Discovery of pyrazine carboxamide CB1 antagonists: the introduction of a hydroxyl group improves the pharmaceutical properties and in vivo efficacy of the series

Structure-activity relationships for a series of pyrazine carboxamide CB1 antagonists are reported. Pharmaceutical properties of the series are improved via inclusion of hydroxyl-containing sidechains. This structural modification sufficiently improved ADME properties of an orally inactive series such that food intake reduction was achieved in rat feeding models. Compound 35 elicits a 46% reduction in food intake in ad libidum fed rats 4-h post-dose.     

Tandem optimization of target activity and elimination of mutagenic potential in a potent series of N-aryl bicyclic hydantoin-based selective androgen receptor modulators

Pharmacokinetic studies in cynomolgus monkeys with a novel prototype selective androgen receptor modulator revealed trace amounts of an aniline fragment released through hydrolytic metabolism. This aniline fragment was determined to be mutagenic in an Ames assay. Subsequent concurrent optimization for target activity and avoidance of mutagenicity led to the identification of a pharmacologically superior clinical candidate without mutagenic potential.     

Residues Met~(76) and Gln~(79) in HLA-G α1 domain involved in KIR2DL4 recognition

INTRODUCTIONThe non-classical HLA class I antigen HLA-G is mainlyexpressed on extravillous cytotrophoblasts that invade de-ciduae in uterine pregnancy. Furthermore, HLA-G canmodulate the function of most immune component cellssuch as NK cells, T cells and…     

RNA干扰的研究进展

RNA干扰是指外源双链RNA进入细胞后引起与其同源的mRNA特异性降解的现象,它是真核生物在长期进化中形成的一种保守的防御机制,对真核生物有着重要的意义,它参与真核生物抵御病毒侵染、阻断转座子的异常活动,调控基因表达。RNA干扰已成为一种进行基因功能分析的强有力的工具,并有望成为最有潜力的基因干预治疗方法。     

温度对波纹龙虾存活、摄食、蜕壳和生长的影响

波纹龙虾是热带和亚热带重要经济虾类,养殖潜力巨大。本文进行温度渐变和骤变对波纹龙虾存活、摄食影响试验,以确定存活和摄食的水温范围;进行了波纹龙虾在不同温度条件下(22、25、28、31、34℃)对其存活率、饵料用效率、蜕壳和生长情况的影响试验,以确定最适养殖水温,试验时间90 d。结果表明:波纹龙虾的生存温度范围为13—36℃,适宜温度为20—30℃。在温度22—31℃范围内,波纹龙虾的存活率和特定生长率随着温度的升高表现为先升后降,在28℃达到最大值,各组之间差异显著(P0.05);温度显著影响波纹龙虾对鲜活饵料的利用效率,饵料系数最高的是31℃组,为6.43±0.28;28℃组的波纹龙虾饵料系数最低,为5.75±0.70,与其它各组有显著差异(P0.05)。波纹龙虾的蜕壳周期随着温度的升高逐渐缩短,31℃组周期最短(16.7 d),22℃蜕壳周期最长(18.8 d),但各组之间差异不显著(P0.05)。综合以上因素考虑,波纹龙虾养殖水温宜控制在28℃。     

BmSE, a SINE family with 3′ ends of (ATTT) repeats in domesticated silkworm (Bombyx mori)

Short interspersed elements (SINEs), which are mainly composed of Bm1, are abundant in the domesticated silkworm. A 294 bp novel SINE family, designated as BmSE, was identified by mining the database of the complete Bombyx mori genome. A representational BmSE element is flanked by an 11 bp target site duplication sequence posterior poly (A) at the 3′ end and has the sequence motifs of an internal promoter of RNA polymerase III, which are similar to that of Bm1. The repetitive elements of BmSE are ...     

黏着斑激酶及其小分子抑制剂作为抗肿瘤药物的研究进展

抗黏着斑激酶是一种非受体型酪氨酸蛋白激酶,在许多肿瘤的发生和发展过程中均有过表达。研究表明,作为细胞内重要的骨架蛋白和调节多种细胞信号通路的关键分子,黏着斑激酶在肿瘤发生、发展、迁移和侵袭的各个阶段都起着重要作用。因此,以黏着斑激酶作为抗肿瘤靶点开发其抑制剂的研究受到广泛关注。综述黏着斑激酶的结构与功能、它与肿瘤的关联及其小分子抑制剂的研究与开发。     

水稻窄叶突变体nal（t）的表型分析与基因定位

在水稻（Oryza sativa）缙恢10号的EMS诱变群体中发现一个窄叶突变体nal（t）,表现出叶片变窄不变短、植株半矮化、节间变细变短和穗长缩短等特性。突变体苗期和成熟期叶片平均宽度为0.99cm和1.42cm,分别为野生型的76%和74%,均达到极显著差异。nal（t）成熟期倒一、倒二、倒三节间长和宽分别为9.16cm、6.97cm、3.57cm和0.31cm、0.36cm、0.45cm,仅为野生型的63%、83%、71%和78%、72%、79%。遗传分析表明该突变性状受1对隐性核基因控制,利用SSR标记将NAL（T）定位在第12染色体长臂RM6869和RM28537之间,遗传距离分别为3.1cM和9.0cM。     

Natural selection maintains the transcribed LTR retrotransposons in Nosema bombycis

Eight intact LTR retrotransposons(Nbr1?Nbr8)have been previously characterized from the genome of Nosema bombycis,a eu-karyotic parasite with a compact and reduced genome.Here we describe six novel transcribed Nbr elements(Nbr9?Nbr14)identified through either cDNA library or RT-PCR.Like previously determined ones,all of them belong to the Ty3/Gypsy superfamily.Retrotransposon diversity and incomplete domains with insertions(Nbr12),deletions(Nbr11)and in-frame stop codons in coding regions(Nbr9)were detected...     

骨形态发生蛋白9通过p38激酶途径调控间充质干细胞C3H10T1/2成骨分化

前期研究发现骨形态发生蛋白9(bone morphogenetic protein 9,BMP9)具有较强的诱导间充质干细胞成骨分化的能力.为进一步揭示其诱导和调控间充质干细胞成骨分化的机理,利用BMP9重组腺病毒感染间充质干细胞C3H10T1/2,通过体外细胞实验和体内动物实验,初步分析BMP9是否可通过p38激酶途径调控间充质干细胞成骨分化.结果发现,BMP9可以通过促进p38激酶磷酸化而导致其活化,p38抑制剂SB203580可抑制由BMP9诱导的C3H10T1/2细胞的碱性磷酸酶(alkalinephosphatase,ALP)活性、骨桥蛋白(osteopontin,OPN)表达和钙盐沉积,而且利用抑制剂SB203580抑制p38激酶活性后,BMP9诱导的Smad经典途径的激活也相应受到抑制,RNA干扰导致p38基因沉默同样也可抑制BMP9诱导的ALP活性、OPN表达、钙盐沉积以及裸鼠皮下异位成骨.因此,BMP9可通过活化p38激酶途径调控间充质干细胞C3H10T1/2成骨分化.