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Haijing Sui,1,&ast; Hong Shen,1,&ast; Chi Zhang,1 Minghui Wang,1 Zhen Zhen,1 Junbo Zhang2 1Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing, People’s Republic of China; 2Department of Otolaryngology, Head and Neck Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Junbo Zhang, Department of Otolaryngology, Head and Neck Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, People’s Republic of China, Email zhangjunbo354@163.com Zhen Zhen, Department of Otolaryngology, Head and Neck Surgery, Peking University First Hospital, Beijing, People’s Republic of China, Email zhen_ent@163.comObjective: This study aimed to explore whether saliva pepsin concentration (SPC) could be regarded as a risk factor for the occurrence and unfavorable control of asthma in children with allergic rhinitis.Methods: A prospective study was conducted on a group of 20 consecutive children newly diagnosed with allergic rhinitis and asthma (referred to as the asthma group). All these children underwent fractional exhaled nitric oxide (FeNO) measurement, lung function tests, and assessment of asthma control using the 7-item Childhood Asthma Control Test (C-ACT) score. Simultaneously, a control group consisting of 20 children with simple allergic rhinitis, matched for baseline characteristics, was included. SPC measurement was performed in the two groups.Results: The SPC value was significantly higher in the asthma group than that in the control group (165.0 ± 82.8 ng/mL vs 68.4 ± 34.5 ng/mL) (P < 0.001). In the asthma group, SPC was independently associated with FeNO, the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC), and forced expiratory flow at 50% and 75% of FVC (FEF50 and FEF75) (all P < 0.05). The severity of nasal symptoms evaluated by the visual analogue scale (N-VAS) was independently associated with FEF75, the maximal mid-expiratory flow (MMEF), and C-ACT score (P < 0.05).Conclusion: Direct pepsin exposure and uncontrolled nasal symptoms may play crucial roles in the pathogenesis and progression of childhood allergic asthma. The SPC value can be considered as a risk factor for asthma in children with allergic rhinitis.Keywords: saliva pepsin concentration, asthma, allergic rhinitis, gastroesophageal reflux disease

Xiao Lei,1,&ast; Guodong Tan,2,&ast; Yiming Wang,3,&ast; Li Chen,4,&ast; Yuan Cao,1 Bingxin Si,2 Zhen Zhen,2 Bei Li,5 Yan Jin,5 Wei Wang,6 Fang Jin1 1Shaanxi Clinical Research Center for Oral Disease & Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 2Air Force Medical Center, Fourth Military Medical University, Beijing, People’s Republic of China; 3Shaanxi Clinical Research Center for Oral Diseases & Department of Oral Surgery, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 4Shaanxi Key Laboratory of Energy Chemical Process Intensification & Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi’an Jiao Tong University, Xi’an, Shaanxi, People’s Republic of China; 5State Key Laboratory of Military Stomatology & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 6State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang Jin, Shaanxi Clinical Research Center for Oral Disease & Department of Orthodontics, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China, Email fangjin191@163.com Wei Wang, State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi Key Laboratory of Oral Diseases, Department of Operative Dentistry and Endodontics, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China, Email weiwang_0510@163.comIntroduction: Osteoarthritis (OA) is a chronic degenerative joint disease accompanied by an elevated macrophage proinflammatory phenotype, which is triggered by persistent pathologically elevated calcium ion levels in mitochondria. However, existing pharmacological compounds targeting the inhibition of mitochondrial calcium ion (m[Ca2+]) influx are currently limited in terms of plasma membrane permeability and low specificity for ion channels and transporters. In the present study, we synthesized mesoporous silica nanoparticle-amidated (MSN)-ethylenebis (oxyethylenenitrilo)tetraacetic acid (EGTA)/triphenylphosphine (TPP)-polyethylene glycol (PEG) [METP] nanoparticles (NPs), which specifically target mitochondria and block excess calcium ion influx.Methods: m[Ca2+] overload in OA mouse bone marrow-derived macrophages (BMDMs) was detected by a fluorescence probe. A tissue in situ fluorescence colocalization assay was used to evaluate METP NP uptake by macrophages. BMDMs from healthy mice were pretreated with a concentration gradient of METP NPs followed by lipopolysaccharide (LPS) stimulation and detection of m[Ca2+] levels in vitro. The optimal METP NP concentration was further applied, and the endoplasmic reticulum (ER) and cytoplasm calcium levels were detected. The inflammatory phenotype was measured by surface markers, cytokine secretion and intracellular inflammatory gene/protein expression. A Seahorse cell energy metabolism assay was performed to elucidate the mechanism by which METP NPs reverse the BMDM proinflammatory phenotype.Results: The present study identified calcium overload in BMDM mitochondria of OA mice. We demonstrated that METP NPs reversed the increased m[Ca2+] levels in mitochondria and the proinflammatory phenotype of BMDMs, with both in vivo and in vitro experiments, via the inhibition of the mitochondrial aspartate-arginosuccinate shunt and ROS production.Conclusion: We demonstrated that METP NPs are effective and highly specific regulators of m[Ca2+] overload. In addition, we demonstrated that these METP NPs reverse the macrophage proinflammatory phenotype by restoring m[Ca2+] homeostasis, thereby inhibiting the tissue inflammatory response and achieving a therapeutic effect for OA.Graphical Abstract: Keywords: nanoparticle, macrophage, mitochondria, calcium homeostasis, osteoarthritis

Xi Chen,1 Lu Gao,1 Zhen Zhen,1 Ying Wang,1 Jia Na,1 Wen Yu,1 Xinyuan Chu,1 Yue Yuan,1 Suyun Qian2 1Department of Cardiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of China; 2Pediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of ChinaCorrespondence: Yue Yuan, Department of Cardiology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, No. 56, Nanlishilu, District Xicheng, Beijing, 100045, People’s Republic of China, Email yuanyuebjdr@163.com; yuanyuebj22@sina.com Suyun Qian, Pediatric Intensive Care Unit, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, No. 56, Nanlishilu, District Xicheng, Beijing, 100045, People’s Republic of China, Email qiansuyunbj12@163.com; suyunqian1211@163.comPurpose: To explore the risk factors and develop predictive models for intravenous immunoglobulin (IVIG) resistance in children with recurrent Kawasaki disease (KD).Patients and Methods: Patients with recurrent KD were retrospectively reviewed. Clinical and laboratory data at recurrence were collected and compared between patients with and without IVIG resistance. The patients were randomly divided into training and validation cohorts for model development and validation. All variables were subjected to standard Lasso and its variant group Lasso analyses, respectively, to construct predictive models. Model performance was evaluated by receiver operating characteristics (ROC) curves, calibration curves, and Hosmer-Lemeshow tests.Results: A total of 90 children with recurrent KD were included. A total of 16 cases were IVIG resistant. The patients with IVIG resistance had higher age and IVIG resistance probability at the first episode, increased CRP levels, neutrophil count, neutrophil percentage, direct bilirubin level, prothrombin time, and international normalized ratio, and decreased lymphocyte count, lymphocyte percentage, and serum sodium levels. Five variables including age and IVIG resistance at the first episode, lymphocytes count, serum sodium levels, and CRP levels were finally selected by standard Lasso (lLasso model) and four variables including age and IVIG resistance at the first episode, neutrophil percentage, and CRP levels were selected by group Lasso (gLasso). ROC curves suggested lLasso and gLasso models had similar excellent discrimination in both the training cohort (0.895 vs 0.906) and the validation cohort (0.855 vs 0.909). Hosmer-Lemeshow tests suggested the two models exerted a good calibration. Two nomograms were also constructed to facilitate the potential application of the two models.Conclusion: Age and IVIG resistance at the first episode and some laboratory variables may be risk factors for IVIG resistance in recurrent KD. Two predictive models for IVIG resistance with excellent performance were established in recurrent KD. External validation should be performed before clinical use.Keywords: recurrent Kawasaki disease, intravenous immunoglobulin, resistance, risk factor, predictive model

Yap-Hang Chan,1 Michael Cheong Ngai,2 Yan Chen,1,3 Mei-Zhen Wu,1 Yu-Juan Yu,1 Zhe Zhen,1 Kevin Lai,1 Ho-Yin Chung,4 Chak-Sing Lau,4 Hung-Fat Tse,1,3 Kai-Hang Yiu1,3 1Cardiology Division, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, Special Administrative Regions, People’s Republic of China; 2Division of Hematology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, Special Administrative Regions, People’s Republic of China; 3Cardiology Division, Department of Medicine, The University of Hong Kong Shenzhen Hospital, Shenzhen, People’s Republic of China; 4Division of Rheumatology, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, Special Administrative Regions, People’s Republic of ChinaCorrespondence: Kai-Hang Yiu, Cardiology Division, Department of Medicine, The University of Hong Kong-Shenzhen Hospital, 1 Haiyuan 1st Road, Futian District, Shenzhen, 518053, Guangdong, People’s Republic of China, Tel +852 22553633, Fax +852 28186304, Email khkyiu@hku.hkBackground and Aim: Rheumatoid arthritis is associated with both abnormal bone metabolism and accelerated vascular aging but a mechanistic link was lacking. This study aims to investigate the role of osteocalcin (OCN)-expressing circulating endothelial progenitor cells (EPCs) in vascular aging, as determined by arterial calcifications in rheumatoid arthritis.Methods: We performed flow cytometry studies in 145 consecutive patients with rheumatoid arthritis to determine osteogenic circulating levels of OCN-positive (OCN+) CD34+KDR+ and OCN+CD34+ versus conventional early EPC CD34+CD133+KDR+. Total calcium load of the thoracic aorta (ascending plus descending) and the carotid arteries were assessed by non-contrast computed tomography (CT) and contrast CT angiography.Results: Osteogenic EPCs OCN+CD34+KDR+ (P = 0.002) and OCN+CD34+ (P = 0.001), together with clinical parameters of age, history of hypertension, systolic blood pressure, serum levels of triglycerides, HbA1c and creatinine, use of leflunomide and brachial-ankle pulse-wave velocity (all P < 0.05), were associated with the clustered presence of aortic and carotid calcification. Multivariable analyses revealed that circulating OCN+CD34+KDR+ (B = 14.4 [95% CI 4.0 to 24.8], P = 0.007) and OCN+CD34+ (B = 9.6 [95% CI 4.9 to 14.3], P < 0.001) remained independently associated with increased aortic calcium load. OCN+CD34+ EPC (B = 0.8 [95% CI 0.1 to 1.5], P = 0.023), but not OCN+CD34+KDR+ EPC (B = 1.2 [95% CI − 0.2 to 2.6], P = 0.09), was further independently associated with carotid calcium load. In comparison, conventional early EPC CD34+CD133+KDR+ had no significant association with aortic or carotid calcium load (P = 0.46 and 0.88, respectively).Conclusion: Circulating level of osteogenic EPC is associated with increased vascular aging in terms of calcification of the large arteries in patients with rheumatoid arthritis. The findings may suggest a role of the bone-vascular axis underlying vascular aging in rheumatic diseases. Further research is needed to characterize the mechanistic links and basis of these observations.Keywords: osteocalcin, endothelial progenitor cells, vascular aging, rheumatoid arthritis

Yunchen Meng,1 Dan Xu,1 Weinan Zhang,1 Wenshu Meng,2 Xingyu Lan,3 Xiaoxi Wang,3 Mingjuan Li,3 Xiaoyan Zhang,1 Yu Zhao,1 Haodong Yang,1 Rong Zhang,3– 6 Zhiping Zhen1 1College of P.E and Sports, Beijing Normal University, Beijing, People’s Republic of China; 2College of Life Sciences, Beijing Normal University, Beijing, People’s Republic of China; 3Department of Neurobiology, School of Basic Medical Sciences, Peking University, Beijing, People’s Republic of China; 4Neuroscience Research Institute, Peking University, Beijing, People’s Republic of China; 5Key Laboratory for Neuroscience, Ministry of Education/National Health and Family Planning Commission, Peking University, Beijing, People’s Republic of China; 6Autism Research Center of Peking University Health Science Center, Beijing, People’s Republic of ChinaCorrespondence: Zhiping Zhen; Rong Zhang, Email zzpxt@bnu.edu.cn; zhangrong@bjmu.edu.cnBackground: Autism spectrum disorder (ASD) is a developmental disorder characterized by social behavior deficits and stereotyped behaviors in childhood that lacks satisfactory medical intervention. Early swimming intervention is a noninvasive method combining enriched environment and exercise, which has been proven to improve brain development in young children and to treat neurodevelopmental diseases.Methods: In this study, we tested the autism-like behavior of rats with deletions in exons 11– 21 of the Shank3 gene and evaluated the effect of early swimming intervention (from postnatal day 8 to 60) on the behavior of this animal model of autism. In addition, the transcriptomes of the striatal tissues of wild-type, Shank3 knockout and Shank3 knockout swimming groups rats were analyzed.Results: Shank3 knockout rats exhibit core symptoms of autism, and early swimming improved the social and stereotyped behaviors in this autism rat model. Transcriptomics results revealed that compared to the wild-type group, 291 differentially expressed genes (DEGs) were identified in the striatum of the Shank3 knockout group. Compared to Shank3 knockout group, 534 DEGs were identified in the striatum of Shank3 knockout swimming group. The DEGs annotated by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway shows that the impacts of Shank3 deletion were primarily reflected in synaptic structure, development, morphology, receptor function and signaling, and swimming primarily changed the terms related to the synapses in the striatum of Shank3 knockout rats, including the morphology, structure, composition, development and regulation of synapses.Conclusion: Early swimming intervention can ameliorate behavioral abnormalities caused by Shank3 knockout, by a mechanism that may involve the process of striatal synaptic development and should be further investigated.Keywords: Shank3, autism, early swimming, behavior, transcriptome

The metabotropic γ-aminobutyric acid type B receptor (GABABR) remains a hotspot in the recent research area. Being an idiosyncratic G-protein coupled receptor family member, the GABABR manifests adaptively tailored functionality under multifarious modulations by a constellation of agents, pointing to cross-talk between receptors and effectors that converge on the domains of mood and memory. This review systematically summarizes the latest achievements in signal transduction mechanisms of the GABABR-effector-regulator complex and probes how the up-and down-regulation of membrane-delimited GABABRs are associated with manifold intrinsic and extrinsic agents in synaptic strength and plasticity. Neuropsychiatric conditions depression and addiction share the similar pathophysiology of synapse inadaptability underlying negative mood-related processes, memory formations, and impairments. In the attempt to emphasize all convergent discoveries, we hope the insights gained on the GABABR system mechanisms of action are conducive to designing more therapeutic candidates so as to refine the prognosis rate of diseases and minimize side effects.

Xiaoqin Zhu,1,2,* Jia Zhu,1,2,* Feifei Sun,1,2,* Zijun Zhen,1,2 Dalei Zhou,1,3 Suying Lu,1,2 Junting Huang,1,2 Yi Que,1,2 Lian Zhang,1,2 Ruiqing Cai,1,2 Juan Wang,1,2 Yizhuo Zhang1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 3Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yizhuo Zhang; Juan Wang Email zhangyzh@sysucc.org.cn; wangjuan@sysucc.org.cnObjective: The association between UGT1A1*6/*28 polymorphisms and treatment outcomes of irinotecan in children remains unknown. This retrospective study investigated the influence of UGT1A1*6/*28 polymorphisms on irinotecan toxicity and survival of pediatric patients with relapsed/refractory solid tumors.Methods: The present study enrolled a total of 44 patients aged younger than 18 years at Sun Yat-sen University Cancer Center between 2014 and 2017.Results: There were 26 boys and 18 girls; the median age at first VIT course was six years (range: 1– 18 years). The tumor types included neuroblastoma (n = 25), rhabdomyosarcoma (n = 11), Wilm’s tumor (n = 4), medulloblastoma (n = 2), and desmoplastic small round cell tumor (n = 2). Overall, 203 courses of VIT regimens were prescribed. Neither UGT1A1*6 nor *28 polymorphisms were associated with the incidence rates of severe (grade III–IV) irinotecan-related toxicities, but tended to reduce the patient overall survival (UGT1A1*6, P = 0.146; UGT1A1*28, P = 0.195). Moreover, patients with mutant UGT1A1*6 genotypes were more likely to develop grade I–IV irinotecan-related diarrhea (P = 0.043) and anemia (P = 0.002). Overall, the UGT1A1*28 polymorphism may play a protective role against irinotecan-related diarrhea and abdominal pain.Conclusion: In relapsed/refractory pediatric solid tumors, the UGT1A1*6 polymorphism was a risk factor of irinotecan-related diarrhea and anemia. The UGT1A1*28 polymorphism may serve a protective role in irinotecan-related abdominal pain and diarrhea. Both mutations had a tendency to be risk factors for survival. Nevertheless, prospective studies are required to verify such conclusions.Keywords: UGT1A1 *6/*28 polymorphism, irinotecan toxicity, pediatric, relapsed/refractory solid tumors

Suying Lu,1,2,* Chengtao Sun,3,* Huimou Chen,1,2,* Chao Zhang,1,4,* Wei Li,5 Liuhong Wu,1,2 Jia Zhu,1,2 Feifei Sun,1,2 Junting Huang,1,2 Juan Wang,1,2 Zijun Zhen,1,2 Ruiqing Cai,1,2 Xiaofei Sun,1,2 Yizhuo Zhang,1,2 Xing Zhang1,6 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, 510060, People’s Republic of China; 2Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, People’s Republic of China; 3Department of Hematology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, People’s Republic of China; 4Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, People’s Republic of China; 5Department of Cardiology, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, People’s Republic of China; 6Department of Medical Melanoma and Sarcoma, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xing ZhangDepartment of Medical Melanoma and Sarcoma, Sun Yat-Sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, Guangdong 510060, People’s Republic of ChinaTel/Fax +86-020-87343629Email zhangxing@sysucc.org.cnYizhuo Zhang Department of Pediatric OncologySun Yat-sen University Cancer Center, 651 East Dongfeng Road, Guangzhou, Guangdong 510060, People’s Republic of ChinaTel/Fax +86-020-87342458Email zhangyzh@sysucc.org.cnPurpose: The goal of the current study was to identify potential prognostic biomarkers of rhabdomyosarcoma (RMS).Materials and Methods: We screened chip sequencing datasets of RMS through the gene expression omnibus (GEO) database. A total of 74 RMS patient tissues and 39 normal muscle cell tissues were analyzed. Limma R software was used to identify the differentially expressed genes (DEGs) between RMS tissues and normal controls. The GO plot R package was used to visualize the results of the GO analysis. We screened for pathaffy package enrichment of DEGs by the Kyoto Encyclopedia of Genes and Genomes (KEGG). The cutoff criterion was a P-value < 0.05. Immunohistochemistry (IHC) was applied to validate the expression of CDK1 (cyclin-dependent kinases 1) and MAD2L1 (Mitotic Arrest Deficient 2 Like 1) in RMS.Results: We obtained a total of 498 up- and 480 down-regulated DEGs. The hub genes are mainly involved in the cell cycle and P53 singling pathway. CDK1 expression was associated with tumor size and COG-STS (Children’s Oncology Group-soft tissue sarcoma) staging of RMS. For the low CDK1 expression group and high CDK1 expression group, the 5-year overall survival (OS) rate was 83.0% vs 63.5% (P = 0.004), and the 5-year event-free survival (EFS) rate was 47.5% vs 27.5% (P = 0.049) respectively. When compared low MAD2L1 expression group with high MAD2L1 expression group, the 5-year OS rate was 80.0% vs 43.2% (P = 0.001), and the 5-year EFS rate was 45.1% vs 21.8% (P = 0.038), respectively. If patients were divided into three groups: low CDK1 and low MAD2L1 expression group, high CDK1 or high MAD2L1 expression group, and high CDK1 and high MAD2L1 expression group, the 5-year OS rate was 87.1%, 58.6%, 39.6% (P = 0.001), while the 5-year EFS rate of RMS patients was 54.2%, 23.2%, 21.7% (P = 0.028), respectively.Conclusion: This study has identified that CDK1 and MAD2L1 were adverse prognostic factors of RMS.Keywords: rhabdomyosarcoma, GEO, TCGA, CDK1, MAD2L1, prognosis

Feifei Sun,1,2,* Suying Lu,1,2,* Zijun Zhen,1,2 Jia Zhu,1,2 Juan Wang,1,2 Junting Huang,1,2 Yu Zhang,1,3 Hui Li,1,4 Ruiqing Cai,1,2 Meiling Liu,1,2 Liuhong Wu,1,2 Xiaofei Sun,1,2 Yizhuo Zhang1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 3Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 4Department of Imaging, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiaofei Sun; Yizhuo Zhang Email sunxf@sysucc.org.cn; zhangyzh@sysucc.org.cnBackground: The prognosis of recurrent or refractory advanced childhood solid tumor patients is very poor and new therapeutic strategies are in urgent need. This study aimed to determine the efficacy and safety of apatinib in pediatric refractory/relapse advanced solid tumor patients.Patients and Methods: The study retrospectively reviewed recurrent or refractory advanced pediatric solid tumor patients who were treated with apatinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor-2 (VEGFR2), at the Sun Yat-sen University Cancer Center (China) from January 2016 to March 2019.Results: Fifty-six patients were included in the safety evaluation and 49 patients were included in the efficacy evaluation. The objective responses rate (ORR) was 26.5% (95% CI 15– 41): 0 CR (complete response) and 13 PR (partial response). Disease control rate (DCR) (CR+PR+SD) was 79.6% (95% CI 65– 90). The median progression-free survival (PFS) was 4.0 months (95% CI 2.6– 5.4). There was no significant difference for ORR or PFS between the A (apatinib monotherapy), A+MT (apatinib combined with oral metronomic therapy) and A+SC (apatinib combined with salvage combination chemotherapy) group (p> 0.05). The most common grade 3 or 4 adverse events were neutropenia (9[16.1%]), thrombocytopenia (8[14.3%]), hand-foot syndrome (3[5.4%]), hypertension (3[5.4%]), anaemia (3[5.4%]) and mucositis (2[3.6%]). Hypertension was the most serious adverse event and one death that occurred was considered as drug-related.Conclusion: Apatinib showed promising clinical activity in heavily treated recurrent or refractory advanced childhood solid tumor patients. However, it is necessary to pay special attention to monitoring blood pressure when using apatinib in children. Prospective randomized controlled clinical trial is warranted.Keywords: apatinib, angiogenesis, cancer, pediatric, vascular endothelial growth factor receptor

Zeli Huang,1,* Bojin Su,2,* Fang Liu,3,* Ning Zhang,1 Yilong Ye,4 Yang Zhang,1 Zhenghe Zhen,1 Shaoqiang Liang,1 Shaobo Liang,1 Lushi Chen,1 Weijun Luo,1 François X Claret,5,6 Ying Huang,7,8 Tao Xu1 1Department of Radiation Oncology, Cancer Center, First People’s Hospital of Foshan, Foshan 528000, Guangdong Province, People’s Republic of China; 2Department of Pathology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong Province, People’s Republic of China; 3Department of Pathology, First People’s Hospital of Foshan, Foshan 528000, Guangdong Province, People’s Republic of China; 4Department of Infection, First People’s Hospital of Foshan, Foshan 528000, Guangdong Province, People’s Republic of China; 5Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; 6Experimental Therapeutics Academic Program and Cancer Biology Program, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX 77030, USA; 7Department of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, People’s Republic of China; 8State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou 510060, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ying HuangDepartment of Radiation Oncology, Cancer Center, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, People’s Republic of ChinaEmail huangying@sysucc.org.cnTao XuDepartment of Radiation Oncology, Cancer Center, First People’s Hospital of Foshan, Foshan 528000, Guangdong Province, People’s Republic of ChinaEmail asian.you@163.comIntroduction: Nasopharyngeal carcinoma (NPC) patients with HBsAg (+) commonly present with high frequencies of distant metastasis and poor survival rate; however, the mechanism has not been elucidated.Materials and Methods: We analyzed the yes-associated protein 1 (YAP1) expression between HBsAg (+) and HBsAg (-) of NPC patients, then analyzed the relationship of YAP1 with survival. We further explored the anti-tumor role in NPC cell lines using YAP1 siRNA technique, and checked whether YAP1 regulatesepithelial–mesenchymal transition ( EMT). The relationship between HBV X protein (HBx) and YAP1 was also tested using Dual-Luciferase reporter assay. Finally, we explored anti-YAP1 to inhibit tumor metastasis using the xenograft mice model.Results: In the current study, we found that YAP1 expression was higher in HBsAg (+) samples than in the HBsAg (-) samples, as a clinical signature, suggesting that YAP1 could be used as a prognostic factor for NPC. Our results showed that the HBx could regulate YAP1, further promoting cellular invasiveness through EMT. Anti-YAP1 can also decrease metastasis in vivo.Conclusion: Our findings suggest that YAP1 is a promising prognostic factor in NPC and could be used as a potential treatment target for NPC with HBV infection.Keywords: YAP1, hepatitis B, HBx, nasopharyngeal carcinoma, metastasis

Jiafei Chen, Chaoyang Zhou, Min He, Zhiming Zhen, Jie Wang, Xiaofei Hu Department of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of ChinaCorrespondence: Xiaofei HuDepartment of Radiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, People’s Republic of ChinaTel +86-23-6876-5419Fax +86-23-6546-3026Email harryzonetmmu@163.comBackground: Endoscopic ultrasonography (EUS) is widely used as a staging modality for gastric cancer. However, the results of studies on the use of EUS for N staging in gastric cancer vary. This study aimed at studying the overall diagnostic accuracy of EUS for N staging of gastric cancer.Methods: Published studies were identified through searching the MEDLINE, Web of Science, EMBASE, SpringerLink and ScienceDirect databases. A bivariate random effect model was used to estimate the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). A hierarchical summary receiver operating characteristic curves (HSROC) based on the pooled data was also computed.Results: Fifty studies (5223 patients) were included in this analysis. The pooled sensitivity, specificity, PLR, NLR and DOR of EUS for N staging were 0.82 (95% CI 0.78 to 0.85), 0.68 (0.63 to 0.73), 2.6 (2.2 to 3.0), 0.27 (0.22 to 0.32), and 10 (8 to 12), respectively. The area under the HSROC was 0.83.Conclusion: The EUS may provide a clinically useful tool to guide physicians in the N staging of gastric cancer. However, physicians must note that the EUS has a relatively low specificity.Keywords: gastric cancer, N staging, endoscopic ultrasound, meta-analysis

Geographically weighted regression (GWR) has become popular in recent years to deal with spatial autocorrelation and heterogeneity in forestry and ecological data. However, researchers have realized that GWR has some limitations, such as correlated model coefficients across study areas, strong influence of outliers, weak data problem, etc. In this study, we applied Bayesian geographically weighted regression (BGWR) and a robust BGWR (rBGWR) to model the relationship between tree crown and diameter using observed tree data and simulated data to investigate model fitting and performance in order to overcome some limitations of GWR. Our results indicated that, for observed tree data, the rBGWR estimated tree crown more accurate than both BGWR and GWR. For the simulated data, 74.1% of the estimated slope coefficients by rBGWR and 73.4% of the estimated slope coefficients by BGWR were not significantly different (α = 0.05) from the corresponding simulated slope coefficients. The estimation of model coefficients by rBGWR was not sensitive to outliers, but the coefficient estimation by GWR was strongly affected by those outliers. The majority of the coefficient estimates by rBGWR and BGWR for weak observations were not significantly (α = 0.05) different from the simulated coefficients. Therefore, BGWR (including rBGWR) may be a better alternative to overcome some limitations of GWR. In addition, both BGWR and rBGWR were more powerful than GWR to detect the spatial areas with non-constant variance or spatial outliers.

Five polymers dispersed liquid crystalline (LC) films were fabricated using photo-polymerizable monomers with different lengths of carbon chains. These LC films have shown different electro-optical (EO) properties. Through their SEM pictures, the relationship between the linear electro-optical effect and the mesh size of the polymer network was explored. With the increase of number of photo-polymerizable monomers, the mesh size of the polymer network would become larger. So the liquid crystal molecules would be easily oriented in the electric field and therefore, the threshold voltage and saturation voltage would decrease. The open state response times were also reduced and the off state response times would be extended. The DFT simulations have shown principal role of the ground state dipole moments in the observed electro-optical efficiency.

Liu Weiran,1,* Zhang Lei,2,* Stephanie Mu-Lian Woo,3,* Tang Anliu,4,* Xie Shumin,4,* Zhang Jing,5,* Zhang Kai,6,* Zhang Zhen7 1Department of Anesthesia, 2Department of Thoracic Surgery, Key Laboratory of Cancer Prevention and Therapy, Tianjin Lung Cancer Center, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China; 3Harvard University, Cambridge, MA, USA; 4Xiangya Medical School of Central South University, Changsha, People's Republic of China; 5Tianjin Medical University, Tianjin, People's Republic of China; 6Department of Cerebral Surgery, Tumor Hospital Xiangya School of Medicine, Central South University, Changsha, People's Republic of China; 7Department of Oncology, Third Xiangya Hospital, Central South University, Changsha, People's Republic of China *These authors contributed equally to this work Background: This study aims to analyze the current status of postoperative pain management in the People's Republic of China's provincial-level hospitals, and the existing knowledge and opinions held by patients regarding these methods. Methods: The 128 participants in this study were urology and hepatobiliary patients from three provincial-level hospitals in Hunan. The questionnaire assessing postoperative pain was designed using the typical pain assessment scales and pain management guidelines as references. Results: 82.8% of study participants claimed that their postoperative pain was relieved within 3 days of their operations. However, while 91.4% of surveyed patients experienced moderate to severe pain, 51.6% received no treatment for their postoperative pain, and 14.9% complained that medical personnel failed to manage their pain. 20.2% were unsatisfied with their pain management, indicating that treatment did not meet their expectations. Furthermore, participants demonstrated a great misunderstanding of pain and analgesics, as 72.6% of patients were unfamiliar with morphine, 51.6% of patients believed only certain types of pain required management, and 18.5% refused to use morphine. Conclusion: In most Chinese provincial-level hospitals, current postoperative pain management methods are able to alleviate the pain experienced by the majority of patients, though pain assessment and therapy procedures are still not standardized. Furthermore, most patients lack a proper understanding of postoperative pain and analgesics. Therefore, pain management education for doctors and patients and their relatives should be implemented in order to improve the quality of postoperative pain management. Keywords: postoperative pain, pain assessment, pain management, pain recognition, pain education

Purpose. To investigate the prognostic factors for visual outcome in traumatic cataract patients. Methods. The demographic features of traumatic cataract patients in Central China were studied. The factors that might influence the visual outcome were analyzed. The sensitivity and specificity of OTS (ocular trauma score) in predicting VA were calculated. Results. The study enrolled 480 cases. 65.5% of patients achieved VA at >20/60. The factors associated with the final VA were initial VA, injury type, wound location, the way of cataract removal, and IOL implantation. The sensitivities of OTS in predicting the VA at NLP (nonlight perception), LP/HM (light perception/hand motion), and ≥20/40 were 100%. The specificity of OTS to predict the final VA at 1/200-19/200 and 20/200-20/50 was 100%. Conclusion. The prognostic factors were initial VA, injury type, wound location, cataract removal procedure, and the way of IOL implantation. The OTS has good sensitivity and specificity in predicting visual outcome in traumatic cataract patients in long follow-up.

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Abstract Regulated cell death (RCD) plays a crucial role in the immune microenvironment, development, and progression of hepatocellular carcinoma (HCC). However, reliable immune-related cell death signatures have not been explored. In this study, we collected 12 RCD modes (e.g., apoptosis, ferroptosis, and cuproptosis), including 1078 regulators, to identify immune-related cell death genes based on HCC immune subgroups. Using a developed competitive machine learning framework, nine genes were screened to construct the immune-related cell death index (IRCDI), which is available for online application. Multi-omics data, along with clinical features, were analyzed to explore the HCC malignant heterogeneity. To validate the efficacy of this model, more than 18 independent cohorts, including survival and diverse treatment cohorts and datasets, were utilized. These findings were further validated using in-house samples and molecular biological experiments. Overall, the IRCDI may have a wide application in individual therapeutic decision-making and improving outcomes for HCC patients.

Abstract Neurodevelopmental disorders are currently one of the major complications faced by patients with congenital heart disease (CHD). Chronic hypoxia in the prenatal and postnatal preoperative brain may be associated with neurological damage and impaired long-term cognitive function, but the exact mechanisms are unknown. In this study, we find that delayed neuronal migration and impaired synaptic development are attributed to altered Atoh1 under chronic hypoxia. This is due to the fact that excessive Atoh1 facilitates expression of Kif21b, which causes excess in free-state α-tubulin, leading to disrupted microtubule dynamic stability. Furthermore, the delay in neonatal brain maturation induces cognitive disabilities in adult mice. Then, by down-regulating Atoh1 we alleviate the impairment of cell migration and synaptic development, improving the cognitive behavior of mice to some extent. Taken together, our work unveil that Atoh1 may be one of the targets to ameliorate hypoxia-induced neurodevelopmental disabilities and cognitive impairment in CHD.

Abstract Background Cotton is an important economic crop and a host of Liriomyza sativae. Pectin methylesterase (PME)-mediated pectin metabolism plays an indispensable role in multiple biological processes in planta. However, the pleiotropic functions of PME often lead to unpredictable effects on crop resistance to pests. Additionally, whether and how PME affects susceptibility to Liriomyza sativae remain unclear. Results Here, we isolated GhPME36, which is located in the cell wall, from upland cotton (Gossypium hirsutum L.). Interestingly, the overexpression of GhPME36 in cotton caused severe susceptibility to Liriomyza sativae but increased leaf biomass in Arabidopsis. Cytological observations revealed that the cell wall was thinner with more demethylesterified pectins in GhPME36-OE cotton leaves than in WT leaves, whereas the soluble sugar content of GhPME36-OE cotton leaf cell walls was accordingly higher; both factors attracted Liriomyza sativae to feed on GhPME36-OE cotton leaves. Metabolomic analysis demonstrated that glucose was significantly differentially accumulated. Transcriptomic analysis further revealed DEGs enriched in glucose metabolic pathways when GhPME36 was overexpressed, suggesting that GhPME36 aggravates susceptibility to Liriomyza sativae by affecting both the structure and components of cell wall biosynthesis. Moreover, GhPME36 interacts with another pectin-modifying enzyme, GhC/VIF1, to maintain the dynamic stability of pectin methyl esterification. Conclusions Taken together, our results reveal the cytological and molecular mechanisms by which GhPME36 aggravates susceptibility to Liriomyza sativae. This study broadens the knowledge of PME function and provides new insights into plant resistance to pests and the safety of genetically modified plants.

This study aimed to investigate the effects of solid-state fermentation products of yeast (SFPY) on liver and intestinal health and disease resistance of common carp (Cyprinus carpio). A total of 200 common carp with an initial average weight of 2.55 ± 0.004 g were divided into 5 groups (4 replications per group and 10 fish per replication), and were fed with one of five diets, including a control diet and 4 diets supplemented with 2‰ (Y2), 3‰ (Y3), 4‰ (Y4), or 5‰ (Y5) SFPY, respectively, for 8 weeks. Results indicated that, the addition of SFPY to the diet of common carp did not affect the growth performance or survival rate of fish (P = 0.253). Interestingly, with the addition of SFPY, the triacylglycerol (TAG) content of the liver presented a linear decreasing tendency (P = 0.004), with significantly decreased in Y4 and Y5 groups (P = 0.035) compared with control. Serum lipopolysaccharide (LPS) content and diamine oxidase (DAO) activity presented a negative linear relationship with the addition of SFPY (P = 0.015, P = 0.030), while serum lipopolysaccharide binding protein (LBP) content first decreased and then increased (P

Abstract Local inflammatory microenvironment in the early stage of myocardial infarction (MI) severely impaired cardiac recovery post-MI. Macrophages play a pivotal role in this process. A classical glycolytic inhibitor, 2-Deoxy-Glucose (2-DG), has been found to regulate the excessive pro-inflammatory macrophage polarization in the infarcted myocardium. This study investigated the effect of 2-DG-loaded chitosan/gelatin composite patch on the infarct microenvironment post-MI and its impact on cardiac repair. The results showed that the 2-DG patch significantly inhibited the expression of inflammatory cytokines, alleviated reactive oxygen species (ROS) accumulation, repressed the proinflammatory polarization of macrophages, attenuated local inflammatory microenvironment in the ischemic hearts, as well as improved cardiac function, reduced scar size, and promoted angiogenesis post-MI. In terms of mechanism, 2-DG exerts anti-inflammatory effects through inhibiting the NF-κB signaling pathway and reducing the assembly and activation of the NLRP3 inflammasome. These findings suggest that 2-DG composite patch may represent a promising therapeutic strategy for cardiac repair after MI.

Abstract Microbes have been demonstrated to be closely linked to diseases that pose a major threat to human health. Computing technologies can help researchers find potential microbe-drug associations more quickly and precisely. In this study, we introduced a novel computational prediction model called GLNNMDA based on global and local features of microbes and drugs to infer possible microbe-drug correlations. In GLNNMDA, we first constructed a heterogeneous network based on known microbe-drug relationships by integrating multiple similarity metrics of drugs and microbes. Subsequently, low-dimensional features will be extracted for nodes in the heterogeneous network by adopting the graph attention encoder. Next, based on combining these low-dimensional features with multiple properties of microbes and drugs to form a new comprehensive feature matrix, we would utilize the GLF module to extract the global and local features for microbes and drugs respectively, and then, we would further fuse these global and local features to come up with predictions of possible microbe-drug associations. Moreover, in order to evaluate the prediction performance of GLNNMDA, under the framework of fivefold cross-validation, intensive comparative experiments and case studies were done on different well-known public databases. The results showed that GLNNMDA obtained the highest AUC values as well as AUPR values of 0.9802 ± 0.0011, 0.9773 ± 0.0021 and 0.8586 ± 0.0004, 0.8008 ± 0.0031 in the two databases, MDAD and aBiofilm, respectively, compared to the state-of-the-art competing prediction methods. In addition, case studies of well-known microorganisms and drugs have demonstrated the effectiveness of GLNNMDA in inferring potential microbial drug associations, which implies that GLNNMDA may be a useful tool for microbe-drug association prediction in the future. The source code is available at: “ https://github.com/KuangHaiYue/GLNNMDA.git ”.

Abstract Paired immunoglobin-like type 2 receptor beta (PILRB) mainly plays a crucial role in regulating innate immunity, but whether PILRB is involved in cancer is poorly understood. Here, we report that PILRB potentiates the PI3K/AKT pathway to drive gastric tumorigenesis by binding and stabilizing IRS4, which could hyperactivate the PI3K/AKT pathway. Firstly, the levels of PILRB are upregulated in human gastric cancer (GC) specimens and associated with poor prognosis in patients with GC. In addition, our data show that PILRB promotes cell proliferation, colony formation, cell migration and invasion in GC cells in vitro and in vivo. Mechanistically, PILRB recruits the deubiquitination enzymes OTUB1 to IRS4 and relieves K48-linked ubiquitination of IRS4, protecting IRS4 protein from proteasomal-mediated degradation and subsequent activation of the PI3K/AKT pathway. Importantly, the levels of PILRB are positively correlated with IRS4 in GC specimens. Meanwhile, we also found that PILRB reprogrammed cholesterol metabolism by altering ABCA1 and SCARB1 expression levels, and PILRB-expression confers GC cell resistance to statin treatment. Taken together, our findings illustrate that the oncogenic role of PILRB in gastric tumorigenesis, providing new insights into the regulation of PI3K/AKT signaling in GC and establishing PILRB as a biomarker for simvastatin therapy resistance in GC.

Fluid shortening is an important ingredient in the production of sponge cake. Peanut oil with 0, 43% and 85% of diacylglycerol content was used as the base oil. Different emulsifiers, such as glycerol monostearate, soy lecithin and sucrose ester, and their respective amounts, were investigated. It was found that the addition of emulsifiers had a positive effect on water-absorbing capacity, air-absorbing capacity and viscosity of the oils. Glycerol monostearate was the preferred emulsifier for fluid shortening with a recommended addition of 1.5%. The effects of different diacylglycerol content on fluid shortening and their impact on sponge cake production was also investigated. The onset oxidation temperature of the oil could be increased from 253.21 °C for PO-TAG-based fluid shortening to 263.70 °C for PO-DAG85-based fluid shortening. And the increase in diacylglycerol content leading to a lower specific gravity of the batter, which was 1.06 g/mL, 1.02 g/mL and 0.98 g/mL prepared by PO-DAG, PO-DAG43 and PO-DAG85 shortening, respectively. The results showed that diacylglycerols can be used as base oils in fluid shortening to improve the crystal network and stability of fluid shortenings, thereby reducing the specific gravity of the batter and improving the structural properties of the cake. This will extend the potential applications of diacylglycerols and increase the variety of base oils available for fluid shortening preparation.

Objectives: Colistin is known as the last resort antibiotic to treat the infections caused by multidrug resistant foodborne pathogens. The emergence and widespread dissemination of plasmid-mediated colistin resistance gene mcr-1 in the Escherichia coli (E. coli) incurs potential threat to public health. Here, we investigated the epidemiology, transmission dynamics, and genetic characterization of mcr-1 harbouring E. coli isolates from poultry originated in Hebei Province, China. Methods: A total of 297 faecal samples were collected from the two large poultry farms in Hebei Province, China. The samples were processed for E. coli identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry and 16S rDNA sequencing. Then, the mcr-1 gene harbouring E. coli strains were identified by polymerase chain reaction and subjected to antimicrobial susceptibility testing by broth microdilution assay. The genomic characterization of the isolates was done by whole genome sequencing using the various bioinformatics tools, and multi-locus sequence typing was done by sequence analysis of the seven housekeeping genes. The conjugation experiment was done to check the transferability of mcr-1 along with the plasmid stability testing. Results: A total of six mcr-1 E. coli isolates with minimum inhibitory concentration of 4 μg/mL were identified from 297 samples (2.02%). The mcr-1 harbouring E. coli were identified as multidrug resistant and belonged to ST101 (n = 4) and ST410 (n = 2). The genetic environment of mcr-1 presented its position on IncHI2 plasmid in 4 isolates and p0111 in 2 isolates, which is a rarely reported plasmid type for mcr-1. Moreover, both type of plasmids was transferable to recipient J53, and mcr-1 was flanked by 3 mobile elements ISApl1, Tn3, and IS26 forming a novel backbone Tn3–IS26-mcr-1– pap2-ISApl1 on the p0111 plasmid. The phylogenetic analysis shared a common lineage with mcr-1 harbouring isolates from the environment, humans, and animals, which indicate its horizontal spread among the diverse sources, species, and hosts. Conclusion: This study recommends the one health approach for future surveillance across multiple sources and bacterial species to adopt relevant measures and reduce global resistance crises.

Background: Long-term physical inactivity probably leads to a co-existence of osteoporosis and sarcopenia which result in a high risk of falls, fractures, disability and even mortality. However, universally applicable and feasible approaches are lacking in the concurrent treatment of osteoporosis and sarcopenia. In this study, we evaluated the effect of strontium zinc silicate bioceramic (SZS) extract on osteoporosis and sarcopenia and explored its underlying mechanisms. Methods: Hindlimb osteoporosis and sarcopenia were established in a tail-suspended rat model. The bones were conducted μCT scanning, histological examination, and gene expression analysis, and the muscles were conducted histological examination and gene expression analysis. In vitro, the effect of SZS extract on osteoblasts was determined by alizarin red S staining, immunofluorescence and qPCR. Similarly, the effect of SZS extract on myoblasts was determined by immunofluorescence and qPCR.. At last, the role of Piezo1 and the change of intracellular calcium ion (Ca2+) were explored through blockading the Piezo1 by GsMTx4 in MC3T3-E1 and C2C12 cells, respectively. Results: We found that SZS extract could concurrently and efficiently prevent bone structure deterioration, muscle atrophy and fibrosis in hind limbs of the tail-suspended rats. The in vivo study also showed that SZS extract could upregulate the mRNA expression of Piezo1, thereby maintaining the homeostasis of bones and muscles. In vitro study demonstrated that SZS extract could promote the proliferation and differentiation of MC3T3-E1 and C2C12 cells by increasing the intracellular Ca2+ in a Piezo1-dependent manner. Conclusion: This study demonstrated that SZS extract could increase Piezo1-mediated intracellular Ca2+, and facilitate osteogenic differentiation of osteoblast and myogenic differentiation of myoblasts, contributing to alleviation of osteoporosis and sarcopenia in a tail-suspended rat model. The translational potential of this article: The current study might provide a universally applicable and efficient strategy to treat musculoskeletal disorders based on bioactive ceramics. The verification of the role of Piezo1-modulated intracellular Ca2+ during osteogenesis and myogenesis provided a possible therapeutic target against mechanical related diseases.

Magnesium alloys have received a lot of attention in aerospace, automotive, electronic communications and other fields due to their low density, high specific strength and damping performance. However, magnesium alloy sheets prepared by conventional thermomechanical processing usually have a strong basal texture, resulting in poor formability. In this paper, Mg–Mn–Ce alloys with good plastic forming ability were prepared by studying and optimizing the annealing process. Under the low-temperature annealing condition, it can promote the static recrystallization and grain refinement of Mg–Mn–Ce alloy, and also eliminate the internal stress. With the increase of annealing temperature, a large amount of dispersed Mg12Ce as a stable second phase effectively hindered the grain boundary migration, while the nanoscale α-Mn forms a fine second phase to inhibit grain growth, and both of them together greatly stabilize the deformation structure of the alloy, and maintain a good grain organization under the condition of annealing temperature of 300 °C and holding time of 30 min. The present work also improves the Arrhenius constitutive equation for the Mg–Mn–Ce alloy with respect to the degree of deviation, which significantly improves the accuracy of the model in predicting the thermoforming behavior. Meanwhile, to address the shortcomings of the traditional forming method of magnesium alloy, the processing process of spreading the centrifugal casting tube flat is proposed, the forming process is simulated, and the location of easy breakage in the forming process is predicted. These findings provide microanalytical support for the improvement of forming properties of magnesium alloys by annealing.

[Objective] The Qinghai-Tibetan Plateau is an important ecological barrier in China, and alpine meadows are an important part of it, and the function of soil and water conservation is an important ecological service function of alpine meadows. Therefore, it is of great significance to carry out the study of soil erosion process in alpine meadows on the Tibetan Plateau to reduce anthropogenic disturbance of soil erosion and to safeguard the ecological security of the southwest region. [Methods] In this study, five different types of slopes, namely, undegraded, mildly degraded, moderately degraded, bare slopes and artificially restored slopes in alpine meadows of the Tibetan Plateau, were selected to analyze the process of flow and sand production on degraded and restored slopes under different rainfall intensities, and to reveal the relationship between the erosion mechanism and water-sand relationship between degraded slopes and restored slopes with artificial vegetation through the simulated rainfall test in the field. [Results] (1) The initial flow production time is relatively short on the undegraded slopes of alpine meadows and the restored slopes with artificial vegetation because of their dense root system, and the water infiltration ability is relatively weak; while on the mildly degraded slopes, the lateral flow and vertical infiltration ability are relatively strong, and the initial flow production time is relatively long. (2) Under regular rainfall conditions (30 and 60 mm/h), the flow rate of mildly degraded slopes is the smallest, and the flow reduction benefit is the highest, reaching 77.13%, the flow rate of artificially restored slopes is close to that of undegraded slopes and is slightly higher than that of mildly degraded slopes; the cumulative flow rate of bare soil slopes is the largest, and it is significantly higher than other slopes; the flow rate of undegraded slopes under extreme rainfall conditions (90 mm/h) is surging, only lower than that of bare slopes and significantly higher than other slopes. Under extreme rainfall conditions (90 mm/h), the flow rate of undegraded slopes increased, which was only lower than that of bare slopes and significantly higher than that of artificially restored slopes. (3) Under regular rainfall conditions (30 and 60 mm/h), the sand reduction benefit of the artificially restored vegetated slopes was the highest, reaching 81.97% and 89.82%, followed by the undegraded slopes, and with the increase of the degradation degree of the vegetation, the sand reduction benefit was gradually reduced; however, under extreme rainfall conditions, the sand reduction benefit of the artificially restored vegetation and the undegraded slopes was almost the same, and the sand production of the moderately degraded slopes was higher than the undegraded slopes, which is significantly higher than the other slopes. However, under extreme rainfall conditions, the sand reduction benefits of artificially restored vegetation and undegraded slopes are almost the same, while the sand production of moderately degraded slopes is 4.59 times of that of undegraded slopes. [Conclusion] The results of these studies can provide important scientific basis for vegetation restoration and ecological security in alpine meadow area.

In this paper, let $ (\mathscr{A}, \mathscr{C}, \mathscr{B}) $ be a recollement of extriangulated categories. We construct a silting object and a tilting object from the two end terms of a recollement. We also show that the reverse direction holds under natural assumptions. Moreover, we show that our gluing preserves cotorsion pairs.