Molecular dynamics simulations provide insights into the origin of gleevec’s selectivity toward human tyrosine kinases

Protein kinases are critical drug targets against cancer. Since the discovery of Gleevec, a specific inhibitor of Abl kinase, the capability of this drug to distinguish between Abl and other tyrosine kinases, such as Src, has been intensely investigated but the origin of Gleevec’s selectivity to Abl against Src is less studied. Here, we performed molecular dynamics (MD) simulations, dynamical cross-correlation matrices (DCCM), dynamical network analysis, and binding free energy calculations to explore Gleevec’s selectivity based on the crystal structures of Abl, Src, and their common ancestors (ANC-AS) and the two constructed mutation systems (AS→Abl and AS→Src). MD simulations revealed that the conformation of the phosphate-binding loop (P-loop) was altered significantly in the AS→Abl system. DCCM results unraveled that mutations increased anticorrelated motions in the AS→Abl system. Community network analysis suggested that the P-loop established special contacts in the AS→Abl system that are devoid in the AS→Src system. The binding free energy calculations unveiled that the affinity of Gleevec to AS→Abl increased to near the Abl level, whereas its affinity to AS→Src decreased to near the Src level. Analysis of individual residue contributions showed that the differences were located mainly at the P-loop. This study is valuable for understanding the sensitivity of Gleevec to human tyrosine kinases.

Communicated by Ramaswamy H. Sarma     

The Smad3-miR-29b/miR-29c axis mediates the protective effect of macrophage migration inhibitory factor against cardiac fibrosis

Although macrophage migration inhibitory factor (MIF) is known to have antioxidant property, the role of MIF in cardiac fibrosis has not been well understood. We found that MIF was markedly increased in angiotension II (Ang-II)-infused mouse myocardium. Myocardial function was impaired and cardiac fibrosis was aggravated in Mif-knockout (Mif-KO) mice. Functionally, overexpression of MIF and MIF protein could inhibit the expression of fibrosis-associated collagen (Col) 1a1, COL3A1 and α-SMA, and Smad3 activation in mouse cardiac fibroblasts (CFs). Consistently, MIF deficiency could exacerbate the expression of COL1A1, COL3A1 and α-SMA, and Smad3 activation in Ang-II-treated CFs. Interestingly, microRNA-29b-3p (miR-29b-3p) and microRNA-29c-3p (miR-29c-3p) were down-regulated in the myocardium of Ang-II-infused Mif-KO mice but upregulated in CFs with MIF overexpression or by treatment with MIF protein. MiR-29b-3p and miR-29c-3p could suppress the expression of COL1A1, COL3A1 and α-SMA in CFs through targeting the pro-fibrosis genes of transforming growth factor beta-2 (Tgfb2) and matrix metallopeptidase 2 (Mmp2). We further demonstrated that Mif inhibited reactive oxygen species (ROS) generation and Smad3 activation, and rescued the decrease of miR-29b-3p and miR-29c-3p in Ang-II-treated CFs. Smad3 inhibitors, SIS3 and Naringenin, and Smad3 siRNA could reverse the decrease of miR-29b-3p and miR-29c-3p in Ang-II-treated CFs. Taken together, our data demonstrated that the Smad3-miR-29b/miR-29c axis mediates the inhibitory effect of macrophage migration inhibitory factor on cardiac fibrosis.     

五大连池火山色木槭叶功能性状特征

植物功能性状反映了植物对生长环境的响应和适应, 是连接植物与环境的桥梁, 研究植物功能性状特征及其随坡向的变化规律, 对认识不同微地形生境下植物群落空间格局形成及适应机制具有重要意义。本文以五大连池不同历史年代的8座火山共有树种色木槭(Acer mono)为研究对象, 测定了9类叶功能性状, 研究了植物叶功能性状在火山间及火山坡向间(阴坡-阳坡)的变化规律, 以期揭示生境对火山植物主要叶功能性状的影响, 以及阴阳坡植物生存策略的变化, 初步探讨了植物对环境的适应机制。结果表明: (1)坡向的变化是造成色木槭叶功能性状差异的重要原因; (2)火山间叶功能性状的差异反映了它们具有不同的资源环境, 色木槭生长主要受氮元素的限制; (3)南北坡向及火山间叶片厚度与叶面积均呈极显著的正相关关系, 叶片厚度与比叶面积在不同火山间均呈显著的正相关关系, 这与色木槭在火山土壤条件下的自我保护密切相关, 色木槭通过这些指标间的功能调节来适应环境的变化, 并形成最佳功能组合。五大连池不同历史年代火山的色木槭采用增加植物叶片叶干物质浓度、叶面积、叶片厚度、叶氮和叶磷浓度提高固碳能力, 通过降低比叶面积和氮磷比来适应干旱、土壤养分贫瘠的环境。     

Effects of experimental warming on wild and transgenic oriental fruit fly,Bactrocera dorsalis

Climate change may influence the application efficiency of transgenic marking, such as in mark–release–recapture (MRR) experiments or sterile insect technique (SIT). Wild and transgenic fruit flies of Bactrocera dorsalis were subjected to oscillating regimes that represent current temperature conditions (mean: 28.6°C) and various future possible scenarios (means: 30.0, 32.5 and 35.0°C). As the temperature was increased to 30.0°C, the negative effects on adult fecundity and demographic parameters (net reproductive rate and intrinsic rate of increase) of only the transgenic cohorts increased. With a moderate warming (32.5°C), negative effects were observed on the net reproductive rate for both fly strains, and these effects on the life‐history traits (adult fecundity and longevity) and intrinsic rate of increase were stronger in the transgenic than in the wild cohorts, with reference to the trait values at 30.0°C. A severe warming (35.0°C) resulted in the failure of all individuals of both fly strains to reach adulthood. We suggest parametrical adjustments or decreased differences in fitness with refined transgenesis under current and future climate conditions, which can reduce the marking limitations of pest management and eradication programmes.     

BH3 mimetics derived from Bim-BH3 domain core region show PTP1B inhibitory activity

A series of our previously described BH3 peptide mimetics derived from Bim-BH3 domain core region were found to exhibit weak to potent PTP1B binding affinity and inhibitory activities via target-based drug screening. Among these compounds, a 12-aa Bim-BH3 core sequence peptide conjugated to palmitic acid (SM-6) displayed good PTP1B binding affinity (K_D?=?8.38?nmol/L), inhibitory activity (IC₅₀?=?1.20?μmol/L) and selectivity against other PTPs (TCPTP, LAR, SHP-1 and SHP-2). Furthermore, SM-6 promoted HepG2 cell glucose uptake and inhibited the expression of PTP1B, indicating that SM-6 could improve the insulin resistance effect in the insulin-resistant HepG2 cell model. These results may indicate a new direction for the application of BH3 peptide mimetics and promising PTP1B peptide inhibitors could be designed and developed based on SM-6.     

RNA结合蛋白PABPC1的功能及生物学作用

多聚腺苷酸结合蛋白(poly (A) binding protein,PABP)家族通常被认为是mRNA poly (A)尾的一种保护屏障.其中细胞质多聚腺苷酸结合蛋白1 (cytoplasmic poly (A) binding protein-1,PABPC1)在高亲和力作用下能够与mRNA中富含腺苷酸的序列结合,在基因转录后调控中发挥着重要作用.同时PABPC1还参与mRNA的许多代谢通路,包括腺苷酸多聚化/脱腺苷酸化、m RNA转运、m RNA翻译、降解及mircoRNA相关调控.近年来关于PABPC1与生殖细胞的发育、心肌肥大和肿瘤的发生发展的报道屡见不鲜,可见PABPC1与细胞的生长发育有密切联系.本文将主要介绍PABPC1的结构、表达调控、功能及其生物学作用.     

黄精种子萌发及组培技术研究

研究了不同的激素对多花黄精种子的萌发及组培的影响。研究结果表明:多花黄精种子萌发的最佳激素条件为6-BA 180.0 mg/L+GA_3 60.0 mg/L,两种激素可能有交互作用;多花黄精块茎外植体的最佳灭菌时间为12 min;最佳诱导外植体愈伤组织培养基为:6-BA 2.0 mg/L+2,4-D 0.2 mg/L+MS,低浓度的6-BA利于多花黄精块茎愈伤诱导;最佳诱芽培养基为:6-BA 6.0 mg/L+NAA 0.2 mg/L+MS和6-BA 4.0 mg/L+TDZ 0.2 mg/L+NAA 0.2 mg/L+MS,低浓度的TDZ对不定芽的诱导和生长有促进作用;最佳生根培养基为:IBA 1.0 mg/L+1/2MS,但是过高浓度的IBA会抑制根的诱导。通过多花黄精的繁殖技术的研究,以期为多花黄精的快繁提供技术支持。     

不同基质和处理对6种山茶花扦插成活率的影响

研究不同基质和处理对6个拟作为年宵花的山茶花新品种扦插成活率的影响。采用3种不同的基质配比和3种不同的处理对6个品种的山茶花进行了扦插试验。结果表明,泥炭与黄土或珍珠岩的混合基质最适合该6个品种的扦插生根,生根粉对6个山茶花品种的成活率影响不大,但插口加裹黄土后能有效提高其成活率。6个品种在最佳的扦插条件下的成活率在85%-92%之间。研究结果为快速大量地生产这些品种提供技术支持。     

环境友好型杨梅园高效栽培类型与综合效益评价

杨梅园实行精耕细作,会造成生物多样性下降、水土流失加重、杨梅病虫害加剧等不良后果。为克服或缓解这些难题,对杨梅林开展了不同类型的混交栽培模式和抚育方式的研究。结果表明:进行机械割草的杨梅园生物多样性较优,其维管束植物总计达78种,而以药剂除草的,总计仅11种,差异极显著;"杨梅针、阔、竹混交林+自然生草+机械割草"、"杨梅纯林+自然生草+机械割草"和"杨梅纯林+清耕(除草剂除草)"等三种栽培与抚育类型的主要病害有杨梅癌肿病等2种,主要虫害有白蚁类、袋蛾类、栗黄枯叶蛾等7种(类),均以针、阔、竹混交栽培模式受害最轻。对"杨梅+蓝莓"、"杨梅+蕨类(种植)"和杨梅自然生草等3种栽培模式以及机械割草、人工割草和药剂除草等3种抚育方式的"三大效益"进行了综合评价。