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Bao-Tao Liu,1 Feng-Jing Song21Department of Basic Veterinary Medicine, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao, People’s Republic of China; 2Institute of Plant Protection, Qingdao Academy of Agricultural Sciences, Qingdao, People’s Republic of ChinaCorrespondence: Bao-Tao LiuDepartment of Basic Veterinary Medicine, College of Veterinary Medicine, Qingdao Agricultural University, Qingdao 266109, People’s Republic of ChinaTel +86 1 346 587 7602Email liubaotao-1986@163.comFeng-Jing SongInstitute of Plant Protection, Qingdao Academy of Agricultural Sciences, Qingdao, People’s Republic of ChinaEmail lcsfj1130@163.comBackground: The concurrence of mcr and carbapenemase genes among Enterobacteriaceae has been a great clinical concern. In our study, we aimed to investigate the prevalence of mcr-positive carbapenem-resistant Enterobacteriaceae (CRE) in fresh vegetables and shed light on the possibility of transmission of mcr-positive CRE via fresh vegetables.Methods: In this study, 712 fresh vegetable samples from 10 provinces in China were collected between May 2017 and Dec 2018 and were screened for mcr and carbapenemase genes. Antibiotic susceptibilities for isolates co-harboring carbapenemase genes and mcr were determined by an agar dilution or a broth microdilution method. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) analysis were also performed. Transferability of the carbapenemase/mcr-bearing plasmids was determined by conjugation, replicon typing and S1-PFGE-Southern blotting. The sequences of these plasmids were analyzed by using whole-genome sequencing with Illumina Hiseq platform.Results: Two E. coli isolates concomitantly carrying mcr-1 and blaNDM-5/9 from leaf rape and spinach, respectively, were found and both isolates showed multidrug resistance. Notably, mcr-1-positive 690 harboring blaNDM-5 and 701 carrying blaNDM-9 belonged to ST156 and ST2847, respectively, similar to the prevalent MLST types of E. coli co-carrying mcr-1 and blaNDM from avian in our previous study. mcr-1 was on ∼33-kb IncX4 plasmid or ∼60-kb IncI2 plasmid, while blaNDM-5/9 was on ∼46-kb IncX3 plasmid or ∼120-kb untypable plasmid. The plasmids were highly similar to those from animals and clinical patients reported in various countries.Conclusion: E. coli isolates concomitantly carrying mcr-1 and blaNDM-5/9 in fresh vegetables may serve as a direct source of pathogens in humans, and such discovery in fresh vegetables emphasizes the importance of prompt surveillance and intervention in limiting the spread of E. coli co-carrying blaNDM and mcr-1. To our knowledge, this is the first report of Enterobacteriaceae co-carrying blaNDM and mcr-1 in fresh vegetables.Keywords: carbapenem resistance, colistin resistance, coexistence, plasmids, Enterobacteriaceae

Objective: To investigate the pollution levels and influencing factors of polybrominated diphenyl ethers (PBDEs) in household dust in five cities in northern China. Methods: Based on the "Chinese Indoor Environment and Health Surveillance" project carried out by the National Institute of Environmental Health, Chinese Center for Disease Control and Prevention in 2018-2019, during the warm season (April 2018 to September 2018) and the cold season (November 2018 to March 2019), Lanzhou in Northwest China, Shijiazhuang in North China, Panjin in Northeast China, Luoyang in Central China, and Qingdao in East China were selected as the research sites. A total of 87 families were recruited to study residences in real-life scenarios. At the same time, dust samples were collected to detect the concentration of PBDEs. The level of household environmental indicators was measured, and the residential building characteristics and family behavior habits were collected through questionnaires. A total of 142 valid dust samples and 140 valid questionnaires were obtained. The differences in PBDE concentrations across seasons, wind zones, residential building characteristics, and family habits were analyzed. The exploratory factor analysis was performed to investigate the possible sources of PBDEs, and multivariate linear regression was used to explore the factors influencing PBDEs in household dust. Results: The M ( Q 1, Q 3 ) of total PBDE concentrations in 142 household dust samples in five cities was 144.51 (106.61, 222.65) ng/g in the warm season and 145.10 (98.57, 180.65) ng/g in the cold season, respectively. There were seasonal differences in the concentration of ∑ 12 PBDEs in Luoyang and Shijiazhuang ( P <0.01). The concentration of BDE-71 was highest among PBDE homologues, followed by BDE-66 and BDE-47. Three factors were extracted by exploratory factor analysis in the warm season, and the cumulative variance contribution rate was 67.90%. The multivariate linear regression showed that the house completion less than ten years [ β (95% CI ): 0.186 (0.013, 0.359)], infrequent home cooking [ β (95% CI ):-0.342 (-0.570, -0.114)], and increased residential PM 10 concentration [ β (95% CI ): 0.001 (0.000, 0.002)] during the warm season, as well as the house far from driveway [ β (95% CI ): 0.093 (0.013, 0.172)], house area less than 90 m 2 [ β (95% CI ):-0.138 (-0.264, -0.013)], and lower residential xylene concentration [ β (95% CI ):-0.006 (-0.011, -0.001)] during the cold season might be related to the elevated concentrations of ∑ 12 PBDEs in household dust. Conclusion: The pollution of PBDEs in household dust in five northern cities is at a medium to high level. Years of house completion, frequency of cooking at home, residential PM 10 concentration, distance from house to driveway, house area, and residential xylene concentration may influence household PBDE concentrations.

Objective: To determine the total and age-specific cut-off values of total prostate specific antigen (tPSA) and the ratio of free PSA divided total PSA (fPSA/tPSA) for screening prostate cancer in China. Methods: Based on the Chinese Colorectal, Breast, Lung, Liver, and Stomach cancer Screening Trial (C-BLAST) and the Tianjin Common Cancer Case Cohort (TJ4C), males who were not diagnosed with any cancers at baseline since 2017 and received both tPSA and fPSA testes were selected. Based on Cox regression, the overall and age-specific (＜60, 60-＜70, and ≥70 years) accuracy and optimal cut-off values of tPSA and fPSA/tPSA ratio for screening prostate cancer were evaluated with time-dependent receiver operating characteristic curve (tdROC) and area under curve (AUC). Bootstrap resampling was used to internally validate the stability of the optimal cut-off value, and the PLCO study was used to externally validate the accuracy under different cut-off values. Results: A total of 5 180 participants were included in the study, and after a median follow-up of 1.48 years, a total of 332 prostate cancer patients were included. In the total population, the tdAUC of tPSA and fPSA/tPSA screening for prostate cancer were 0.852 and 0.748, respectively, with the optimal cut-off values of 5.08 ng/ml and 0.173, respectively. After age stratification, the age specific cut-off values of tPSA in the <60, 60-<70, and ≥70 age groups were 3.13, 4.82, and 11.54 ng/ml, respectively, while the age-specific cut-off values of fPSA/tPSA were 0.153, 0.135, and 0.130, respectively. Under the age-specific cut-off values, the sensitivities of tPSA screening for prostate cancer in males <60, 60-70, and ≥70 years old were 92.3%, 82.0%, and 77.6%, respectively, while the specificities were 84.7%, 81.3%, and 75.4%, respectively. The age-specific sensitivities of fPSA/tPSA for screening prostate cancer were 74.4%, 53.3%, and 55.9%, respectively, while the specificities were 83.8%, 83.7%, and 83.7%, respectively. Both bootstrap's internal validation and PLCO external validation provided similar results. The combination of tPSA and fPSA/tPSA could further improve the accuracy of screening. Conclusion: To improve the screening effects, it is recommended that age-specific cut-off values of tPSA and fPSA/tPSA should be used to screen for prostate cancer in the general risk population.

Background: The coexistence of emphysema and lung nodules could interact with each other and then lead to potential higher lung cancer risk. The study aimed to explore the association between emphysema combined with lung nodules and lung cancer risk., Methods: A total of 21,949 participants from the National Lung Screening Trial (NLST) who underwent low-dose computed tomography (LDCT) examination were included. Participants were categorized into four groups (NENN group (non-emphysema and non-nodules), E group (emphysema without nodules), N group (nodules without emphysema), and E + N group (nodules with emphysema)) according to whether there were lung nodules and emphysema. Multivariable Cox regression and stratified analyses were performed to estimate the association between the four groups and lung cancer risk., Results: Among the 21,949 participants, there were 9,040 (41.2%), 5,819 (26.5%), 4,737 (21.6%), and 2,353 (10.7%) participants in the NENN group, E group, N group, and E + N group. The risk of lung cancer incidence increased in turn in NENN group, E group, N group and E + N group. Compared with NENN group, the age-adjusted hazard ratios (HRs) (95% confidence intervals (CIs)) of lung cancer incidence were 2.07 (1.69 - 2.54) for E group, 4.13 (3.47 - 5.05) for N group, and 6.26 (5.14 - 7.62) for E + N group. The association was robust to adjustment for potential confounders (1.83 (1.47 - 2.27) for E group, 3.97 (3.24 - 4.86) for N group, and 5.23 (4.28 - 6.48) for E + N group). Comparable results as the lung cancer incidence were observed for lung cancer mortality, whether in age-adjusted model (E group: 1.85 (1.39 - 2.46), N group: 2.49 (1.89 - 3.29), E + N group: 4.27 (3.21 - 5.68)) or fully adjusted model (E group: 1.56 (1.15 - 2.11), N group: 2.43 (1.81 - 3.26), E + N group: 3.39 (2.50 - 4.61)). However, the trend of all-cause mortality risk among the four groups was somewhat different from that of lung cancer risk, whether in age-adjusted model (1.37 (1.21 - 1.54) for E group, 1.06 (0.92 - 1.21) for N group, and 1.75 (1.51 - 2.02) for E + N group) or fully adjusted model (1.26 (1.10 - 1.44) for E group, 1.09 (0.94 - 1.27) for N group, and 1.52 (1.30 - 1.79) for E + N group)., Conclusion: Based on a large-scale lung cancer screening trial in the United States, this study demonstrated that either emphysema or lung nodules can increase lung cancer risk, and lung nodules combined with emphysema can further increase the lung cancer risk and all-cause mortality. The significance of these findings for lung cancer screening should be evaluated., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright 2024, Liu et al.)

Leukemia is a type of malignant hematological disease that is generally resistant to chemotherapy and has poor therapeutic outcomes. Werner (WRN) DNA helicase, an important member of the RecQ family of helicases, plays an important role in DNA repair and telomere stability maintenance. WRN gene dysfunction leads to premature aging and predisposes humans to various types of cancers. However, the biological function of WRN in cancer remains unknown. In this study, the expression of this RecQ family helicase was investigated in different types of leukemia cells, and the leukemia cell line K562 with high WRN expression was selected to construct a WRN knockdown cell line. The results showed that WRN knockdown inhibited leukemia occurrence and development by regulating the proliferation, cell cycle, differentiation, and aging of cells and other biological processes. The results of transcriptome sequencing revealed that WRN promoted the sensitivity of leukemia cells to the DNA damage inducer Etoposide by regulating cell cycle-related proteins, such as CDC2, cyclin B1, p16, and p21, as well as key proteins in DNA damage repair pathways, such as p53, RAD50, RAD51, and MER11. Our findings show that WRN helicase is a promising potential target for leukemia treatment, providing new ideas for the development of targeted drugs against leukemia., Competing Interests: Declaration of competing interest All authors declared no potential conflicts of interest with respect to the research, author- ship, and/or publication of this article., (Copyright © 2023. Published by Elsevier B.V.)

Endophytic bacteria play crucial roles in the growth and bioactive compound synthesis of host plants. In this study, the composition and diversity of endophytic bacteria in the roots, stems, and leaves from 3-year-old artificially cultivated Huperzia serrata were investigated using Illumina HiSeq sequencing technology. Total effective reads were assigned to 936 operational taxonomic units (OTUs), belonging to 12 phyla and 289 genera. A total of 28, 3, and 2 OTUs were exclusive to the roots, stems, and leaves, respectively. The bacterial richness and diversity in the roots were significantly lower than those in the leaves and stems. The dominant genera with significant distribution differences among these plant tissue samples were Burkholderia-Caballeronia-Paraburkholderia, Sphingomonas, Acidibacter, Bradyrhizobium, Bryobacter, Methylocella, Nocardioides, Acidothermus , and Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium . Furthermore, the differences in the bacterial communities associated with these plant tissue samples were visualized using principal coordinate analysis and cluster pedigree diagrams. Linear discriminant analysis effect size explained statistically significant differences among the endophytic bacterial microbiota in these plant tissue samples. Overall, this study provides new insights into the diversity and distribution patterns of endophytic bacteria in the different tissues of H. serrata ., Competing Interests: The authors declare there are no competing interests.

The global spread of colistin or carbapenem-resistant Enterobacteriaceae (CRE) has been a pressing threat to public health. Members of Enterobacteriaceae, especially Proteus mirabilis and Escherichia coli, have been prevalent foodborne pathogens and such pathogens from fresh vegetables have triggered foodborne illness in China. However, reports about CRE, especially P. mirabilis from fresh vegetables, are still lacking. In this study, we identified five bla NDM -positive P. mirabilis and five bla NDM -positive generic E. coli concurrently from five fresh vegetables in two markets from China, and four of the five E. coli also carried mcr-1. The 10 isolates were characterized with methods including antimicrobial susceptibility testing, conjugation, whole-genome sequencing and phylogenetic analysis. All 10 isolates were multidrug-resistant (MDR). bla NDM-5 in five E. coli isolates and one P. mirabilis carrying bla NDM-5 was located on similarly transferable IncX3 plasmids, while transferably untypable plasmids were the carriers of bla NDM-1 in four P. mirabilis isolates from different types of vegetables/markets. mcr-1 in the four bla NDM - 5 -positive E. coli was located on similarly non-conjugative IncHI2 MDR plasmids lacking transfer region. Notably, IS CR1 complex class 1 integron capable of capturing bla NDM-1 was found on all untypable plasmids from P. mirabilis , and five copies of IS CR1 complex class 1 integron containing bla NDM-1 even occurred in one P. mirabilis , which showed high-level carbapenem resistance. Plasmid and phylogenetic analysis revealed that the bla NDM -positive P. mirabilis and E. coli from fresh vegetables might be derived from animals and transmitted to humans via the food chain. The concurrence of bla NDM -positive P. mirabilis and E. coli carrying both mcr-1 and bla NDM in different types of fresh vegetables eaten raw is alarming and threatens food safety. Sustained surveillance of these foodborne pathogens among fresh vegetables is urgent to ensure the health of food consumers. We report for the first time the concurrence of bla NDM -positive P. mirabilis and mcr-1 -bearing E. coli carrying bla NDM from the same fresh vegetables.

Objective: To investigate the ABC prognostic classification and the updated version of Model for End-stage Liver Disease (MELD) score 3.0 and Chinese Group on the Study of Severe Hepatitis B ACLF Ⅱ score (COSSH-ACLF Ⅱ score) to evaluate the prognostic value in acute-on-chronic liver failure (ACLF). Methods: ABC classification was performed on a 1 409 follow-up cohorts. The area under the receiver operating characteristic curve (AUROC) was used to analyze MELD, MELD 3.0, COSSH-Ⅱ and COSSH-Ⅱ score after 3 days of hospitalization (COSSH-Ⅱ-3d). The prognostic predictive ability of patients were evaluated for 360 days, and the prediction differences of different classifications and different etiologies on the prognosis of ACLF were compared. Results: The survival curve of 1 409 cases with ACLF showed that the difference between class A, B, and C was statistically significant, Log Rank (Mantel-Cox) χ 2 =80.133, P <0.01. Compared with class A and C, χ 2 =76.198, P <0.01, the difference between class B and C, was not statistically significant χ 2 =3.717, P >0.05. AUROC [95% confidence interval (CI)] analyzed MELD, MELD 3.0, COSSH-Ⅱ and COSSH-Ⅱ-3d were 0.644, 0.655, 0.817 and 0.839, respectively ( P <0.01). COSSH-Ⅱ had better prognostic predictive ability with class A ACLF and HBV-related ACLF (HBV-ACLF) for 360-days, and AUROC (95% CI) were 0.877 and 0.881, respectively ( P <0.01), while MELD 3.0 prognostic predictive value was not better than MELD. Conclusion: ACLF prognosis is closely related to ABC classification. COSSH-Ⅱ score has a high predictive value for the prognostic evaluation of class A ACLF and HBV-ACLF. COSSH-Ⅱ score has a better prognostic evaluation value after 3 days of hospitalization, suggesting that attention should be paid to the treatment of ACLF in the early stage of admission.

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a newly proposed definition of fatty liver disease (FLD) independent of excessive alcohol consumption (EAC) and hepatitis viral infection. Evidence on the mortality risk in different types of FLD [nonalcoholic FLD (NAFLD), alcoholic FLD (AFLD), and MAFLD] is sparse, hindering the identification of high-risk populations for preferential clinical surveillance., Methods: A total of 11,000 participants in the Third National Health and Nutrition Examination Survey were enrolled. Participants were categorized into three groups [FLD( - ), MAFLD( - ), and MAFLD( +)] according to FLD and MAFLD criteria, and further categorized into six groups by EAC. Multivariate Cox proportional hazard model was used to estimate the risk of all-cause, cardiovascular-related, and cancer-related mortality., Results: During a median follow-up of 23.2 years, a total of 3240 deaths were identified. Compared with FLD( - )/EAC( - ) participants, MAFLD( +) individuals had higher all-cause mortality risk [hazard ratio (HR) = 1.28, 95% confidence interval (CI) = 1.18-1.39] regardless of EAC status [MAFLD( +)/NAFLD: HR = 1.22, 95%CI = 1.11-1.34; MAFLD( +)/AFLD: HR = 1.83, 95%CI = 1.46-2.28], while not for MAFLD( - ) individuals. Furthermore, diabetes-driven-MAFLD had higher mortality risk (HR = 2.00, 95%CI = 1.77-2.27) followed by metabolic dysregulation-driven-MAFLD (HR = 1.30, 95%CI = 1.06-1.60) and overweight/obesity-driven-MAFLD (HR = 1.11, 95%CI = 1.00-1.22). Additionally, MAFLD( - ) participants with elevated fibrosis score were also associated with statistically significantly higher mortality risk (HR = 3.23, 95%CI = 1.63-6.40)., Conclusions: Utilizing a representative sample of the US population, we proved the validity of MAFLD subtype and fibrosis score, rather than the traditional definition (NAFLD and AFLD), in the risk stratification of FLD patients. These findings may be applied to guide the determination of surveillance options for FLD patients., (© 2022. Asian Pacific Association for the Study of the Liver.)

Background: Maternal smoking during pregnancy may be associated with low birth weight (LBW) in offspring and global risk estimates have not been summarized previously. We aimed to systematically explore evidence regarding maternal smoking and the LBW risk in offspring globally and examine possible causes of heterogeneity across relevant studies., Methods: Comprehensive search of PubMed, Ovid Embase, Ovid Medline (R), and Web of science from inception until October 2021 was carried out. A random-effects meta-analysis was used to estimate the pooled odds ratio (OR) and corresponding 95% confidence interval (CI). Restricted cubic spline analysis with three knots was used to further examine the dose-response relationship., Results: Literature searches yielded 4940 articles, of which 53 met inclusion criteria (comprising 55 independent studies). Maternal smoking during pregnancy was significantly associated with the risk of LBW in offspring (OR = 1.89, 95% CI = 1.80-1.98). Furthermore, an obvious dose-response relationship between the amount of cigarettes daily smoked in pregnancy and the risk of LBW in offspring was observed. The results of subgroup analyses indicated that the risk of maternal smoking on LBW was larger in more recently conducted studies (P = 0.020) and longer period of active smoking during pregnancy (P = 0.002). No evidence of publication bias was found., Conclusions: In summary, maternal smoking in pregnancy was significantly associated with a higher risk of LBW in offspring on a global scale. The risk of maternal smoking on infant LBW seems to be increasing over time, and was higher with longer smoking duration throughout pregnancy and more cigarettes smoked daily., (© 2022. Children's Hospital, Zhejiang University School of Medicine.)

The investigation of allosteric effects in biomolecular structures is of great current interest in diverse areas, from fundamental biological enquiry to drug discovery. Here we present ProteinLens, a user-friendly and interactive web application for the investigation of allosteric signalling based on atomistic graph-theoretical methods. Starting from the PDB file of a biomolecule (or a biomolecular complex) ProteinLens obtains an atomistic, energy-weighted graph description of the structure of the biomolecule, and subsequently provides a systematic analysis of allosteric signalling and communication across the structure using two computationally efficient methods: Markov Transients and bond-to-bond propensities. ProteinLens scores and ranks every bond and residue according to the speed and magnitude of the propagation of fluctuations emanating from any site of choice (e.g. the active site). The results are presented through statistical quantile scores visualised with interactive plots and adjustable 3D structure viewers, which can also be downloaded. ProteinLens thus allows the investigation of signalling in biomolecular structures of interest to aid the detection of allosteric sites and pathways. ProteinLens is implemented in Python/SQL and freely available to use at: www.proteinlens.io., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Objective: To investigate the clinical characteristics, incidence trend, underlying diseases, causative drug and prognosis of drug-induced liver injury (DILI), so as to provide basis for its prevention and treatment. Methods: A retrospective study was conducted on 2 820 DILI cases who were admitted to our hospital from January 2002 to December 2015, and their clinical characteristics, incidence trends, underlying related diseases, causative drug, treatment and outcome were analyzed. Results: Among 2 820 DILI cases, the ratio of male to female was 1:1.44, and the age was (44.00±16.32) years old. According to the clinical classification of DILI, there were 2 353 cases (83.43%) of hepatocyte injury, 353 cases (12.51%) of cholestatic type and 114 cases (4.04%) of mixed type. In the three clinical classification of DILI, there was no statistically significant difference in the ratio of male to female (χ(2) = 3.032, P > 0.05). However, the difference in the ratio of male to female between different age groups was statistically significant (χ(2) = 48.367, P < 0.001). Among the patients with liver disease and acute liver disease admitted to our hospital from January 2002 to December 2015, the proportion of DILI and acute DILI showed an overall upward trend. The main underlying related diseases of 2 820 DILI cases were fever (15.14%), skin diseases (11.84%), cardiovascular and cerebrovascular diseases (11.17%). Chinese herbal patent medicines (37.49%), antibiotics (15.85%), antipyretic-analgesics (14.37%), and so on were the main causative drugs involved, and the prognostic differences among the three clinical classifications of DILI in terms of cure, improvement, ineffectiveness, and death were statistically significant ( H = 61.300, P < 0.001). Conclusion: In recent years, among the patients with liver disease in our hospital, the proportion of DILI has shown an obvious upward trend, involving a variety of underlying diseases and causative drugs, and thus it needs clinical attention.

Twenty-four patients with cold, dampness, obstructive ankylosing spondylitis were treated with sulfasalazine and sulfasalazine in combination with moxibustion for 3 weeks. The results showed that the combined treatment of traditional Chinese and western medicine was significantly higher than those of western medicine treatment, meanwhile, the scoreofsymptoms quantification, C-reactive protein and erythrocyte sedimentation rate of the integrated Chinese and western medicine treatment were significantly lower than those of western medicine treatment, and the level of physical signs was significantly higher than that of western medicine treatment, and there were no significant differences in adverse reactions. Moxibustion combined with sulfasalazine in the treatment of cold and damp obstructive ankylosing spondylitis can effectively improve the characteristics of the body, relieve pain symptoms and improve the prognosis.

The study explores the application of Tanreqing Injection into brain components in brain diseases. The components of Tanreqing Injection and its existing components in rat cerebrospinal fluid were qualitatively analyzed by liquid chromatography-mass spectrometry(LC-MS). The possible mechanism of action of Tanreqing Injection into brain on brain diseases was predicted by network pharmacological theory. In this study, 17 brain-entry components of Tanreqing Injection were founded, and 222 core targets were obtained from network pharmacological results. The biological processes include 31 items such as negative regulation of apoptotic process, MAPK cascade, Ras protein signal transduction, and 22 items such as PI3 K-Akt signal transduction, MAPK signal transduction and neurotrophic factor signal transduction. Nine brain diseases including stroke, migraine and meningioma were screened out by predicting the effect of Tanreqing Injection on brain components, which provide ideas and directions for further study of a certain encephalopathy and lay a theoretical foundation for further revealing its molecular mechanism.

Background: The concurrence of mcr and carbapenemase genes among Enterobacteriaceae has been a great clinical concern. In our study, we aimed to investigate the prevalence of mcr -positive carbapenem-resistant Enterobacteriaceae (CRE) in fresh vegetables and shed light on the possibility of transmission of mcr -positive CRE via fresh vegetables., Methods: In this study, 712 fresh vegetable samples from 10 provinces in China were collected between May 2017 and Dec 2018 and were screened for mcr and carbapenemase genes. Antibiotic susceptibilities for isolates co-harboring carbapenemase genes and mcr were determined by an agar dilution or a broth microdilution method. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) analysis were also performed. Transferability of the carbapenemase/ mcr -bearing plasmids was determined by conjugation, replicon typing and S1-PFGE-Southern blotting. The sequences of these plasmids were analyzed by using whole-genome sequencing with Illumina Hiseq platform., Results: Two E. coli isolates concomitantly carrying mcr-1 and bla NDM-5/9 from leaf rape and spinach, respectively, were found and both isolates showed multidrug resistance. Notably, mcr-1 -positive 690 harboring bla NDM-5 and 701 carrying bla NDM-9 belonged to ST156 and ST2847, respectively, similar to the prevalent MLST types of E. coli co-carrying mcr-1 and bla NDM from avian in our previous study. mcr-1 was on ~33-kb IncX4 plasmid or ~60-kb IncI2 plasmid, while bla NDM-5/9 was on ~46-kb IncX3 plasmid or ~120-kb untypable plasmid. The plasmids were highly similar to those from animals and clinical patients reported in various countries. Conclusion: E. coli isolates concomitantly carrying mcr-1 and bla NDM-5/9 in fresh vegetables may serve as a direct source of pathogens in humans, and such discovery in fresh vegetables emphasizes the importance of prompt surveillance and intervention in limiting the spread of E. coli co-carrying bla NDM and mcr-1 . To our knowledge, this is the first report of Enterobacteriaceae co-carrying bla NDM and mcr-1 in fresh vegetables., Competing Interests: The authors report no conflicts of interest in this work., (© 2019 Liu and Song.)

Background: Despite its high contagiousness, high recurrence rate and potential for malignant transformation, effective treatments for condyloma acuminatum (CA) have not yet been developed. Accordingly, it is necessary to clarify the mechanisms underlying CA development., Aim: To investigate the expression and significance of the proteins Wnt-1 and TSLC1 in patients with CA and in normal foreskin controls., Methods: Wnt-1 and TSLC1 were assessed by immunohistochemistry in 45 patients with CA., Results: Positive expression rates of Wnt-1 and TSLC1 were 82.22% (37/45) and 37.78% (17/45), respectively, in CA tissues, and 29.17% (7/24) and 91.67% (22/24), respectively, in normal foreskin controls. Wnt-1 expression intensity in CA was markedly higher (positive to strongly positive) than that in normal controls (negative to weakly positive), whereas TSLC1 expression intensity ranged from weakly positive to positive in CA, and nearly strongly positive in the normal control group. The differences in the positive expression rate and expression intensity of Wnt-1 and TSLC1 between the two groups were statistically significant (P < 0.05). In addition, Wnt-1 and TSLC1 were negatively correlated. (r = -0.336, P < 0.05)., Conclusions: Overexpression of Wnt-1 and low expression of TSLC1 may be associated with the growth of CA. These findings may provide a basis for the development of therapies to prevent recurrence or malignant transformation of CA., (© 2019 British Association of Dermatologists.)

The presence of mobilized colistin resistance (mcr) genes is a global concern. However, data concerning mcr in fresh vegetables, a reservoir for antibiotic resistance genes, are still rare. In this study, mcr genes were analysed in 528 vegetable samples from 53 supermarkets or farmer's markets in 23 cities of 9 provinces in China, and the mcr-positive Enterobacteriaceae were characterized. Nineteen (3.6%) samples carried one or more mcr-positive isolates, and the highest three detection rates were found in carrot, pak choi and green pepper. Twenty-four mcr-1-positive isolates (23 Escherichia coli and one Enterobacter cloacae) were obtained, and E. coli isolates showed high genetic diversity. Different multilocus sequence type (MLST) isolates were also observed within the same sample. All 24 isolates showed multidrug resistance, and 14 carried bla CTX-M genes. Most isolates harbored similarly conjugative IncX4-type (∼33 kb) or IncI2-type (∼60 kb) mcr-1-bearing plasmids. The sequenced prevalent IncX4 plasmid and IncI2 plasmid from tomato were similar to the relevant plasmids from animals and clinical isolates in various countries. mcr-1-bearing IncHI2/ST3 plasmid highly similar to that carrying 14 resistance genes from E. coli of chicken was also observed. In conclusion, a high prevalence of mcr-1 in fresh vegetables was found in China, and the dissemination of mcr-1 was mediated by similar IncX4 or IncI2 plasmids. The plasmids from vegetables showed high similarity to plasmids from clinical isolates, indicating MCR-1-producers in ready-to-eat vegetables may pose a huge threat to public health and measures need to be taken to ensure food safety., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: To investigate the potential application values of screening on breast cancer, using the single-nucleotide polymorphisms (SNPs) that were identified from the genome- wide association studies (GWASs). Methods: Two million Chinese women aged 35-69 years were simulated, based on both age distributions, age-specific incidence rates of breast cancer and the distribution of known risk factors, in 2013. Twenty-three SNPs identified from GWAS were further simulated. Both genetic-related risks explained by each SNPs and the improvement on the risks under reclassification, were used to select SNPs for the prediction on breast cancer among the targeted high-risk population. Further analyses were conducted to investigate the following items as: improvements on detection rates of breast cancer among the high-risk populations, areas under the curve (AUC) and the odds ratio ( OR ) among women at high risk. Results: A total of 12 SNPs were eligible for targeting the high-risk population of breast cancer. When high-risk populations were defined as women whose predicted risks were higher than the 95(th) predicted risk of the whole population, the detection rate (146.99/100 000) among high-risked women predicted by 12 SNPs would be significantly lower than 177.46/100 000, which was predicted by the known risk factors ( P <0.001), among the high-risked women. Among those women at high risk, the detection rate (229.00/100 000) predicted by integrating known risk factors and 12 SNPs was significantly higher than that predicted by known risk factors ( P <0.001). Also, the AUC increased from 64.4% to 67.8% ( P <0.001), and the OR of increased from 3.32 to 4.33, predicted by integrating known risk factors and 12 SNPs, for women at high risk on breast cancer. Conclusion: Targeted SNPs that were identified from genome- wide association studies could be used to improve the detection rates as well as the overall accuracy of risk prediction so as to identify the potential high-risk women on breast cancer before carrying on the screening program.

Objective: To investigate the anti-neuroinflammation effect of extract of Fructus Schisandrae chinensis (EFSC) on lipopolysaccharide (LPS)-induced BV-2 cells and the possible involved mechanisms., Methods: Primary cortical neurons were isolated from embryonic (E17-18) cortices of Institute of Cancer Research (ICR) mouse fetuses. Primary microglia and astroglia were isolated from the frontal cortices of newborn ICR mouse. Different cells were cultured in specific culture medium. Cells were divided into 5 groups: control group, LPS group (treated with 1 μg/mL LPS only) and EFSC groups (treated with 1 μg/mL LPS and 100, 200 or 400 mg/mL EFSC, respectively). The effect of EFSC on cells viability was tested by methylthiazolyldiphenyltetrazolium bromide (MTT) colorimetric assay. EFSC-mediated inhibition of LPS-induced production of pro-inflammatory mediators, such as nitrite oxide (NO) and interleukin-6 (IL-6) were quantified and neuron-protection effect against microglia-mediated inflammation injury was tested by hoechst 33258 apoptosis assay and crystal violet staining assay. The expression of pro-inflammatory marker proteins was evaluated by Western blot analysis or immunofluorescence., Results: EFSC (200 and 400 mg/mL) reduced NO, IL-6, inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expression in LPS-induced BV-2 cells (P<0.01 or P<0.05). EFSC (200 and 400 mg/mL) reduced the expression of NO in LPS-induced primary microglia and astroglia (P<0.01). In addition, EFSC alleviated cell apoptosis and inflammation injury in neurons exposed to microglia-conditioned medium (P<0.01). The mechanistic studies indicated EFSC could suppress nuclear factor (NF)-?B phosphorylation and its nuclear translocation (P<0.01). The anti-inflammatory effect of EFSC occurred through suppressed activation of mitogen-activated protein kinase (MAPK) pathway (P<0.01 or P<0.05)., Conclusion: EFSC acted as an anti-inflammatory agent in LPS-induced glia cells. These effects might be realized through blocking of NF-κB activity and inhibition of MAPK signaling pathways.

The emergence and spread of multidrug resistance (MDR) plasmids carrying the colistin resistance gene mcr-1 has become a major public health concern. However, there is a paucity of data regarding the prevalence of mcr-1 plasmids concomitantly carrying bla CTX-M and oqxAB, an efflux pump that confers resistance to multiple agents. In this study, we determined the prevalence and characteristics of plasmids coharboring mcr-1, oqxAB, and bla CTX-M as well as those harboring oqxAB and bla CTX-M in Escherichia coli from food-producing animals. We isolated 493 E. coli strains, and mcr-1, bla NDM , and bla CTX-M were present in 140 (28.4%), 51 (10.3%), and 195 (39.6%) of the isolates, respectively. The two most prevalent plasmid-mediated quinolone resistance genes were oqxAB (34.5%) and qnrS (29.4%). Nine IncHI2/ST3 plasmids co-carrying mcr-1, oqxAB, and bla CTX-M were found, and similar IncHI2/ST3 plasmids mediated dissemination of these resistance genes. Two sequenced MDR IncHI2/ST3 plasmids coharboring mcr-1, oqxAB, and bla CTX-M showed high similarity to reference plasmid pHNSHP45-2, although they were from different regions in China. Colocalization of oqxAB and bla CTX-M on the same plasmid was found in 28 isolates, including the nine plasmids harboring mcr-1. The co-dissemination of oqxAB and bla CTX-M was mediated by diverse F33:A-:B- plasmids and similar IncHI2/ST3 plasmids. Pulsed-field gel electrophoresis and multilocus sequence typing analysis of donor isolates revealed heterogeneous patterns indicating that clonal dissemination was unlikely. The high incidence of similar IncHI2/ST3 plasmids simultaneously possessing mcr-1, oqxAB, and bla CTX-M poses a great threat to public health.

Vegetables harboring bacteria resistant to antibiotics are a growing food safety issue. However, data concerning carbapenem-resistant Enterobacteriaceae (CRE) in ready-to-eat fresh vegetables is still rare. In this study, 411 vegetable samples from 36 supermarkets or farmer's markets in 18 cities in China, were analyzed for CRE. Carbapenemase-encoding genes and other resistance genes were analyzed among the CRE isolates. Plasmids carrying carbapenemase genes were studied by conjugation, replicon typing, S1-PFGE southern blot, restriction fragment length polymorphism (RFLP), and sequencing. CRE isolates were also analyzed by pulsed-field gel electrophoresis (PFGE). Ten vegetable samples yielded one or more CRE isolates. The highest detection rate of CRE (14.3%, 4/28) was found in curly endive. Twelve CRE isolates were obtained and all showed multidrug resistance: Escherichia coli , 5; Citrobacter freundii , 5; and Klebsiella pneumoniae , 2. All E. coli and C. freundii carried bla NDM , while K. pneumoniae harbored bla KPC-2 . Notably, E. coli with bla NDM and ST23 hypervirulent Klebsiella pneumoniae (hvKP) carrying bla KPC-2 were found in the same cucumber sample and clonal spread of E. coli, C. freundii , and K. pneumoniae isolates were all observed between vegetable types and/or cities. IncX3 plasmids carrying bla NDM from E. coli and C. freundii showed identical or highly similar RFLP patterns, and the sequenced IncX3 plasmid from cucumber was also identical or highly similar (99%) to the IncX3 plasmids from clinical patients reported in other countries, while bla KPC-2 in K. pneumoniae was mediated by similar F35:A-:B1 plasmids. Our results suggest that both clonal expansion and horizontal transmission of IncX3- or F35:A-:B1-type plasmids may mediate the spread of CRE in ready-to-eat vegetables in China. The presence of CRE in ready-to-eat vegetables is alarming and constitutes a food safety issue. To our knowledge, this is the first report of either the C. freundii carrying bla NDM , or K. pneumoniae harboring bla KPC-2 in vegetables. This is also the first report of ST23 carbapenem-resistant hvKP strain in vegetables.

This paper aimed to explore the molecular mechanism of Xingnaojing injection and its scientific connotation of compatibility mechanism from a new perspective on bioinformatics and network biology. Based on the analysis function of intergrative pharmacology platform V1.0, the compatibility mechanism of this prescription was investigated by constructing the herbs-compounds-targets network. Seven hundreds and ninety-five targets from the prescription were screened out, then 302 hub nodes were included in drug targets-disease targets network. Enrichment analysis showed that it was related to MAPK cascade, negative/positive regulation of apoptotic process and other biological functions as well as PI3K/AKT, neurotrophin and other signal pathways. The target functions of different drugs were similar, complementing each other, and belonging to the common signaling pathway with asynergistic effect. Based on analysis of core components-key targets-main pathway network, among totally 25 core components and 29 key targets, musk had 15 and 25 respectively.SLC1A2, AR, PGR, CAT, NMDA receptors and other targets were associated with cerebral infarction. Musk, gardenia and borneol compatibility can play a bidirectional regulation of apoptosis; musk and gardenia showed synergistic effect on Ras signaling pathway, indicating that musk was the main ingredient of the injection and the other three drugs played the role of assistance. This study could not only provide the bioinformatics support in compatibility mechanism of Xingnaojing injection, but also provide theoretical support for its formula rationality., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Chinese Pharmaceutical Association.)

The shortage of molecular information for taxol-producing fungi has greatly impeded the understanding of fungal taxol biosynthesis mechanism. In this study, the transcriptome of one taxol-producing endophytic fungus Cladosporium cladosporioides MD2 was sequenced for the first time. About 1.77 Gbp clean reads were generated and further assembled into 16,603 unigenes with an average length of 1110 bp. All of the unigenes were annotated against seven public databases to present the transcriptome characteristics of C. cladosporioides MD2. A total of 12,479 unigenes could be annotated with at least one database, and 1593 unigenes could be annotated in all queried databases. In total, 8425 and 3350 unigenes were categorized into 57 GO functional groups and 262 KEGG pathways, respectively, exhibiting the dominant GO terms and metabolic pathways in the C. cladosporioides MD2 transcriptome. One potential and partial taxol biosynthetic pathway was speculated including 9 unigenes related to terpenoid backbone biosynthesis and 40 unigenes involved in the biosynthetic steps from geranylgeranyl diphosphate to 10-deacetylbaccatin III. These results provided valuable information for the molecular mechanism research of taxol biosynthesis in C. cladosporioides MD2.

Objective: To investigate the relationship between tissue distributions of modified Wuzi Yanzong prescription (, MWP) in rats and meridian tropism theory., Methods: A high-performance liquid chromatography with Fourier transform-mass spectrometry (HPLC-FT) method was used to identify the metabolites of MWP in different tissues of rats after continued oral administration of MWP for 7 days. The relationship between MWP and meridian tropism theory was studied according to the tissue distributions of the metabolites of MWP in rats and the relevant literature., Results: Nineteen metabolites, mainly flavanoid compounds, were detected in the different rat tissues and classified to each herb in MWP. Further, it was able to establish that the tissue distributions of the metabolites of MWP were consistent with the descriptions of meridian tropism of MWP available in literature, this result might be useful in clarifying the mechanism of MWP on meridian tropism. In the long run, these data might provide scientific evidence of the meridian tropism theory to further promote the reasonable, effective utilization, and modernization of Chinese medicine., Conclusion: The tissue distributions of MWP in vivo were consistent with the descriptions of meridian tropism of MWP.

Objectives: The aim of this study was to investigate the differences in main characteristics, reporting and methodological quality between prospectively registered and nonregistered systematic reviews., Study Design and Setting: PubMed was searched to identify systematic reviews of randomized controlled trials published in 2015 in English. After title and abstract screening, potentially relevant reviews were divided into three groups: registered non-Cochrane reviews, Cochrane reviews, and nonregistered reviews. For each group, random number tables were generated in Microsoft Excel, and the first 50 eligible studies from each group were randomly selected. Data of interest from systematic reviews were extracted. Regression analyses were conducted to explore the association between total Revised Assessment of Multiple Systematic Review (R-AMSTAR) or Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) scores and the selected characteristics of systematic reviews., Results: The conducting and reporting of literature search in registered reviews were superior to nonregistered reviews. Differences in 9 of the 11 R-AMSTAR items were statistically significant between registered and nonregistered reviews. The total R-AMSTAR score of registered reviews was higher than nonregistered reviews [mean difference (MD) = 4.82, 95% confidence interval (CI): 3.70, 5.94]. Sensitivity analysis by excluding the registration-related item presented similar result (MD = 4.34, 95% CI: 3.28, 5.40). Total PRISMA scores of registered reviews were significantly higher than nonregistered reviews (all reviews: MD = 1.47, 95% CI: 0.64-2.30; non-Cochrane reviews: MD = 1.49, 95% CI: 0.56-2.42). However, the difference in the total PRISMA score was no longer statistically significant after excluding the item related to registration (item 5). Regression analyses showed similar results., Conclusion: Prospective registration may at least indirectly improve the overall methodological quality of systematic reviews, although its impact on the overall reporting quality was not significant., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Screening has been always considered as a double-edged sword. Cancer screening could save lives in some cases, however, in other cases, it might also turn people into overdiagnosis. Overdiagnosis is the diagnosis of cancer that will never cause symptoms or death during a patient's lifetime. Therefore, overdiagnosis might lead to unnecessary treatments and lifetime surveillance, and then increase economic burden and psychological burden. In this review, we focus on how to correctly evaluate the overdiagnosis rate, and how to avoid or reduce the harms caused by overdiagnosis in the future according to the reasons associated with overdiagnosis. After systematically reviewing the previous studies, we will try to identify the potential reasons associated with overdiagnosis in breast cancer screening with mammography, address how to correctly evaluate the overdiagnosis rate, and finally provide some suggestions to reduce the overdiagnosis.

In this study, the inhibitory effect and mechanism of rifampicin on the activity of tyrosinase were investigated for developing a novel tyrosinase inhibitor. It was found to have a significant inhibition on the activity of tyrosinase (IC 50 =90±0.6μM). From the kinetics analysis, it was proved to be a reversible and noncompetitive type inhibitor of the enzyme with the K I value of 94±3.5μM. The results obtained from intrinsic fluorescence quenching indicated that rifampicin could interact with tyrosinase. In particular, the drastic decrease of fluorescence intensity was due to the formation of a rifampicin-enzyme complex in a static procedure which was mainly driven by hydrophobic forces and hydrogen bonding. Moreover, the ANS-binding fluorescence analysis suggested that rifampicin binding to tyrosinase changed the polarity of the hydrophobic regions. Molecular docking analysis further revealed that the hydrogen bonds were generated between rifampicin and amino residues Leu7, Ser52, and Glu107 in the B chain of the enzyme. And the hydrophobic forces produced through the interaction of rifampicin with B chain residues Pro9, Pro14, and Trp106. This work identified a novel tyrosinase inhibitor and potentially contributed to the usage of rifampicin as a potential hyperpigmentation drug., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study investigated the characteristics of Escherichia coli isolates carrying mcr-1-bla NDM from a chicken farm in China. Of the 78 E. coli isolates, 21 clonally unrelated isolates carried mcr-1-bla NDM Diverse IncI2 plasmids disseminated mcr-1 , while the dissemination of bla NDM was mediated by diverse IncB/O plasmids. More striking was the colocalization of resistance genes mcr-1 and bla NDM-4 in an IncHI2/ST3 plasmid, which might pose a great challenge for public health., (Copyright © 2017 American Society for Microbiology.)

We report the presence of mcr-1 in Escherichia coli and carbapenem-resistant Cronobacter sakazakii from the same diseased chicken. The mcr-1 gene linked with ISApl1 was located on two different IncI2 plasmids, including one multidrug plasmid in E. coli, whereas fosA3-bla NDM-9 was on an IncB/O plasmid in C. sakazakii The development of the fosA3-bla NDM-9 resistance region was mediated by IS26 The colocation of mcr-1 or bla NDM-9 with other resistance genes will accelerate the dissemination of the two genes., (Copyright © 2017 American Society for Microbiology.)

Modified Wu-Zi-Yan-Zong prescription (MWP), a traditional Chinese medicinal decoction, has possessed the neuroprotective and anti-inflammatory properties. The mechanisms associated with these properties, however, are not completely understood. We designed the experiments to elucidate the antineuroinflammatory property of MWP in BV2 microglia activated by β -amyloid (A β ), which is a characteristic feature of Alzheimer's disease (AD). The composition of MWP was studied using HPLC. BV2 microglia cells were then treated with A β in the presence or absence of MWP. The effects of MWP treatment on A β -activated neuroinflammation were determined using PCR, western blotting, and immunofluorescence staining. MWP significantly inhibited the mRNA expression of inflammatory mediators such as IL-1 β , IL-6, TNF- α , and MCP-1, as well as the expression of inducible nitric oxide synthase (iNOS) in A β -activated BV2 microglia. MWP also inhibited the nuclear translocation and signaling pathway of nuclear factor kappa B (NF- κ B) by suppressing inhibitor of nuclear factor- κ B (I κ B) degradation and downregulating I κ B kinase β (IKK β ) phosphorylation. Moreover, MWP decreased extracellular regulated protein kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) phosphorylation, which is an important signaling pathway for proinflammatory gene expression. We concluded that MWP could suppress neuroinflammatory responses in A β -activated BV2 microglia via the NF- κ B and ERK/p38 MAPK signaling cascades and could prove an effective therapeutic agent for the prevention and treatment of neuroinflammatory diseases such as AD.

Cohort evidence that links long-term exposures to air pollution and mortality comes largely from the United States and European countries. We investigated the relationship between long-term exposures to particulate matter <10μm in diameter (PM10), nitrogen dioxide (NO2), and sulfur dioxide (SO2) and mortality of lung cancer in Northern China. A cohort of 39,054 participants were followed during 1998-2009. Annual average concentrations for PM10, NO2, and SO2 were determined based on data collected from central monitoring stations. Lung cancer deaths (n=140) were obtained from death certificates, and hazard ratios (HRs) were estimated using Cox proportional hazards models, adjusting for age, gender, BMI, education, marital status, smoking status, passive smoking, occupation, alcohol consumption, etc. Each 10mg/m(3) increase in PM10 concentrations was associated with a 3.4%-6.0% increase in lung cancer mortality in the time-varying exposure model and a 4.0%-13.6% increase in the baseline exposure model. In multi-pollutant models, the magnitude of associations was attenuated, most strongly for PM10. The association was different in men and women, also varying across age categories and different smoking status. Substantial differences exist in the risk estimates for participants based on assignment method for air pollution exposure., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This work aims to evaluate the anti-neuroinflammatory effects of natural sesquiterpene dimer caruifolin D from Artemisia absinthium L., which is an edible vegetable or traditional medicinal food in East Asia due to its sedation, anti-asthma and antipruritic effects. In this study, we reported that caruifolin D significantly inhibited the productions of various neuroinflammatory mediators from microglia in response to bacterial lipopolysaccharide stimulation. Moreover, anti-inflammatory mechanism study showed that caruifolin D markedly suppressed the production of intracellular reactive oxygen species, which was an important player involved in neuroinflammation, leading to inhibitory effects on the activations of protein kinase C (PKC) and c-Jun N-terminal kinase (JNK), which were two major neuroinflammatory signaling pathways in the brains. Furthermore, caruifolin D protected neurons against microglia-mediated neuronal inflammatory damages by up-regulating neuronal viability and maintaining healthy neuronal morphology. Taken together, these results expanded our knowledge about the anti-neuroinflammatory and neuroprotective mechanism of Artemisia absinthium L., and also suggested that caruifolin D was a major anti-inflammatory component from Artemisia absinthium L., which might be developed as a drug candidate for neuroinflammation-related diseases., (Copyright © 2015 Elsevier B.V. All rights reserved.)

TNF receptor-associated factor 6 (TRAF6) is a key hub protein involved in Toll-like receptor-dependent inflammatory signaling pathway, and it recruits additional proteins to form multiprotein complexes capable of activating downstream NF-κB inflammatory signaling pathway. Ubiquitin-proteasome system (UPS) plays a crucial role in various protein degradations, such as TRAF6, leading to inhibitory effects on inflammatory response and immunologic function. However, whether ubiquitination-dependent TRAF6 degradation can be used as a novel anti-inflammatory drug target still remains to be explored. FMHM, a bioactive natural small molecule compound extracted from Chinese herbal medicine Radix Polygalae, suppressed acute inflammatory response by targeting ubiquitin protein and inducing UPS-dependent TRAF6 degradation mechanism. It was found that FMHM targeted ubiquitin protein via Lys48 site directly induced Lys48 residue-linked polyubiquitination. This promoted Lys48 residue-linked polyubiquitin chain formation on TRAF6, resulting in increased TRAF6 degradation via UPS and inactivation of downstream NF-κB inflammatory pathway. Consequently, FMHM down-regulated inflammatory mediator levels in circulation, protected multiple organs against inflammatory injury in vivo, and prolong the survival of endotoxemia mouse models. Therefore, FMHM can serve as a novel lead compound for the development of TRAF6 scavenging agent via ubiquitination-dependent mode, which represents a promising strategy for treating inflammatory diseases.

Stalk rots are destructive diseases in maize around the world, and are most often caused by the pathogen Pythium, Fusarium and other fungi. The most efficient management for controlling stalk rots is to breed resistant cultivars. Pythium stalk rot can cause serious yield loss on maize, and to find the resistance genes from the existing germplasm is the basis to develop Pythium-resistance hybrid lines. In this study, we investigated the genetic resistance to Pythium stalk rot in inbred line Qi319 using F2 and F2:3 population, and found that the resistance to Pythium inflatum in Qi319 was conferred by two independently inherited dominant genes, RpiQI319-1 and RpiQI319-2. Linkage analysis uncovered that the RpiQI319-1 co-segregated with markers bnlg1203, and bnlg2057 on chromosome 1, and that the RpiQI319-2 locus co-segregated with markers umc2069 and bnlg1716 on chromosome 10. The RpiQI319-1 locus was further mapped into a ~500-kb interval flanked by markers SSRZ33 and SSRZ47. These results will facilitate marker-assisted selection of Pythium stalk rot-resistant cultivars in maize breeding. To our knowledge, this is the first report on the resistance to P. inflatum in the inbred line Qi319, and is also the first description of two independently inherited dominant genes conferring the resistance of Pythium stalk rot in maize.

Objective of the study was to investigate the expression and significance of XIAP and c-jun in Condyloma acuminatum. The immunohistochemistry SABC method was adopted to detect the expression of XIAP and c-jun in Condyloma acuminatum. The positive expression rate of XIAP and c-jun in Condyloma acuminatum was 80% (32/40) and 90% (36/40) separately and the intensity of expression was usually ++ ~ +++. While in control group, the positive expression rate of XIAP and c-jun was 27.8% (5/18) and 16.7 % (3/18) separately, and the intensity of expression was - ~ ++. There was statistical significance of the positive expression rate and the expression intensity of XIAP and c-jun between the two groups (P<0.05). Besides, the positive correlation existed between expression of XIAP and c-jun (r=0.306 P<0.01). The over-expression of XIAP and c-jun in Condyloma acuminatum may be associated with the growth of Condyloma acuminatum.

MC13 is a novel coumarin compound found in Murraya, an economic crop whose leaves are widely used as condiment (curry) in cuisine. The aims of the present study were to investigate the neuroprotective effects of MC13 on microglia-mediated inflammatory injury model as well as potential molecular mechanism. Cell viability and apoptosis assay demonstrated that MC13 was not toxic to neurons and significantly protected neurons from microglia-mediated inflammatory injury upon lipopolysaccharide (LPS) stimulation. Results showed that MC13 markedly inhibited LPS-induced production of various inflammatory mediators, including nitrite oxide (Griess method), TNF-α and IL-6 (ELISA assay) in a concentration-dependent manner. Mechanism study showed that MC13 could suppress the activation of NF-κB, which was the central regulator for inflammatory response, and also decreased the interaction of TGF-β-activated kinase 1 (TAK1)-binding protein (TAB2) with TAK1 and TNF receptor associated factor (TRAF6), leading to the decreased phosphorylation levels of NF-κB upstream regulators such as IκB and IκB kinase (IKK). MC13 also significantly down-regulated the phosphorylation levels of ERK and p38 MAPKs, which played key roles in microglia-mediated inflammatory response. Furthermore, MC13 inhibited Jak2-dependent Stat1/3 signaling pathway activation by blocking Jak2 phosphorylation, Stat1/3 phosphorylation, and nuclear translocation. Taken together, our results demonstrated that MC13 protected neurons from microglia-mediated neuroinflammatory injury by inhibiting TRAF6-TAK1-NF-κB, p38/ERK MAPKs, and Jak2-Stat1/3 pathways. Finally, MC13 might interact with LPS and interfere LPS-binding to cell membrane surface. These findings suggested that coumarin might act as a potential medicinal agent for treating neuroinflammation as well as inflammation-related neurodegenerative diseases., (© 2015 Wiley Periodicals, Inc.)

[To explore the effect of Humifuse Euphorbia Herb ( HEH) on alleviating insulin resistance in type 2 diabetic KK-Ay mice. Totally 40 KK-Ay mice fed with high-fat diet were divided into four groups: the metformin group, the model group, the HEH low-dose group and the HEH high-dose group, and orally administrated with metformin hydrochloride (250 mg x kg(-1)), distilled water, humifuse euphorbia herb 1 g x kg(-1) and 2 g x kg(-1). Besides, C57BL/6J mice with ordinary feed were taken as the normal control group and orally administrated with equal distilled water. The oral administration for the five groups lasted for eight weeks. Before and after the experiment, weight, fasting glucose and insulin tolerance were determined. The morphological changes in pancreas were observed through hematoxylin-eosin (HE) staining on pancreatic tissue sections. The serum insulin, TNF-α, IL-6, adiponectin (ADPN) and leptin (LEP) were detected by ELISA. The results showed that HEH could reduce weight and fasting glucose in KK-Ay mice, alleviate hyperinsulinemia, reduce blood glucose-time AUC, increase 30-min blood glucose decline rate, relieve insulin resistance, significantly ameliorate the pathomorphological changes in pancreas in each group, decrease serum TNF-α, IL-6 and leptin levels in KK-Ay mice and rise serum ADPN level. This study proved that humifuse euphorbia herb can ameliorate the insulin resistance in KK-Ay mice, and its mechanism may be related to the effect on inflammatory factors and adipocytokines.

Protosappanin B (PTB) is a bioactive dibenzoxocin derivative isolated from Caesalpinia sappan L. Here, we investigated the neuroprotective effects and the potential mechanisms of PTB on oxygen-glucose deprivation (OGD)-injured PC12 cells. Results showed that PTB significantly increased cell viability, inhibited cell apoptosis and up-regulated the expression of growth-associated protein 43 (a marker of neural outgrowth). Moreover, our study revealed that PTB effectively maintained mitochondrial homeostasis by up-regulation of mitochondrial membrane potential (MMP), inhibition of cytochrome c release from mitochondria and inactivation of mitochondrial caspase-9/3 apoptosis pathway. Further study showed that PTB significantly promoted cytoplasmic component degradation of p53 protein, a key negative regulator for mitochondrial function, resulting in a release of Bcl-2 from p53-Bcl-2 complex and an enhancing translocation of Bcl-2 to mitochondrial outer membrane. Finally, we found the degradation of p53 protein was induced by PTB via activation of a MDM2-dependent ubiquitination process. Taken together, our findings provided a new viewpoint of neuronal protection strategy for anoxia and ischemic injury with natural small molecular dibenzoxocin derivative by activating ubiquitin-dependent p53 protein degradation as well as increasing mitochondrial function., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Caesalpinia sappan L. (Lignum Sappan) is a Chinese medicinal plant for treating ischemic cerebral apoplexy. Deoxysappanone B (DSB), a homoisoflavone compound isolated from C. sappan L. (Lignum Sappan), was studied for anti-neuroinflammatory and neuroprotective properties using lipopolysaccharide (LPS)-induced BV-2 microglia neuroinflammation model and LPS-induced microglia-neuron co-culture system. Our findings showed that DSB effectively inhibited BV-2 microglia-mediated neuroinflammatory mediators׳ release including NO, PGE₂, TNF-α, IL-6 and reactive oxygen species. Moreover, DSB markedly protected neurons against inflammatory microglia-mediated neurotoxicity in a microglia-neuron co-culture system. Mechanism study revealed that DSB blocked two major neuroinflammation-related signaling pathways including IKK-IκB-nuclear factor kappaB (NF-κB) and p38/ERK mitogen-activated protein kinase (MAPK) cascades, further leading to the inhibition of neuroinflammatory mediators׳ production. The present study provides evidence that the anti-neuroinflammatory and neuroprotective effect of DSB are due to the suppression of neuroinflammatory mediators׳ production as well as inflammation-induced neurotoxicity through regulation of multi-targets. Therefore, DSB may serve as a neuroprotective agent for the treatment of neuroinflammatory disorders and inflammation-related neuronal injury., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Based on a digital micromirror device (DMD) processor as the multi-wavelength narrow-band tunable filter, we demonstrate a multi-port tunable fiber laser through experiments. The key property of this laser is that any lasing wavelength channel from any arbitrary output port can be switched independently over the whole C-band, which is only driven by single DMD chip flexibly. All outputs display an excellent tuning capacity and high consistency in the whole C-band with a 0.02 nm linewidth, 0.055 nm wavelength tuning step, and side-mode suppression ratio greater than 60 dB. Due to the automatic power control and polarization design, the power uniformity of output lasers is less than 0.008 dB and the wavelength fluctuation is below 0.02 nm within 2 h at room temperature.

As angiogenesis is an important target for antitumour drugs, the agents that inhibit angiogenesis may help reduce the use of chemotherapy by blocking tumour blood supply. In this study, we investigated a potent angiogenesis inhibitor, ASC, a steroidal saponin compound, which has been purified from Ophitopogin japonicus (L.f) Ker.-Gawl. Our observations showed that ASC significantly suppressed human umbilical vein endothelial cell (HUVECs) growth both in vitro and in vivo. This may be resulted from the G2/M cell cycle arrest effects of ASC. Moreover, ASC inhibited HUVECs invasion and tube formation processes, which were associated with endothelial cells remodelling. A mechanism study indicated that ASC down-regulated the expression of Src tyrosine kinase, further leading to the blockage of Akt-dependent matrix metalloproteinases (mainly for MMP-9) signalling pathway, which was functionally associated with angiogenic blood vessels. Finally, ASC significantly inhibited angiogenesis and MMPs/VEGF expression in the subcutaneously injected matrigel in C57/BL mice. These findings suggest that ASC might be a potential drug candidate in anti-angiogenesis and anticancer therapies., (© 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

As an efficient method for inducing tumor cell apoptosis, ROS can be constantly formed and accumulated in NADPH oxidase overactivated-cells, resulting in further mitochondrial membrane damage and mitochondria-dependent apoptosis. In addition, JNK mitogen-activated protein kinase (JNK MAPK) signal also acts as a vital candidate pathway for inducing tumor cell apoptosis by targeting mitochondrial death pathway. However, the relationship between NADPH oxidase-ROS and JNK MAPK signal still remains unclear. Here, we discovered a novel self-driven signal circuit between NADPH oxidase-ROS and JNK MAPK, which was induced by a cytotoxic steroidal saponin (ASC) in hepatoma carcinoma cells. NADPH oxidase-dependent ROS production was markedly activated by ASC and directly led to JNK MAPK activation. Moreover, antioxidant, NADPH oxidase inhibitor and specific knock-out for p47 subunit of NADPH oxidase could effectively block NADPH oxidase-ROS-dependent JNK activation, suggesting that NADPH oxidase is an upstream regulator of JNK MAPK. Conversely, a specific JNK inhibitor could inhibit ASC-induced NADPH oxidase activation and down-regulate ROS levels as well, indicating that JNK might also regulate NADPH oxidase activity to some extent. These observations indicate that NADPH oxidase and JNK MAPK activate each other as a signal circuit. Furthermore, drug pretreatment experiments with ASC showed this signal circuit operated continuously via a self-driven mode and finally induced apoptosis in hepatoma carcinoma cells. Taken together, we provide a proof for inducing hepatoma carcinoma cell apoptosis by activating the JNK-NADPH oxidase-ROS-dependent self-driven signal circuit pathway., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: There is controversy about the effectiveness of directly observed treatment (DOT) for anti-tuberculosis treatment. This systematic review aimed to synthesise evidence from studies that compared DOT and self-administered treatment (SAT) or different types of DOT for anti-tuberculosis treatment., Methods: Multiple databases were searched by two independent reviewers to identify relevant randomised (RCTs) and non-randomised studies. The risk of bias was independently assessed by two reviewers, and studies at high risk of bias were excluded. Data extraction was conducted by one reviewer and checked by a second reviewer. Primary outcome measures were cure and treatment success., Results: We included eight RCTs and 15 non-randomised studies that were predominantly conducted in low- and middle-income countries. There was no convincing evidence that clinic DOT was more effective than SAT. Evidence from both RCTs and non-randomised studies suggested that community DOT was more effective than SAT. Community DOT was as effective as, or more effective than, clinic DOT. There was no statistically significant difference in results between family and non-family community DOT., Conclusions: Community DOT by non-family members might be the best option if it is more convenient to patients and less costly to health services than clinic DOT.

Aim: To assess the clinical significance of pouch size in total gastrectomy for gastric malignancies., Methods: We manually searched the English-language literature in PubMed, Cochrane Library, Web of Science and BIOSIS Previews up to October 31, 2013. Only randomized control trials comparing small pouch with large pouch in gastric reconstruction after total gastrectomy were eligible for inclusion. Two reviewers independently carried out the literature search, study selection, data extraction and quality assessment of included publications. Standard mean difference (SMD) or relative risk (RR) and corresponding 95%CI were calculated as summary measures of effects., Results: Five RCTs published between 1996 and 2011 comparing small pouch formation with large pouch formation after total gastrectomy were included. Eating capacity per meal in patients with a small pouch was significantly higher than that in patients with a large pouch (SMD = 0.85, 95%CI: 0.25-1.44, I(2) = 0, P = 0.792), and the operative time spent in the small pouch group was significantly longer than that in the large pouch group [SMD = -3.87, 95%CI: -7.68-(-0.09), I (2) = 95.6%, P = 0]. There were no significant differences in body weight at 3 mo (SMD = 1.45, 95%CI: -4.24-7.15, I(2) = 97.7%, P = 0) or 12 mo (SMD = -1.34, 95%CI: -3.67-0.99, I(2) = 94.2%, P = 0) after gastrectomy, and no significant improvement of post-gastrectomy symptoms (heartburn, RR = 0.39, 95%CI: 0.12-1.29, I(2) = 0, P = 0.386; dysphagia, RR = 0.86, 95%CI: 0.58-1.27, I(2) = 0, P = 0.435; and vomiting, RR = 0.5, 95%CI: 0.15-1.62, I(2) = 0, P = 0.981) between the two groups., Conclusion: Small pouch can significantly improve the eating capacity per meal after surgery, and may improve the post-gastrectomy symptoms, including heartburn, dysphagia and vomiting.

Previous studies suggested that smoking and passive smoking could increase the risk of breast cancer, but the results were inconsistent, especially for Chinese females. Thus, we systematically searched cohort and case-control studies investigating the associations of active and passive smoking with breast cancer risk among Chinese females in four English databases (PubMed, Embase, ScienceDirect, and Wiley) and three Chinese databases (CNKI, WanFang, and VIP). Fifty-one articles (3 cohort studies and 48 case-control studies) covering 17 provinces of China were finally included in this systematic review. Among Chinese females, there was significant association between passive smoking and this risk of breast cancer [odds ratio (OR): 1.62; 95% confidence interval (CI): 1.39-1.85; I2 = 75.8%, P < 0.001; n = 26] but no significant association between active smoking and the risk of breast cancer (OR: 1.04; 95% CI: 0.89-1.20; I2 = 13.9%, P = 0.248; n = 31). The OR of exposure to husband's smoking and to smoke in the workplace was 1.27 (95% CI: 1.07-1.50) and 1.66 (95% CI: 1.07-2.59), respectively. The OR of light and heavy passive smoking was 1.11 and 1.41, respectively, for women exposed to their husband's smoke (< 20 and ≥ 20 cigarettes per day), and 1.07 and 1.87, respectively, for those exposed to smoke in the workplace (< 300 and ≥ 300 min of exposure per day). These results imply that passive smoking is associated with an increased risk of breast cancer, and the risk seems to increase as the level of passive exposure to smoke increases among Chinese females. Women with passive exposure to smoke in the workplace have a higher risk of breast cancer than those exposed to their husband's smoking.

Air pollution in China comes from multiple sources, including coal consumption, construction and industrial dust, and vehicle exhaust. Coal consumption in particular directly determines the emissions of three major air pollutants: dust, sulfur dioxide (SO(2)), and nitrogen oxide (NOx). The rapidly increasing number of civilian vehicles is expected to bring NOx emission to a very high level. Contrary to expectations, however, existing data show that the concentrations of major pollutants [particulate matter-10 (PM10), SO(2), and nitrogen dioxide (NO(2))] in several large Chinese cities have declined during the past decades, though they still exceed the national standards of ambient air quality. Archived data from China does not fully support that the concentrations of pollutants directly depend on local emissions, but this is likely due to inaccurate measurement of pollutants. Analyses on the cancer registry data show that cancer burden related to air pollution is on the rise in China and will likely increase further, but there is a lack of data to accurately predict the cancer burden. Past experience from other countries has sounded alarm of the link between air pollution and cancer. The quantitative association requires dedicated research as well as establishment of needed monitoring infrastructures and cancer registries. The air pollution-cancer link is a serious public health issue that needs urgent investigation.

Background: For decades, studies have been performed to evaluate the association between ABO blood groups and risk of cancer. However, whether ABO blood groups are associated with overall cancer risk remains unclear. We therefore conducted a meta-analysis of observational studies to assess this association., Materials and Methods: A search of Pubmed, Embase, ScienceDirect, Wiley, and Web of Knowledge databases (to May 2013) was supplemented by manual searches of bibliographies of key retrieved articles and relevant reviews. We included case-control studies and cohort studies with more than 100 cancer cases., Results: The search yielded 89 eligible studies that reported 100,554 cases at 30 cancer sites. For overall cancer risk, the pooled OR was 1.12 (95%CI: 1.09-1.16) for A vs. non- A groups, and 0.84 (95%CI: 0.80-0.88) for O vs. non-O groups. For individual cancer sites, blood group A was found to confer increased risk of gastric cancer (OR=1.18; 95%CI: 1.13-1.24), pancreatic cancer (OR=1.23; 95%CI: 1.15-1.32), breast cancer (OR=1.12; 95%CI: 1.01-1.24), ovarian cancer (OR=1.16; 95%CI: 1.04-1.27), and nasopharyngeal cancer (OR=1.17; 95%CI: 1.00-1.33). Blood group O was found to be linked to decreased risk of gastric cancer (OR=0.84; 95%CI: 0.80-0.88), pancreatic cancer (OR=0.75; 95%CI: 0.70-0.80), breast cancer (OR=0.90; 95%CI: 0.85-0.95), colorectal cancer (OR=0.89; 95%CI: 0.81-0.96), ovarian cancer (OR=0.76; 95%CI: 0.53-1.00), esophagus cancer (OR=0.94; 95%CI: 0.89-1.00), and nasopharyngeal cancer (OR=0.81; 95%CI: 0.70-0.91)., Conclusions: Blood group A is associated with increased risk of cancer, and blood group O is associated with decreased risk of cancer.

Background: Several studies have previously focused on associations between the (GT)n repeat polymorphism of the heme oxygenase-1 (HO-1) gene promoter region and risk of cancers, but results are complex. We conducted the present meta-analysis to integrate relevant findings and evaluate the association between HO-1 (GT)n repeat polymorphism and cancer susceptibility., Materials and Methods: Published literature was retrieved from the PubMed/MEDLINE, EMBASE and ISI Web of Science databases before November 2013. For all alleles and genotypes, odds ratios were pooled to assess the strength of the associations using either fixed-effects or random-effects models according to heterogeneity. Subgroup analysis was conducted according to ethnicity and histopathology., Results: A total of 10 studies involving 2,367 cases and 2,870 controls were identified. The results showed there was no association between HO-1 (GT)n repeat polymorphism and the cancer risk both at the allelic and genotypic level. However, in the stratified analysis, we observed an increased risk of squamous cell carcinoma in persons carrying the LL genotype and the LL+LS genotype as compared with those carrying the SS genotype. When the LS and SS genotypes were combined, the odds ratio for squamous cell carcinoma in LL-genotype carriers, were also significantly increased. No publication bias was observed., Conclusions: The LL genotype and L-allele carrying genotypes (LL+LS) of HO-1 (GT)n repeat polymorphism are potential genetic factors for developing squamous cell carcinoma. More large and well-designed studies are required for further validations.