Design,synthesis, quantum chemical studies and biological activity evaluation of pyrazole–benzimidazole derivatives as potent Aurora A/B kinase inhibitors

Novel pyrazole–benzimidazole derivatives have been designed and synthesized. The entire target compounds were determined against cancer cell lines U937, K562, A549, LoVo and HT29 and were screened for Aurora A/B kinase inhibitory activity in vitro. The compounds 7a, 7b, 7i, 7k and 7l demonstrated significant cancer cell lines and Aurora A/B kinase inhibitory activities. Molecular modeling studies suggested the derivatives have bound in the active site of Aurora A kinase through the formation of four hydrogen bonds. Quantum chemical studies were carried out on these compounds to understand the structural features essential for activity. The cellular activity of 7k was also tested by immunofluorescence.     

Kronecker积在分析多因子非平衡实验中的应用

以Kroneckert积和效应矩阵为工具,阐明了一种分析多因子缺值实验的严格、有效、方便的新方法。     

疼痛患者脊髓脑脊液中强啡肽含量的分析

本文观察了疼痛患者脊髓脑脊液中强啡肽含量的变化。共收集３１例急性疼痛患者和１４例慢性疼痛患者的脊髓脑脊液,测定其中的强啡肽含量,与２７例无痛患者的结果进行比较,并结合被测者的性别、年龄、体重、血压、脉搏、体温等一般情况进行分析。结果表明,慢性痛患者脑脊液中强啡肽含量显著升高,而急性痛患者则略有降低。判别分析表明,急性痛患者的强啡肽含量及其他临床资料有明显的特点（判别准确率８２％）;慢性痛患者未见明显特征。作者认为,在更广泛地收集临床资料和检验结果的基础上,进一步研究不同病因的疼痛患者的临床特征,可能有助于对疼痛疾病进行鉴别诊断     

Highly luminescent S,N co‐doped carbon quantum dots‐sensitized chemiluminescence on luminol–H2O2 system for the determination of ranitidine

S,N co‐doped carbon quantum dots (N,S‐CQDs) with super high quantum yield (79%) were prepared by the hydrothermal method and characterized by transmission electron microscopy, photoluminescence, UV–Vis spectroscopy and Fourier transformed infrared spectroscopy. N,S‐CQDs can enhance the chemiluminescence intensity of a luminol–H₂O₂ system. The possible mechanism of the luminol–H₂O₂–(N,S‐CQDs) was illustrated by using chemiluminescence, photoluminescence and ultraviolet analysis. Ranitidine can quench the chemiluminescence intensity of a luminol–H₂O₂–N,S‐CQDs system. So, a novel flow‐injection chemiluminescence method was designed to determine ranitidine within a linear range of 0.5–50 μg ml^?1 and a detection limit of 0.12 μg ml^?1. The method shows promising application prospects.     

Influence of membrane-cortex linkers on the extrusion of membrane tubes

The cell membrane is an inhomogeneous system composed of phospholipids, sterols, carbohydrates, and proteins that can be directly attached to underlying cytoskeleton. The protein linkers between the membrane and the cytoskeleton are believed to have a profound effect on the mechanical properties of the cell membrane and its ability to reshape. Here, we investigate the role of membrane-cortex linkers on the extrusion of membrane tubes using computer simulations and experiments. In simulations, we find that the force for tube extrusion has a nonlinear dependence on the density of membrane-cortex attachments: at a range of low and intermediate linker densities, the force is not significantly influenced by the presence of the membrane-cortex attachments and resembles that of the bare membrane. For large concentrations of linkers, however, the force substantially increases compared with the bare membrane. In both cases, the linkers provided membrane tubes with increased stability against coalescence. We then pulled tubes from HEK cells using optical tweezers for varying expression levels of the membrane-cortex attachment protein Ezrin. In line with simulations, we observed that overexpression of Ezrin led to an increased extrusion force, while Ezrin depletion had a negligible effect on the force. Our results shed light on the importance of local protein rearrangements for membrane reshaping at nanoscopic scales.     

菜用和观赏甘薯种质资源遗传多样性分析

为了发掘菜用和观赏甘薯优异种质资源,通过对国家种质徐州甘薯试管苗库中1000余份资源材料进行鉴定,筛选了96份优异种质。利用30对SSR引物对入选材料进行了遗传多样性和群体结构分析,明确了这些材料遗传差异;并对入选材料12个表型质量性状进行主成分和聚类分析。结果表明:扩增的总条带数为275条,其中多态性条带为269条,多态率97.8%;利用DPS软件计算入选材料间的Nei72遗传距离为0.15~0.76,平均遗传距离0.66;群体结构分为3个组群,与分子标记聚类结果相似,表明入选材料有较大的遗传差异性;表型质量性状主成分分析得到5个主要成分,其累计贡献率达到80.50%;利用表型质量性状,可聚为8个组群。本研究通过分子标记与表型质量性状分析为下一步杂交选育菜用和观赏甘薯新品种提供了亲本选择信息。     

8-氯腺苷诱导的组蛋白H3K79双甲基化促进NBS1和p21的基因转录激活

组蛋白H3第79位赖氨酸甲基化（H3K79me）修饰有单甲基、双甲基及三甲基3种形式,是常染色质的标志.然而,对于组蛋白H3K79三种甲基化各自在基因转录、DNA损伤修复中所起的作用尚不十分清楚.本研究以8-氯腺苷（8-Cl-Ado）为DNA双链断裂（DNA double-stranded breaks,DSB）诱导剂,采用Western 印迹,在人肺癌细胞H1299检测出了DNA修复分子NBS1、细胞周期检验点相关分子p21,并发现H3K79me1、H3K79me2和H3K79me3三种甲基化修饰的组蛋白明显增加;染色质免疫共沉淀结合实时定量PCR实验显示,只H3K79me2与DNA损伤检验点分子p21、DNA修复分子NBS1的启动子区域相结合,说明H3K79双甲基化修饰与这些基因的转录激活有关.结果提示,在8-氯腺苷引起 DSB时,是H3K79me2、而不是H3K79me1和H3K79me3参与NBS1和p21基因转录激活时的染色质重塑.8-氯腺苷诱导H3K79双甲基化增强、促进H3K79me2所在染色质区域的NBS1和p21基因转录激活可能是8-Cl-Ado抑制肿瘤细胞生长作用机制之一.     

<Emphasis Type="Italic">Drosophila</Emphasis> as a platform to predict the pathogenicity of novel aminoacyl-tRNA synthetase mutations in CMT

Charcot-Marie-Tooth disease (CMT) is the major form of inherited peripheral neuropathy in humans. CMT is clinically and genetically heterogeneous and four aminoacyl-tRNA synthetases have been implicated in disease etiology. Mutations in the YARS gene encoding a tyrosyl-tRNA synthetase (TyrRS) lead to Dominant Intermediate CMT type C (DI-CMTC). Three dominant YARS mutations were so far associated with DI-CMTC. To further expand the spectrum of CMT causing genetic defects in this tRNA synthetase, we performed DNA sequencing of YARS coding regions in a cohort of 181 patients with various types of peripheral neuropathy. We identified a novel K265N substitution that in contrast to all previously described mutations is located at the anticodon recognition domain of the enzyme. Further genetic analysis revealed that this variant represents a benign substitution. Using our recently developed DI-CMTC Drosophila model, we tested in vivo the pathogenicity of this new YARS variant. We demonstrated that the developmental and behavioral defects induced by all DI-CMTC causing mutations were not present upon ubiquitous or panneuronal TyrRS K265N expression. Thus, in line with our genetic studies, functional analysis confirmed that the K265N substitution does not induce toxicity signs in Drosophila. The consistency observed throughout this work underscores the robustness of our DI-CMTC animal model and identifies Drosophila as a valid read-out platform to ascertain the pathogenicity of novel mutations to be identified in the future.