Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents

Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino-3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI(50) values ranging from 0.33 to 3.45μM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC(50) values of 2.2-3.0μM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase.     

Different HCV Genotype Distributions of HIV-Infected Individuals in Henan and Guangxi,China

Background

Due to shared transmission routes, hepatitis C virus (HCV) infection is highly prevalent among people infected with human immunodeficiency virus (HIV). Highly active antiretroviral therapy (HAART) is associated with hepatotoxicity, leading to the negative effects on patients with HIV/HCV co-infection. In order to provide valuable information for HCV management in this particular population, we investigated the HCV genotypes in HIV-infected individuals from Henan and Guangxi, the two provinces with the most HIV-infected cases in China.

Methods

Individuals, who acquired HIV infection through various risk routes, were recruited from Henan and Guangxi. Test of antibodies against HCV (anti-HCV) was conducted, and detection of HCV RNA was performed by PCR amplification. HCV subtypes were determined by direct sequencing of amplicons, followed by phylogenetic analysis.

Results

We recruited a total of 1,112 HIV-infected people in this present study. Anti-HCV was detected from 218 (50.1%) patients from Henan and 81 (12.0%) patients from Guangxi, respectively. The highest prevalence of HIV/HCV co-infection was observed from FBDs (former blood donors) (87.2%) in Henan and IDUs (intravenous drug users) (81.8%) in Guangxi, respectively. The seroprevalence rate of HCV among people with sexual contact was significantly higher in Henan than in Guangxi (18.7% vs. 3.5%, P<0.05). The positive rate of HCV RNA in Henan and Guangxi was 30.6% (133/435) and 11.2% (76/677), respectively. Moreover, we found that 20 anti-HCV negative samples were HCV positive by PCR amplification. HCV subtype 1b (52.7%) was predominant in Henan, followed by subtype 2a (41.9%). The most frequently detected subtypes in Guangxi were 6a (35.6%) and 3b (32.9%).

Conclusion

The HCV genotype distributions were different in HIV-infected people from Henan and Guangxi. HIV/HCV co-infection was not only linked to the transmission routes, but also associated with the geographic position.     

Redox regulation of plant stem cell fate

Despite the importance of stem cells in plant and animal development, the common mechanisms of stem cell maintenance in both systems have remained elusive. Recently, the importance of hydrogen peroxide (H₂O₂) signaling in priming stem cell differentiation has been extensively studied in animals. Here, we show that different forms of reactive oxygen species (ROS) have antagonistic roles in plant stem cell regulation, which were established by distinct spatiotemporal patterns of ROS‐metabolizing enzymes. The superoxide anion () is markedly enriched in stem cells to activate WUSCHEL and maintain stemness, whereas H₂O₂ is more abundant in the differentiating peripheral zone to promote stem cell differentiation. Moreover, H₂O₂ negatively regulates biosynthesis in stem cells, and increasing H₂O₂ levels or scavenging leads to the termination of stem cells. Our results provide a mechanistic framework for ROS‐mediated control of plant stem cell fate and demonstrate that the balance between and H₂O₂ is key to stem cell maintenance and differentiation.     

Integrating Multi-Omics for Uncovering the Architecture of Cross-Talking Pathways in Breast Cancer

Cross-talk among abnormal pathways widely occurs in human cancer and generally leads to insensitivity to cancer treatment. Moreover, alterations in the abnormal pathways are not limited to single molecular level. Therefore, we proposed a strategy that integrates a large number of biological sources at multiple levels for systematic identification of cross-talk among risk pathways in cancer by random walk on protein interaction network. We applied the method to multi-Omics breast cancer data from The Cancer Genome Atlas (TCGA), including somatic mutation, DNA copy number, DNA methylation and gene expression profiles. We identified close cross-talk among many known cancer-related pathways with complex change patterns. Furthermore, we identified key genes (linkers) bridging these cross-talks and showed that these genes carried out consistent biological functions with the linked cross-talking pathways. Through identification of leader genes in each pathway, the architecture of cross-talking pathways was built. Notably, we observed that linkers cooperated with leaders to form the fundamentation of cross-talk of pathways which play core roles in deterioration of breast cancer. As an example, we observed that KRAS showed a direct connection to numerous cancer-related pathways, such as MAPK signaling pathway, suggesting that it may be a central communication hub. In summary, we offer an effective way to characterize complex cross-talk among disease pathways, which can be applied to other diseases and provide useful information for the treatment of cancer.     

Diabetic Patients Could Do As Well as Non-Diabetic Patients without Inflammation on Peritoneal Dialysis

Background

Diabetic patients on peritoneal dialysis (PD) have lower survival and are more likely complicated with inflammation than their non-diabetic counterparts. Here, we explored the interaction effects between diabetes and inflammation on the survival of PD patients.

Methods

Overall, 2,264 incident patients were enrolled from a retrospective cohort study in China. Patients were grouped according to the baseline levels of high-sensitive C-reactive protein (hsCRP, ≤3 mg/L or >3 mg/L) or serum albumin (SA, ≥38 g/L or <38 g/L). Then, several multivariable adjusted stratified Cox regression models were constructed for these groups to explore the predicted role of diabetes on all-cause or cardiovascular death under inflammatory or non-inflammatory conditions.

Results

Diabetics on PD were more likely to have inflammation than non-diabetics on PD, and they presented with elevated hsCRP (52.7% vs. 47.3%, P = 0.03) or decreased SA (77.9% vs. 62.7%, P < 0.001) levels. After stratification by size of center and controlling for confounding factors, diabetes was found to predict all-cause death in patients with hsCRP >3 mg/L or SA <38 g/L but not in patients with hsCRP ≤3 mg/L or SA ≥38 g/L. Similarly, the presence of diabetes was an indication of cardiovascular death in patients with hsCRP >3 mg/L or SA <38 g/L. However, if further adjusted by baseline cardiovascular disease, the predicted role of diabetes on death related to cardiovascular disease in patients with SA <38 g/L disappeared.

Conclusion

Diabetic patients could do as well as non-diabetic patients without inflammation on peritoneal dialysis. Active strategies should be implemented to improve inflammation status in diabetic patients on PD.     

Composition and dynamics of microbial community in a zeolite biofilter-membrane bioreactor treating coking wastewater

In this study, a lab-scale anaerobic/anoxic/zeolite biofilter-membrane bioreactor (A₁/A₂/ZB-MBR) was designed to treat coking wastewater. The 454 pyrosequencing was used to obtain the composition and dynamics of microbial community about the treatment system. The results showed that the system yielded stable effluent chemical oxidation demand (158.5?±?21.8 mg/L) and ammonia (8.56?±?7.30 mg/L), but fluctuant total nitrogen (31.4–165.1 mg/L) concentrations. In addition, 66,256 16S rRNA gene sequences were obtained from A₂ and ZB-MBR, and the microbial diversity and richness for five samples were determined. Although community compositions in the five samples were quite different, bacteria assigned to phylum Proteobacteria and class Flavobacteria commonly existed and dominated the microbial populations. The pyrosequencing analysis revealed that the microbial community shifted in the ZB-MBR with the presence of zeolite. Some taxa began to appear in ZB-MBR and contributed to the system performance. Additionally, Nitrosomonas and Nitrobacter gradually became the dominant ammonia-oxidizing bacteria and nitrite-oxidizing bacteria during the operation, respectively, which are favorable for the stabilized ammonia removal. Our results proved that the ZB-MBR is an alternative technique for treating coking wastewater.     

萎缩芽胞杆菌CKL1促盐胁迫下燕麦生长活性及其功能基因分析

【背景】青海省特殊生境孕育了特殊微生物资源。【目的】探究适合生活于高原生境的芽胞杆菌菌源。【方法】采用平板对峙法、显色法对萎缩芽胞杆菌（Bacillus atrophaeus） CKL1的拮抗、产吲哚乙酸活性进行测定,并检测耐低温、耐盐性及菌株对盐胁迫下燕麦品种（Avena sativa）“青燕1号”种子萌发、幼苗生长效应及叶绿素、脯氨酸、丙二醛的含量变化,利用二代测序技术对菌株进行基因组测序并分析相关功能基因。【结果】菌株CKL1对禾谷镰孢菌（Fusarium graminearum）、锐顶镰孢菌（Fusarium acuminatum）表现出显著的拮抗活性（抑菌圈直径>15 mm）;与Salkowski比色液反应变红,能在NaCl浓度为13%的LB培养基及4℃低温下生长,表现出一定的产吲哚乙酸、耐盐及耐低温活性;盐胁迫下,菌株CKL1对“青燕1号”种子萌发及幼苗生长具有显著促进作用,叶绿素及脯氨酸含量显著增加,丙二醛含量下降,增强了燕麦的抗盐性。菌株CKL1基因组全长为14 281 280 bp,与GO功能数据库比对注释到3 303个功能基因;基因组编码与脂肽类化合物itur...