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Abstract Mangroves are ecosystems that grow in the intertidal areas of coastal zones, playing crucial ecological roles and possessing unique economic and social values. They have garnered significant attention and research interest. Semantic segmentation of mangroves is a fundamental step for further investigations. However, mangrove remote sensing images often have large dimensions, with a substantial portion of the image containing mangrove features. Deep learning convolutional kernels may lead to inadequate receptive fields for accurate mangrove recognition. In mangrove remote sensing images, various challenges arise, including the presence of small and intricate details aside from the mangrove regions, which intensify the segmentation complexity. To address these issues, this paper primarily focuses on two key aspects: first, the exploration of methods to achieve a large receptive field, and second, the fusion of multi-scale information. To this end, we propose the Multi-Scale Fusion Attention Network (MSFANet), which incorporates a multi-scale network structure with a large receptive field for feature fusion. We emphasize preserving spatial information by integrating spatial data across different scales, employing separable convolutions to reduce computational complexity. Additionally, we introduce an Attention Fusion Module (AFM). This module helps mitigate the influence of irrelevant information and enhances segmentation quality. To retain more semantic information, this paper introduces a dual channel approach for information extraction through the deep structure of ResNet. We fuse features using the Feature Fusion Module (FFM) to combine both semantic and spatial information for the final output, further enhancing segmentation accuracy. In this study, a total of 230 images with dimensions of 768 pixels in width and height were selected for this experiment, with 184 images used for training and 46 images for validation. Experimental results demonstrate that our proposed method achieves excellent segmentation results on a small sample dataset of remote-sensing images, with significant practical value. This paper primarily focuses on three key aspects: the generation of mangrove datasets, the preprocessing of mangrove data, and the design and training of models. The primary contribution of this paper lies in the development of an effective approach for multi-scale information fusion and advanced feature preservation, providing a novel solution for mangrove remote sensing image segmentation tasks. The best Mean Intersection over Union (MIoU) achieved on the mangrove dataset is 86%, surpassing other existing models by a significant margin.

In recent years, most of the coal mines in Zhungeer Coalfield have entered the mining of the second main coal seams, such as 6#, 10# and 11#, with an average thickness of more than 10 m, so most of the coal mines use fully mechanized caving mining technology for mining. Affected by the mining of the upper coal seam, the overburden movement, ground pressure appearance and roof weighting source of the lower fully mechanized top coal caving face are more complex. In this paper, the laws of overburden movement and ground pressure appearance of the fully mechanized top coal caving face under the disturbance of the upper coal seam are studied; taking Huangyuchuan 226 upper 02 fully mechanized top coal caving face as an example, by using the methods of theoretical analysis, similar simulation and field measurement. The main conclusions are as follows: before the middle rock stratum is not completely broken, the overburden is characterized by layered collapse, the damage scope develops upward in a stepped manner, and the lower fully mechanized top coal caving face appears small periodic weighting with large weighting step distance and small strength; when the middle rock stratum is completely broken, the damaged areas of the two coal seams will be connected, the overburden will sink in a large range of steps, and the lower fully mechanized top coal caving face is prone to sudden changes in rock pressure such as frame pressing and roof fall; after the middle rock stratum is completely broken, the overburden appears a “bench beam” structure, and the fracture boundary cracks are increasing, the lower fully mechanized top coal caving face appears large periodic weighting, and the weighting step decreases and the strength increases. At the same time, through the research on the movement law of overburden, the source of roof weighting under the upper coal seam disturbance is analyzed, and the calculation method of support load is determined. Taking Huangyuchuan 226 upper 02 fully mechanized top coal caving face as an example, targeted comprehensive control measures such as controlling mining height and increasing support working resistance are formulated, which have achieved good control effect after on-site implementation.

Abstract Background Tumor angiogenesis, immunosuppression, and progression are all closely correlated with the tumor microenvironment (TME). Immune evasion is supported by both M2 phenotype tumor-associated macrophages (TAMs) and vascular aberrations in the TME. TME reprogramming is a promising therapeutic approach for treating tumors. Anti-angiogenesis has the power to control the polarization of macrophages, prevent progression, and increase drug penetration. Additionally, polyamine blocking therapy can increase CD8+ T cell infiltration and decrease immunosuppressive cells. These results led to developing a potential therapeutic regimen that targets TAMs and angiogenesis to reprogram the osteosarcoma TME. Results For the targeted biomimetic co-delivery of regorafenib and alpha-difluoromethylornithine via the mannose receptor, which is overexpressed in both TAMs and osteosarcoma cells, mannosylated poly(lactide-co-glycolide)-polyethylene glycol nanoparticles (Man-NPs) were synthesized. The superior physiological properties and intratumoral accumulation of the Man-NPs efficiently promoted TAMs polarization and inhibited angiogenesis. Macrophage repolarization further activated immune cells, which contributed to remodeling the TME. Conclusion Overall, these findings suggested that using Man-NPs as an immunotherapeutic approach to treat osteosarcoma may be promising. Graphical Abstract

In this study, we investigate the impact of COVID-19 on academic achievement in Texas public schools. Demographic and Grade 5 STAAR test data were collected from 1155 public school districts for 2018–2019 and 2020–2021. Multiple regression was adopted to analyze the differences between rural and non-rural districts, as well as the impact of demographic characteristics on students’ achievement. The results reveal significant differences in demographic characteristics between the two academic years, with non-rural districts exhibiting a greater decline in academic achievement than rural districts. Additionally, the findings suggest that higher teacher salaries correlate with better academic performance across various subjects and that English learners require additional support to acquire content knowledge and skills. We further confirm that the COVID-19 pandemic has disrupted the academic learning experience of Texas students, with rural districts displaying more resilience than non-rural districts.

Osteosarcoma survival rates have been largely unchanged for several decades, and treatment response is variable. Here, the authors analyzed genomic, transcriptomic and epigenomic data from 121 osteosarcoma patients and identify subtypes related to treatment outcome.

Abstract Osteosarcoma is the most common primary bone tumor, with a poor prognosis owing to the lack of efficient molecular-based targeted therapies. Previous studies have suggested an association between CD151 and distinct consequences in osteosarcoma tumorigenicity. However, the potential of CD151 as a therapeutic target has not yet been sufficiently explored. Here, we performed integrated transcriptomic and metabolomic analyses of osteosarcoma and identified sphingolipid metabolism as the top CD151-regulated pathway. CD151 regulates sphingolipid metabolism primarily through SPTCL1, the first rate-limiting enzyme in sphingolipid biosynthesis. Mechanistically, depletion of CD151 enhanced c-myc polyubiquitination and subsequent degradation. c-myc is vital for the transcriptional activation of SPTLC1. Functionally, sphingolipid synthesis and the SPTLC1 inhibitor, myriocin, significantly suppressed the clonogenic growth of CD151-overexpression cells. Importantly, myriocin selectively restrained CD151-high expression tumor growth in preclinical patient-derived xenograft models. Collectively, these data establish that CD151 is a key mediator of sphingolipid metabolism and provide a new approach to developing novel CD151-based targeted therapies for osteosarcoma.

Objective To retrospectively analyze and compare the relationship between the success rate of patient‐derived xenograft (PDX) modeling of osteosarcoma and prognosis (3‐year overall survival rate and disease‐free survival rate) and incidence of lung metastasis. Methods The sample group consisted of 57 osteosarcoma patients with definite pathological diagnoses from Shanghai General Hospital from 2015–2017. PDX models in 57 patients were analyzed by retrospective analyses. Among the patients currently inoculated, 20 were tumorigenic in the PDX model, and 37 were nontumorigenic. According to the tumorigenicity of PDXs, the corresponding osteosarcoma patients were divided into two groups. The effects of clinically related indicators on the model were retrospectively compared. The patients were followed, and the 3‐year survival, 3‐year disease‐free survival (DFS), and lung metastasis rates were collected. The relationship between the modeling success and patient prognosis was investigated. Results In the chemotherapy‐treated group, the PDX modeling success rate was 17.4%, and in the nonchemotherapy group, the success rate was 47.1%. The success of PDX modeling was related to whether patients received chemotherapy. The success rate of PDX modeling is significantly reduced after receiving chemotherapy. The 3‐year overall survival rate of the PDX‐grafted group was 49.23%, and that of the PDX‐nongrafted group was 65.71%. There was a significant difference between the two groups, showing a strong negative correlation between the 3‐year survival rate and the success rate of the PDX model. The 3‐year disease‐free survival rate of the PDX‐grafted group was 29.54%. The 3‐year DFS of the PDX‐nongrafted group was 50.34%. There was a significant difference between the two groups. Lower grafted rates indicate a higher DFS rate. The incidence of lung metastasis in the PDX‐grafted group was 32.4%, and that in the nongrafted group was 13.1%. There was a significant difference between the two groups. The successful establishment of the PDX model indicates that patients are more likely to have lung metastases. Conclusions The success of PDX modeling often indicates poor prognosis (low 3‐year overall survival rate and disease‐free survival rate) and a greater possibility of lung metastasis. Therefore, PDX modeling in osteosarcoma patients can accurately predict the prognosis of patients and the risk of lung metastasis in advance to help us develop better therapeutic strategies.

Texas–Mexico border region is a unique place where two countries and culture connected. We sought to investigate border school district students’ academic performance as measured by Texas standardized test: the State of Texas Assessments of Academic Readiness (STAAR). To do so, we first used propensity score matching (PSM) techniques to analyze data collected from a public database: Texas Assessment Management System (TAMS). Specifically, we provided a PSM analysis of non-border and border school districts regarding their demographic characteristics [i.e., identified as a rural district, percentage of economically disadvantaged (ED) students, percentage of English learners (ELs), mobility rate, instructional hours, principal experience, teacher experience, teacher–student ratio, and teacher turnover rate]. Then, multiple regression analyses were conducted to compare Texas border and non-border school students’ reading, math, and science achievements, respectively, based on a matching sample with control for demographic variables. The results of the current study indicate that no significant difference was found between border and non-border school districts, regarding students’ academic performance in reading, math, and science, when districts were matched and demographic characteristics were controlled. We further found that demographic variables, such as percent of ED students, principal experience, and teacher turnover rate, significantly impact students’ academic achievement. Such findings have suggested that the achievement gap between border and non-border districts can be closed if extra support can be provided to ED students, and funding could be allocated in border districts to maintain experienced principals and teachers.

A grating-assisted hybrid plasmonic slot resonator is proposed and theoretically investigated as an on-chip surface-enhanced Raman scattering (SERS) sensor. A dielectric Bragg grating and a gold baffle are introduced into the hybrid plasmonic slot waveguide as two mirrors to form a plasmonic–dielectric cavity, in which the constructive interference of the input pump light greatly enhances the electric field. The grating reflects the wasted pump light for reverse secondary coupling and acts as a built-in notch filter for filtering out pump light from Raman scattered light simultaneously, improving the coupling efficiency and realizing a compact and miniaturized on-chip SERS sensor. Both the volumetric electric field enhancement and Raman collection efficiency are taken into account. The proposed scheme provides a simple, effective and universal method for improving the performance of the plasmonic-antennas-type waveguide-based SERS sensors.

IntroductionPsittacosis, caused by Chlamydia psittaci, is widespread throughout the world. In humans, C. psittaci infection may lead to severe conditions and complications, including sepsis and multiple organ failure. We report a cluster of cases caused by C. psittaci in Zhejiang Province, 2021, which led to one death and three cases of hospitalization.MethodsThe cases were confirmed by nest-PCR, RT-PCR, and mNGS.ResultsThe four cases were related and the sequences obtained from the samples were closely correlated with those from Taiwan.DiscussionThis study is the first to report on the case of death from psittacosis in Zhejiang Province, and our results help to assess the disease and recommend effective measures to prevent further spread of C. psittaci.

BackgroundPapillary thyroid cancer (PTC) is the most common subtype of thyroid cancer and is characterized by an overall good prognosis and early-stage lymph node metastasis. The immune microenvironment is believed to play a crucial role in PTC initiation, progression and metastasis. However, to our knowledge, prognostic tools for thyroid cancer metastasis based on immune scores have not been adequately explored. This study aimed to construct a clinical nomogram to predict lymph node metastasis in patients with PTC.MethodsThe genomic data and clinical-pathological characteristics of 447 PTC subjects were obtained from TCGA (The Cancer Genome Atlas data). Logistic regression models were performed for univariate and multivariate analyses to identify significant prediction factors. A prognostic nomogram was built based on the multivariate analysis results. The concordance index (C-index) and calibration curve were used to assess the predictive accuracy and discriminative ability of the model.ResultsThe patients were divided into two subgroups based on immune scores. We found that patients with high immune scores had significantly higher lymph node metastasis risks (OR and 95% confidence interval [CI]: 1.774[1.130-2.784]) than those with low immune scores. The C-index for lymph node metastasis was 0.722 (95% CI, 0.671‐0.774), which had a favorable performance for clinical prediction. The calibration curve for lymph node metastasis showed significant agreement between the nomogram prediction and actual observation.ConclusionHigh immune scores are significantly correlated with higher lymph node metastasis risk in patients with PTC. Immune score-based prognostic nomograms may help to predict lymph node metastasis and have potential clinical application possibilities.

Abstract While long noncoding RNAs (lncRNAs) have been reported to play an important role in human cancer types, they remain poorly understood in papillary thyroid carcinoma (PTC). The aim of this study was to use genome-wide expression profiling to identify lncRNAs acting as competing endogenous RNAs (ceRNAs) in PTC. We constructed a ceRNA network based on our lncRNA microarray data and validated the correlation between myocardial infarction-associated transcript lncRNA (MIAT), miRNA-150-5p, and EZH2 in vitro and in vivo. We found 15 lncRNAs, 28 miRNAs, and hundreds of mRNAs involved in this ceRNA network. Splendid positive correlations were found between the MIAT and EZH2 expression in types of cancer in TCGA data. Besides, significant differences in MIAT/EZH2 expression were found among various clinicopathological features. Gain- and loss-of-function experiments revealed that MIAT inhibited cell proliferation and migration in vitro. Moreover, EZH2 was identified as a direct downstream target of miR-150-5p in PTC cells. Restoration of EZH2 expression partially abolished the biological effects of miR-150-5p. Furthermore, overexpression of MIAT was inversely correlated with miR-150-5p expression. Knockdown of MIAT produced significant behavioral alter maybe partly due to the function of the MIAT-150-5p-EZH2 network. Our findings suggest MIAT may inhibit EZH2 expression and promote PTC cell invasion via the miR-150/EZH2 pathway. Therefore, MIAT may serve as a valuable prognostic biomarker and therapeutic target for PTC.

Signal transducer and activator of transcription 3 (STAT3) plays essential roles in cancer progression and has been considered as a promising target for cancer therapy. Here, we used a dual luciferase assay to identify that pectolinarigenin inhibited STAT3 transcriptional activity. Further, results showed pectolinarigenin inhibited constitutive and IL6 induced STAT3 signaling, diminished the accumulation of STAT3 in the nucleus, dimerization and blocked STAT3 DNA binding activity. Mechanism investigations indicated that pectolinarigenin disturbed the STAT3/DNMT1/HDAC1 complex formation in the promoter region of SHP-1, which reversely mediates STAT3 signaling, leading to the upregulation of SHP-1 expression in osteosarcoma. We also found pectolinarigenin significantly suppressed osteosarcoma growth, induced apoptosis. In addition, pectolinarigenin blocked tumor cells migration, invasion and reserved EMT phenotype. In spontaneous tibial injection and patient-derived xenograft models of osteosarcoma, we identified administration (i.p.) of pectolinarigenin (20 mg/kg/2 days and 50 mg/kg/2 days) blocked STAT3 activation and disturbed tumor growth and metastasis with superior pharmacodynamic properties. Taken together, our findings demonstrate that pectolinarigenin may be a candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity.

Various proteins with antibacterial, anticoagulant, and anti-inflammatory properties have been identified in the buccal glands of jawless blood-sucking vertebrate lampreys. However, studies on endogenous peptides in the buccal gland of lampreys are limited. In this study, 4528 endogenous peptides were identified from 1224 precursor proteins using peptidomics and screened for bioactivity in the buccal glands of the lamprey, Lethenteron camtschaticum. We synthesized four candidate bioactive peptides (VSLNLPYSVVRGEQFVVQA, DIPVPEVPILE, VVQLPPVVLGTFG, and VPPPPLVLPPASVK), calculated their secondary structures, and validated their bioactivity. The results showed that the peptide VSLNLPYSVVRGEQFVVQA possessed anti-inflammatory activity, which significantly increased the expression of anti-inflammatory factors and decreased the expression of inflammatory factors in THP-1 cells. The peptide VVQLPPVVLGTFG showed antibacterial activity against some gram-positive bacteria. The peptide VSLNLPYSVVRGEQFVQA possessed good ACE inhibitory activity at low concentrations, but no dose-related correlation was observed. Our study revealed that the buccal glands of the jawless vertebrate lamprey are a source of multiple bioactive peptides, which will provide new insights into the blood-sucking mechanism of lamprey.

Abstract Background Osteosarcoma (OS) is the most common primary bone cancer in adolescents and lung metastasis is the leading cause of death in patients with OS. However, the molecular mechanisms that promote OS growth and metastasis remain unknown. Methods We investigated the expression of myosin light chain kinase family members between metastasis and non-metastasis patients in the TARGET database and ensured that only myosin light chain kinase family member 4 (MYLK4) had higher expression in metastatic osteosarcoma patients. Then we confirmed the results by immunohistochemistry (IHC) and Western blotting (WB) of OS tissues. The effect of MYLK4 on the metastasis and proliferation of OS cells was investigated by wound healing, Transwell and colony-formation assays. Mass spectrum analysis was used to ensure the new binding protein of MYLK4. Tissue microarrays analysis was used to show the correlation between MYLK4 and pEGFR (Y1068). A series of in vivo experiments were conducted to reveal the mechanisms by which MYLK4 modulated the metastasis and proliferation of OS. Results Myosin Light Chain Kinase Family Member 4 (MYLK4) was significantly upregulated in metastatic human OS tissues. Growth and metastasis of OS could be accelerated by MYLK4 overexpression, whereas silencing MYLK4 expression resulted in decreased cell growth and metastasis. Mechanistically, mass spectrum analysis showed that MYLK4 interacted with the epidermal growth factor receptor (EGFR) in osteosarcoma cells and promoted growth and metastasis via the EGFR signaling pathway. Tissue microarrays analysis also showed that MYLK4 expression had a positive correlation with the expression of pEGFR (Y1068). Moreover, the EGFR inhibitor gefitinib could partially reverse the effect of cell proliferation and metastasis caused by MYLK4 overexpression. Importantly, the combination of MYLK4 and EGFR inhibitors had synergistic effects on growth and metastasis of OS in vitro and in vivo. Conclusion Our results indicate that MYLK4 promotes OS growth and metastasis by activating the EGFR signaling pathway and can be a novel therapeutic target for the treatment of OS patients.

Abstract Establishment of reliable pedigree information of different lineages is crucial for selective breeding and stock enhancement programs. However, owing to the absence of a reliable assay for parentage assignment, such information is lacking in orange‐spotted grouper (Epinephelus coioides), which is an economically important coral‐reef fish. In this study, we developed two multiplex microsatellite polymerase chain reaction systems that consisted of 12 microsatellite markers (seven in system A and five in system B) for parentage assignment of orange‐spotted groupers. The theoretical exclusion probability per locus ranged from 0.079 to 0.436 when both parents were unknown (E‐1P) and from 0.191 to 0.614 when one parent was known (E‐2P). The combined exclusion probability values of 12 loci were 98.8% (E‐1P) and 100% (E‐2P), respectively. The accuracy of the parentage test for a mixed family (15 dams and 12 sires, 226 offspring) was 100%. In addition, two wild populations (79 individuals) were added as interferential offspring, only four of which were misassigned to the stock. The success rate of assignment was 98.69%. We provide a reliable microsatellite‐based assay for parentage assignment in orange‐spotted groupers, which will be useful for selective breeding and stock enhancement programs for this species and maybe other groupers.

Abstract Objective Controversy still exists regarding the volume of radiation for head and neck cancer of unknown primary (HNCUP). Theoretically, elective mucosal irradiation (EMI) should achieve a balance between survival and toxicity. This prospective study was conducted to evaluate the long‐term benefit of EMI in Chinese HNCUP patients. Methods A phase II, single‐arm trial was performed at two centers in China. HNCUP patients with pathologically confirmed metastatic squamous cell carcinoma or poorly differentiated carcinoma were enrolled. Patients with metastatic lymph nodes limited to level IV and/or the supraclavicular fossa were excluded. The EMI approach was specifically customized to Chinese patients by differentiating HNCUP as putative nasopharyngeal carcinoma (NPC) or non‐putative NPC. The primary endpoint was 3‐year mucosal recurrence‐free survival (MRFS). Results A total of 48 patients were enrolled between 02/02/2010 and 08/01/2018; 46 patients were analyzed, including 24 putative NPC and 22 non‐putative NPC patients. No primary recurrence was observed during a median follow‐up period of 70 months, and only 1 patient experienced out of field recurrence in the contralateral neck. The 3‐year MRFS was 90.6% (95%CI: 76.4%‐96.4%). The 5‐year MRFS, regional‐recurrence free survival (RRFS) and overall survival (OS) were 90.6% (95%CI: 76.4%‐96.4%), 86.0% (95%CI: 71.1%‐93.7%), and 90.6% (95%CI: 76.4%‐96.4%), respectively. No grade 4 acute or late toxicities occurred, and the most frequent grade 3 acute toxicity was oral mucositis (45.7%). Conclusion To the best of our knowledge, this is the first prospective study to evaluate the long‐term outcomes of EMI in Chinese HNCUP patients. Excellent MRFS and OS rates were observed. Further randomized studies are warranted.

Overexpression of the multidrug resistance (MDR)-related protein P-glycoprotein (PGP1), which actively extrudes chemotherapeutic agents from cells and significantly decreases the efficacy of chemotherapy, is viewed as a major obstacle in osteosarcoma chemotherapy. Anlotinib, a novel tyrosine kinase inhibitor (TKI), has good anti-tumor effects in a variety of solid tumors. However, there are few studies on the mechanism of anlotinib reversing chemotherapy resistance in osteosarcoma. In this study, cellular assays were performed in vitro and in vivo to evaluate the MDR reversal effects of anlotinib on multidrug-resistant osteosarcoma cell lines. Drug efflux and intracellular drug accumulation were measured by flow cytometry. The vanadate-sensitive ATPase activity of PGP1 was measured in the presence of a range of anlotinib concentrations. The protein expression level of ABCB1 was detected by Western blotting and immunofluorescence analysis. Our results showed that anlotinib significantly increased the sensitivity of KHOSR2 and U2OSR2 cells (which overexpress PGP1) to chemotherapeutic agents in vitro and in a KHOSR2 xenograft nude mouse model in vivo. Mechanistically, anlotinib increases the intracellular accumulation of PGP1 substrates by inhibiting the efflux function of PGP1 in multidrug-resistant cell lines. Furthermore, anlotinib stimulated the ATPase activity of PGP1 but affected neither the protein expression level nor the localization of PGP1. In animal studies, anlotinib in combination with doxorubicin (DOX) significantly decreased the tumor growth rate and the tumor size in the KHOSR2 xenograft nude mouse model. Overall, our findings suggest that anlotinib may be useful for circumventing MDR to other conventional antineoplastic drugs.

Abstract Background Timolol Maleate is a non-selective beta-adrenergic blocker that is commonly used to treat open-angle glaucoma. Despite its topical administration, ophthalmic timolol enters systemic circulation and produces a systemic beta-adrenergic blockade. We report a case of long-term timolol use that uncovered and worsened an underlying cardiac conduction defect demonstrated as a third degree atrioventricular (AV) block. Case presentation A 62-year old male with a 13-year history of glaucoma was hospitalized due to shortness of breath, dizziness, and amaurosis. Electrocardiography indicated a heart rate (HR) of 29 bpm with complete atrioventricular (AV) block, and the HR was significantly increased with the treatment of isoprenaline. However, the patient experienced bradycardic episodes (− 20 Δbpm) immediately after self-administration of timolol eye drops. The AV block and bradycardia resolved 48-h after timolol cessation. The man was discharged 1 week later with an asymptomatic first-degree A-V block. However, he presented with a worsened A-V block at his one-year checkup. Conclusion We conclude that chronic topical timolol administration may aggravate a cardiac conduction defect leading to an AV block that is only temporarily resolved by timolol cessation. Patients taking timolol should be routinely monitored for cardiovascular aberrations and if any detected, immediately discontinue timolol therapy. Individuals experiencing timolol induced cardiovascular side effects should receive long term follow-up even if symptoms resolve, as they may be indicative of an underlying conduction defect.

Achilles tendon rupture prognosis is usually unsatisfactory. After the tendon is injured, it may not function properly because of the fibrotic healing response, which restrains tendon motion. Inflammatory monocytes and tissue-resident macrophages are indispensable regulators in tissue repair, fibrosis, and regeneration. Exosomes from macrophages are crucial factors in tissue microenvironment regulation following tissue injury. This study therefore aimed to clarify the roles of macrophage exosomes in tendon injury (TI) repair. The results show that macrophages play a role after TI. M1 macrophages were increased relative to peritendinous fibrosis after TI. High-throughput sequencing showed abnormal expression of circular RNAs (circRNAs) between exosomes from M2 and M0 macrophages. Among the abnormal expressions of circRNA, circRNA-Ep400 was significantly increased in M2 macrophage exosomes. The results also show that M2 macrophage-derived circRNA-Ep400-containing exosomes are important for promoting peritendinous fibrosis after TI. Bioinformatics and dual-luciferase reporting experiments confirmed that miR-15b-5p and fibroblast growth factor (FGF)-1/7/9 were downstream targets of circRNA-Ep400. High circRNA-Ep400-containing exosome treatment inhibited miR-15b-5p, but promoted FGF1/7/9 expression in both fibroblasts and tenocytes. Furthermore, high circRNA-Ep400-containing exosome treatment promoted fibrosis, proliferation, and migration in both fibroblasts and tenocytes. Taken together, the results show that M2 macrophage-derived circRNA-Ep400-containing exosomes promote peritendinous fibrosis after TI via the miR-15b-5p/FGF-1/7/9 pathway, which suggests novel therapeutics for tendon injury treatment.

Osteosarcoma is the most common primary malignant bone tumor, and there are few ideal clinically available drugs. The bromodomain and extraterminal domain (BET) protein is an emerging target for aggressive cancer, but therapies targeting the BET in osteosarcoma have been unsuccessful in clinical trials to date, and further exploration of specific BET inhibitors is of great significance. In our study, we demonstrated that NHWD-870, a potent BET inhibitor in a phase I clinical trial, significantly inhibited tumor proliferation and promoted cell apoptosis by reversing the oncogenic signature in osteosarcoma. More importantly, we identified NHWD-870 impeded binding of BRD4 to the promoter of GP130 leading to diminished activation of JAK/STAT3 signaling pathway. Furthermore, GP130 knockdown significantly sensitizes the chemosensitivity in vitro. In OS cell-derived xenografts, NHWD-870 effectively inhibited the growth of osteosarcoma. Beyond that, NHWD-870 effectively inhibited the differentiation and maturation of precursor osteoclasts in vitro and attenuated osteoclast-mediated bone loss in vivo. Finally, we confirmed the efficacy of synthetic lethal effects of NHWD-870 and cisplatin in antagonizing osteosarcoma in a preclinical PDX model. Taken together, these findings demonstrate that NHWD-870, as an effective BET inhibitor, may be a potential candidate for osteosarcoma intervention linked to its STAT3 signaling inhibitory activity. In addition, NHWD-870 appears to be a promising therapeutic strategy for bone-associated tumors, as it interferes with the vicious cycle of tumor progression and bone destruction.

Abstract Long noncoding RNAs (lncRNAs) are known to be key regulators of numerous biological processes, and substantial evidence supports that abnormal lncRNA expression plays a significant role in tumorigenesis and tumor progression. However, the mechanism by which lncRNAs function in thyroid carcinoma are still unclear. To investigate the role of lncRNAs in the tumorigenesis of papillary thyroid carcinoma (PTC), we analyzed lncRNA data in The Cancer Genome Atlas RNA‐Seq database. A comparison of lncRNAs in cancerous thyroid tissues and normal tissues revealed hundreds of differentially expressed lncRNAs. Of 7589 lncRNAs identified in 561 thyroid cancer cases (503 cancerous tissues and 58 normal tissues), the expression levels of 144 were found to be aberrant (|log2 fold change| >2 and adjusted P

Abstract Background Osteosarcoma (OS) is a common malignant cancer in children and adolescents and has a cure rate that has not improved in the last two decades. CYT997 (lexibulin) is a novel potent microtubule-targeting agent with various anticancer activities, such as proliferation inhibition, vascular disruption, and cell cycle arrest and apoptosis induction, in multiple cancers. However, the direct cytotoxic mechanisms of CYT997 have not yet been fully characterized. Methods We evaluated apoptosis and autophagy in human osteosarcomas after treatment with CYT997 and investigated the underlying mechanisms. To explore relationships, we used the reactive oxygen species (ROS) scavenger N-acetyl cysteine (NAC), PERK inhibitor GSK2606414, ERO1 inhibitor EN460 and mitochondrial targeted protection peptide elamipretide. BALB/c-nu mice were inoculated with 143B tumor cells to investigate the in vivo effect of CYT997. Results We explored the efficacy and mechanism of CYT997 in osteosarcoma (OS) in vitro and in vivo and demonstrated that CYT997 potently suppresses cell viability and induces apoptosis and autophagy. CYT997 triggered production of ROS and exerted lethal effects via endoplasmic reticulum (ER) stress in OS cells. NAC attenuated these effects. The PERK inhibitor GSK2606414, which can block the ER stress pathway, reduced ROS production and enhanced cell viability. Moreover, activation of ERO1 in the ER stress pathway was responsible for inducing ROS production. ROS produced by the mitochondrial pathway also aggravate ER stress. Protection of mitochondria can reduce apoptosis and autophagy. Finally, CYT997 prominently reduced tumor growth in vivo. Conclusions This study suggests that CYT997 induces apoptosis and autophagy in OS cells by triggering mutually enhanced ER stress and ROS and may thus be a promising agent against OS.

Ischemic stroke leads to hypoxia-induced neuronal death and behavioral abnormity, and is a major cause of death in the modern society. However, the treatments of this disease are limited. Brilliant Blue FCF (BBF) is an edible pigment used in the food industry that with multiple aromatic rings and sulfonic acid groups in its structure. BBF and its derivatives were proved to cross the blood-brain barrier and have advantages on the therapy of neuropsychiatric diseases. In this study, BBF, but not its derivatives, significantly ameliorated chemical hypoxia-induced cell death in HT22 hippocampal neuronal cell line. Moreover, protective effects of BBF were attributed to the inhibition of the extracellular regulated protein kinase (ERK) and glycogen synthase kinase-3β (GSK3β) pathways as evidenced by Western blotting analysis and specific inhibitors. Furthermore, BBF significantly reduced neurological and behavioral abnormity, and decreased brain infarct volume and cerebral edema induced by middle cerebral artery occlusion/reperfusion (MCAO) in rats. MCAO-induced increase of p-ERK in ischemic penumbra was reduced by BBF in rats. These results suggested that BBF prevented chemical hypoxia-induced otoxicity and MCAO-induced behavioral abnormity via the inhibition of the ERK and GSK3β pathways, indicating the potential use of BBF for treating ischemic stroke

Major Depressive Disorder (MDD) with childhood trauma is one of the functional subtypes of depression. Frequency-dependent changes in the amplitude of low-frequency fluctuations (ALFF) have been reported in MDD patients. However, there are few studies on ALFF about MDD with childhood trauma. Resting-state functional magnetic resonance imaging was used to measure the ALFF in 69 MDD patients with childhood trauma (28.7 ± 9.6 years) and 30 healthy subjects (28.12 ± 4.41 years). Two frequency bands (slow-5: 0.010–0.027 Hz; slow-4: 0.027–0.073 Hz) were analyzed. Compared with controls, the MDD with childhood trauma had decreased ALFF in left S1 (Primary somatosensory cortex), and increased ALFF in left insula. More importantly, significant group × frequency interactions were found in right dorsal anterior cingulate cortex (dACC). Our finding may provide insights into the pathophysiology of MDD with childhood trauma.

In this three-phase, systematic review, we comprehensively synthesize research on bilingual education in higher education institutions over a 19-year period, starting from the initiation of this top-down educational provision across mainland China. In this context, although English has no official status, it is highly regarded and widely used as a medium of instruction alongside Chinese. We critically examine studies ( n = 1,632) published in both English and Chinese outlets on academic discourse that deliberate on what was studied, how it was studied , and what the publication trend was . We argue that scholarly attention should continue to revolve around the benefits of bilingual programs, due to the lack of rigorous empirical evidence that attests to the effectiveness of bilingual education in Chinese higher education. Our review echoes similar research syntheses conducted in Europe and worldwide and is, therefore, expected to shed light on the policy implications and the practice of bilingual education in higher education on a global scale. Recommendations for future research are provided.

This is the first genetic evaluation of hatchery-based stock enhancement of black sea bream (Acanthopagrus schlegelii) in the South China Sea after a two-year monitoring period. In this study, microsatellite DNA markers were used to calculate the contribution rate and analyze genetic changes before and after stock enhancement. Two out of one hundred and sixty nine individuals from three recaptured populations were assigned to broodstock with a contribution rate of 1.18%, revealing that the hatchery-released juvenile fish could survive in the natural environment and had a positive effect on population replenishment in wild black sea bream abundance. However, we found that the release population had the lowest genetic diversity and significant genetic differentiation from other populations. In addition, genetic diversity detected in the recaptured population was lower than that in the wild population, and their genetic differentiation reached a significant level. Our results suggested that releasing cultured black sea bream juveniles with low genetic quality might be genetically harmful for the maintenance of wild genotypes. Therefore, it is necessary to assess the genetic variation of the hatchery population before implementing a stock enhancement and establish a long-term evaluation for monitoring the genetic effect caused by releasing this fish species.

Mathematics is a core content area in the science, technology, engineering, and mathematics (STEM) fields and is vital to student learning in the other STEM subjects. The purpose of this study was to investigate the math performance of fifth- and eighth-grade students in 1170 Texas school districts. We conducted growth hierarchical linear modeling in SAS 9.4 in order to explore the effects of time, district-level characteristics, and their interaction on student performance as measured by the State of Texas Assessments of Academic Readiness (STAAR) math test across three performance levels (i.e., approaching, meeting, and mastering grade level) over three academic years: 2016–2019. The overall findings indicated that, over time, Texas school districts improved in the percentage of students who approached, met, and mastered grade-level performance on the STAAR math test. The results also indicated that five district-level variables consistently and significantly impacted Grade 5 and 8 students’ math achievement at three performance levels. Significant positive factors included the percentage of English learner students and principal years of experience; significant negative factors were the percentage of economically challenged students, student mobility rate, and teacher turnover rate.

In this study, we described and compared an English as a foreign language (EFL) teacher’s pedagogical behaviors in traditional and problem-based learning (PBL) classroom settings in a Chinese university. In spring 2019, we collected six 45-min videos, three in each condition, covering three modules: (a) warm-up and vocabulary, (b) essay structure, and (c) writing. The analyses of the teacher’s pedagogical behaviors and her interaction with students indicated that the instructor spent most of the instructional time delivering higher-order thinking content in both traditional and PBL classes. The teacher’s activity structure influenced students’ communication mode. Although the instructor provided students with more group discussion activities in the PBL classroom, lecturing was observed to be the primary delivery method in both classes. These results suggest that the application of PBL strategies in the EFL classroom did not significantly restructure the teacher’s pedagogical behaviors, and thus, failed to achieve the goal of providing students with more opportunities for improving their expressive English language proficiency. These findings underscore the need to develop an effective PBL-related curriculum and professional development opportunities for EFL teachers to effectively implement the PBL approach in the classroom.

Single-stage nitrite shunt denitrification (through nitrite rather than nitrate) with low dissolved oxygen (DO) supply is a better alternative in terms of energy-efficiency, short-footprint, and low C/N-ratio requirement. This study investigates the optimal DO level with temperature effect, with saline sewage at the fixed hydraulic and solids retention times of 8 h and 8 d, respectively. Moreover, 16S rRNA gene sequencing analysis corresponding with total nitrogen (TN) and chemical oxygen demand (COD) removals in each operating condition were performed. Results showed that DO of 0.3 mg/L at 20 °C achieved over 60.7% and over 97.9% of TN and COD removal, respectively, suggesting that such condition achieved effective nitrite-oxidizing bacteria inhibition and efficient denitrification. An unexpected finding was that sulfur-reducing Haematobacter and nitrogen-fixing Geofilum and Shinella were highly abundant with the copredominance of ammonia-oxidizing Comamonas and Nitrosomonas, nitrite-oxidizing Limnohabitans, and denitrifying Simplicispira, Castellaniella, and Nitratireductor. Further, canonical correspondence analysis (CCA) with respect to the operating conditions associated with phenotype prediction via R-based tool Tax4Fun was performed for a preliminary diagnosis of microbial functionality. The effects of DO, temperature, nitrite, and nitrate in various extents toward each predominant microbe were discussed. Collectively, DO is likely pivotal in single-stage nitrite shunt denitrification, as well as microbial communities, for energy-efficient saline sewage treatment.

Background: Osteosarcoma is the most common primary malignant bone tumor in children and adolescents and is characterized by frequent metastasis and resistance to chemotherapy. Because osteosarcoma cells are not highly susceptible to current chemotherapy drugs, new alternative strategies for the treatment of osteosarcoma are needed. This study was undertaken to investigate the inhibitory effects of a new synthetic ursolic acid derivative IUA on osteosarcoma cells and to explore its molecular mechanism. We also intended to identify new therapeutic candidates. Methods: We used MTT assay to assess the effect of IUA on the proliferation of osteosarcoma cells. Western-blot analysis was performed to examine downstream molecular events. The Annexin V method was used to evaluate the effect of IUA on apoptosis of osteosarcoma cells. The cell cycle of IUA-treated cells was examined by flow cytometry, and the in vivo effects of this new ursolic acid derivative were evaluated in a mouse osteosarcoma model. Results: The results showed that the new synthetic ursolic acid derivative IUA significantly decreased viability of osteosarcoma cells in vitro and in vivo. It could also induce apoptosis and G1 phase arrest of osteosarcoma cells. The JNK signaling pathway was significantly inhibited, and cleaved caspase-3 protein was increased. Conclusion: We concluded that the new synthetic ursolic acid derivative IUA induces proliferation inhibition and apoptosis of osteosarcoma cells in vitro and in vivo via the down-regulation of the JNK signaling pathway, making it a promising agent for the prevention and treatment of human osteosarcoma.

This study compares the science achievement growth trajectories of fifth-grade students in rural and nonrural school districts in Texas. Using a growth hierarchical linear model, we explored the effects of time, school location (rural vs. nonrural), and their interaction on students’ science performance as measured by the high-stakes State of Texas Assessment of Academic Readiness (STAAR) science test over five academic years. We found that rural school students lagged in science at the initial stage when STAAR was first administered in the 2011−2012 school year. With time, the gap between rural and nonrural district students’ science performance persisted. We further added eight district-level factors that might influence students’ academic performance into the model and found that three variables (i.e., student mobility rate, percentage of students identified ELs, and teacher turnover rate) constantly influenced students’ science scores. The implications for teaching pedagogy and research are discussed regarding science education in Texas rural districts.

This study focuses on comparing the growth trajectory of border and non-border school districts regarding their fifth-grade students’ performance on a standardized reading test. Using a growth hierarchical linear model, we investigated the effect of time, school location, and their interaction on students’ reading performance through the State of Texas Assessment of Academic Readiness (STAAR) reading test in five recent school years. It was found that border school students lagged behind in reading at the initial stage when STAAR was first administered. As time went by, the gap between border and non-border district students’ reading performance remained. Implications for teaching pedagogy and research are discussed regarding the preparation of border district students to become bilingual, bicultural, and biliterate.

We investigated the antitumor effect and mechanism of hematoporphyrin monomethyl ether-mediated photodynamic therapy (HMME-PDT) in sarcomas. Intracellular uptake of HMME by osteosarcoma cells (LM8 and K7) was time- and dose-dependent, while this was not observed for myoblast cells (C2C12) and fibroblast cells (NIH/3T3). HMME-PDT markedly inhibited the proliferation of sarcoma cell lines (LM8, MG63, Saos-2, SW1353, TC71, and RD) (P

Previous studies indicated that estrogen could improve endothelial function. However, whether estrogen protects vascular complications of diabetes has yet to be clarified. The study was designed to investigate the action of 17ß-estradiol on vascular endothelium in streptozotocin (STZ)-induced diabetic rats. Ovariectomized female Sprague-Dawley rats were administered with streptozotocin to produce an ovariectomized-diabetic (OVS) model which manifested as dysfunction of aortic dilation and contraction ability. Meanwhile, OVS animals with 17ß-estradiol supplementation significantly improved aortic function. Accordingly, nitric oxide synthase-3 (NOS-3), Akt, PI3K and estrogen receptor α (ERα) protein expression in aorta declined in the OVS group. Such effects were partially restored by estrogen replacement. The presence of 17ß-estradiol similarly counteracted the reduction of cyclic guanosine monophosphate (cGMP), the enhanced expression of inducible NOS (NOS-2) and NO metabolites (nitrite and nitrate), as well as the increase of matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1), which is an index of arterial compliance. 17ß-estradiol could also decrease ROS production in vascular endothelium. In EA hy 926 cells we found that ER antagonist, wortmannin and Akt inhibitor could block improvement effects of 17ß-estradiol. These results strongly suggest that functional impairment of the ERα/NOS-3 signaling network in OVS animals was partially restored by 17ß-estradiol administration, which provides experimental support for estrogen recruitment to improve vascular outcomes in female diabetes after endogenous hormone depletion.

Background: The function of H3F3A G43W mutation, which has been observed in almost all GCTB, remains poorly characterized. Breakthrough in malignant GCTB has been trapped by the lack of clinical available drugs, limited canonical patient samples and paucity of fidelity preclinical models., Methods: Tumor samples obtained from a malignant GCTB was implanted in immunodeficient mice for the generation of PDX. Histological examination and short tandem repeat (STR) were used for inherited features analyses. An epigenetic/transcriptional targeted compound library was selected for drug screening. The in vivo effects of selected drug were validated in PDX model., Results: We established the PDX model with recurrent malignant GCTB specimens, histological examination and STR analyses revealed that PDX and their corresponding parental patients shared the same STRs and histologic features, suggesting common origins. ITF-2357 was the most significant compound with an IC50 lower than 0.1 uM. The results of the drug screening and in vivo PDX validation demonstrated that ITF-2357 might be a promising drug targeted H3F3A G34W mutation MGCTBs., Conclusion: Our study demonstrates that PDX model maintained the same histologic and genetic features as those in the original patient. targeting HDAC through ITF-2357 effectively overcomes malignant GCTB progression in vitro and in vivo., Translational Potential Statement: As PDX retain the principal histologic and genetic characteristics of the primary tumors, mad it a valuable research tool in predictive clinical efficacy. In this study, we first established a malignant GCTB PDX model, which might further accelerate the progress of drug development in malignant GCTB., Competing Interests: All authors declare that they have no conflicts of interest concerning this article., (© 2021 Department of Orthopaedic, Shanghai General Hospital, Shanghai JiaoTong Univeraity school of medicine.)

Aging drives the accumulation of senescent cells (SnCs) by secreting factors that cause the senescence-associated secretory phenotype (SASP), including stem cells in the bone marrow, which contribute to aging-related bone degradation. Osteoarthritis (OA) is a serious chronic injury disease, and increasing age is a major risk factor. The accumulation of SnCs may accelerate the development of OA, and the accumulation of SnCs may benefit from its resistance to apoptotic stimuli. Therefore, local elimination of SnCs could be a promising treatment for OA. Apoptosis inhibitor protein (IAP) is an important antiapoptotic protein in vivo. AT-406 is a small molecule inhibitor of the IAP genes and also regulates the transcription of several genes. Here, we show that SnCs upregulate the antiapoptotic proteins c-IAP1, c-IAP2 and XIAP.The combined inhibition of c-IAP1, c-IAP2 and XIAP using siRNA or AT-406 specifically induce the apoptosis of SnCs.In addition, XIAP and STX17 bind to each other to regulate the fusion of autophagosomes and lysosomes in SnCs, which in turn, affects the fate of SnCs. It is worth noting that the clearance of SnCs attenuated the secretion of SASP and created a proregenerative environment. Most importantly, local clearance of SnCs significantly attenuated the progression of osteoarthritis in rats without significant toxic effects. Thus, local elimination of SnCs may be a potential treatment for OA. This is the first report of inhibition of IAPs for clearing SnCs and suggests that eradication of SnCs may be a new strategy for the treatment of age-related diseases., (Copyright © 2019 Elsevier B.V. All rights reserved.)