黄芪建中汤肠内灌注对抗生素相关性腹泻患者肠道菌群、粘膜功能及炎性因子表达的影响

背景临床对抗生素相关性腹泻(antibiotic-associated diarrhea,AAD)尚无特效疗法,一般采用支持治疗与重建正常菌群-微生物制剂,但疗效不理想.黄芪建中汤源自张仲景《金匮要略》,为温阳健脾代表方,具有和胃止痛、温中健脾等功效.目的分析黄芪建中汤肠内灌注对抗生素相关性腹泻患者肠道菌群结构、肠粘膜功能损伤及炎性因子表达的影响.方法选取2016-12/2018-12于本院接受治疗的脾胃虚寒型AAD患者148例,随机数字表法将患者分成2组,分别为对照组(74例)口服双歧杆菌四联活菌片,观察组(74例)在对照组基础上采用黄芪建中汤肠内灌注.观察患者临床疗效、血清炎性因子含量、T淋巴细胞亚群、肠道菌群结构及肠粘膜屏障功能改善情况.结果观察组患者总有效率为94.59%,高于对照组79.73%,差异有统计学意义(P<0.05);治疗后2组患者血清白细胞介素-6(interleukin-6,IL-6)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、降钙素原(procalcitonin,PCT)及C反应蛋白(C-reactive protein,CRP)含量较治疗前降低,且观察组血清IL-6、TNF-α、PCT及CRP含量低于对照组,差异有统计学意义(P<0.05);治疗后2组患者粪便内双歧杆菌、肠杆菌及乳杆菌较治疗前升高,观察组粪便内双歧杆菌、肠杆菌及乳杆菌高于对照组,差异有统计学意义(P<0.05);治疗后2组患者血清细菌内毒素(endotoxin,BT)、D-乳酸(D-lactic acid,D-LC)及二胺氧化酶(diamine oxidase,DAO)含量较治疗前降低,观察组患者血清BT、D-LC及DAO含量低于对照组,差异有统计学意义(P<0.05).结论黄芪建中汤肠内灌注治疗AAD有效率高于双歧杆菌四联活菌片,能够可降低AAD患者血清炎性因子水平,加强机体免疫力,改善患者肠粘膜屏障功能与肠道菌群结构.

The first offshore natural gas hydrate production test in South China Sea

Natural gas hydrates (NGH)is one of key future clean energy resources.Its industrialized development will help remit the huge demand of global natural gas,relieve the increasing pressure of the environment, and play a vital role in the green sustainable growth of human societies.Based on nearly two decades' studying on the reservoir characteristics in the South China Sea (SCS)and the knowledge of reservoir system,the China Geological Survey (CGS)conducted the first production test on an optimal target selected in Shenhu area SCS in 2017.Guided by the "three-phase control"exploitation theory which focused on formation stabilization,technologies such as formation fluid extraction,well drilling and completing, reservoir stimulating,sand controlling,environmental monitoring,monitoring and preventing of secondary formation of hydrates were applied.The test lasted for 60 days from May 10^th when starting to pump, drop pressure and ignite to well killing on July 9^th,with gas production of 3.09×10^5 m^3 in total,which is a world record with the longest continuous duration of gas production and maximal gas yield.This successful test brings a significant breakthrough on safety control of NGH production.

The second natural gas hydrate production test in the South China Sea

Clayey silt reservoirs bearing natural gas hydrates(NGH)are considered to be the hydrate-bearing reservoirs that boast the highest reserves but tend to be the most difficult to exploit.They are proved to be exploitable by the first NGH production test conducted in the South China Sea in 2017.Based on the understanding of the first production test,the China Geological Survey determined the optimal target NGH reservoirs for production test and conducted a detailed assessment,numerical and experimental simulation,and onshore testing of the reservoirs.After that,it conducted the second offshore NGH production test in 1225 m deep Shenhu Area,South China Sea(also referred to as the second production test)from October 2019 to April 2020.During the second production test,a series of technical challenges of drilling horizontal wells in shallow soft strata in deep sea were met,including wellhead stability,directional drilling of a horizontal well,reservoir stimulation and sand control,and accurate depressurization.As a result,30 days of continuous gas production was achieved,with a cumulative gas production of 86.14×104 m3.Thus,the average daily gas production is 2.87×10^4 m^3,which is 5.57 times as much as that obtained in the first production test.Therefore,both the cumulative gas production and the daily gas production were highly improved compared to the first production test.As indicated by the monitoring results of the second production test,there was no anomaly in methane content in the seafloor,seawater,and atmosphere throughout the whole production test.This successful production test further indicates that safe and effective NGH exploitation is feasible in clayey silt NGH reservoirs.The industrialization of hydrates consists of five stages in general,namely theoretical research and simulation experiments,exploratory production test,experimental production test,productive production test,and commercial production.The second production test serves as an important step from the exploratory production test to experimental production test.

Preliminary results of environmental monitoring of the natural gas hydrate production test in the South China Sea

Natural gas hydrate (NGH)is considered as one of the new clean energy sources of the 21st century with the highest potential.The environmental issues of NGH production have attracted the close attention of scientists in various countries.From May 10 to July 9,2017,the first offshore NGH production test in the South China Sea (SCS)was conducted by the China Geological Survey.In addition,environmental security has also been effectively guaranteed via a comprehensive environmental monitoring system built during the NGH production test.The monitoring system considered sea-surface atmosphere methane and carbon dioxide concentrations,dissolved methane in the sea water column,and the seafloor physical oceanography and marine chemistry environment.The whole process was monitored via multiple means, in multiple layers,in all domains,and in real time.After the production test,an environmental investigation was promptly conducted to evaluate the environmental impact of the NGH production test. The monitoring results showed that the dissolved methane concentration in seawater and the near-seabed environment characteristics after the test were consistent with the background values,indicating that the NGH production test did not cause environmental problems such as methane leakage.

百部叶碱核心骨架新合成策略探索:含三个连续手性中心双环中间体的对映选择性构筑

本文研究了百部叶碱核心骨架新合成策略中一个含三个连续手性中心双环中间体的对映选择性构筑.以本实验室发展的(S)-苹果酰亚胺为手性源,后者经三步反应转化为氮上带亲核性烯丙基硅烷取代基的苹果酰亚胺.正丁基格氏试剂对上述苹果酰亚胺的加成区域选择性地引入百部叶碱的C-3侧链.关键的环化反应为三氟化硼合乙醚引发的分子内氮杂Sakurai反应.该反应能高产率地进行,但生成4个非对映立体异构体.通过细致的二维核Overhauser效应(NOESY)研究确定了上述4个非对映立体异构体中两新形成手性中心的立体化学,并确定了主要立体异构体(产率:35%)为合成百部叶碱天然对映体所需.Wacker氧化生成标题化合物及少量区域异构体(醛),比例为18:1,合并产率50%.

A Stepwise Annulation for the Transformation of Cyclic Ketones to Fused 6 and 7-Membered Cyclic Enimines and Enones

The efficient construction of functionalized polycyclic structures is an imports nt objective in organic synthesis.Herein,we disclose a three-step"[2+n]"annulation method for the transformation of cyclic ketones to fused enimines and enones.The method relies on the Suzuki coupling reaction and the amide reductive alkenylation reaction.A series of fused bicyclic(6/6,6/7,8/7)and tricyclic(6/6/6;6/6/7,6/5/7)ring systems bearing an α,β-enimine or an α,β-enone functionality have been synthetized in good overall yields.

Metal-free synthesis of quinolines by direct condensation of amides with alkynes: revelation of N-aryl nitrilium intermediates by 2D NMR techniques

Employing triflic anhydride/2-fluoropyridine as an activation system, the coupling reactions of secondary N-aryl amides with terminal alkynes yielded substituted quinolines in moderate to excellent yields. The reaction tolerated both electron-donating and electron-withdrawing groups at the benzamide moiety. Electron-rich aryl acetylenes served as excellent coupling partners, and aliphatic terminal alkynes such as cyclopropyl and conjugate vinyl acetylenes could also be used as reaction partners. By means of 2 D NMR techniques(heteronuclear multiple bond correlation(HMBC), heteronuclear single quantum correlation(HSQC)),nitrilium ions were probed as reactive intermediates which are in contrast with that suggested by Movassaghi on the basis of in situ IR monitoring experiments. On the basis of these results, a plausible mechanism for the formation of quinolines was suggested.

An attempted approach to the tricyclic core of haliclonin A：Structural elucidation of the final product by 2D NMR

We describe the design and execution of a novel synthetic route to the tricyclic core of haliclonin A,a tetracyclic marine natural product.The approach features Bachi＇s thiol-medicated free radical cyclization of alkenyl isocyanide to build the bridged ring system,and ring-closing metathesis（RCM） reaction to form the macrocycle.Execution of the synthetic plan ultimately resulted in a diazatricyclic compound.By means of 2D NMR techniques,the structure of this compound was revealed to an unexpected product 8.Analysis of the synthetic pathways allowed concluding that the unexpected product is a result of an ＂unexpected＂ migration of olefinic bond during dioxolanation of the 2-cyclohexenone derivative 7.This investigation also resulted in a concise construction of the functionalized hexahydro-1H-isoindole-1,5（4H）-dione 12 and the macrocyclic tricyclic ring system 8.

Towards Reaction Control:An Expeditious Access to Racemic 5-Substituted Tetramates and 5-Substituted Tetramic Acids from Malimides

A versatile and divergent two-step transformation of malimides to racemic tetramates and tetramic acids is de-scribed.The method consists of Grignard reagent addition with malimides to give hemiaminals and concentrated HCl-promoted chemoselective transformations of the latter.When running the reaction in CH2Cl2 and in the pres-ence of 2.5 molar equiv.of conc.HCl,5-alkyltetramates were formed,while in neat conc.HCl,5-alkyltetramic ac-ids were obtained.Using this method,a variety of title compounds were prepared in good to excellent yields(82%-99%,and 76%/85%).The work also constitutes a formal racemic total synthesis of reutericyclin.On the basis of the experimental evidences and of a deuterium labeling experiment,a plausible reaction mechanism was proposed.This work thus demonstrated two new types of step economical and chemodivergent transformations starting from malic acid.