GABAB 受体变构剂药学研究进展

Y-氨基丁酸B受体(GABAB receptor,GABABR)是最具有药理学意义的药物靶点之一,具有复杂而精细的激活机制.传统的GABABR靶点药物开发集中于激动剂和拮抗剂,这类药物受到多种因素的制约,包括较强的副作用、药物代谢困难、机体耐药性明显等.变构剂结合于正构位点之外,能够调节GABABR异源二聚体亚基或结构域间的相互作用.正向变构剂(positive allosteric modulators,PAMs)和负向变构剂(negative allosteric modulators,NAMs)分别可以提高或降低GABABR的活性,并具有较高的特异性和药物安全性,同时还能够保持GABABR信号在时间和空间上的可控性.变构剂为GABABR靶点药物开发提供了新思路.     

胆道镜结合微爆破碎石治疗复杂性胆道结石

目的：探讨微爆破碎石用于治疗复杂胆道结石的治疗体会。方法：在胆道镜直视下,分别在术中和术后对158例复杂的胆道结石患者进行微爆破碎石,然后用取石网取出碎石,泥沙状结石随液体流出或让其自行流入肠道。结果：158例患者156例取石成功。取石成功率98.73%。明显提高了胆道取石的成功率。无1例出现胆道穿孔、瘘道穿孔及胆道出血等严重并发症。结论：在胆道镜下,采用微爆破碎石术治疗复杂的胆道结石是一种安全、可靠、高效的方法,可以明显提高结石的取净率。     

GABAB受体变构剂药学研究进展

Y-氨基丁酸B受体(GABAB receptor,GABABR)是最具有药理学意义的药物靶点之一,具有复杂而精细的激活机制.传统的GABABR靶点药物开发集中于激动剂和拮抗剂,这类药物受到多种因素的制约,包括较强的副作用、药物代谢困难、机体耐药性明显等.变构剂结合于正构位点之外,能够调节GABABR异源二聚体亚基或结构域间的相互作用.正向变构剂(positive allosteric modulators,PAMs)和负向变构剂(negative allosteric modulators,NAMs)分别可以提高或降低GABABR的活性,并具有较高的特异性和药物安全性,同时还能够保持GABABR信号在时间和空间上的可控性.变构剂为GABABR靶点药物开发提供了新思路.     

湖南瓦乡人体质特征研究

本文对308例(男156例,女152例)世居在湖南省沅陵县的瓦乡人进行了70项体质人类学指标(观察项目25项,测量项目45项)的调查, 并计算了21项体质指数, 对部分指数进行了分型统计。结果表明: 湖南瓦乡人毛发浓密, 黑而平直; 上睑皱褶出现率较高, 眼裂开度中等, 上斜型眼裂; 少蒙古褶; 鼻根较高, 鼻梁男多直形、女多凹形, 鼻基上翘, 鼻翼高度中等; 口裂宽度中度, 上唇皮肤部多正唇, 红唇较厚; 耳壳多椭圆或卵圆形, 耳垂形状多圆形。体质特征表现为身材矮短, 体型中间型; 窄肩型; 中腿型; 超狭面型; 圆头型、高头型、中头型; 中鼻型。与我国南方其他27个少数民族群体的头面部及身高10项测量值进行聚类分析, 结果显示湖南瓦乡人体质特征与云南独龙族及拉祜族最接近, 与广西傈僳族、广西侗族及湘西土家族次之。湖南瓦乡人属于蒙古人种的南亚类型, 具有现代黄种人的容貌特征。     

Statistical optimization of a culture medium for biomass and poly(3-hydroxybutyrate) production by a recombinant Escherichia coli strain using agroindustrial byproducts.

A statistically based Plackett-Burman screening design identified milk whey and corn steep liquor concentrations as well as ionic strength (based on phosphate buffer concentration) as the three main independent components of the culture medium that significantly (p < 0.05) influenced biomass and poly(3-hydroxybutyrate) (PHB) production in recombinant cells of Escherichia coli. This strain carries a plasmid encoding phb genes from a natural isolate of Azotobacter sp. Response surface methodology, using a central composite rotatable design, demonstrated that the optimal concentrations of the three components, defined as those yielding maximal biomass and PHB production in shaken flasks, were 37.96 g deproteinated milk whey powder/l, 29.39 g corn steep liquor/l, and 23.76 g phosphates/l (r2 = 0.957). The model was validated by culturing the recombinant cells in medium containing these optimal concentrations, which yielded 9.41 g biomass/l and 6.12 g PHB/l in the culture broth. Similar amounts of PHB were obtained following batch fermentations in a bioreactor. These results show that PHB can be produced efficiently by culturing the recombinant strain in medium containing cheap carbon and nitrogen sources.     

MiR-21在结缔组织病并间质性肺病患者外周血中的表达及临床意义

目的:探讨miR-21在结缔组织病(Connective tissue disease, CTD)并间质性肺病(Interstitial lung disease, ILD)患者外周单个核细胞中的表达及临床意义。方法:选择2015年1月-2018年6月我院收治的202例CTD患者,将其分为CTD-ILD组(n=58)和CTD无ILD组(n=152),对CTD-ILD患者的临床资料进行归纳分析,对不同结缔组织病合并间质性肺疾病组间的临床表现、胸部影像表现进行比较分析。收集两组外周血分离其外周血单个核细胞并采用实时荧光定量PCR法检测各组外周血单个核细胞中miR-21的表达水平,分析CTD-ILD组miR-21与患者临床特征的关系。结果:CTD-ILD的影像学表现多种多样:网格影在SSc、RA、PM/DM患者中多见;蜂窝影多见于SSc的患者;实变影多见于SLE、PM/DM的患者。CTD-ILD组外周单个核细胞中miR-21表达水平较对照组增高,并与肺功能DLCO呈负相关。结论:不同CTD-ILD的发病率不同,临床特点及影像学也各有差异。miR-21对评估CTD-ILD的病变严重程度具有一定价值,可作为诊断CTD-ILD的血清标志物辅助ILD早期诊断与病变程度评估。     

湖南侗族体质现状及其与30年前资料的比较

对湖南通道侗族自治县326(男118,女108)例正常成年侗族进行了活体观察与活体测量,分析了侗族的体质特征及其对应分型,通过与30年前同一地区的资料进行动态比较分析显示,湖南侗族身高没有明显变化,头面部的形态有向长窄高变化的趋势,女性体质特征变化较男性更明显。同时,湖南侗族与我国南方其他19个群体聚类分析结果表明,湖南侗族体质特征与广西侗族、湖北侗族、广西彝族和瑶族,以及贵州三都布依族较接近。     

Elimination of d-Lactate Synthesis Increases Poly(3-Hydroxybutyrate) and Ethanol Synthesis from Glycerol and Affects Cofactor Distribution in Recombinant Escherichia coli

The effect of eliminating d-lactate synthesis in poly(3-hydroxybutyrate) (PHB)-accumulating recombinant Escherichia coli (K24K) was analyzed using glycerol as a substrate. K24KL, an ldhA derivative, produced more biomass and had altered carbon partitioning among the metabolic products, probably due to the increased availability of carbon precursors and reducing power. This resulted in a significant increase of PHB and ethanol synthesis and a decrease in acetate production. Cofactor measurements revealed that cultures of K24K and K24KL had a high intracellular NADPH content and that the NADPH/NADP⁺ ratio was higher than the NADH/NAD⁺ ratio. The ldhA mutation affected cofactor distribution, resulting in a more reduced intracellular state, mainly due to a further increase in NADPH/NADP⁺. In 60-h fed-batch cultures, K24KL reached 41.9 g·liter⁻¹ biomass and accumulated PHB up to 63% ± 1% (wt/wt), with a PHB yield on glycerol of 0.41 ± 0.03 g·g⁻¹, the highest reported using this substrate.Poly(3-hydroxybutyrate) (PHB) is the best-known and most common polyhydroxyalkanoate (PHA). PHAs are polymers with thermoplastic properties that are totally biodegradable by microorganisms present in most environments and that can be produced from different renewable carbon sources (38). Accumulated as intracellular granules by many bacteria under unfavorable conditions (1, 21), PHAs are carbon and energy reserves and also act as electron sinks, enhancing the fitness and stress resistance of bacteria and contributing to redox balance (12, 30). Escherichia coli offers a well-defined physiological environment for the construction and manipulation of various metabolic pathways to produce different bioproducts, such as PHB, from cost-effective carbon sources.In recent years, a significant increase in the production of biodiesel has caused a sharp fall in the cost of glycerol, the main by-product of biodiesel synthesis. As a result, glycerol has become a very attractive substrate for bacterial fermentations (10), specially for reduced products, such as PHB (36). The E. coli strain used in this work, K24K, carries phaBAC, the structural genes responsible for PHB synthesis, from Azotobacter sp. strain FA8 (23) (Table ​(Table1).1). The pha genes in K24K are expressed from a chimeric promoter and consequently are not subject to the genetic regulatory systems present in natural PHA producers. Because of this, it can be assumed that regulation of PHA synthesis in the recombinants is restricted by enzyme activity levels, modulated principally by substrate availability. In most natural producers, and also in PHB-producing E. coli recombinants, PHB is synthesized through the condensation of two molecules of acetyl-coenzyme A (acetyl-CoA), catalyzed by an acetoacetyl-CoA transferase or 3-ketothiolase, resulting in acetoacetyl-CoA. This compound is subsequently reduced by an NAD(P)H-dependent acetoacetyl-CoA reductase to R-(−)-3-hydroxybutyryl-CoA, which is then polymerized by a specific PHA synthase (34).

TABLE 1.

E. coli strains, plasmids, and oligonucleotides used in this study