聚酮化合物非天然延伸单元的生物合成与结构改造应用

聚酮天然产物包括10000多种具有广泛生物活性的分子,是获批临床药物中最著名的类别之一。已知活性先导化合物通常需要经过结构修饰改良其吸收、分布、代谢和排泄等特性,从而促进成药开发,但针对聚酮化合物的结构修饰极具挑战,需要应对聚酮骨架中大量的立体中心以及多个惰性碳原子,导致化学合成手段难以对聚酮骨架进行精准和高效的衍生化,因此,通过合成生物学方法实现其结构优化就成为了研究者们关注的热点。自然界中,绝大多数聚酮化合物主要由简单的乙酸盐和丙酸盐结构单元通过聚酮合酶组装而成,而少数存在的具有特殊结构单元的聚酮案例给了研究者以灵感——通过设置和引入非天然结构单元从而有选择性地高效改造聚酮结构。聚酮骨架的生物合成有赖于一个起始单元与多个延伸单元的组装,因此,通过人工设计延伸单元向聚酮引入预期结构被认为是精准高效改造聚酮的有力突破点。本文在此总结了近十年来报道的聚酮非天然延伸单元的三种重要的酶促合成方法,通过挖掘新颖的延伸单元合成酶并探索其底物宽泛性,或利用酶工程手段改造延伸单元合成酶的底物催化范围,获得了大量自然界不存在的延伸单元。此外,本文还归纳了利用非天然延伸单元对聚酮结构进行改造的案例,借助聚酮的天然合成途径或利用改造的合成途径达到预期目的。最后,作者讨论了该研究领域内存在的一些制约因素以及可优化的研究方向,包括聚酮合酶对非天然延伸单元的兼容性问题、非天然延伸单元的前体供给等。近年来,利用非天然延伸单元改造聚酮结构的研究兴趣和热度日益高涨,本文绘制了一份基于延伸单元改造聚酮结构研究的简明清晰的图谱,期望为加速聚酮类药物的高效开发打下坚实基础。

美国在“印太经济框架”下对中国—东盟数字经济合作的遏制及中国的应对策略

东南亚是全球数字经济发展最迅猛的地区之一,与东盟的数字经济合作已成为区域经济合作的竞争焦点。美国“印太经济框架”(IPEF)启动后,从产业、科技、投资、贸易等4个方面对中国—东盟数字经济合作进行遏制。但IPEF具有不需要美国国会批准、不是一个自由贸易协定、不涉及实质利益、不涉及关税豁免、不涉及更宽的市场准入“五个不”的特点和属性,其实施前景充满了巨大的不确定性。未来,中国要加紧制定经贸、金融领域的反围堵与反制裁预案,进一步增强数字经济产业链供应链韧性,强化中国在区域经济中的“头雁”作用,提升与东盟的数字技术合作交流及应用水平,建立数字经济合作制度,积极牵头构建相关规则体系,全面化解IPEF带来的挑战。

Cell metabolism pathways involved in the pathophysiological changes of diabetic peripheral neuropathy

Diabetic peripheral neuropathy is a common complication of diabetes mellitus.Elucidating the pathophysiological metabolic mechanism impels the generation of ideal therapies.However,existing limited treatments for diabetic peripheral neuropathy expose the urgent need for cell metabolism research.Given the lack of comprehensive understanding of energy metabolism changes and related signaling pathways in diabetic peripheral neuropathy,it is essential to explore energy changes and metabolic changes in diabetic peripheral neuropathy to develop suitable treatment methods.This review summarizes the pathophysiological mechanism of diabetic peripheral neuropathy from the perspective of cellular metabolism and the specific interventions for different metabolic pathways to develop effective treatment methods.Various metabolic mechanisms(e.g.,polyol,hexosamine,protein kinase C pathway)are associated with diabetic peripheral neuropathy,and researchers are looking for more effective treatments through these pathways.

共建繁荣家园视域下打造中国—东盟创新共同体的路径探析

共建繁荣家园的核心内涵是追求共同利益、实现互利共赢。共建繁荣家园的提出为中国—东盟科技合作赋予了新内涵、新使命,打造中国—东盟创新共同体是共建繁荣家园在科技领域实践的必要举措。可以紧密结合共建繁荣家园的各项要求,从加强顶层设计、开展差异化科技合作、打造多元化服务体系、搭建立体式金融支持体系、强化科技人才支撑等方面,探索打造创新理念共鸣、科技成果共享、科技信息共通、创新链条共建、科技人才共育的中国—东盟创新共同体。

中国—东盟自由贸易区3.0版建设路径探析

自2020年起,中国与东盟互为第一大贸易伙伴,双边经贸合作进入全新阶段。中国—东盟自由贸易区升级版协定已签署超过七年,与RCEP、CPTPP等最新的国际经贸规则相比,还存在贸易便利化政策水平有待提高、服务贸易开放承诺水平不高、未涉及新贸易方式和新贸易需求的内容、投资政策不够便利等问题。在中国—东盟自由贸易区3.0版建设中,可以在对标RCEP、CPTPP等先进自由贸易规则的基础上,提高谈判标准,探索解决目前RCEP实施过程中存在的困难问题,进一步提升贸易便利化水平和投资自由化水平、拓展新贸易方式和新贸易需求、创新通关便利化条款。

广西向海经济高质量发展对策研究

近年来,广西全力打造向海经济,加快建设海洋强区,海洋经济提质增效进展较快,向海经济发展取得了显著成效,但同时海洋经济规模总体偏小、海洋产业结构不优、区域海洋产业同构化与低度化并存、海洋科研成果转化程度低等问题仍然存在。“十四五”时期,广西要转变海洋经济发展思路,把调整优化广西海洋产业结构作为向海经济高质量发展的重要支撑,为加快建设海洋强区提供有力保障,通过升级海洋产业结构、优化海洋产业布局、增强海洋科技创新能力、打造高层次产业发展平台、壮大海洋人才队伍、深化对外开放合作等措施,推动广西向海经济高质量发展。

中国—东盟科技合作现状及对策研究

目前新一轮科技革命和产业变革正在重塑世界经济结构和竞争格局,在此背景下,加强中国与东盟的科技合作具有重要的现实意义。文章在系统分析中国—东盟深化科技合作取得的成效和存在问题的基础上,提出搭建全方位的国际科技合作平台、构建中国—东盟协同创新网络、发挥企业在中国—东盟科技合作中的主体作用、构建国际科技合作的人才支撑体系、打造中国—东盟国际科技合作的金融支持体系、扩大国际科技专项合作项目的规模和影响等深化中国—东盟科技合作的对策建议。

第12届中国—东盟智库战略对话论坛会议综述

2019年9月17日,第12届中国—东盟智库战略对话论坛在中国广西南宁举行,与会国内外专家学者围绕“汇聚智慧共识,共绘合作发展愿景”的会议主题,以及“新时代中国—东盟命运共同体建设”“中美贸易摩擦对中国—东盟产业合作的影响”“推进中国—东盟次区域合作”和“中国—东盟跨境旅游合作与人文交流”等4个议题展开深入交流及研讨。本文对与会专家学者的主要观点进行综述。

承德地区主要水系水环境质量综合评价与分析

为探究承德地区主要水系水质状况及污染特征,选取承德市地表水水质监测站2017~2020年29个断面监测数据,采用单因子评价法、综合污染指数法和主成分分析法对承德地区主要水系水环境质量进行综合评价。评价结果表明,总体来看2017~2020年承德地区主要水系整体水质较好;从时间上来看,2019、2020年承德地区主要水系水质较2017、2018年有较为明显提升;从空间上来看,宫后和承钢大桥断面污染相对较为严重。承德地区水系水质主要受总磷、COD和高锰酸盐指数影响较大。

中国与东盟农业科技合作的成效、问题与建议

为了不断提高中国与东盟的农业科技合作水平,从农作物优良品种技术合作、现代农业装备技术合作、农村生态能源利用合作、动植物疫苗防控体系合作、农业信息化开发合作和农作物防灾减灾等六个方面总结了当前中国与东盟农业科技合作的现状。结果表明,中国与东盟农业科技合作存在以下问题:合作模式单一且层次低,合作项目可持续性不强,合作缺乏统筹协调机制,合作国科技创新条件差。基于此,本文提出了如下政策建议:理顺发展思路,科学制定规划;加大科技投入,拓宽合作渠道;鼓励多元主体,实现协同发展;确定重点领域,提升合作层次。

等离子体技术在反渗透复合膜制备中的研究进展

简述了国外等离子体聚合制备反渗透复合膜的研究进展,重点阐述了复合膜制备过程中的功能单体和反应器类型、聚合时间、放电功率和单体流速等实验参数对复合膜性能的影响,并对等离子体制备反渗透复合膜的发展进行了展望。

Light-absorbing Particles in Snow and Ice: Measurement and Modeling of Climatic and Hydrological impact

Light absorbing particles（LAP, e.g., black carbon, brown carbon, and dust） influence water and energy budgets of the atmosphere and snowpack in multiple ways. In addition to their effects associated with atmospheric heating by absorption of solar radiation and interactions with clouds, LAP in snow on land and ice can reduce the surface reflectance（a.k.a., surface darkening）, which is likely to accelerate the snow aging process and further reduces snow albedo and increases the speed of snowpack melt. LAP in snow and ice（LAPSI） has been identified as one of major forcings affecting climate change, e.g.in the fourth and fifth assessment reports of IPCC. However, the uncertainty level in quantifying this effect remains very high. In this review paper, we document various technical methods of measuring LAPSI and review the progress made in measuring the LAPSI in Arctic, Tibetan Plateau and other mid-latitude regions. We also report the progress in modeling the mass concentrations, albedo reduction, radiative forcing, and climatic and hydrological impact of LAPSI at global and regional scales. Finally we identify some research needs for reducing the uncertainties in the impact of LAPSI on global and regional climate and the hydrological cycle.

Klebsiella pneumoniae invasive liver abscess syndrome with purulent meningitis and septic shock: A case from China's Mainland

We present a rare case of invasive liver abscess syndrome due to Klebsiella pneumoniae (K. pneumoniae) with metastatic meningitis and septic shock. A previously healthy, 55-year-old female patient developed fever, liver abscess, septic shock, purulent meningitis and metastatic hydrocephalus. Upon admission, the clinical manifestations, laboratory and imaging examinations were compatible with a diagnosis of K. pneumoniae primary liver abscess. Her distal metastasis infection involved meningitis and hydrocephalus, which could flare abruptly and be life threatening. Even with early adequate drainage and antibiotic therapy, the patient’s condition deteriorated and she ultimately died. To the best of our knowledge, this is the first case of K. pneumoniae invasive liver abscess syndrome with septic meningitis reported in China's Mainland. Our findings reflect the need for a better understanding of the epidemiology, risk factors, complications, comorbid medical conditions and treatment of this disease.

Urbanization Impact on Regional Climate and Extreme Weather:Current Understanding,Uncertainties,and Future Research Directions

Urban environments lie at the confluence of social,cultural,and economic activities and have unique biophysical characteristics due to continued infrastructure development that generally replaces natural landscapes with built-up structures.The vast majority of studies on urban perturbation of local weather and climate have been centered on the urban heat island(UHI)effect,referring to the higher temperature in cities compared to their natural surroundings.Besides the UHI effect and heat waves,urbanization also impacts atmospheric moisture,wind,boundary layer structure,cloud formation,dispersion of air pollutants,precipitation,and storms.In this review article,we first introduce the datasets and methods used in studying urban areas and their impacts through both observation and modeling and then summarize the scientific insights on the impact of urbanization on various aspects of regional climate and extreme weather based on more than 500 studies.We also highlight the major research gaps and challenges in our understanding of the impacts of urbanization and provide our perspective and recommendations for future research priorities and directions.

Expression of B7-H4 and hepatitis B virus X in hepatitis B virus-related hepatocellular carcinoma

AIM: To investigate the expression and clinical significance of B7-H4 and hepatitis B virus X(HBx) protein in hepatitis B virus-related hepatocellular carcinoma(HBV-HCC).METHODS: The expression of B7-H4 in the human HCC cell lines Hep G2 and Hep G2.2.15 were detected by western blot, flow cytometry, and immunofluorescence. The expression of B7-H4 and HBx in 83 HBV-HCC was detected by immunohistochemistry, and the relationship with clinicopathological features was analyzed. Paraffin sections were generated from 83 HBV-HCC patients(22 females and 61 males) enrolled in this study. The age of these patients ranged from 35 to 77 years, with an average of 52.5 ± 11.3 years. All experiments were approved by the Ethics Committees of the Second Affiliated Hospital, Zhejiang University School of Medicine.RESULTS: B7-H4 was significantly upregulated in Hep G2.2.15 cells compared to Hep G2 cells. Specifically, the protein expression of B7-H4 in the lysates of Hep G2 cells was more than that in Hep G2.2.15 cells. In addition, HBx was expressed only in Hep G2.2.15 cells. Similar data were obtained by flow cytometry. The positive rates of B7-H4 and HBx in the tissues of 83 HBV-HCC patients were 68.67%(57/83) and 59.04%(49/83), respectively. The expression of HBx was correlated with tumor node metastases(TNM) stage, and the expression of B7-H4 was positively correlated with HBx(rs = 0.388; p < 0.01). The expression level of B7-H4 in HBx-positive HBV-HCC tissues was substantially higher than that in HBx-negative HBV-HCC tissues. The expression level of B7H4 was negatively related to tumor TNM stage.CONCLUSION: Higher expression of HBx and B7-H4 was correlated with tumor progression of HBV-HCC, suggesting that B7-H4 may be involved in facilitating HBV-related hepatocarcinogenesis.

Cannulation of the intradiverticular papilla using a duodenoscope:Is it a safe method?

Endoscopic cannulation of the biliary tract is a challenging technique in cases of periampullary diverticula.Many new devices and new manipulations for successful biliary cannulation have been reported.Endoscopy used to locate and cannulate a papilla hidden within a duodenal diverticulum is an effective method.However,the question of which endoscope should be chosen for this procedure,duodenoscope or gastroscope,waits to be answered.

Clonal Selection Based Memetic Algorithm for Job Shop Scheduling Problems

A clonal selection based memetic algorithm is proposed for solving job shop scheduling problems in this paper. In the proposed algorithm, the clonal selection and the local search mechanism are designed to enhance exploration and exploitation. In the clonal selection mechanism, clonal selection, hypermutation and receptor edit theories are presented to construct an evolutionary searching mechanism which is used for exploration. In the local search mechanism, a simulated annealing local search algorithm based on Nowicki and Smutnicki＇s neighborhood is presented to exploit local optima. The proposed algorithm is examined using some well-known benchmark problems. Numerical results validate the effectiveness of the proposed algorithm.

低温等离子体处理改性阴离子交换膜对柠檬酸选择透过性影响

以柠檬酸-硫酸钠混合溶液模拟无机电解质-有机电解质混合溶液体系,利用低温等离子体技术,对电渗析核心部件-阴离子交换膜进行等离子体丙烯酰胺接枝改性,提高膜表面荷电性及交联程度,强化孔径筛分效应及同性电荷排斥效应,提高阴离子交换膜对无机电解质盐类与有机电解质混合物的选择性能,增加电渗析对无机电解质-有机电解质混合体系的分离精度和效率。由于等离子体改性选取4因素(膜接枝时间、辉光放电电流大小、放电电流时长、丙烯酰胺接枝液浓度),8水平作为研究条件,试验工作量太大,故采用均匀试验设计方法进行研究,以柠檬酸为考察指标,研究改性膜对柠檬酸和无机电解质选择透过性影响。并利用DPS数据处理软件进行统计分析并得到最优组合。研究结果表明:膜接枝时间对实验结果影响最为显著,在离子交换膜接枝时间为70 min,放电时间为2 min,接枝浓度为2%,放电电流为4.1 A的条件下。柠檬酸损失率最小为26.3%,损失率较原膜36.2%降低9.9%,电渗析对混合体系的选择分离性能有了一定程度提高。

Pathological significance of abnormal recepteur d'origine nantais and programmed death ligand 1 expression in colorectal cancer

BACKGROUND Programmed death ligand 1(PD-L1) immunotherapy remains poorly efficacious in colorectal cancer(CRC). The recepteur d'origine nantais(RON) receptor tyrosine kinase plays an important role in regulating tumor immunity.AIM To identify the patterns of RON and PD-L1 expression and explore their clinical significance in CRC.METHODS Gene expression data from the Gene Expression Omnibus database(GEO;n = 290) and patients at the First Affiliated Hospital, Zhejiang University School of Medicine(FAHZUSM;n = 381) were analyzed to determine the prognostic value of RON and PD-L1 expression within the tumor microenvironment of CRC. HT29 cell line was treated with BMS-777607 to explore the relationship between RON activity and PD-L1 expression. Signaling pathways and protein expression perturbed by RON inhibition were evaluated by cellular immunofluorescence and Western blot.RESULTS In the GEO patient cohort, cut-off values for RON and PD-L1 expression were determined to be 7.70 and 4.3, respectively. Stratification of patients based on these cutoffs demonstrated that high expression of RON and PD-L1 was associated with a poor prognosis. In the FAHZUSM cohort, rates of high expression of RON in tumor cells, high PD-L1 expression in tumor cells and tumor infiltrating monocytes, and both high RON and high PD-L1 expression in the tumor microenvironment were 121(32%), 43(11%), 91(24%), and 51(13.4%), respectively. High expression of RON was significantly correlated with high expression of PD-L1 in the tumor cell compartment(P < 0.001). High expression of RON and that of PD-L1 were independent prognostic factors for poorer overall survival. Concurrent high expression of both RON and PD-L1 in the tumor microenvironment was significantly associated with a poor prognosis. In vitro, BMS-777607 inhibited the phosphorylation of RON, inhibited PD-L1 expression, and attenuated activation of the ERK1/2 and AKT signaling pathways in CRC cells.CONCLUSION RON, PD-L1, and their crosstalk are significant in predicting the prognostic value of CRC. Moreover, phosphorylation of RON upregulates PD-L1 expression, which provides a novel approach to immunotherapy in CRC.

Genetic variants at 10q 23.33 are associated with plasma lipid levels in a Chinese population

Plasma lipid abnormalities are implicated in the pathogenic process of type 2 diabetes. The IDE-KIFII-HHEX gene cluster on chromosome 10q23.33 has been identified as a susceptibility locus for type 2 diabetes. We hy- pothesized that genetic variants at 10q23.33 may be associated with plasma lipid concentrations. Seven tagging single nucleotide polymorphisms （SNPs： rs7923837, rs2488075, rs947591, rs11187146, rs5015480, rs4646957 and rs1111875） at 10q23.33 were genotyped in 3,281 subjects from a Han Chinese population, using the Taq- Man OpenArray and Sequenom MassARRAY platforms. Multiple linear regression analyses showed that SNP rs7923837 in the 3＂-flanking region of HHEX was significantly associated with triglyceride levels （P = 0.019, 0.031 mmol/L average decrease per minor G allele） and that rs2488075 and rs947591 in the downstream region of HHEX were significantly associated with total cholesterol levels （P = 0.041, 0.058 mmol/L average decrease per minor C allele and P = 0.018, 0.063 mmol/L average decrease per minor A allele, respectively）. However, the other four SNPs （rs11187146, rs5015480, rs4646957 and rs1111875） were not significantly associated with any plasma lipid concentrations in this Chinese population. Our data suggest that genetic variants in the IDE-KIF11- HHEX gene cluster at 10q23.33 may partially explain the variation of plasma lipid levels in the Hart Chinese pop- ulation. Further studies are required to confirm these findings in other populations.