Reconciling ASPP-p53 binding mode discrepancies through an ensemble binding framework that bridges crystallography and NMR data.

ASPP2 and iASPP bind to p53 through their conserved ANK-SH3 domains to respectively promote and inhibit p53-dependent cell apoptosis. While crystallography has indicated that these two proteins employ distinct surfaces of their ANK-SH3 domains to bind to p53, solution NMR data has suggested similar surfaces. In this study, we employed multi-scale molecular dynamics (MD) simulations combined with free energy calculations to reconcile the discrepancy in the binding modes. We demonstrated that the binding mode based solely on a single crystal structure does not enable iASPP's RT loop to engage with p53's C-terminal linker-a verified interaction. Instead, an ensemble of simulated iASPP-p53 complexes facilitates this interaction. We showed that the ensemble-average inter-protein contacting residues and NMR-detected interfacial residues qualitatively overlap on ASPP proteins, and the ensemble-average binding free energies better match experimental KD values compared to single crystallgarphy-determined binding mode. For iASPP, the sampled ensemble complexes can be grouped into two classes, resembling the binding modes determined by crystallography and solution NMR. We thus propose that crystal packing shifts the equilibrium of binding modes towards the crystallography-determined one. Lastly, we showed that the ensemble binding complexes are sensitive to p53's intrinsically disordered regions (IDRs), attesting to experimental observations that these IDRs contribute to biological functions. Our results provide a dynamic and ensemble perspective for scrutinizing these important cancer-related protein-protein interactions (PPIs).

Interaction between the VP2 protein of deformed wing virus and host snapin protein and its effect on viral replication.

Introduction: Deformed wing virus (DWV) is one of the causative agents of colony collapse disorder. The structural protein of DWV plays a vital role in the process of viral invasion and host infection; however, there is limited research on DWV. Methods and Results: In this study, we screened the host protein snapin, which can interact with the VP2 protein of DWV, using the yeast two-hybrid system. Through computer simulation and GST pull-down and CO-IP assays, an interaction between snapin and VP2 was confirmed. Furthermore, immunofluorescence and co-localization experiments revealed that VP2 and snapin primarily co-localized in the cytoplasm. Consequently, RNAi was used to interfere with the expression of snapin in worker bees to examine the replication of DWV after the interference. After silencing of snapin, the replication of DWV in worker bees was significantly downregulated. Hence, we speculated that snapin was associated with DWV infection and involved in at least one stage of the viral life cycle. Finally, we used an online server to predict the interaction domains between VP2 and snapin, and the results indicate that the interaction domain of VP2 was approximately located at 56-90, 136-145, 184-190, and 239-242 aa and the snapin interaction domain was approximately located at 31-54 and 115-136 aa. Conclusion: This research confirmed that DWV VP2 protein could interacts with the snapin of host protein, which provides a theoretical basis for further investigation of its pathogenesis and development of targeted therapeutic drugs.

Real role of growth factor receptor-binding protein 10: Linking lipid metabolism to diabetes cardiovascular complications.

Cardiovascular complications of patients with type 2 diabetes mellitus (T2DM) threaten the health and life of numerous individuals. Recently, growth factor receptor-binding protein 10 (GRB10) was found to play a pivotal role in vascular complications of T2DM, which participates in the regulation of lipid metabolism of T2DM patients. The genetic variation of GRB10 rs1800504 is closely related to the risk of coronary heart disease in patients with T2DM. The development of GRB10 as a key mediator in the association of lipid metabolism with cardiovascular complications in T2DM is detailed in and may provide new potential concerns for the study of cardiovascular complications in T2DM patients.

Designing a multi-epitope vaccine against coxsackievirus B based on immunoinformatics approaches.

Coxsackievirus B (CVB) is one of the major viral pathogens of human myocarditis and cardiomyopathy without any effective preventive measures; therefore, it is necessary to develop a safe and efficacious vaccine against CVB. Immunoinformatics methods are both economical and convenient as in-silico simulations can shorten the development time. Herein, we design a novel multi-epitope vaccine for the prevention of CVB by using immunoinformatics methods. With the help of advanced immunoinformatics approaches, we predicted different B-cell, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) epitopes, respectively. Subsequently, we constructed the multi-epitope vaccine by fusing all conserved epitopes with appropriate linkers and adjuvants. The final vaccine was found to be antigenic, non-allergenic, and stable. The 3D structure of the vaccine was then predicted, refined, and evaluated. Molecular docking and dynamics simulation were performed to reveal the interactions between the vaccine with the immune receptors MHC-I, MHC-II, TLR3, and TLR4. Finally, to ensure the complete expression of the vaccine protein, the sequence of the designed vaccine was optimized and further performed in-silico cloning. In conclusion, the molecule designed in this study could be considered a potential vaccine against CVB infection and needed further experiments to evaluate its safety and efficacy.

XDH genotypes through gene-gene interactions with NUDT15 affect azathioprine-induced leukopenia in Chinese patients.

Aim: To investigate whether genotypes of XDH, GMPS and MOCOS were associated with azathioprine-induced adverse drug reaction (ADR) and had the gene-gene interactions with NUDT15 rs116855232 to induce leukopenia. Methods: Patients who had taken azathioprine were recruited. Genotyping of those gene was performed. Risk factor to ADR was analyzed by logistic regression. The generalized multifactor dimensionality reduction (GMDR) was assessed based on gene-gene interactions with ADR. Results: A total of 111 patients were included in this study, all of whom were Han Chinese. XDH rs2295475 was a risk factor of myelotoxicity (p = 0.022). NUDT15 rs116855232 was a risk factor of myelotoxicity, grade ≥2 leukopenia and drug treatment termination (p-values were <0.05). Rs2295475 and rs116855232 had a gene-gene interaction. The model was associated with grade ≥2 leukopenia (OR: 17.99; 95% CI: 4.11-78.81). Conclusion: Combined testing genotype for rs2295475 and rs116855232 could improve the prediction of azathioprine-induced leukopenia.

Quality of life and its influencing factors among people living with HIV/AIDS in Hangzhou City / 预防医学

Objective @#To investigate the quality of life among people living with HIV/AIDS in Hangzhou City and analyze the influencing factors, so as to provide insights into the control of AIDS.@*Methods @#From 1 January 2014 to 30 June 2018, the demographic characteristics, medical expenditures and disease status were collected from HIV/AIDS patients living in Hangzhou City, and the quality of life was assessed using the simplified Chinese version of Medical Outcomes Study-HIV Health Survey ( MOS-HIV ). Factors affecting the quality of life were identified among HIV/AIDS patients using multivariable linear regression analysis. @*Results @#A total of 2 808 HIV/AIDS patients were surveyed, including 1 684 cases with HIV infections and 1 124 cases with AIDS. The participants included 2 510 men ( 89.39% ) and 298 women ( 10.61% ), and were predominantly at ages of 25 to 39 years ( 1 531 cases, 54.52% ). The physical and mental health scores were 53.87±6.96 and 46.03±9.09, respectively. Multivariable linear regression analysis identified age, average monthly income, self-paid medical expenses during the past year, and the latest CD4+T cell count as factors affecting physical and mental health ( P<0.05 ).@*Conclusions @#The quality of life is low among people living with HIV/AIDS in Hangzhou City, and is associated with age, income, medical expenditures and CD4+T cell count.

Identification of a novel host protein interacting with the structural protein VP2 of deformed wing virus by yeast two-hybrid screening.

Deformed wing virus (DWV) interacting with Varroa destructor is a possible cause of honeybee colony mortality. VP2 is the structural protein of DWV but its function remains unknown. To clarify the function of VP2 and screen for novel binding proteins that interact with VP2, we carried out a membrane protein yeast two-hybrid screening using VP2 as bait. Subsequently, the interaction between VP2 and the host interacting protein [heat shock protein 10 (Hsp10)] was further verified using glutathione S-transferase pull-down assay in vitro and co-immunoprecipitation assay in cells. Furthermore, fluorescence confocal microscopy revealed that VP2 and Hsp10 were mainly co-localized in the cytoplasm. Using real-time polymerase chain reaction, we found that Hsp10 expression in DWV-infected worker honey bees were downregulated compared with that in healthy honey bees. Additionally, we showed that overexpression of VP2 protein could reduce the expression of Hsp10. These results suggest that Hsp10 plays a vital role in host immunity and antiviral effects.

HIV/AIDS case detection and influencing factors for late diagnosisin Hangzhou from 2013 to 2018 / 预防医学

Objective@#To analyze current situation of HIV/AIDS case detection and factors associated with late diagnosis among the newly diagnosed cases from 2013 to 2018 in Hangzhou, so as to provide basis for improving the detection capacity of HIV. @*Methods@#The data of HIV testing and newly diagnosed HIV/AIDS cases in Hangzhou from 2013 to 2018 were collected through the China AIDS Prevention and Control Information System. The proportion of HIV antibody detection and positive cases in different regions, detection ways and high-risk groups were analyzed. The influencing factors for late diagnosis were analyzed by multivariate logistic regression model. @*Results@#The proportions of cases with HIV detected, HIV positive and late diagnosis increased from 2013 to 2018, and the annual ones were 24.99%, 6.95 per ten thousand and 30.07%, respectively. The results of the multivariate logistic regression analysis showed that people who were male ( OR=1.656, 95%CI: 1.351-2.030 ) and aged older ( OR: 1.912-5.117, 95%CI: 1.250-7.904 ) had higher risks of late diagnosis; who detected HIV through pre-test of receiving blood ( OR=4.429, 95%CI:2.217-9.225 ) , other inpatient detection ( OR=2.137, 95%CI: 1.615-2.826 ) , preoperative testing ( OR=2.137, 95%CI: 1.615-2.826 ) and testing of STD clinic attendants ( OR=1.359, 95%CI: 1.007-1.834 ) had higher risks of late diagnosis compared to those diagnosed at VCT clinics; who diagnosed at CDCs ( OR=0.714,95%CI: 0.558-0.915 ) and community health centers ( OR=0.645, 95%CI: 0.441-0.943 ) had lower risks of late diagnosis than those diagnosed in hospitals; who were infected by heterosexual contact ( OR=1.299, 95%CI: 1.130-1.493 ) had a higher risk of late diagnosis than MSM; who had history of STD ( OR=0.818, 95%CI: 0.706-0.948 ) had a lower risk of late diagnosis than who did not.@*Conclusions@# HIV testing and case detection had been expanded, but late diagnosis had not been improved in Hangzhou from 2013 to 2018. Age, sex, route and institution of diagnosis, transmission route and history of STD were influencing factors of late diagnosis.

Identification of the Novel Host Protein Interacting With the Structural Protein VP1 of Chinese Sacbrood Virus by Yeast Two-Hybrid Screening.

Chinese sacbrood virus (CSBV) is the major cause and lead to the collapse of Apis cerana colonies. VP1, the structural protein of CSBV, shows the highest variation in the amino acid sequences among proteins from different CSBV strains as well as exhibits excellent immunogenicity. However, its function with host protein still remains unclear. To clarify its function with host protein, we screened out host cellular proteins that interact with VP1 using the membrane protein yeast two-hybrid system. In addition, we verified interactions between heat shock protein 70 cognate 5 (Hsp70-c5) and VP1 using glutathione S-transferase (GST) pull-down and co-immunoprecipitation assays. VP1 and Hsp70-c5 were colocalized in the cytoplasm and nucleus. Using western blot and real-time polymerase chain reaction (PCR), Hsp70-c5 expression in CSBV-infected larvae was upregulated compared with that in healthy larvae. We observed that when we silenced Hsp70-c5, VP1 expression was significantly downregulated. These results demonstrate that Hsp70-c5 is involved in at least one stage(s) of the viral life cycle.

Associations of TRAF1/C5 rs10818488 and rs3761847 polymorphisms with genetic susceptibility to rheumatoid arthritis: a case-control study and updated meta-analysis.

The results on associations of tumor necrosis factor (TNF)-receptor associated factor 1/complement component 5 (TRAF1/C5) rs10818488 and rs3761847 polymorphisms with rheumatoid arthritis (RA) are controversial, thus this study was performed to examine whether the aforementioned polymorphisms were associated with RA in a Chinese population. Furthermore, an updated meta-analysis was conducted. The polymorphisms were genotyped in 328 Chinese RA patients and 449 healthy controls. Studies examining the association of TRAF1/C5 rs10818488 and/or rs3761847 polymorphism with RA were exhaustively searched. No significant difference in either genotype or allele distribution between RA patients and controls was found. The updated meta-analysis was conducted based on 19 articles including the present study. A significant association of RA with TRAF1/C5 rs10818488 polymorphism G allele in Europeans (OR = 0.843, 95% CI = 0.730-0.975, p = 0.021) and in Asians (OR = 1.070, 95% CI = 1.009-1.136, p = 0.024) was found. Additionally, a significant association of RA with TRAF1/C5 rs10818488 polymorphism G allele under the recessive model in Asians (OR = 1.129, 95% CI = 1.023-1.246, p = 0.016) and in Africans (OR = 0.657, 95% CI = 0.507-0.851, p = 0.001) was found. Only a borderline significant association of RA with TRAF1/C5 rs3761847 polymorphism A allele was found in Europeans. Non-significant associations of RA with TRAF1/C5 rs10818488 and rs3761847 polymorphisms were found in our study. The updated meta-analysis results demonstrate that TRAF1/C5 rs10818488 polymorphism is associated with RA in Europeans, Asians and Africans, and TRAF1/C5 rs3761847 polymorphism is associated with RA in Europeans with borderline significant evidence.

[Activation of nuclear factor-κB subunit p50/p65 enhances gefitinib resistance of lung adenocarcinoma H1650 cell line].

OBJECTIVE: To explore the intrinsic connection between activation of classical nuclear factor-κB (NF-κB) pathway and gefitinib resistance in human lung adenocarcinoma H1650 cells. METHODS: Human lung adenocarcinoma H1650 cells were exposed to gefitinib continuously for 60 days to obtain resistant H1650 cells. The expressions of P-IκBα, P-p50 and P-p65 in the cytoplasm or nuclei were detected using Western blotting in human lung adenocarcinoma HCC827 cells, parental H1650 cells and gefitinib-resistant H1650 cells. The effects of gefitinib alone or in combination with PDTC on the survival rate and expressions of NF-κB P-p50 and P-p65 were compared among the 3 cell lines. RESULTS: Gefitinib-resistant H1650 cells showed increased cytoplasmic and nuclear P-IκBα expressions. The expressions of P-p50 and P-p65 differed significantly among the 3 cell line, decreasing in the order of resistant H1650 cells, parental H1650 cells, and gefitinib sensitive HCC827 cell lines (P<0.05 or 0.01). Treatment with gefitinib alone resulted in a significantly lower cell inhibition rate in resistant H1650 cells than in the parental H1650 cells (P<0.05) and HCC827 cells (P<0.01). The resistant H1650 cells had a significantly higher expression of P-p50 and P-p65 than other two cell lines (P<0.05). In both the resistant and parental H1650 cells, gefitinib significantly lowered P-p50 and P-p65 expressions (P<0.05 or 0.01), and the combined treatment with gefitinib and PDTC significantly decreased the cell survival rate and further lowered the cytoplasmic and nuclear expressions of P-p50 and P-p65 (P<0.01 or 0.01). CONCLUSION: The activation of classical NF-κB pathway is a key factor contributing to transformation of the parental H1650 cells into gefitinib-resistant cells. Gefitinib combined with PDTC can inhibit P-IκBα production and NF-κB P-p50 and P-p65 activation to suppress the survival of residual H1650 cells and the generation of gefitinib-resistant cells.

Association study of AFF1 rs340630 polymorphism with genetic susceptibility to rheumatoid arthritis in Chinese population.

This study was performed to examine whether the AF4/FMR2 family, member 1 (AFF1) rs340630 polymorphism is involved in the genetic background of rheumatoid arthritis (RA) in a Chinese population. Two different study groups of RA patients and controls (328 RA patients and 449 healthy controls in the first study group; 232 RA patients and 313 controls in the second study group) were included in our study. Overall, there was no significant difference in either genotype (P=0.71 and 0.64 in the first and second study group, respectively) nor allele (in the first study group: A vs G, P=0.65, OR=1.05, 95%CI=0.85-1.29; in the second study group: G vs A, P=0.47, OR=1.10, 95%CI=0.86-1.40) frequencies of AFF1 rs340630 polymorphism between RA patients and controls. Our study represents the first report assessing the association of AFF1 rs340630 polymorphism with RA risk. No significant evidence was found for the dominant or recessive models. Further case-control studies with larger sample sizes and fine-mapping studies are needed to clarify the role of AFF1 in the genetic basis of RA.

Toxicological profile and safety pharmacology of a single dose of fibroblast activation protein-α-based doxorubicin prodrug: in-vitro and in-vivo evaluation.

Fibroblast activation protein-α (FAPα) is a promising tumor-associated target expressed by reactive stromal fibroblasts in tumor tissue. FAPα has a postprolyl peptidase activity and can specifically cleave N-terminal benzyloxycarbonyl (Z)-blocked peptides, such as the substrate Z-Gly-Pro-AMC. Doxorubicin (DOX) is an effective antitumor drug, but its application is greatly limited by toxic adverse effects owing to poor tumor selectivity. Based on these facts, we previously designed a FAPα-targeting prodrug of doxorubicin (FTPD) which can be selectively hydrolyzed by FAPα. FTPD can retain potent antitumor efficacy and has favorable tumor targeting. The present study aimed to further evaluate the toxicological profile and the safety pharmacological property of FTPD in vitro and in vivo. The cytotoxicity assay showed that FTPD displayed markedly lower cytotoxicity to 3T3 cells and HEK-293 cells compared with DOX. In the short-term toxicity study, mice treated with 25 mg/kg of FTPD showed no obvious change in the appearance and general behavior, and no case of mortality was observed within 14 days. Unlike DOX, FTPD exhibited reduced toxicity to heart, liver, kidney, spleen as well as peripheral white blood cells in mice. Moreover, open file test and general pharmacology study were also conducted correspondingly in mice and beagle dogs. It was found that FTPD may not produce significant pharmacological effects on spontaneous locomotor activity and cardiovascular-respiratory system except for a transient decreasing in systolic blood pressure. Taken together, the results of this work suggest that FTPD has more favorable toxicological profile and better drug safety compared with its parent drug DOX.

Association study of AFF1 rs340630 polymorphism with genetic susceptibility to rheumatoid arthritis in Chinese population

This study was performed to examine whether the AF4/FMR2 family, member 1 (AFF1) rs340630 polymorphism is involved in the genetic background of rheumatoid arthritis (RA) in a Chinese population. Two different study groups of RA patients and controls (328 RA patients and 449 healthy controls in the first study group; 232 RA patients and 313 controls in the second study group) were included in our study. Overall, there was no significant difference in either genotype (P=0.71 and 0.64 in the first and second study group, respectively) nor allele (in the first study group: A vs G, P=0.65, OR=1.05, 95%CI=0.85-1.29; in the second study group: G vs A, P=0.47, OR=1.10, 95%CI=0.86-1.40) frequencies of AFF1 rs340630 polymorphism between RA patients and controls. Our study represents the first report assessing the association of AFF1 rs340630 polymorphism with RA risk. No significant evidence was found for the dominant or recessive models. Further case-control studies with larger sample sizes and fine-mapping studies are needed to clarify the role of AFF1 in the genetic basis of RA.

Interaction analysis between BLK rs13277113 polymorphism and BANK1 rs3733197 polymorphism, MMEL1/TNFRSF14 rs3890745 polymorphism in determining susceptibility to rheumatoid arthritis.

Two pairwise genetic interactions (B cell lymphocyte kinase (BLK) rs13277113,B cell scaffold protein with ankyrin repeats 1 (BANK1) rs3733197and BLK rs13277113 membrane metalloendopeptidase like 1 (MMEL1)/ tumor necrosis factor receptor superfamily member 14 (TNFRSF14) rs3890745) have been demonstrated in determining susceptibility to rheumatoid arthritis (RA) without replication, thus this study was performed to examine whether abovementioned genetic polymorphisms were associated with RA and further tests were performed to see whether aforementioned genetic interactions existed in RA among Chinese population. A total of 328 patients with RA and 449 healthy control subjects were included in the current study. The polymorphisms were genotyped using the ligase detection reaction-polymerase chain reaction (LDR-PCR) technology. The association of RA with each polymorphism was analyzed by multivariate logistic regression model. Interaction analysis was done by multiple methods. Significant difference in genotype distribution of BLK rs13277113 polymorphism between RA patients and healthy controls was found (p = 1.01 × 10-2). The major allele A of BLK rs13277113 polymorphism was significantly increased in RA patients compared with controls (OR = 1.36, 95% CI = 1.08-1.71, p = 9.27 × 10-3). Significant association of RA with the major allele A of BLK rs13277113 polymorphism under dominant model was also detected (OR = 2.74, 95% CI = 1.42-5.29, p = 2.73 × 10-3). However, we did not find significant association between neither BANK1 rs3733197 polymorphism nor MMEL1/TNFRSF14 rs3890745 polymorphism and RA. Non-significant evidence was found for neither additive nor multiplicative interaction for these two pairwise genetic polymorphisms (BLK rs13277113-BANK1 rs3733197; BLK rs13277113-MMEL1/TNFRSF14 rs3890745). Significant association of RA with G allele of BANK1 rs3733197 polymorphism was only found among individuals carrying A/A genotype of the BLK rs13277113 polymorphism (OR = 1.49, 95% CI = 1.01-2.18, p = .04). In summary, our results indicated that the BLK rs13277113 polymorphism was involved in the genetic background of RA in Chinese population and the association of BANK1 rs3733197 polymorphism with RA was dependent on the genotype of BLK rs13277113 polymorphism, highlighting B-cell response implicated in the pathogenesis of RA.

A novel FAPα-based Z-Gly-Pro epirubicin prodrug for improving tumor-targeting chemotherapy.

Fibroblast activation protein-α (FAPα) is a serine protease of the post-prolyl peptidase family that is specifically expressed in the majority of human epithelial tumors, but not in normal tissues. In this study, we demonstrated the anti-tumor activity of a novel targeting drug formed by conjugating epirubicin (EPI) with an FAPα-specific dipeptide (Z-Gly-Pro) and named it Z-GP-EPI. Consistent with this tumor-targeting delivery strategy, the results illustrated that Z-GP-EPI could release EPI efficiently after incubating with FAPα and could exhibit similar antitumor effects as EPI in vitro in FAPα over-expressed tumor cells (4T1/FAPα+). Furthermore, the evaluation of antitumor activity of Z-GP-EPI in vivo was implemented in a 4T1/FAPα+ tumor-bearing mice xenograft model. Our results illustrated that Z-GP-EPI had similar antitumor effects in 4T1/FAPα+ tumor-bearing mice and showed no visible cardiotoxicity side effects compared with free EPI. Thus, our study indicated that this FAPα-activated prodrug targeting strategy may provide a new mechanism for the targeted delivery of antitumor agents and improve their safety levels.

Identifying Potential Norovirus Epidemics in China via Internet Surveillance.

BACKGROUND: Norovirus is a common virus that causes acute gastroenteritis worldwide, but a monitoring system for norovirus is unavailable in China. OBJECTIVE: We aimed to identify norovirus epidemics through Internet surveillance and construct an appropriate model to predict potential norovirus infections. METHODS: The norovirus-related data of a selected outbreak in Jiaxing Municipality, Zhejiang Province of China, in 2014 were collected from immediate epidemiological investigation, and the Internet search volume, as indicated by the Baidu Index, was acquired from the Baidu search engine. All correlated search keywords in relation to norovirus were captured, screened, and composited to establish the composite Baidu Index at different time lags by Spearman rank correlation. The optimal model was chosen and possibly predicted maps in Zhejiang Province were presented by ArcGIS software. RESULTS: The combination of two vital keywords at a time lag of 1 day was ultimately identified as optimal (ρ=.924, P<.001). The exponential curve model was constructed to fit the trend of this epidemic, suggesting that a one-unit increase in the mean composite Baidu Index contributed to an increase of norovirus infections by 2.15 times during the outbreak. In addition to Jiaxing Municipality, Hangzhou Municipality might have had some potential epidemics in the study time from the predicted model. CONCLUSIONS: Although there are limitations with early warning and unavoidable biases, Internet surveillance may be still useful for the monitoring of norovirus epidemics when a monitoring system is unavailable.

The clinical efficacy and safety evaluation of ticagrelor for acute coronary syndrome in general ACS patients and diabetic patients: A systematic review and meta-analysis.

OBJECTIVE: In this study, a systematic evaluation was conducted to estimate the efficacy and safety of ticagrelor for treating acute coronary syndrome (ACS) in general ACS patients and a diabetes mellitus (DM) group. METHODS: A search of PubMed, Cochrane Central Register of Controlled Trials, Web of Science, CNKI databases was conducted to analyze relevant randomized controlled trails (RCTs) of ticagrelor treating ACS during 2007 to 2015. Article screening, quality accessing and data extracting was independently undertaken by two reviewers. A meta-analysis was performed to clarify the efficacy and safety of ticagrelor in general ACS patients, and a meta-regression analysis was taken to demonstrate the efficacy and safety of ticagrelor in DM patients compared with general ACS patients. RESULT: Twenty-two studies with 35004 participants were included. The meta-analysis result implicated that ticagrelor could: 1) reduce the incidence of the composite endpoint [OR = 0.83, 95%CI (0.77, 0.90), P<0.00001] and the incidence of myocardial infarction [OR = 0.81, 95%CI (0.74, 0.89), P = 0.0001]; 2) not statistically reduce the incidence of cardiovascular death, the incidence of stroke and the incidence of bleeding events; 3) increase the incidence of dyspnea [OR = 1.90, 95%CI (1.73, 2.08), P<0.00001] compared with clopidogrel. Meanwhile, compared with prasugrel, ticagrelor could 1) reduce the platelet reactivity of patients at maintenance dose [MD = -44.59, 95%CI (-59.16, -30.02), P<0.00001]; 2) not statistically reduce the incidence of cardiovascular death, the platelet reactivity of patients 6 hours or 8 hours after administration, or the incidence of bleeding events; 3) induce the incidence of dyspnea [OR = 13.99, 95%CI (2.58, 75.92), P = 0.002]. Furthermore, the result of meta-regression analysis implicated that there was a positive correlation between DM patients and the platelet reactivity of patients 6 hours and 8 hours after administration, but there was no obvious correlation between DM patients and general ACS patients in other endpoints. CONCLUSION: Ticagrelor could reduce the incidence of composite endpoint of cardiovascular death, myocardial infarction and stroke as well as platelet reactivity in DM patients with ACS, while not increasing the risk of bleeding. Because there are differences in platelet reactivity between DM patients and general ACS patients, we suggest that caution is needed when using ticagrelor in clinical applications.

A study on associations of single-nucleotide polymorphisms within H19 and HOX transcript antisense RNA (HOTAIR) with genetic susceptibility to rheumatoid arthritis in a Chinese population.

OBJECTIVE: The purpose of our study was to examine whether the H19 rs2839698, rs217727, and HOX transcript antisense RNA (HOTAIR) rs12826786 polymorphisms were associated with genetic susceptibility to rheumatoid arthritis (RA) in a Chinese population. METHODS: A total of 777 participants were enrolled in this study, including 328 RA patients and 449 healthy controls. The H19 rs2839698, rs217727, and HOTAIR rs12826786 polymorphisms were detected by the ligase detection reaction-polymerase chain reaction (LDR-PCR) technology. RESULTS: No significant difference in genotype distribution between RA patients and healthy controls was found (P = 0.38 for rs2839698; P = 0.79 for rs217727; P = 0.39 for rs12826786). The difference in allele frequencies between RA patients and controls was also non-significant (rs2839698 T versus C, P = 0.23, odds ratio (OR) = 1.15, 95% confidence interval (CI) = 0.92-1.43; rs217727 C versus T, P = 0.55, OR = 1.07, 95% CI = 0.87-1.32; and rs12826786 T versus C, P = 0.32, OR = 1.14, 95% CI = 0.88-1.47). We have also evaluated the relationships of above-mentioned polymorphisms with risk of RA under dominant model and recessive model, but non-significant evidence was found. No significant evidence was detected for the relationships of H19 rs2839698, rs217727, and HOTAIR rs12826786 polymorphisms with risk of different serotypes of RA. CONCLUSIONS: Our results indicated that H19 rs2839698, rs217727, and HOTAIR rs12826786 polymorphisms might not be involved in the genetic background of RA in Chinese.

Unexpected Diversity and High Abundance of Putative Nitric Oxide Dismutase (Nod) Genes in Contaminated Aquifers and Wastewater Treatment Systems.

It has recently been suggested that oxygenic dismutation of NO into N2 and O2 may occur in the anaerobic methanotrophic "Candidatus Methylomirabilis oxyfera" and the alkane-oxidizing gammaproteobacterium HdN1. It may represent a new pathway in microbial nitrogen cycling catalyzed by a putative NO dismutase (Nod). The formed O2 enables microbes to employ aerobic catabolic pathways in anoxic habitats, suggesting an ecophysiological niche space of substantial appeal for bioremediation and water treatment. However, it is still unknown whether this physiology is limited to "Ca Methylomirabilis oxyfera" and HdN1 and whether it can be coupled to the oxidation of electron donors other than alkanes. Here, we report insights into an unexpected diversity and remarkable abundance of nod genes in natural and engineered water systems. Phylogenetically diverse nod genes were recovered from a range of contaminated aquifers and N-removing wastewater treatment systems. Together with nod genes from "Ca Methylomirabilis oxyfera" and HdN1, the novel environmental nod sequences formed no fewer than 6 well-supported phylogenetic clusters, clearly distinct from canonical NO reductase (quinol-dependent NO reductase [qNor] and cytochrome c-dependent NO reductase [cNor]) genes. The abundance of nod genes in the investigated samples ranged from 1.6 × 107 to 5.2 × 1010 copies · g-1 (wet weight) of sediment or sludge biomass, accounting for up to 10% of total bacterial 16S rRNA gene counts. In essence, NO dismutation could be a much more widespread physiology than currently perceived. Understanding the controls of this emergent microbial capacity could offer new routes for nitrogen elimination or pollutant remediation in natural and engineered water systems. IMPORTANCE: NO dismutation into N2 and O2 is a novel process catalyzed by putative NO dismutase (Nod). To date, only two bacteria, the anaerobic methane-oxidizing bacterium "Ca Methylomirabilis oxyfera" and the alkane-oxidizing gammaproteobacterium HdN1, are known to harbor nod genes. In this study, we report efficient molecular tools that can detect and quantify a wide diversity of nod genes in environmental samples. A surprisingly high diversity and abundance of nod genes were found in contaminated aquifers as well as wastewater treatment systems. This evidence indicates that NO dismutation may be a much more widespread physiology in natural and man-made environments than currently perceived. The molecular tools presented here will facilitate further studies on these enigmatic microbes in the future.