Design,synthesis, and biological evaluation of novel carbazole derivatives as potent DNMT1 inhibitors with reasonable PK properties

The DNA methyltransferases (DNMTs) were found in mammals to maintain DNA methylation. Among them, DNMT1 was the first identified, and it is an attractive target for tumour chemotherapy. DC_05 and DC_517 have been reported in our previous work, which is non-nucleoside DNMT1 inhibitor with low micromolar IC₅₀ values and significant selectivity towards other S-adenosyl-_L-methionine (SAM)-dependent protein methyltransferases. In this study, through a process of similarity-based analog searching, a series of DNMT1 inhibitors were designed, synthesized, and evaluated as anticancer agents. SAR studies were conducted based on enzymatic assays. And most of the compounds showed strong inhibitory activity on human DNMT1, especially WK-23 displayed a good inhibitory effect on human DNMT1 with an IC₅₀ value of 5.0 µM. Importantly, the pharmacokinetic (PK) profile of WK-23 was obtained with quite satisfying oral bioavailability and elimination half-life. Taken together, WK-23 is worth developing as DNMT1-selective therapy for the treatment of malignant tumour.     

左右半结肠癌多组学分子特征差异的研究进展

结肠癌(colon cancer,CC)是一种常见的恶性肿瘤,其发病率和死亡率均占癌症前列.根据解剖学位置,CC可分为左半结肠癌(left-sided colon cancer,LCC)和右半结肠癌(right-sided colon cancer,RCC),两者在临床特征上表现出较大的差异.近些年来,随着生物学技术和...     

阿尔泰蝠蛾(鳞翅目:蝠蛾科)活蛹性别的无损鉴别方法

通过观察阿尔泰蝠蛾雌雄蛹的外部形态结构,并测量其体征和体重数据,寻找可用于鉴别蛹性别的无损方法;再借助于解剖等方法鉴别蛹的确切性别,检测鉴别方法的准确性。结果显示,雌雄蛹在体征和体重数据的分布范围上有重叠,不能籍此区分其雌雄性。然而,雄蛹腹面第8腹节和第9腹节间分节明显,第9腹节未向第8腹节纵伸,生殖孔位于第9腹节上,生殖孔两侧各有一球形突起,生殖孔前缘与肛门前缘间的距离短于肛门的长度;雌蛹不具备以上特征。基于这些特征开发的鉴别阿尔泰蝠蛾蛹雌雄的方法,鉴别活蛹的准确率均为100%(n=180)。该方法对活蛹无损伤、准确、可靠、简便易学。     

应用X光荧光法检测硫的化学位移和研究病毒感染植物中硫状态的改变

应用双晶X光荧光光谱仪研究生理性和病理性植物组织中某些元素的分布特征已有报道。本研究工作中采用日本国东芝厂出品的AFV701型双晶X光荧光光谱仪,测定并比较了植物感染病毒前、后的叶片中,不同硫状态相对比例的改变。应用此仪器首先测定各种标准硫化物硫状态的化学位移数值,在确定标准图谱及可分性之后,再测定感染蚕豆萎蔫病毒(BBWV)、黄瓜花叶病毒(CMV)、芜菁花叶病毒(TuMV)的茄、苋色藜、烟草和萝卜等四种寄主植物的显症病叶中不同硫状态的相对比例。发现应用此技术能明显地区别出病态植物与健康植物中硫状态相对比例的变化差异。     

Immune-related microRNAs are abundant in breast milk exosomes

Breast milk is a complex liquid rich in immunological components that affect the development of the infant's immune system. Exosomes are membranous vesicles of endocytic origin that are found in various body fluids and that can mediate intercellular communication. MicroRNAs (miRNAs), a well-defined group of non-coding small RNAs, are packaged inside exosomes in human breast milk. Here, we identified 602 unique miRNAs originating from 452 miRNA precursors (pre-miRNAs) in human breast milk exosomes using deep sequencing technology. We found that, out of 87 well-characterized immune-related pre-miRNAs, 59 (67.82%) are presented and enriched in breast milk exosomes (P < 10(-16), χ(2) test). In addition, compared with exogenous synthetic miRNAs, these endogenous immune-related miRNAs are more resistant to relatively harsh conditions. It is, therefore, tempting to speculate that these exosomal miRNAs are transferred from the mother's milk to the infant via the digestive tract, and that they play a critical role in the development of the infant immune system.     

人γ干扰素突变体(rIFN-γ132-PGIL)的构建及其生物学活性的测定

利用DNA重组技术,去掉人γ干扰素(IFNγ)基因3′端含编码多肽羧基(C)端11个氨基酸的核苷酸序列,与编码P,G,I,L的DNA序列相连接,构成IFNγ突变体(rIFN-γ132-PGIL)基因,将后者插入pBV220P_RP_L串连启动子下游,转化大肠杆菌DH5α,在CIts857基因的调节下,通过升温诱导,获得了高效表达,表达量约占菌体可溶性蛋白的30％以上,抗病毒活性平均可达4.9×10~-8U/L,比母体菌株高10倍。SDS—PAGE结果表明,rIFN-γ132—PGIL分子量为17kd。     

根癌农杆菌介导AtNHX1基因转化番茄的研究

构建AtNHX1基因植物表达载体,通过农杆菌介导法将其转入番茄。探讨了外植体类型、农杆菌菌株和不同筛选标记对芽诱导分化的影响。对抗性植株进行PCR检测,获得15株转基因植株。对转基因番茄T1代进行80mmol/LNaHCO胁迫处理,转基因植株的相对生长量高于对照植株,显示AtNHX1基因的导入提高了番茄对碱性盐的耐受性。     

短嘴金丝燕回声定位叫声特征

2012年6月,对湖南省石门县壶瓶山国家级自然保护区神景洞短嘴金丝燕的回声定位叫声进行研究,在黑暗山洞内使用录音仪器录制其自由飞行状态的声音后使用声音软件进行分析.短嘴金丝燕捕食归巢时,快速飞入洞口,在洞内有光区域不发声,到达洞内黑暗区域后开始发出回声定位叫声,且飞行速度减慢.声音分析结果表明其回声定位叫声为双脉冲组的噪声脉冲串型(noise burst),组内脉冲间隔很短[(6.6±0.42)ms],组间脉冲间隔较长[(99.3±3.86) ms],两者差异显著(P＜0.01).对比第一、第二脉冲声音参数发现,主频和脉冲时程差异不显著,第一、第二脉冲主频分别为(6.2±0.08) kHz和(6.2±0.10) kHz (P＞0.05);脉冲时程分别为(2.9±0.12) ms和(3.2±0.17) ms (P＞0.05);最高和最低频率差异显著,第一、第二脉冲最高频率分别为(20.1±1.10) kHz和(15.4±0.98) kHz (P＜0.01),最低频率分别为(3.7±0.12) kHz和(4.0±0.09)kHz (P＜0.05);第一脉冲频宽((16.5±1.17) kHz)宽于第二脉冲((11.4±1.01) kHz) (P＜0.01);且第一脉冲能量[(-32.5±0.60) dB]高于第二脉冲[(-35.2±0.94) dB] (P＜0.05).另外,短嘴金丝燕在黑暗山洞内的回声定位叫声还包含了部分超声波,最高频率可达33.2 kHz.     

CaMBP-10的cDNA克隆和表达及钙调素结合活性分析

采用RT PCR法 ,从中国大白菜中分离了编码CaMBP 1 0的cDNA克隆 .该cDNA全长 4 96bp ,编码 92个氨基酸 ,3′端含有 2 1 6bp的非编码区和poly A尾 .将此BP 1 0cDNA的成熟蛋白序列导入表达质粒pET1 5b并转化至大肠杆菌E .coliBL2 1 (DE3)condonplus RIL进行表达 .以免疫印迹和钙调素结合分析法对重组BP 1 0进行鉴定 ,证明其保持了与天然BP 1 0相同的钙调素结合活性 .氨基酸和核苷酸序列分析结果显示 ,它与植物转脂蛋白高度同源 ,特别是含有 8个保守半胱氨酸 .BP 1 0与转脂蛋白之间具极为相似的理化性质如分子量、等电点、热稳定性等 .据此认为 ,CaMBP 1 0是转脂蛋白家族的新成员 ,Ca2 + CaM信号系统可能参与植物转脂蛋白功能的调节