriptomes in rat hippocampus by hybrid-sequencing, predict isoform-specific translational status, and reconstruct open reading frames validated by mass spectrometry.

Summary: Circular RNAs (circRNAs), an important class of regulatory RNAs, have been shown to be the most prevalent in the brain compared with other tissues. However the processes governing their biogenesis in neurons are still elusive. Moreover, little is known about whether and how different biogenesis factors work in synchrony to generate neuronal circRNAs. To address this question, we pharmacologically inhibited the spliceosome and profiled rat neuronal circRNAs using RNA sequencing. We identified over 100 circRNAs that were up-regulated and a few circRNAs that were down-regulated upon spliceosome inhibition. Bioinformatic analysis revealed that up-regulated circRNAs possess significantly longer flanking introns compared with the un-changed circRNA population. Moreover, the flanking introns of up-regulated circRNAs harbor a higher number of distinct repeat sequences and more reverse complementary motifs compared with the unchanged circRNAs. Taken together, our data demonstrate that the biogenesis of circRNAs containing distinct intronic features becomes favored under conditions of limited spliceosome activity. : Biological Sciences; Molecular Biology; Cell Biology; Omics Subject Areas: Biological Sciences, Molecular Biology, Cell Biology, Omics

Abstract Synovial-derived cells, found in the synovial membrane of human joints, were obtained by digestion of the synovial membrane and were subsequently expanded in vitro. The identity of synovial-derived cells has long been a topic of debate. The terms “type B synoviocytes,” “fibroblast-like synoviocytes (FLS),” “synovium-derived mesenchymal stem cells (MSCs),” and “synovial fibroblasts (SF)” appeared in different articles related to human synovial-derived cells in various disease models, yet they seemed to be describing the same cell type. However, to date, there is no clear standard to distinguish these terms; thus, the hypothesis that they represent the same cell type is currently inconclusive. Therefore, this review aims to clarify the similarities and differences between these terms and to diffuse the chaotic nomenclature of synovial-derived cells.

Abstract Background Isolated rectus femoris (RF) contracture is encountered very rarely in orthopaedic practices. There are few reports on its imaging manifestations and no cases reported to be treated with arthroscopy. Case presentation A 11-year-old girl with a more than 7 years history of restricted left knee flexion was presented. The clinical assessment and magnetic resonance imaging (MRI) findings were detailed here. A strip-like induration was palpated in the left thigh, which tends to be more obvious with knee flexion. MRI demonstrated a hypointensity band connected the anterior inferior iliac spine with the patella, and marked atrophy of the left RF muscle. Fibrosis contracture band was confirmed with arthroscope, then divided by radiofrequency ablation (RFA) under arthroscopic observation. Followed by debridement of the fibrillar connective tissue and hemostasis around the broken ends. The movement of left knee joint significantly improved after the operation, and the patient recovered nearly full range of motion of this joint after 6 months. Conclusion The specific MRI findings could assist in confirming clinical early diagnosis of isolated RF contracture. Arthroscopic RFA treatment is an effective technique to treat this disorder with minimally incision.

Abstract Transcription initiated at alternative sites can produce mRNA isoforms with different 5ʹUTRs, which are potentially subjected to differential translational regulation. However, the prevalence of such isoform‐specific translational control across mammalian genomes is currently unknown. By combining polysome profiling with high‐throughput mRNA 5ʹ end sequencing, we directly measured the translational status of mRNA isoforms with distinct start sites. Among 9,951 genes expressed in mouse fibroblasts, we identified 4,153 showed significant initiation at multiple sites, of which 745 genes exhibited significant isoform‐divergent translation. Systematic analyses of the isoform‐specific translation revealed that isoforms with longer 5ʹUTRs tended to translate less efficiently. Further investigation of cis‐elements within 5ʹUTRs not only provided novel insights into the regulation by known sequence features, but also led to the discovery of novel regulatory sequence motifs. Quantitative models integrating all these features explained over half of the variance in the observed isoform‐divergent translation. Overall, our study demonstrated the extensive translational regulation by usage of alternative transcription start sites and offered comprehensive understanding of translational regulation by diverse sequence features embedded in 5ʹUTRs.

Abstract Translational regulation is mediated through the interaction between diffusible trans‐factors and cis‐elements residing within mRNA transcripts. In contrast to extensively studied transcriptional regulation, cis‐regulation on translation remains underexplored. Using deep sequencing‐based transcriptome and polysome profiling, we globally profiled allele‐specific translational efficiency for the first time in an F1 hybrid mouse. Out of 7,156 genes with reliable quantification of both alleles, we found 1,008 (14.1%) exhibiting significant allelic divergence in translational efficiency. Systematic analysis of sequence features of the genes with biased allelic translation revealed that local RNA secondary structure surrounding the start codon and proximal out‐of‐frame upstream AUGs could affect translational efficiency. Finally, we observed that the cis‐effect was quantitatively comparable between transcriptional and translational regulation. Such effects in the two regulatory processes were more frequently compensatory, suggesting that the regulation at the two levels could be coordinated in maintaining robustness of protein expression.

The authors wish to make the following correction to their paper [...]

Synovium-derived mesenchymal stromal cells (SMSCs) may play an important role in the pathogenesis of rheumatoid arthritis (RA) and show promise for therapeutic applications in RA. In this study, a whole-genome microarray analysis was used to detect differential gene expression in SMSCs from RA patients and healthy donors (HDs). Our results showed that there were 4828 differentially expressed genes in the RA group compared to the HD group; 3117 genes were upregulated, and 1711 genes were downregulated. A Gene Ontology analysis showed significantly enriched terms of differentially expressed genes in the biological process, cellular component, and molecular function domains. A Kyoto Encyclopedia of Genes and Genomes analysis showed that the MAPK signaling and rheumatoid arthritis pathways were upregulated and that the p53 signaling pathway was downregulated in RA SMSCs. Quantitative real-time polymerase chain reaction was applied to verify the expression variations of the partial genes mentioned above, and a western blot analysis was used to determine the expression levels of p53, p-JNK, p-ERK, and p-p38. Our study found that differentially expressed genes in the MAPK signaling, rheumatoid arthritis, and p53 signaling pathways may help to explain the pathogenic mechanism of RA and lead to therapeutic RA SMSC applications.

Aurantio-obtusin, an anthraquinone compound, isolated from dried seeds of Cassia obtusifolia L. (syn. Senna obtusifolia; Fabaceae) and Cassia tora L. (syn. Senna tora). Although the biological activities of Semen Cassiae have been reported, the anti-inflammatory mechanism of aurantio-obtusin, its main compound, on RAW264.7 cells, remained unknown. We investigated the anti-inflammatory effect of aurantio-obtusin on lipopolysaccharide- (LPS)-induced RAW264.7 cells in vitro and elucidated the possible underlying molecular mechanisms. Nitric oxide production (NO) and prostaglandin E2 (PGE2) were measured by the Griess colorimetric method and enzyme-linked immunosorbent assay (ELISA), respectively. Protein expression levels of cyclooxygenase 2 (COX-2) were monitored by cell-based ELISA. Interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) synthesis were analyzed using ELISA. The mRNA expression of nitric oxide synthase (iNOS), COX-2, and the critical pro-inflammatory cytokines (IL-6 and TNF-α) were detected by quantitative real-time PCR. Aurantio-obtusin significantly decreased the production of NO, PGE2, and inhibited the protein expression of COX-2, TNF-α and IL-6, which were similar to those gene expression of iNOS, COX-2, TNF-α and IL-6 (p < 0.01). Consistent with the pro-inflammatory gene expression, the Aurantio-obtusin efficiently reduced the LPS-induced activation of nuclear factor-κB in RAW264.7 cells. These results suggested that aurantio-obtusin may function as a therapeutic agent and can be considered in the further development of treatments for a variety of inflammatory diseases. Further studies may provide scientific evidence for the use of aurantio-obstusin as a new therapeutic agent for inflammation-related diseases.

Scutellaria baicalensis Georgi has long been used in traditional medicine to treat various such widely varying diseases and has been listed in the Chinese Pharmacopeia, the Japanese Pharmacopeia, the Korean Pharmacopoeia and the European Pharmacopoeia. Flavonoids, especially wogonin, wogonoside, baicalin, and baicalein, are its main functional ingredients with various pharmacological activities. Although pharmaological studies for these flavonoid components have been well conducted, the molecular mechanism of their biosynthesis remains unclear in S. baicalensis. In this study, Illumina/Solexa deep sequencing generated more than 91 million paired-end reads and 49,507 unigenes from S. baicalensis roots, stems, leaves and flowers. More than 70% unigenes were annotated in at least one of the five public databases and 13,627 unigenes were assigned to 3,810 KEGG genes involved in 579 different pathways. 54 unigenes that encode 12 key enzymes involved in the pathway of flavonoid biosynthesis were discovered. One baicalinase and three baicalein 7-O-glucuronosyltransferases genes potentially involved in the transformation between baicalin/wogonoside and baicalein/wogonin were identified. Four candidate 6-hydroxylase genes for the formation of baicalin/baicalein and one candidate 8-O-methyltransferase gene for the biosynthesis of wogonoside/wogonin were also recognized. Our results further support the conclusion that, in S. baicalensis, 3,5,7-trihydroxyflavone was the precursor of the four above compounds. Then, the differential expression models and simple sequence repeats associated with these genes were carefully analyzed. All of these results not only enrich the gene resource but also benefit research into the molecular genetics and functional genomics in S. baicalensis.

Our objective was to evaluate the feasibility, safety, and efficacy of intravenous (IV) infusion of allogenic mesenchymal stem cells (MSCs) in ankylosing spondylitis (AS) patients who are refractory to or cannot tolerate the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs). AS patients enrolled in this study received four IV infusions of MSCs on days 0, 7, 14, and 21. The percentage of ASAS20 responders (the primary endpoint) at the fourth week and the mean ASAS20 response duration (the secondary endpoint) were used to assess treatment response to MSC infusion and duration of the therapeutic effects. Ankylosing Spondylitis Disease Activity Score Containing C-reactive Protein (ASDAS-CRP) and other preestablished evaluation indices were also adopted to evaluate the clinical effects. Magnetic resonance imaging (MRI) was performed to detect changes of bone marrow edema in the spine. The safety of this treatment was also evaluated. Thirty-one patients were included, and the percentage of ASAS20 responders reached 77.4% at the fourth week, and the mean ASAS20 response duration was 7.1 weeks. The mean ASDAS-CRP score decreased from 3.6 ± 0.6 to 2.4 ± 0.5 at the fourth week and then increased to 3.2 ± 0.8 at the 20th week. The average total inflammation extent (TIE) detected by MRI decreased from 533,482.5 at baseline to 480,692.3 at the fourth week ( p > 0.05) and 400,547.2 at the 20th week ( p < 0.05). No adverse effects were noted. IV infusion of MSCs is a feasible, safe, and promising treatment for patients with AS.

Interleukin-21 (IL-21) is a cytokine that plays a crucial role in pathogenesis and activity of the rheumatoid arthritis (RA). Meanwhile, genetic polymorphisms in the IL-21 gene may alter its expression. Previous studies have reported conflicting results assessing the association between the IL-21 rs6822844 G/T polymorphism and RA risk. Thus, it's necessary to perform a meta-analysis to definite above relationship. PubMed database was searched for all papers published until October 20, 2019. Nine case-control studies with 9998 cases and 10742 controls were retrieved based on the search criteria at last. Odds ratio (95% confidence interval) was used to calculate the strength of this association. Publication bias was detected using both Begg's and Egger's tests. Overall, the IL-21 rs6822844 G/T polymorphism was found to be significantly associated with decreased RA risk (e.g. T-allele versus G-allele: OR = 0.81, 95% CI = 0.72-0.91, P < 0.001). In addition, decreased RA risk was also detected both in Asians (eg: TT+TG versus GG: OR = 0.42, 95% CI = 0.31-0.56, P < 0.001) and Caucasians (eg: TT+TG versus GG: OR = 0.85, 95% CI = 0.80-0.91, P < 0.001). A similar trend in association was found in the source of the control and genotype method subgroups. Furthermore, subgroup analysis of rheumatoid factor status revealed a protective relationship between the IL-21 rs6822844 G/T polymorphism and RF+/RF- RA risk. A similar relationship was noted in the anti-citrullinated protein antibody status subgroup. The results of the present study suggest that the IL-21 rs6822844 G/T polymorphism was significantly associated with decreased RA susceptibility. [ABSTRACT FROM AUTHOR]

Pandemic influenza A virus (IAV) outbreaks occur when strains from animal reservoirs acquire the ability to infect and spread among humans. The molecular basis of this species barrier is incompletely understood. Here we combine metabolic pulse labeling and quantitative proteomics to monitor protein synthesis upon infection of human cells with a humanand a bird-adapted IAV strain and observe striking differences in viral protein synthesis. Most importantly, the matrix protein M1 is inefficiently produced by the bird-adapted strain. We show that impaired production of M1 from bird-adapted strains is caused by increased splicing of the M segment RNA to alternative isoforms. Strain-specific M segment splicing is controlled by the 3′ splice site and functionally important for permissive infection. In silico and biochemical evidence shows that avian-adapted M segments have evolved different conserved RNA structure features than human-adapted sequences. Thus, we identify M segment RNA splicing as a viral host range determinant. [ABSTRACT FROM AUTHOR]

This study compared knee stability and alterations in the composition of synovial fluid among patients who underwent arthroscopic anterior cruciate ligament (ACL) reconstruction with either a hamstring autograft or a hamstring allograft. This prospective cohort study enrolled 175 patients. Of these patients, 90 underwent hamstring tendon autograft ACL reconstruction. The remaining patients (n=85) underwent hamstring tendon allograft ACL reconstruction. All of the patients had a minimum of 1 year of follow-up (mean, 2.5 years). Side-to-side differences and the proportion of mononuclear cells in knee joint synovial fluid were measured at 5 time points (preoperatively and at postoperative weeks 1, 3, 6, and 12). During the early postoperative phase, side-to-side knee laxity was greater among the allograft group compared with the autograft group (P<.001). Additionally, among the allograft group, the proportion of mononuclear cells remained high at weeks 6 and 12 (mean, 90.0% and 88.9%, respectively) compared with a normal level in the autograft group (mean, 45.1% and 65.7%, separately). However, no significant difference was found between the 2 groups at final follow-up for range of motion, results of the Lachman test, results of the anterior drawer test, results of the pivot shift test, Lysholm score, bone tunnel enlargement, and graft failure rate (P>.05). These findings showed that, in the early postoperative phase, ACL reconstruction with a hamstring allograft resulted in greater knee laxity and immunologic response compared with the hamstring autograft group. However, at relatively long-term follow-up, both grafts achieved similar objective and subjective outcomes. [Orthopedics. 2017; 40(5):e892-e897.]. [ABSTRACT FROM AUTHOR]