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Xinling Zhao,1,2,&ast; Huijin Jie,3,&ast; Jun Wang,1 Yu Liu,4 Yilin Liu,2 Fuyi Qin,2 Qing Long,2 Xi Hou,5 Xin-Wen Zhang,6 Wenzhi Wu,7 Xiaoqin Wu,2 Jing Li,8 Yong Zeng2 1Department of Clinical Psychology, People’s Hospital of Chongqing Liang Jiang New Area, Chongqing, People’s Republic of China; 2Department of Psychiatry, the Second Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 3Haining Fourth People’s Hospital, Haining, People’s Republic of China; 4Department of Psychiatry, the First Affiliated Hospital of Kunming Medical University, Kunming, People’s Republic of China; 5Department of Clinical Psychology, The Sixth Affiliated Hospital of Kunming Medical University, Yuxi, People’s Republic of China; 6Department of Psychiatry, Hong He Second People’s Hospital, Jian Shui, People’s Republic of China; 7Faculty of psychology, Beijing Normal University, Beijing, People’s Republic of China; 8Sichuan Provincial Center for Mental Health, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jing Li; Yong Zeng, Email lijingjingjing222@163.com; zengyong@kmmu.edu.cnBackground: Adolescents with major depressive (MDD) episodes associated with childhood trauma have a poorer response to treatment and a higher risk of suicide. The underlying etiology is unclear. Brain-derived neurotrophic factor (BDNF) could improve depressive symptoms by down-regulating mammalian target of rapamycin (mTOR) signaling pathways, which was involved in adverse environmental stimuli during neurodevelopment. BDNF and mTOR have not been reported simultaneously in adolescents with major depressive episodes associated with childhood trauma.Methods: Childhood Trauma Questionnaire-Short Form (CTQ-SF), Children’s Depression Inventory (CDI) and Children’s Depression Rating Scale-Revised (CDRS-R) were used to evaluate the recruited adolescents with major depression episodes. Serum BDNF and p-mTOR levels were measured by ELISA in 31 adolescents with major depression episodes with childhood trauma and 18 matched healthy control.Results: The serum levels of BDNF were significantly lower (p< 0.001); and the serum levels of p-mTOR were high (p=0.003) in the adolescents with the first episode of major depressive episode accompanied by childhood trauma. Of the 31 adolescents with major depressive episodes, 17 had suicide or self-injury. Compared with the healthy control group, the serum levels of BDNF in patients with suicide or self-injury were lower than those without suicide or self-injury(p< 0.001); the serum levels of p-mTOR were higher than those without suicide or self-injury (p=0.01). While in patients without suicide or self-injury, only serum p-mTOR was significantly higher than that in healthy group (p=0.028). BDNF was negatively correlated with CDRS-R (r=− 0.427, p=0.006), p-mTOR was positively correlated with CDI (r=0.364, p=0.048). According to Receiver Operating Characteristic Curve (ROC), the combination of serum BDNF and p-mTOR levels have better diagnostic value.Conclusion: Neurotrophic and signaling pathways, involving BDNF and p-mTOR, may play a role in adolescent MDD with a history of childhood trauma, especially patients with suicide and self-injury tendencies.Keywords: brain-derived neurotrophic factor, p-mTOR, major depressive disorder, suicide, adolescent, childhood trauma

To understand the molecular mechanisms that mediate the anti-hepatitis B virus (HBV) effect of interferon (IFN) therapy, we conduct high-throughput bimolecular fluorescence complementation screening to identify potential physical interactions between the HBx protein and 145 IFN-stimulated genes (ISGs). Seven HBx-interacting ISGs have consistent and significant inhibitory effects on HBV replication, among which TRIM5γ suppresses HBV replication by promoting K48-linked ubiquitination and degradation of the HBx protein on the K95 ubiquitin site. The B-Box domain of TRIM5γ under overexpression conditions is sufficient to trigger HBx degradation and is responsible both for interacting with HBx and recruiting TRIM31, which is an ubiquitin ligase that triggers HBx ubiquitination. High expression levels of TRIM5γ in IFN-α-treated HBV patients might indicate a better therapeutic effect. Thus, our studies identify a crucial role for TRIM5γ and TRIM31 in promoting HBx degradation, which may facilitate the development of therapeutic agents for the treatment of patients with IFN-resistant HBV infection.

Fuxun Zhang1,2 &ast;, Yang Xiong1,2 &ast;, Feng Qin,1 Jiuhong Yuan1,2 1Andrology Laboratory, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiuhong Yuan, Department of Urology, Institute of Urology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China, Email jiuhongyuan2107@163.comAbstract: The meaning of sleep has puzzled people for millennia. In modern society, short sleep duration is becoming a global problem. It has been established that short sleep duration can increase the risk of several diseases, such as cardiovascular and metabolic diseases. Currently, a growing body of research has revealed a possible link between sleep disorders and erectile dysfunction (ED). However, the mechanisms linking short sleep duration and ED are largely unknown. Thus, we provide a review of clinical trials and animal studies. In this review, we propose putative pathways connecting short sleep duration and ED, including neuroendocrine pathways and molecular mechanisms, aiming to pave the way for future research. Meanwhile, the assessment and improvement of sleep quality should be recommended in the diagnosis and treatment of ED patients.Keywords: erectile dysfunction, molecular mechanisms, sleep disorder, short sleep duration, signaling pathway

Electrospray (ES) has attracted significant interest due to its advantages in generating uniform droplets and enabling controlled deposition. However, the complex interactions and droplet motion mechanisms between fluids and electric fields are still not well understood. Herein, this study presents a three-dimensional numerical model based on the volume of fluid and Lagrangian approaches to simulate the ES process in the pulsed jet mode. The model accurately captures the morphology and the atomization characteristics in the pulsed jet mode of ES. The effects of voltage and Reynolds number on the length of the non-atomized zone (including quasi-static Taylor cone, transition zone, and jet), diameter of the jet breakup, and atomization characteristics are discussed. Also, the mechanism of atomized droplets is revealed by analyzing the magnitudes of different types of forces imposing on the droplets in the electric field. The results indicate that higher Reynolds numbers lead to increased length of non-atomized zone and diameter of jet breakup, while the elevated voltages enhance atomization. Electric and Coulomb forces are, respectively, the dominant forces of forming the jet and expanding the atomization angle. Coulomb force increases the atomization angle, and electric field force increases the velocity of atomized droplets. Gravity and drag-force effects are relatively negligible throughout the atomization process. These findings contribute to a better understanding of the electrospray mechanisms and provide insights for optimizing electrospray applications. [ABSTRACT FROM AUTHOR]

Yang Yao,1,2,* Xinggen Fang,1,* Jinlong Yuan,1 Feiyun Qin,1 Tao Yu,1 Dayong Xia,1,3 Zhenbao Li,1 Niansheng Lai1,3 1Department of Neurosurgery, First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, Anhui Province, People’s Republic of China; 2Department of Nursing, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, Anhui Province, People’s Republic of China; 3Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution (Wannan Medical College), Wuhu, 241001, Anhui Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Niansheng Lai; Zhenbao LiDepartment of Neurosurgery, First Affiliated Hospital of Wannan Medical College (Yijishan Hospital), 2 West Zheshan Road, Wuhu, 241001, Anhui Province, People’s Republic of ChinaTel +86-15155308793Fax +86-05535739594Email mlns@wnmc.edu.cn; zhenbaoli123@126.comObjective: Aneurysmal subarachnoid hemorrhage (aSAH) is a severe form of stroke characterized by high rates of mortality and disability. Identifying circulating biomarkers is helpful to improve outcomes. In this study, for the first time, we identify interleukin-6 (IL-6) in cerebrospinal fluid (CSF) small extracellular vesicles (sEVs) as potential biomarkers for prognosis of aSAH.Methods: We extracted small extracellular vesicles from the CSF of 103 aSAH patients and 40 healthy controls in a prospective observational study. Subsequently, we measured IL-6sEVs levels using an enzyme-linked immunosorbent assay. Results were statistically analyzed to determine the function of IL-6sEVs for disease monitoring of aSAH.Results: CSF IL-6 sEVs showed distinct pattern differences between healthy controls and aSAH patients. The concentration of IL-6sEVs in CSF is significantly correlated with the severity of aSAH patients. The areas under the receiver operating characteristic curves of IL-6sEVs for identifying severe aSAH patient from aSAH patients were 0.900. After multivariate logistic regression analysis, IL-6sEVs were associated with neurological outcome at 1 year. IL-6sEVs levels were greater and positively associated with disease processes and outcome.Conclusion: There is a neuroinflammatory cascade in aSAH patients. IL-6sEVs in CSF may be a biomarker for the progression of aSAH.Keywords: subarachnoid hemorrhage, cerebrospinal fluid, small extracellular vesicles, interleukin-6, biomarker

Zika virus (ZIKV) has become a public health threat due to its global transmission and link to severe congenital disorders. The host immune responses to ZIKV infection have not been fully elucidated, and effective therapeutics are not currently available. Herein, we demonstrated that cholesterol-25-hydroxylase (CH25H) was induced in response to ZIKV infection and that its enzymatic product, 25-hydroxycholesterol (25HC), was a critical mediator of host protection against ZIKV. Synthetic 25HC addition inhibited ZIKV infection in vitro by blocking viral entry, and treatment with 25HC reduced viremia and conferred protection against ZIKV in mice and rhesus macaques. 25HC suppressed ZIKV infection and reduced tissue damage in human cortical organoids and the embryonic brain of the ZIKV-induced mouse microcephaly model. Our findings highlight the protective role of CH25H during ZIKV infection and the potential use of 25HC as a natural antiviral agent to combat ZIKV infection and prevent ZIKV-associated outcomes, such as microcephaly.

New influenza vaccines that provide effective and broad protection are desperately needed. Live attenuated viruses are attractive vaccine candidates because they can elicit both humoral and cellular immune responses. However, recent formulations of live attenuated influenza vaccines (LAIVs) have not been protective. We combined high-coverage transposon mutagenesis of influenza virus with a rapid high-throughput screening for attenuation to generate W7-791, a live attenuated mutant virus strain. W7-791 produced only a transient asymptomatic infection in adult and neonatal mice even at doses 100-fold higher than the LD50 of the parent strain. A single administration of W7-791 conferred full protection to mice against lethal challenge with H1N1, H3N2, and H5N1 strains, and improved viral clearance in ferrets. Adoptive transfer of T cells from W7-791-immunized mice conferred heterologous protection, indicating a role for T cell-mediated immunity. These studies present an LAIV development strategy to rapidly generate and screen entire libraries of viral clones.

Chirality of materials are known to affect optical, magnetic and electric properties, causing a variety of nontrivial phenomena such as circular dichiroism for chiral molecules, magnetic Skyrmions in chiral magnets and nonreciprocal carrier transport in chiral conductors. On the other hand, effect of chirality on superconducting transport has not been known. Here we report the nonreciprocity of superconductivity-unambiguous evidence of superconductivity reflecting chiral structure in which the forward and backward supercurrent flows are not equivalent because of inversion symmetry breaking. Such superconductivity is realized via ionic gating in individual chiral nanotubes of tungsten disulfide. The nonreciprocal signal is significantly enhanced in the superconducting state, being associated with unprecedented quantum Little-Parks oscillations originating from the interference of supercurrent along the circumference of the nanotube. The present results indicate that the nonreciprocity is a viable approach toward the superconductors with chiral or noncentrosymmetric structures.

Yuanxiang Lu,1,2,* Dongxiao Li,3,* Ge Liu,1,4 Erwei Xiao,1 Senmao Mu,1 Yujin Pan,1 Fangyuan Qin,5 Yaping Zhai,5 Shaofeng Duan,6 Deyu Li,1,2 Guoyi Yan1,4 1Department of Hepatobiliary Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2School of Clinical Medicine, Zhengzhou University, Zhengzhou, People’s Republic of China; 3Department of Gastroenterology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 4School of Clinical Medicine, Henan University, Kaifeng, People’s Republic of China; 5Henan Eye Hospital, Henan Provincial People’s Hospital and People’s Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 6School of Pharmacy, Henan University, Kaifeng, People’s Republic of China*These authors contributed equally to this workCorrespondence: Deyu Li; Guoyi YanDepartment of Hepatobiliary Surgery, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou 450003, People’s Republic of ChinaEmail lidy0408@sohu.com; ygyxyz307@hotmail.comIntroduction: The poorly differentiated pancreatic adenocarcinoma (PDAC) is an extremely lethal neoplasm without effective biomarkers for early detection and prognosis prediction, which is characteristically unresponsive to chemotherapeutic regimens. This study aims at searching for key genes which could be applied as novel prognostic biomarkers and therapeutic targets in PDAC.Methods: Clinical samples were collected and a comprehensive differential analysis of seven PDAC samples by integrating RNA-seq data of tumor tissues and matched normal tissues from both our cohort and gene expression profiling interactive analysis (GEPIA) were performed to discover potential prognostic genes in PDAC. Pathway enrichment analysis was carried out to determine the biological function of PDAC differentially expressed genes (DEGs), and protein-protein interaction (PPI) network was constructed for functional modules analysis. Real-time PCR was performed to validate expression of hub genes.Results: A total of 126 PDAC-specific expressed genes identified from seven PDAC samples were predominantly enriched in cell adhesion, integral component of membrane, signal transduction and chemical carcinogenesis, IL-17 signaling pathway, indicating that obtained genes might play a unique role in PDAC tumorigenesis. Furthermore, survival analysis revealed that five genes (CEACAM5, KRT6A, KRT6B, KRT7, KRT17) which exhibited high expression levels in tumor tissues were obviously correlated with the prognosis of PDAC patients and KRT7 was positively correlated with KRT6A, KRT6B, KRT17 expression. In addition, real-time PCR demonstrated that the expression level of the hub genes was consistent with RNA-seq analysis.Discussion: The current study suggested that CEACAM5, KRT6A, KRT6B, KRT7, and KRT17 may represent novel prognostic biomarkers as well as novel therapeutic targets for poorly differentiated PDAC.Keywords: pancreatic adenocarcinoma, biomarker, differentially expressed genes, RNA-seq, prognosis

Background: Preclinical and clinical evidence indicates that proton pump inhibitors (PPIs) may indirectly diminish the microbiome diversity, thereby reducing the effectiveness of immune checkpoint inhibitors (ICIs). Conversely, recent publications have shown that PPIs could potentially enhance the response to ICIs. The precise mechanism through which PPIs modulate the ICIs remains unclear. In this study, we discovered a novel molecular function of PPIs in regulating immune invasion, specifically through inducing PD‐L1 translocation in various tumor cells. Methods: C57BL/6 mice subcutaneous transplantation model is used to verify the potential efficacy of PPIs and PD‐L1 antibody. Western blotting analysis and phosphorylated chip are used to verify the alteration of PD‐L1‐related pathways after being treated with PPIs. The related gene expression is performed by qRT‐PCR and luciferase reporter analysis. We also collected 60 clinical patients diagnosed with esophageal cancer or reflux esophagitis and then detected the expression of PD‐L1 in the tissue samples by immunohistochemistry. Results: We observed that the IC50 of tumor cells in response to PPIs was significantly higher than that of normal epithelial cells. PPIs significantly increased the expression of PD‐L1 on cell membrane at clinically relevant concentrations. Furthermore, pre‐treatment with PPIs appeared to synergize the efficiency of anti‐PD‐L1 antibodies in mouse models. However, PPI administration did not alter the transcription or total protein level of PD‐L1 in multiple tumor cells. Using a phosphorylated protein chip, we identified that PPIs enhanced the phosphorylation of GSK3β, then leading to PD‐L1 protein translocation to the cell membranes. The capacity of PPIs to upregulate PD‐L1 was negated following GSK3β knockout. Furthermore, our clinical data showed that the PPIs use resulted in increased PD‐L1 expression in esophageal cancer patients. Conclusion: We mainly address a significant and novel mechanism that the usage of PPIs could directly induce the expression of PD‐L1 by inducing GSK3β phosphorylation and facilitate primary tumor progression and metastasis. [ABSTRACT FROM AUTHOR]

UnlabelledInfluenza virus mRNA synthesis by the RNA-dependent RNA polymerase involves binding and cleavage of capped cellular mRNA by the PB2 and PA subunits, respectively, and extension of viral mRNA by PB1. However, the mechanism for such a dynamic process is unclear. Using high-throughput mutagenesis and sequencing analysis, we have not only generated a comprehensive functional map for the microdomains of individual subunits but also have revealed the PA linker to be critical for polymerase activity. This PA linker binds to PB1 and also forms ionic interactions with the PA C-terminal channel. Nearly all mutants with five-amino-acid insertions in the linker were nonviable. Our model further suggests that the PA linker plays an important role in the conformational changes that occur between stages that favor capped mRNA binding and cleavage and those associated with viral mRNA synthesis.ImportanceThe RNA-dependent RNA polymerase of influenza virus consists of the PB1, PB2, and PA subunits. By combining genome-wide mutagenesis analysis with the recently discovered crystal structure of the influenza polymerase heterotrimer, we generated a comprehensive functional map of the entire influenza polymerase complex. We identified the microdomains of individual subunits, including the catalytic domains, the interaction interfaces between subunits, and nine linkers interconnecting different domains. Interestingly, we found that mutants with five-amino-acid insertions in individual linkers were nonviable, suggesting the critical roles these linkers play in coordinating spatial relationships between the subunits. We further identified an extended PA linker that binds to PB1 and also forms ionic interactions with the PA C-terminal channel.

Yun Liu,1,* Ying-Ling Miao,2,* Feng Qin,1 Cen Cao,1 Xiao-Lin Yu,1 Yu-Han Wu,1 Tian-Lu Wang,1 Ruo-Gu Xu,1 Liu Zhao,3 Fan Wu,1 Zheng-Chuan Zhang,1 Jia-Min Yang,1 Yang Yang,1 Xin Xie,1 Li-Ming Zhang,2 Fei-Long Deng1 1Department of Oral Implantology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 2School of Materials Science and Engineering, Sun Yat-Sen University, Guangzhou, Guangdong, People’s Republic of China; 3School of Chemistry, Beihang University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Li-Ming ZhangSchool of Materials Science and Engineering, Sun Yat-Sen University, No. 135, Xingang Xi Road, Guangzhou 510275, People’s Republic of ChinaTel +86 020-84112354Email ceszhlm@mail.sysu.edu.cnFei-Long DengDepartment of Oral Implantology, Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-Sen University, No. 56, Lingyuan Xi Road, Guangzhou 510000, People’s Republic of ChinaTel +86 020-83863002Email dengfl@mail.sysu.edu.cnBackground: Critical-sized bone defects raise great challenges. Zein is of interest for bone regeneration, but it has limited ability to stimulate cell proliferation. In this regard, a poly (aspartic acid) (PAsp)-zein hybrid is promising, as PAsp can promote rat bone marrow stromal cell (rBMSCs) proliferation and osteogenic differentiation. This research aimed to develop electrospun PAsp-modified zein nanofibers to realize critical-sized bone defects repair.Methods: Three groups of PAsp-modified zein nanofibers were prepared, they were PAsp grafting percentages of 0% (zein), 5.32% (ZPAA-1), and 7.63% (ZPAA-2). Using rBMSCs as in vitro cell model and SD rats as in vivo animal model, fluorescence staining, SEM, CCK-8, ALP, ARS staining, μCT and histological analysis were performed to verify the biological and osteogenic activities for PAsp-modified zein nanofibers.Results: As the Asp content increased from 0% to 7.63%, the water contact angle decreased from 129.8 ± 2.3° to 105.5 ± 2.5°. SEM, fluorescence staining and CCK-8 assay showed that ZPAA-2 nanofibers had a superior effect on rBMSCs spreading and proliferation than did zein and ZPAA-1 nanofibers, ALP activity and ARS staining showed that ZPAA-2 can improve rBMSCs osteogenic differentiation. In vivo osteogenic activities was evaluated by μCT analysis, HE, Masson and immunohistochemical staining, indicating accelerated bone formation in ZPAA-2 SD rats after 4 and 8 weeks treatment, with a rank order of ZPAA-2 > ZPAA-1 > zein group. Moreover, the semiquantitative results of the Masson staining revealed that the maturity of the new bone was higher in the ZPAA-2 group than in the other groups.Conclusion: Electrospun PAsp-modified zein can provide a suitable microenvironment for osteogenic differentiation of rBMSCs, as well as for bone regeneration; the optimal membrane appears to have a PAsp grafting percentage of 7.63%.Keywords: electrospun, osteogenesis, poly (aspartic acid), zein

OBJECTIVE: Prostate cancer (PCa) is the most common malignant tumor in the male genitourinary system. Once PCa has metastasized, it is very difficult to cure. The purpose of this study was to investigate the prognostic risk factor analysis of patients with different prostate- specific antigen (PSA) levels in distant metastatic PCa. At the same time, we construct effective models for predicting the survival rate of prostate cancer patients. PATIENTS AND METHODS: Data on prostate cancer patients with the presence of distant metastases were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. PCa patients with distant metastases were categorized into two groups based on PSA levels, one with PSA <20 ng/mL and the other with PSA ≥20 ng/mL. Univariate and multivariate COX regression analyses were used to identify independent factors affecting the prognosis of the patients. A nomogram was constructed using the independent prognostic factors, and the results were evaluated using calibration curves, timeROC curves, and Kaplan-Meier curves. RESULTS: In the PSA <20 ng/mL group, there were a total of 1,832 patients. COX regression analysis showed that age, marital status, N stage, grade, Gleason score, and medical household income inflation were independent prognostic factors for overall survival (OS) in patients. In addition, we found that age, marital status, N stage, bone metastasis, grade, and Gleason score were independent prognostic factors for cancer-specific survival (CSS) in patients. In the PSA ≥20 ng/mL group, there were a total of 5,314 patients. It was found that age, ethnicity, marital status, bone metastasis, first malignant primary indicator, grade, Gleason score, and medical household income inflation were patients' independent prognostic factors for OS. For CSS, we found that age, ethnicity, marital status, T stage, radiotherapy, bone metastasis, Gleason score, and Median household income inflation were independent prognostic factors. Constructing a nomogram can accurately predict the prognosis of this group of patients. CONCLUSIONS: We found different independent prognostic factors for different PSA levels in patients with distant metastatic PCa. A new nomogram was constructed to predict OS and CSS in patients, which helps in clinical-assisted decision-making. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer, and its molecular pathogenesis is unclear. In this study, we investigated the prognostic value of essential meiotic endonuclease 1 (EME1) in kidney renal clear cell carcinoma (KIRC). MATERIALS AND METHODS: We downloaded the RNA-Seq expression of 526 KIRC tissues and 72 normal tissues from the TCGA database and the corresponding clinical data. The gene expression profiles associated with four clear cell renal cell carcinomas were downloaded from the GEO database for analysis. The expression of EME1 in clear renal cell carcinoma and its correlation with the clinical baseline data were analyzed. Kaplan-Meier survival curve analysis was performed to assess the relationship between EME1 and patient survival. Enrichment analysis was performed to elucidate the possible functions of EME1. We also analyzed the relationship between the EME1 expression and immune infiltration through TIMER2.0 and TISIDB online databases as well as the relationship between EME1 and common immune checkpoints. RESULTS: EME1 was identified as a risk factor for overall survival in clear cell renal cell carcinoma with a hazard ratio of 3.201 (95% con- fidence interval: 2.430-4.215; p < 0.001). EME1 was highly expressed in KIRC compared to that in normal tissues (p < 0.001) and in the worse TNM stages and late stages (stage 3/4) (p < 0.001). High EME1 expression was strongly associated with the advanced T stage (p = 0.003), advanced N stage (p = 0 .002), a nd a dvanced M stage (p = 0 .006). R esearch d ata on K IRC were simultaneously collected and analyzed from the GEO database, including GSE40435, GSE53000, GSE68417, and GSE53757. EME1 predicted the survival status in KIRC patients (AUC = 0.62). We further established a nomogram including the correlation between the high and low EME1 expression, and EME1 was found to contribute to the prediction of the probability of patient survival with a c-index = 0.796. Kaplan-Meier analysis revealed a lower likelihood of survival with a high EME1 expression (p < 0.001). In addition, further bioinformatics analysis suggested that EME1 may be associated with the extent of immune infiltration in KIRC. CONCLUSIONS: An increased expression of EME1 in KIRC is thus associated with advanced clinicopathological features, possibly acting as a potential biomarker of poor prognosis in KIRC. [ABSTRACT FROM AUTHOR]

In this paper, the class of S-generalized distances such that the involved t-conorms S are ordinal sums is discussed. It is shown that these S-generalized distances can be thought of as families of generalized distances with respect to some Archimedean t-conorms. We also deal with the S-generalized distance aggregations, which merge a family of Si-generalized distances into a new S-generalized distance. [ABSTRACT FROM AUTHOR]

Fenju Qin,1,2 Tao Shen,1 Honglong Cao,3 Junchao Qian,4 Dan Zou,1 Mingkang Ye,1 Hailong Pei21Department of Biotechnology and Bioengineering, Suzhou University of Science and Technology, Suzhou 215009, People’s Republic of China; 2School of Radiation Medicine and Protection, Medical College of Soochow University, Suzhou 215123, People’s Republic of China; 3School of Electronic & Information Engineering, Soochow University, Suzhou 215006, People’s Republic of China; 4Jiangsu Key Laboratory for Environment Functional Materials, Suzhou University of Science and Technology, Suzhou 215009, People’s Republic of ChinaIntroduction: The ratio of Ce3+,/Ce4+, in their structure confers unique functions on cerium oxide nanoparticles (CeO2NPs) containing rare earth elements in scavenging free radicals and protecting against oxidative damage. The potential of CeO2NPs to protect testosterone synthesis in primary mouse Leydig cells during exposure to 1,800 MHz radiofrequency (RF) radiation was examined in vitro.Methods: Leydig cells were treated with different concentrations of CeO2NPs to identify the optimum concentration for cell proliferation. The cells were pretreated with the optimum dose of CeO2NPs for 24 hrs and then exposed to 1,800 MHz RF at a power density of 200.27 μW/cm2, (specific absorption rate (SAR), 0.116 W/kg) for 1 hr, 2 hrs, or 4 hrs. The medium was used to measure the testosterone concentration. The cells were collected to determine the antioxidant indices (catalase [CAT], malondialdehyde [MDA], and total antioxidant capacity [T-AOC]), and the mRNA expression of the testosterone synthase genes (Star, Cyp11a1, and Hsd-3β) and clock genes (Clock, Bmal1, and Rorα).Results: Our preliminary result showed that 128 μg/mL CeO2NPs was the optimum dose for cell proliferation. Cells exposed to RF alone showed reduced levels of testosterone, T-AOC, and CAT activities, increased MDA content, and the downregulated genes expression of Star, Cyp11a1, Hsd-3β, Clock, Bmal1, and Rorα. Pretreatment of the cells with 128 μg/mL CeO2NPs for 24 hrs followed by RF exposure significantly increased testosterone synthesis, upregulated the expression of the testosterone synthase and clock genes, and increased the resistance to oxidative damage in Leydig cells compared with those in cells exposed to RF alone.Conclusion: Exposure to 1,800 MHz RF had adverse effects on testosterone synthesis, antioxidant levels, and clock gene expression in primary Leydig cells. Pretreatment with CeO2NPs prevented the adverse effects on testosterone synthesis induced by RF exposure by regulating their antioxidant capacity and clock gene expression in vitro. Further studies of the mechanism underlying the protective function of CeO2NPs against RF in the male reproductive system are required.Keywords: CeO2NPs radiofrequency radiation, Leydig cell, testosterone synthesis, clock genes, antioxidant

Fen Qin,1,* Quan Wang,2,* Chunlian Zhang,1 Caiyun Fang,1 Liping Zhang,1 Hailin Chen,1 Mi Zhang,3 Fei Cheng3 1Department of Obstetrics and Gynecology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China; 2Department of Stomatology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China; 3Department of Cardiology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China *These authors contributed equally to this work Purpose: Antifungal drugs are used frequently in the treatment of vulvovaginal candidiasis (VVC), but have shown controversial results. In this study, we aimed to evaluate the effectiveness of different antifungal drugs in the treatment of VVC and to provide an evidence-based reference for clinical use.Methods: The published studies on the effectiveness of antifungal drugs in the treatment of VVC (up to April 2018) were retrieved from PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov. We sifted through the literature according to Patients, Interventions, Comparisons and Outcomes principle, extracted data on the basic characteristics of the study, and evaluated the quality of included studies. We used R software for statistical analysis.Results: In total, 41 randomized controlled trials were included in this meta-analysis. The relative risk of VVC associated with ten drugs, including placebo, fluconazole, clotrimazole, miconazole, itraconazole, ketoconazole, econazole, butoconazole, terbinafine, and terconazole, was analyzed. The following drugs appeared to show more efficacy than placebo in the treated patients: fluconazole (OR =6.45, 95% CrI 4.42–9.41), clotrimazole (OR =2.99, 95% CrI 1.61–5.55), miconazole (OR =5.96, 95% CrI 3.17–11.2), itraconazole (OR =2.29, 95% CrI 1.21–4.33), ketoconazole (OR =2.40, 95% CrI 1.55–3.71), butoconazole (OR =1.18, 95% CrI 1.06–1.31), and terconazole (OR =5.60, 95% CrI 2.78–11.3). The value of surface under the cumulative ranking curve of each drug was as follows: placebo (0.5%), fluconazole (91.5%), clotrimazole (61.8%), miconazole (33.8%), itraconazole (50.5%), ketoconazole (42.8%), econazole (46.8%), butoconazole (82.2%), terbinafine (20.9%), and terconazole (65.0%).Conclusion: Antifungal drugs are effective in the treatment of VVC. Fluconazole appeared to be the best drug for the treatment of VVC according to our analysis. Keywords: vulvovaginal candidiasis, antifungal drugs, randomized controlled trials, network meta-analysis