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Kai Yao,1,* Yongbo Peng,2,* Qiyu Tang,3 Kaixuan Liu,3 Cheng Peng3 1Department of Vascular Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China; 2College of Pharmacy, Chongqing Medical University, Chongqing, People’s Republic of China; 3Department of Plastic Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Cheng Peng, Email pcheng83@csu.edu.cnIntroduction: Photoaging-induced skin damage leads to appearance issues and dermatoma. Selenium nanoparticles (SeNPs) possess high antioxidant properties but are prone to inactivation. In this study, human serum albumin/SeNPs (HSA-SeNPs) were synthesized for enhanced stability.Methods: HSA-SeNPs were prepared by self-assembling denatured human serum albumin and inorganic selenite. The cytotoxicity of HSA-SeNPs was assessed using the MTT method. Cell survival and proliferation rates were tested to observe the protective effect of HSA-SeNPs on human skin keratinocytes against photoaging. Simultaneously, ICR mice were used for animal experiments. H&E and Masson trichromatic staining were employed to observe morphological changes in skin structure and collagen fiber disorders after UVB irradiation. Quantitative RT-PCR was utilized to measure changes in mRNA expression levels of factors related to collagen metabolism, inflammation, oxidative stress regulation, and senescence markers.Results: The HSA-SeNPs group exhibited significantly higher survival and proliferation rates of UVB-irradiated keratinocytes than the control group. Following UVB irradiation, the back skin of ICR mice displayed severe sunburn with disrupted collagen fibers. However, HSA-SeNPs demonstrated superior efficacy in alleviating these symptoms compared to SeNPs alone. In a UVB-irradiated mice model, mRNA expression of collagen type I and III was dysregulated while MMP1, inflammatory factors, and p21 mRNA expression were upregulated; concurrently Nrf2 and Gpx1 mRNA expression were downregulated. In contrast, HSA-SeNPs maintained the mRNA expression of those factors to be stable In addition, the level of SOD decreased, and MDA elevated significantly in the skin after UVB irradiation, but no significant differences in SOD and MDA levels between the HSA-SeNPs group with UVB irradiation and the UVB-free untreated group.Discussion: HSA-SeNPs have more anti-photoaging effects on the skin than SeNPs, including the protective effects on skin cell proliferation, cell survival, and structure under photoaging conditions. HSA-SeNPs can be used to protect skin from photoaging and repair skin injury caused by UVB exposure.Keywords: selenium nanoparticles, human serum albumin, skin photoaging, senescence, SOD

Jingyi Lao,1,* Yijie Zeng,1,* Zhangying Wu,1 Gaohong Lin,1 Qiang Wang,1 Mingfeng Yang,1 Si Zhang,1 Danyan Xu,1 Min Zhang,1 Kexin Yao,1 Shuang Liang,1 Qin Liu,1 Jiafu Li,1 Xiaomei Zhong,1 Yuping Ning1– 4 1Geriatric Neuroscience Center, The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2The First School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China; 3Guangdong Engineering Technology Research Center for Translational Medicine of Mental Disorders, Guangzhou, People’s Republic of China; 4Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yuping Ning; Xiaomei Zhong, The Affiliated Brain Hospital of Guangzhou Medical University, No. 36, Mingxin Road, Liwan District, Guangzhou, Guangdong, People’s Republic of China, Email ningjeny@126.com; lovlaugh@163.comBackground: Late-life depression (LLD) is characterized by disrupted brain networks. Resting-state networks in the brain are composed of both stable and transient topological structures known as microstates, which reflect the dynamics of the neural activities. However, the specific pattern of EEG microstate in LLD remains unclear.Methods: Resting-state EEG were recorded for 31 patients with episodic LLD (eLLD), 20 patients with remitted LLD (rLLD) and 32 healthy controls (HCs) using a 64-channel cap. The clinical data of the patients were collected and the 17-Item Hamilton Rating Scale for Depression (HAMD) was used for symptom assessment. Duration, occurrence, time coverage and syntax of the four microstate classes (A-D) were calculated. Group differences in EEG microstates and the relationship between microstates parameters and clinical features were analyzed.Results: Compared with NC and patients with rLLD, patients with eLLD showed increased duration and time coverage of microstate class D. Besides, a decrease in occurrence of microstate C and transition probability between microstate B and C was observed. In addition, the time coverage of microstate D was positively correlated with the total score of HAMD, core symptoms, and miscellaneous items.Conclusion: These findings suggest that disrupted EEG microstates may be associated with the pathophysiology of LLD and may serve as potential state markers for the monitoring of the disease.Keywords: late-life depression, microstate, electroencephalogram, resting-state networks

Lian Weng,1– 3,* Xiongjunjie Luo,1– 3,* Yuxi Luo,1– 3 Qian Zhang,1– 3 Kaitao Yao,1– 3 Junjie Tan,1– 3 Yiran Yin1– 3 1Department of orthopedics, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan Province, 646000, People’s Republic of China; 2Sichuan Provincial Laboratory of Orthopedic Engineering, Luzhou, Sichuan Province, 646000, People’s Republic of China; 3Department of Clinical Medicine, Southwest Medical University, Luzhou, 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yiran Yin, Department of Orthopaedics, The Affiliated Hospital of Southwest Medical University, No. 25 Tai Ping Street, Jiang Yang District, Luzhou, Sichuan Province, 646000, People’s Republic of China, Tel +13982457750, Email yiranyin@swmu.edu.cnBackground: Sleep apnea syndrome(SAS) and osteoarthritis (OA) are two prevalent diseases that often coexist, but the causal relationship between them remains unclear. In light of this, our team utilizes Mendelian Randomization and bioinformatics analysis methods to investigate the potential association between the two diseases.Methods: In this study, we utilized GWAS data pertaining to SAS and OA to assess the causal relationship between the two diseases through Mendelian randomization (MR) analysis. We then employed transcriptomic data to perform differential gene identification, WGCNA, shared gene determination, functional enrichment analysis, and colocalization analysis, all designed to further elucidate the mechanisms underlying the association between the two diseases. In the end, we utilized Mendelian randomization (MR) analysis again to delve deeper into the relationship between the two diseases and immune cells.Results: Our research findings indicate that SAS is a risk factor for OA (p = 0.000004), knee OA (p = 0.0000001) and hip OA(p = 0.001). Furthermore, OA (p = 0.000195), knee OA (p = 0.001) are significant risk factors for SAS. However, there is no clear evidence that hip OA (p = 0.892) is a risk factor for SAS. Interestingly, the genes shared between OA and SAS are significantly enriched in leukocyte migration, leukocyte chemotaxis. Moreover, colocalization analysis suggests that the genes JUNB, COL8A1, FOSB, and IER2 may be key genes associated with both diseases. Furthermore, 57 immune cell phenotypes are associated with SAS, 95 with OA, and 6 shared between both diseases.Conclusion: This research confirmed the bidirectional causal relationship between SAS and OA. Notably, the 4 genes (JUNB, COL8A1, FOSB, IER2) and 6 immune phenotypes are crucial for both diseases, these provide hopeful targets for future interventions against these two diseases.Keywords: sleep apnea syndrome, osteoarthritis, Mendelian randomization, bioinformatics

Kaifang Yao,1,* Zhihan Chen,1,* Yanwei Li,1 Baomin Dou,1 Zhifang Xu,1– 3 Yajing Ma,1 Simin Du,1 Jiangshan Wang,1 Jiangjiang Fu,1 Qi Liu,1 Zezhi Fan,1 Yangyang Liu,1– 3 Xiaowei Lin,1– 3 Yuan Xu,1– 3 Yuxin Fang,1– 3 Shenjun Wang,1– 3 Yi Guo1,3,4 1Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin City, People’s Republic of China; 2School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin City, People’s Republic of China; 3National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin City, People’s Republic of China; 4School of Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin City, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Guo; Shenjun Wang, School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, No. 10 Poyang Lake Road, Tuanbo New Town, Jinghai District, Tianjin, 301617, People’s Republic of China, Tel +86 22-5959-6290, Email guoyi_168@163.com; shenjunwang@163.comPurpose: Acupuncture (ACU) has been demonstrated to alleviate inflammatory pain. Mechanoreceptors are present in acupuncture points. When acupuncture exerts mechanical force, these ion channels open and convert the mechanical signals into biochemical signals. TRPA1 (T ransient receptor potential ankyrin 1) is capable of sensing various physical and chemical stimuli and serves as a sensor for inflammation and pain. This protein is expressed in immune cells and contributes to local defense mechanisms during early tissue damage and inflammation. In this study, we investigated the role of TRPA1 in acupuncture analgesia.Patients and Methods: We injected complete Freund’s adjuvant (CFA) into the mouse plantars to establish a hyperalgesia model. Immunohistochemistry and immunofluorescence analyses were performed to determine the effect of acupuncture on the TRPA1 expression in the Zusanli (ST36). We used TRPA1−/− mouse and pharmacological methods to antagonize TRPA1 to observe the effect on acupuncture analgesia. On this basis, collagenase was used to destroy collagen fibers at ST36 to observe the effect on TRPA1.Results: We found that the ACU group vs the CFA group, the number of TRPA1-positive mast cells, macrophages, and fibroblasts at the ST36 increased significantly. In CFA- inflammatory pain models, the TRPA1−/− ACU vs TRPA1+/+ ACU groups, the paw withdrawal latency (PWL) and paw withdrawal threshold (PWT) downregulated significantly. In the ACU + high-, ACU + medium-, ACU + low-dose HC-030031 vs ACU groups, the PWL and PWT were downregulated, and in carrageenan-induced inflammatory pain models were consistent with these results. We further found the ACU + collagenase vs ACU groups, the numbers of TRPA1-positive mast cells, macrophages, and fibroblasts at the ST36 were downregulated.Conclusion: These findings together imply that TRPA1 plays a significant role in the analgesic effects produced via acupuncture at the ST36. This provides new evidence for acupuncture treatment of painful diseases.Keywords: acupuncture, TRPA1, ST36, inflammation, immune, analgesia

Jie Liu,1,&ast; Ke Zhao,2,&ast; Wei Kang,1,&ast; Siyu Tong,1 Yao Xu,1 Wei Jin,1 Mengxuan Qiao,1 Yuan Li,1 Lan Hong,3 Keqing Yao,4,5 Tiansheng Zheng6 1School of Mental Health, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2Lishui Second People’s Hospital Affiliated to Wenzhou Medical University, Lishui, People’s Republic of China; 3The Third Hospital of Quzhou, Quzhou, People’s Republic of China; 4Shenzhen Mental Health Center, Shenzhen, Guangdong, People’s Republic of China; 5Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China; 6The Affiliated Kangning Hospital of Wenzhou Medical University Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Keqing Yao, Shenzhen Mental Health Center, Shenzhen Kangning Hospital, Shenzhen, Guangdong, People’s Republic of China, Tel +86-755-82927264, Email KQKangning@gmail.com Tiansheng Zheng, The Affiliated Kangning Hospital of Wenzhou Medical University Zhejiang Provincial Clinical Research Center for Mental Disorder, Wenzhou, People’s Republic of China, Email sky.tsh@163.comIntroduction: Non-suicidal self-injury (NSSI) is becoming an increasingly prevalent phenomenon among adolescents, endangering their health. The aims of this study were to 1) explore the associations between borderline personality features, alexithymia and NSSI and 2) examine if alexithymia mediates the relationships between borderline personality features and both the severity of NSSI and the various functions that maintain NSSI in adolescents.Methods: This cross-sectional study recruited 1779 outpatient and inpatient aged 12– 18 years from psychiatric hospitals. All adolescents completed a structured four-part questionnaire including demographic items, the Chinese version of the Functional Assessment of Self-Mutilation, the Borderline Personality Features Scale for Children and the Toronto Alexithymia Scale.Results: The structural equation modelling results indicated that alexithymia partially mediated the associations between borderline personality features and both the severity of NSSI and the emotion regulation function of NSSI (B = 0.058 and 0.099, both p < 0.001), after controlling for age and sex.Discussion: These findings suggest that alexithymia may play a role in the mechanism and treatment of NSSI among adolescents with borderline personality features. Further longitudinal studies are essential to validate these findings.Keywords: self-harm, health, emotion regulation, structural equation modelling

Xiaoou Li,1 Wei Gao,2 Zhonglan Jia,3 Kaihu Yao,2 Jinyan Yang,1 Jingjing Tong,4 Yajuan Wang5 1Department of Neonatology, Haidian District Maternal and Child Health Care Hospital, Beijing, 100080, People’s Republic of China; 2Key Laboratory of Major Diseases in Children, Ministry of Education, National Key Discipline of Pediatrics (Capital Medical University), Laboratory of Dermatology, Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, 100045, People’s Republic of China; 3Department of Clinical Laboratory, Haidian District Maternal and Child Health Care Hospital, Beijing, 100080, People’s Republic of China; 4Department of Neonatology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, 100026, People’s Republic of China; 5Department of Neonatology, Children’s Hospital, Capital Institute of Pediatrics, Beijing, 100020, People’s Republic of ChinaCorrespondence: Yajuan Wang, Department of Neonatology, Children’s Hospital, Capital Institute of Pediatrics, No. 2 Yabao Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Tel +86-10-85695631, Email cxswyj@vip.sina.comPurpose: We investigate the drug resistance, serotype and multilocus sequence typing (MLST) of Group B streptococcus (GBS) strains obtained from pregnant women and neonates in a hospital in Beijing.Patients and Methods: In this cross-sectional study, 1470 eligible pregnant women at a gestational age of 35– 37 weeks presented to our department between May 2015 and May 2016 were included. Vaginal and rectal samples from pregnant women together with sampling from neonatal samples were collected to screen GBS. GBS strains were subject to drug resistance and serotype analysis and MLST.Results: GBS strains were isolated from 111 pregnant women (7.6%) and 6 neonates (0.99%) from 606 matched neonates. 102 strains from pregnant women and 3 strains from neonates were included in the drug sensitivity test, serotyping and MLST typing. All these strains were susceptible to ampicillin, penicillin, ceftriaxone, vancomycin, linezolid, and meropenem. Sixty strains (58.8%) showed multi-drug resistance. Serious cross-resistance was seen between erythromycin and clindamycin. There were eight serotypes, and 37 strains (36.3%) showed a serotype of type III serving as the major type. All 102 GBS strains isolated from pregnant samples could be divided into 18 STs types. They belonged to five clonal complexes and five single clones, with the predominant type of ST19/III, ST10/Ib, and ST23/Ia, with CC19 as the most common type. Three GBS strains isolated from neonates covered two serotypes (ie type III and Ia) that were consistent with those of the mothers.Conclusion: Serotype III was the predominant serotype of GBS in this study. The predominant MLST type was ST19, ST10, and ST23, with ST19/III, ST10/Ib, and ST23/Ia serving as the most prevalent and CC19 as the most common clonal complex. GBS strains from neonates were consistent in the clonal complex, serotype, and MLST with these isolated from the mothers.Keywords: Group B streptococcus, multilocus sequence typing, drug resistance, molecular epidemiology

Zhiyong Lyu,1 Jing Li,2 Jinghui Zhen,1 Wei Shi,3 Qingying Meng,1 Wei Zhou,1 Jingyun An,1 Kaihu Yao,3,&ast; Fang Dong1,&ast; 1Department of Clinical Laboratory Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China; 2Department of Clinical Laboratory, Capital Institute of Pediatrics, Beijing, People’s Republic of China; 3Beijing Key Laboratory of Pediatric Respiratory Infection Diseases, Key Laboratory of Major Diseases in Children, Ministry of Education, National Clinical Research Center for Respiratory Diseases, National Key Discipline of Pediatrics (Capital Medical University), Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Fang Dong; Kaihu Yao, Department of Clinical Laboratory Center, Beijing Children’s Hospital Affiliated to Capital Medical University, No. 56 Nan Lishi Road, Beijing, 100045, People’s Republic of China, Email fangd32@163.com; yaokaihu@bch.com.cnIntroduction: Streptococcus pneumoniae (S. pneumoniae) is a major pathogen causing death in children. Few studies have evaluated the importance of S. pneumoniae in the identified bacteria in clinical work. This retrospective study aimed to reveal the rank of S. pneumoniae in determined bacteria isolated from children in Beijing, China, as well as the antimicrobial resistance of this pathogen.Methods: The number of specimen for bacterial culture and of bacterial species were cumulated and ranked based on the data of the two largest children’s hospitals in Beijing from 2015 to 2021. The temporal change of S. pneumoniae culture, as well as the clinical data of S. pneumoniae isolates were collected and analyzed. The minimum inhibitory concentrations of antimicrobial agents were determined by BD Phoenix 100 automated system or Vitek 2 automated system for antimicrobial susceptibility testing. The breakpoints recommended by CLSI were adopted.Results: During the 7-year study period, a total of 45,631 bacterial isolates were cultured from 462,144 submitted specimens, in which S. pneumoniae was the third frequent agent following S. aureus and H. influenza, and accounting for 8.79% of the isolates (4011/45,631). In the 4011 S. pneumoniae isolates, 2239 and 997 ones were, respectively, isolated from sputum and bronchial lavage fluid. Most of S. pneumoniae strains were identified in winter (34.7%) and spring (26.1%), and were mainly isolated from patients under 5 years old (77.1%). Low susceptible rate (27.6%) of CSF isolates was determined to penicillin according to the parenteral meningitis breakpoints, while high susceptible rate (56.9%) of non-CSF isolates was obtained according to the parenteral non-meningitis breakpoints. The isolates showed low sensitivity to erythromycin and tetracycline (< 5%). All isolates were susceptible to vancomycin and linezolid.Conclusion: The present results demonstrated that S. pneumoniae was one of the most commonly detected bacteria in current pediatric clinical tests, especially in young children under 5 years old, which emphasized the importance of prevention. Penicillin could still be the first empiric choice to treat non-meningitis pneumococcal infections, while erythromycin should not be involved in the treatment.Keywords: Streptococcus pneumoniae, antimicrobial resistance, children, China

Fei Wu,1– 3,&ast; Jie Chen,4,&ast; Kang Yao,1 Daming Fan,5 Minglei Wang,2 Yongjun Liu,1 Shouhu Xin,1 Zeqiang Sun,1 Shun Li,1 Yang Sun,6 Qingyong Liu1 1Department of Urology, the First Affiliated Hospital of Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250014, People’s Republic of China; 2Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250117, People’s Republic of China; 3Department of Urology, Shandong Provincial Hospital, Shandong First Medical University, Jinan, 250021, People’s Republic of China; 4Department of Urology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250013, People’s Republic of China; 5Department of Pathology, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250013, People’s Republic of China; 6Department of Dermatology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang Sun; Qingyong Liu, Email sunyang@qiluhospital.com; liuqingyong@sdhospital.com.cnIntroduction: A primary impediment to the efficacy of immune checkpoint inhibitors is the lack of biomarkers for therapeutic responses and prognosis. Although patients with clear cell renal cell carcinoma (ccRCC) could be precisely selected for targeted therapy based on somatic mutations, it remains controversial to choose the suitable patients with a high response rate to immune checkpoint inhibitors (ICIs). The immune-dependent roles of tumor suppressor PTEN in the formation of tumor immune microenvironment remain elusive.Methods: We comprehensively analyzed the genomic and transcriptomic data from multiple ccRCC datasets, including bulk-RNA sequencing and single-cell RNA sequencing data. In vitro, immunoblotting, qRT-PCR, and RNA sequencing were conducted in ccRCC cell lines upon PTEN depletion. Gene ontology and gene set enrichment analysis were performed to screen the critical pathway and molecules in response to PTEN deletion. Immunohistochemistry staining and further bioinformatic analysis were used to validate our data.Results: Based on multi-omics analysis of public datasets of renal cancer, the frequently mutated or deleted PTEN was found to be correlated with a suppressive tumor immune microenvironment in ccRCC. Furthermore, we depleted PTEN via CRISPR-Cas9 in Caki-1 cells, which led to the upregulation of multiple neutrophil chemokines, particularly CXCL1, CXCL2, CXCL5, CXCL6, and CXCL8. The roles of neutrophil chemokines and neutrophil markers were further validated and investigated for the association with prognosis in vitro, clinical samples, and the publicly available databases. The expression of CXCL1, CXCL8, and neutrophil markers, S100A9 and BCL2A1, were significantly associated with a poor immunotherapy-related prognosis in public dataset of renal cancer patients receiving ICIs treatment.Conclusion: These results add a new layer to understanding the association between PTEN status and the role of neutrophil infiltration in ccRCC. Moreover, our findings propose low expression of PTEN as candidate factor of resistance to anti-PD-1-based immunotherapy in ccRCC.Keywords: PTEN, kidney cancer, CXCL1, renal cancer, prognosis

Qianxue Mou,1 Ke Yao,1 Meng Ye,1 Bowen Zhao,1 Yuanyuan Hu,1 Xiaotong Lou,1 Huixia Li,2 Hong Zhang,1 Yin Zhao1 1Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of China; 2Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Hong ZhangDepartment of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of ChinaEmail tjyksys@163.comCorrespondence: Yin ZhaoDepartment of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People’s Republic of ChinaEmail zhaoyin85@hust.edu.cnPurpose: Optic nerve injury (ONI) causes neuroinflammation and neurodegeneration leading to visual deficits. The response of microglia has emerged as an impactful component of etiology in neurodegeneration. This study aimed to investigate the effect of SIRT1-mTORC1 signaling pathway in microglia regulation after ONI.Methods: Cx3Cr1-CreERT2/RaptorF/F and Cx3Cr1-CreERT2/Sirt1F/F mice were used to delete Raptor and Sirt1 in microglia, respectively. Optic nerve crush (ONC) model was established to mimic ONI. PLX5622, a highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in optic nerve. Ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to detect microglial activation. Retinal ganglion cells (RGCs) were quantified by Nissl staining and retinal whole-mount immunostaining with RNA-binding protein with multiple splicing (RBPMS). Axonal damage was valued by transmission electron microscopy (TEM).Results: Microglial activation emerged on day 3 post ONC and was earlier than RGCs loss which occurred at day 5 after injury. Depleting microglia with PLX5622 could attenuate the loss of RGCs and axon damage after ONC. Gain- and loss-of-function studies revealed that SIRT1 determined the activation of microglia in optic nerve. In addition, microglia-specific deletion of Raptor resulted in decreased microglial activation. Interestingly, activating mTORC1 with CCT007093 could reverse the function of SIRT1 in regulating the process of microglial activation mediated RGCs loss.Conclusion: Our study reveals a potential novel mechanism of SIRT1-mTORC1 pathway in microglia regulation, and indicates a therapeutic potential for the protection of RGCs in ONI.Keywords: microglia, retinal ganglion cells, optic nerve injury, SIRT1, mTORC1

Ningcen Li,1,2,&ast; Yi Guo,1,3,4,&ast; Yinan Gong,1– 3 Yue Zhang,1,2 Wen Fan,5 Kaifang Yao,1,2 Zhihan Chen,1,2 Baomin Dou,1,2 Xiaowei Lin,1,3,4 Bo Chen,1– 3 Zelin Chen,1– 3 Zhifang Xu,1– 3 Zhongxi Lyu1– 3 1Research Center of Experimental Acupuncture Science, Tianjin University of Traditional Chinese Medicine, Tianjin City, People’s Republic of China; 2School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin City, People’s Republic of China; 3National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin City, People’s Republic of China; 4School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin City, People’s Republic of China; 5Suzuka University of Medical Science, Suzuka City, Japan&ast;These authors contributed equally to this workCorrespondence: Zhifang Xu; Zhongxi LyuSchool of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, No. 10 Poyang Lake Road, Tuanbo New Town, Jinghai District, Tianjin, 301617, People’s Republic of ChinaTel/Fax +86 22-5959-6290Email xuzhifangmsn@hotmail.com; 1025117807@qq.comAbstract: Inflammation plays a significant role in the occurrence and development of multiple diseases. This study comprehensively reviews and presents literature from the last five years, showing that acupuncture indeed exerts strong anti-inflammatory effects in multiple biological systems, namely, the immune, digestive, respiratory, nervous, locomotory, circulatory, endocrine, and genitourinary systems. It is well known that localized acupuncture-mediated anti-inflammatory effects involve the regulation of multiple populations and functions of immune cells, including macrophages, granulocytes, mast cells, and T cells. In acupuncture stimulation, macrophages transform from the M1 to the M2 phenotype and the negative TLR4 regulator PPARγ is activated to inhibit the intracellular TLR/MyD88 and NOD signaling pathways. The downstream IκBα/NF-κB and P38 MAPK pathways are subsequently inhibited by acupuncture, followed by suppressed production of inflammasome and proinflammatory mediators. Acupuncture also modulates the balance of helper T cell populations. Furthermore, it inhibits oxidative stress by enhancing SOD activity via the Nrf2/HO-1 pathway and eliminates the generation of oxygen free radicals, thereby preventing inflammatory cell infiltration. The anti-inflammatory effects of acupuncture on different biological systems are also specific to individual organ microenvironments. As part of its anti-inflammatory action, acupuncture deforms connective tissue and upregulates the secretion of various molecules in acupoints, further activating the NF-κB, MAPK, and ERK pathways in mast cells, fibroblasts, keratinocytes, and monocytes/macrophages. The somatic afferents present in acupuncture-activated acupoints also convey sensory signals to the spinal cord, brainstem, and hypothalamic neurons. Upon information integration in the brain, acupuncture further stimulates multiple neuro-immune pathways, including the cholinergic anti-inflammatory, vagus-adrenal medulla-dopamine, and sympathetic pathways, as well as the hypothalamus-pituitary-adrenal axis, ultimately acting immune cells via the release of crucial neurotransmitters and hormones. This review provides a scientific and reliable basis and viewpoints for the clinical application of acupuncture in various inflammatory conditions.Keywords: inflammation, acupuncture, immune, vagus, sympathetic nerve

Hengli Yang,1,2,* Wenbin Cai,3,* Wei Lv,2 Ping Zhao,2 Yamei Shen,4 Longfang Zhang,1 Bin Ma,1 Lijun Yuan,2 Yunyou Duan,2 Kechun Yao11Department of Ultrasound Diagnosis, Air Force General Hospital, Beijing, People’s Republic of China; 2Department of Ultrasound Diagnosis, Tang Du Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China; 3Special Diagnosis Department, General Hospital of Tibet Military Command, Lhasa, People’s Republic of China; 4Department of Ultrasound Diagnosis, Shaanxi Provincial People’s Hospital, Xi’an, People’s Republic of China *These authors contributed equally to this workCorrespondence: Yunyou DuanDepartment of Ultrasound Diagnosis, Tang Du Hospital, Fourth Military Medical University, Xi’an 710038, People’s Republic of ChinaEmail duanyy@fmmu.edu.cnKechun YaoDepartment of Ultrasound Diagnosis, Air Force General Hospital, Beijing 100036, People’s Republic of ChinaEmail yaokc1959@hotmail.comBackground: Currently, effective detection and treatment of cutaneous malignant melanoma (CMM) still face severe challenges. Ultrasound molecular imaging as a noninvasive and easy-to-operate method is expected to bring improvements for tumor detection.Purpose: The aim of this research is to prepare novel phase-change ultrasound contrast agents, Nds-IR780, which can perform not only dual-mode molecule-targeted imaging but also targeted photothermal therapy for CMM.Methods: A double emulsion process was used to prepare the Nds-IR780. Then, the entrapment rate and drug loading of IR-780 iodide in Nds-IR780 were detected by high-performance liquid chromatography. The biocompatibility of Nds-IR780 was evaluated by a CCK-8 assay and the characteristics and stability of that were verified through the particle size analyzer, laser scanning confocal microscopy (LSCM) and transmission electron microscopy (TEM). The abilities of dual-mode molecule-targeted imaging and targeted photothermal therapy for Nds-IR780 were confirmed via the in vitro and in vivo experiments.Results: Nds-IR780 had good size distribution, polydispersity index, stability and biosafety. The in vitro and in vivo experiments confirmed that Nds-IR780 were capable of targeting CMM cells with high affinity (22.4±3.2%) and facilitating dual-mode imaging to detect the primary lesion and sentinel lymph nodes (SLNs) of CMM. Furthermore, the photothermal ablation of CMM mediated by Nds-IR780 was very effective in vivo.Conclusion: The newly prepared Nds-IR780 were observed to be effective targeted theranostic probe for the precise detection and targeted treatment of CMM.Keywords: CMM, dual-mode phase-change nanodroplets, targeted accurate diagnosis and treatment

Na Han,1,2,* Fang Yuan,2,3,* Peng Xian,2,3,* Nan Liu,2,3 Jianmin Liu,4 Haiyan Zhang,1,2 Huayong Zhang,5 Kai Yao,6 Gangjun Yuan2,3 1Health Examination and Oncology Screening Center, Chongqing University Cancer Hospital, Chongqing 400030, People’s Republic of China; 2Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing 400030, People’s Republic of China; 3Department of Urology, Chongqing University Cancer Hospital, Chongqing 400030, People’s Republic of China; 4Department of Otolaryngology Head and Neck Surgery, People’s Hospital of Deyang, Deyang 618000, People’s Republic of China; 5Department of Thyroid and Breast Surgery, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, People’s Republic of China; 6Department of Urology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Gangjun YuanDepartment of Urology, Chongqing University Cancer Hospital, Chongqing 400030, People’s Republic of ChinaTel +86 23 6507 5629Email freeman17@126.comKai YaoDepartment of Urology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, People’s Republic of ChinaTel +86 20 8734 3840Email yaokai@sysucc.org.cnBackground: Bladder cancer (BC) is one of the most prevalent malignancies of the genitourinary system, yet the underlying mechanism of BC progression still remains unclear. Growth arrest and DNA damage-inducible 45 alpha (GADD45a) is a repressive gene implicated in cell cycle regulation, as well as in human cancers development. However, its role in BC remains to be determined.Methods: First, quantitative real-time polymerase chain reaction (PCR) and Western blot assays were used to detect GADD45a expression in BC tissues and adjacent non-tumor tissues, as well as in bladder cancer cell lines, respectively. Then, cell counting kit-8 (CCK-8) assays, colony formation assays, and flow cytometry assays were used to measure the ability of cell growth, proliferation and cell cycle distribution. Lentiviral infection technology was used to increase gene expression, while siRNA interfering technology was used to knockdown gene expression. Finally, nude mice were used to construct tumor-burdened models in vivo by injecting tumor cells subcutaneously.Results: PCR results showed that the level of GADD45a mRNA and protein levels were lower in BC tissues than in adjacent normal tissues. After increasing GADD45a expression, both the ability of growth and proliferation of BC cells were seriously impaired. Additionally, the upregulation of GADD45a expression resulted in BC cell cycle in G2/M and S phases in a p53-regulated pathway.Conclusion: GADD45a-mediated cell cycle inhibition is regulated by p53 in bladder cancer cells.Keywords: GADD45a, bladder cancer, cell cycle, p53, proliferation

Bin Gu,1 Meng Li,2 Yan Zhang,3 Lingyun Li,4 Kun Yao,5 Shizhi Wang3 1Department of Neurosurgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; 2Department of Neurosurgery, Suqian First Hospital, Suqian, China; 3Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China; 4Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, China; 5Department of Developmental Genetics, Nanjing Medical University, Nanjing, China Purpose: We previously identified human herpesvirus 6 (HHV-6) infection in the pathogenesis of glioma. Direct repeat (DR)7, encoded by HHV-6, has been reported to possess malignant transforming activity and involved in Hodgkin’s lymphoma carcinogenesis. Here, we aimed to determine the role of DR7 in the development and progression of glioma. Patients and methods: A total of 27 glioma and 30 normal brain tissues were collected for detection of DR7. Glioma cell proliferation, colony formation, cell cycle, migration, invasion and angiogenesis were evaluated by Cell Counting Kit-8 (CCK-8), soft agar, propidium iodide staining, wound healing, Transwell and chick embryo chorioallantoic membrane assays, respectively. The potential mRNA targets of DR7 were determined using mRNA microarray and validated via Western blot and ELISA. Results: DR7 could be detected in the 13 glioma tissues with a positive rate of 48.15%, but only the 5 normal brain tissues with a lower positive rate of 16.7%. The two strains of cells isolated from glioma tissues were also found to express DR7. CCK-8 and soft agar assays showed enhanced proliferation and colony formation in the cells expressing DR7 which might be in relation to acceleration of the G1/S phase transition by DR7. Further analyses showed that DR7 could promote glioma cell migration, invasion and angiogenesis. Expression profiles identified hundreds of differentially expressed mRNAs, among which P53, extracellular matrix (ECM) fibronectin, integrin receptor ITGβ5 and specific inhibitors of MMPs, tissue inhibitor of MMPs (TIMP)-2 and TIMP-4, were downregulated, whereas ECM-degrading proteinase MMP-3, proinflammatory cytokines IL-1β, IL-6 and IL-8, were upregulated by DR7, respectively. Conclusion: We observed existence of DR7 in the glioma tissues, and overexpression of DR7 could promote glioma cell development and progression, which might be through creating an inflammatory microenvironment and enhancing degradation of ECM. Keywords: HHV-6, DR7, development, progression, glioma

Kai Yao, Yong-fei Zhao, Heng-bing Zu Department of Neurology, Jinshan Hospital Affiliated to Fudan University, Shanghai 201508, China Purpose: As a novel antidepressant drug, agomelatine has good therapeutic effect on the mood disorder and insomnia in Alzheimer’s disease (AD). Recent studies have shown the neuroprotective function of agomelatine, including anti-oxidative and anti-apoptosis effect. However, it remains unclear whether agomelatine exerts neuroprotection in AD. Thus, the neuroprotective effect of agomelatine against amyloid beta 25–35 (Aβ25–35)-induced toxicity in PC12 cells was evaluated in this study. Methods: The concentration of malondialdehyde (MDA), LDH, and ROS was investigated to evaluate oxidative damage. The expression of P-tau, tau, PTEN, P-Akt, Akt, P-GSK3β, and GSK3β proteins was assessed by Western blotting. Our results demonstrated that Aβ25–35 significantly increased the content of MDA, LDH, and ROS. Meanwhile, Aβ25–35 upregulated the expression of P-tau and PTEN as well as downregulated P-Akt and P-GSK3β expression. These effects could be blocked by agomelatine pretreatment. Furthermore, luzindole, the melatonin receptor (MT) antagonist, could reverse the neuroprotective effect of agomelatine. Conclusion: The results demonstrated that antidepressant agomelatine might prevent the tau protein phosphorylation and oxidative damage induced by Aβ25–35 in PC12 cells by activating MT-PTEN/Akt/GSK3β signaling. This study provided a novel therapeutic target for AD in the future. Keywords: agomelatine, Alzheimer’s disease, oxidative stress, tau hyperphosphorylation

Bin Gu,1 Lingyun Li,2 Meng Li,3 Jinfeng Wang,4 Guofeng Zhang,4 Kun Yao,4 Shizhi Wang5 1Department of Neurosurgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; 2Department of Developmental Genetics, Nanjing Medical University, Nanjing, China; 3Department of Neurosurgery, Suqian First Hospital, Suqian, China; 4Department of Microbiology and Immunology, Nanjing Medical University, Nanjing, China; 5Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China Purpose: We previously found the involvement of human herpesvirus 6 (HHV-6) infection in the pathogenesis of glioma. U94/rep, encoded by HHV-6, has been identified to play a vital role in viral gene expression and latency. Recent studies have shown its inhibition of angiogenesis and tumorigenesis in endothelial cells and prostate cancer cell line PC3, respectively. Here, we aimed to investigate the role of U94/rep in the development and progression of glioma.Patients and methods: A total of 20 glioma tissues with positive HHV-6 infection were used for detection of U94/rep. MTT, soft agar, propidium iodide staining, wound healing, Transwell, and chick embryo chorioallantoic membrane assays were applied for evaluation of glioma cells’ proliferation, colony formation, cell cycle, migration, invasion, and angiogenesis, respectively.Results: U94/rep transcripts could be detected in 11 out of 20 glioma tissues with positive HHV-6 infection. Furthermore, MTT and soft agar assays revealed that overexpression of U94/rep inhibited glioma cell proliferation and colony formation, which may be attributed to the cell cycle arrest at S phase induced by U94/rep. Further analysis demonstrated that U94/rep inhibited glioma cells’ migration and invasion and ex vivo angiogenesis. Reduced expression of proangiogenic factors, vascular endothelial growth factor and basic fibroblast growth factor, and type IV collagenases, MMP-2 and MMP-9, was detected in cells overexpressing U94/rep. These decreased factors may undermine glioma cell migration, invasion, and angiogenesis.Conclusion: Our results demonstrated that U94/rep could inhibit malignant phenotypes of glioma cells, indicating that it is a potential target for therapeutic intervention. Keywords: HHV-6, U94/rep, tumorigenesis, glioma

Qiang-Hua Zhou,1,2,* Chuang-Zhong Deng,1,* Jie-Ping Chen,1 Kang-Bo Huang,1,2 Ting-Yu Liu,1,2 Kai Yao,1,2 Zhuo-Wei Liu,1,2 Zi-Ke Qin,1,2 Yong-Hong Li,1,2 Sheng-Jie Guo,1,2 Yun-Lin Ye,1,2 Fang-Jian Zhou,1,2 Wenlin Huang,1,3 Ran-Yi Liu,1 Hui Han1,2 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; 2Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, China; 3Guangdong Provincial Key Laboratory of Tumor Targeted Drugs, Guangzhou Enterprise Key Laboratory of Gene Medicine, Guangzhou Doublle Bioproducts Co. Ltd., Guangzhou, China *These authors contributed equally to this work Purpose: Molecular biomarkers, especially serologic factors, have been widely applied in cancer diagnosis and patient follow-up. However, there are few valuable prognostic factors in penile squamous cell carcinoma (PSCC). Here, the authors investigated whether laminin gamma 2 (LAMC2) expression, especially serum LAMC2 (sLAMC2) level, was a suitable prognostic factor that could aid in the prediction of survival in PSCC.Patients and methods: This study included 114 PSCC patients. Reverse transcription-quantitative polymerase chain reaction, Western blotting, and immunohistochemistry were performed to detect LAMC2 expression; enzyme-linked immunosorbent assays were used to test sLAMC2 concentration; and a Transwell assay and an in vivo experiment in nude mice were used to test PSCC cell migration, invasion, and metastasis. The chi-squared test was used to analyze the association between LAMC2 level and clinical parameters, the Cox proportional hazards regression model was used to evaluate the hazard ratio for death, and Kaplan–Meier analysis with a log-rank test was used for the survival analysis.Results: LAMC2 was overexpressed in PSCC tissues, and the LAMC2 expression level was higher in metastatic lymph node (LN) tissues than in primary cancer tissues; moreover, the LAMC2 levels in primary cancer tissues and sLAMC2 were higher in patients with LN metastasis than in those without LN metastasis. Upregulated LAMC2 facilitated the migration, invasion, and epithelial-to-mesenchymal transition of PSCC cells in vitro and promoted LN metastasis of PSCC cells in nude mice. Elevated LAMC2 levels were strongly correlated with advanced clinicopathologic parameters, especially LN metastasis, in PSCC patients and predicted shorter disease-specific survival. The predictive value of sLAMC2 is superior to that of C-reactive protein and squamous cell carcinoma antigen previously reported in PSCC patients, and a stratification analysis revealed that the level of sLAMC2 had a higher predictive value for disease-specific survival in early penile cancer (especially at the N0/X stage) than in later-stage penile cancer.Conclusion: These findings suggest that sLAMC2 is a potential serologic prognostic marker in PSCC and could aid in risk stratification in early-stage PSCC patients. Keywords: penile neoplasms, serum markers, laminin, gamma 2, neoplasm metastasis

Yong-Jiang Li,1,* Kai Yao,2,* Min-Xun Lu,2 Wen-Biao Zhang,1 Cong Xiao,2 Chong-Qi Tu2 1Department of Oncology, 2Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, People’s Republic of China *These authors contributed equally to this work Abstract: The prognostic role of the C-reactive protein to albumin ratio (CRP/Alb ratio) in patients with osteosarcoma has not been investigated. A total of 216 osteosarcoma patients were enrolled in the study. Univariate and multivariate survival analyses between the groups were performed and Kaplan–Meier analysis was conducted to plot the survival curves. Receiver operating characteristic curves were generated and areas under the curve (AUCs) were compared to assess the discriminatory ability of the inflammation-based indicators, including CRP/Alb ratio, Glasgow prognostic score (GPS), neutrophil–lymphocyte ratio (NLR), and platelet–lymphocyte ratio (PLR). The optimal cutoff value was 0.210 for CRP/Alb ratio with a Youden index of 0.319. Higher values of CRP/Alb ratio were significantly associated with poorer overall survival in univariate (HR =2.62, 95% CI =1.70–4.03; P

Kai-Hong Zhao,1 Can Zhang,2 Yue Bai,1 Yan Li,1 Xun Kang,1 Jian-Xin Chen,1 Kun Yao,3 Tao Jiang,4 Xiao-Song Zhong,2 Wen-Bin Li1 1Department of Glioma, 2Clinical Center of Gene And Cell Engineering, Beijing Shijitan Hospital, 3Department of Neurosurgery, Beijing Tiantan Hospital, 4Department of Pathology, Sanbo Brain Hospital, Capital Medical University, Beijing, People’s Republic of China Abstract: Leptomeningeal metastasis (LM) of high-grade glioma is a highly lethal disease requiring new effective therapeutic measures. For both de novo or relapsed glioma with LM, intrathecal cytarabine chemotherapy is not frequently used for first-line and relapse protocols. We encountered a clinical case demonstrating effective application of cytarabine in high-grade glioma with LM, prompting us to explore the effects of cytarabine on malignant glioma and molecular mechanisms of such effects through in vivo and in vitro experiments. The U87 cell line was selected to represent human glioma for studies. Cell viability was measured by MTT assay, plate colony formation assay, and trypan-blue dye exclusion test. Apoptosis was assessed by flow cytometry. Protein expression levels were detected by Western blot assay and immunohistochemistry. mRNA expression was examined by quantitative real-time reverse transcription polymerase chain reaction. Cytarabine inhibited tumor growth during the in vivo experiment. The present study confirmed that cytarabine inhibits proliferation and promotes apoptosis of U87 cells, and molecular analysis of this effect showed that cytarabine significantly reduces expression of phosphatidylinositol 3-kinase/serine/threonine kinase also known as the protein kinase B/mechanistic target of rapamycin (PI3K/Akt/mTOR) pathway, Ki-67, BCL2, and 4-1BB, and upregulates Bax and cleaved caspase-3. Our findings indicated that intrathecal administration of cytarabine manifests potential in prophylaxis and treatment of malignant glioma with LM. Effective medications for high-grade glioma with LM should contain cytarabine. Keywords: leptomeningeal metastases, malignant glioma, cytarabine, PI3K/Akt/mTOR

Katharine Yao,1 Mark Sisco,2 Isabelle Bedrosian3 1Division of Surgical Oncology, Department of Surgery, 2Division of Plastic Surgery, Department of Surgery, NorthShore University HealthSystem, Evanston, IL, 3Department of Surgery, MD Anderson Cancer Center, Houston, TX, USA Abstract: There has been an increasing trend in the use of contralateral prophylactic mastectomy (CPM) in the United States among women diagnosed with unilateral breast cancer, particularly young women. Approximately one-third of women ,40 years old are undergoing CPM in the US. Most studies have shown that the CPM trend is mainly patient-driven, which reflects a changing environment for newly diagnosed breast cancer patients. The most common reason that women choose CPM is based on misperceptions about CPM’s effect on survival and overestimation of their contralateral breast cancer (CBC) risk. No prospective studies have shown survival benefit to CPM, and the CBC rate for most women is low at 10 years. Fear of recurrence is also a big driver of CPM decisions. Nonetheless, studies have shown that women are mostly satisfied with undergoing CPM, but complications and subsequent surgeries with reconstruction have been associated with dissatisfaction with CPM. Studies on surgeon’s perspectives on CPM are sparse but show that the most common reasons surgeons discuss CPM with patients is because of a suspicious family history or for a patient who is a confirmed BRCA mutation carrier. Studies on the cost–effectiveness of CPM have been conflicting and are highly dependent on patient’s quality of life after CPM. Most recent guidelines for CPM are contradictory. Future areas of research include the development of interventions to better inform patients about CPM, modification of the guidelines to form a more consistent statement, longer term studies on CBC risk and CPM’s effect on survival, and prospective studies that track the psychosocial effects of CPM on body image and sexuality. Keywords: contralateral breast cancer, surgical decision making

In this paper, we try to apply the advantages of principal component analysis (PCA) and online learning to the calculation of optimal portfolio investments. Each of these methods is widely used separately. This is done in order to make it possible to use online learning algorithms for high-dimension portfolios., Author(s): G. Beliavsky [sup.1], N. Danilova [sup.1], K. Yao [sup.1] Author Affiliations: (1) https://ror.org/01tv9ph92, grid.182798.d, 0000 0001 2172 8170, Operations Research, Mathematics, Mechanics and Computer Sciences Institute of Southern Federal [...]

The mission of HL-2A is to explore the key physical topics relevant to ITER and to the advanced tokamak operation (e.g. the operation of future HL-2M), such as the access of H-mode, energetic particle physics, edge-localized mode (ELM) mitigation/suppression and disruption mitigation. Since the 2016 Fusion Energy Conference, the HL-2A team has focused on the investigations on the following areas: (i) pedestal dynamics and L-H transition, (ii) techniques of ELM control, (iii) turbulence and transport, (iv) energetic particle physics. The HL-2A results demonstrated that the increase of mean shear flow plays a key role in triggering L-I and I-H transitions, while the change of flow is mainly induced by the ion pressure gradient. Both mitigation and suppression of ELMs were realized by laser blow-off seeded impurity (Al, Fe, W). The 30% Ne mixture supersonic molecular beam injection seeding also robustly induced ELM mitigation. The ELMs were mitigated by low-hybrid current drive. The stabilization of m/n = 1/1 ion fishbone activities by electron cyclotron resonance heating was found on the HL-2A. A new m/n = 2/1 ion fishbone activity was observed recently, and the modelling indicated that passing fast ions dominantly contribute to the driving of 2/1 fishbone. The non-linear coupling between the toroidal Alfven eigenmode and tearing mode (TM) led to the generation of a high frequency mode with the toroidal mode number n = 0. The turbulence was modulated by TM when the island width exceeds a threshold and the modulation is localized merely in the inner area of the islands. Meanwhile, turbulence radial spread took place across the island region.