Kinetics for Hybridization ---北京思尔成生物

专利名称：芳基和杂芳基取代的四氢异喹啉及其阻断去甲肾上腺素、多巴胺和5－羟色胺重摄取的用途
专利类型：发明专利
发明人：J·P·贝克,M·A·库里,M·A·史密斯
申请号：CN00818078.4
申请日：20001103
公开号：CN1414953A
公开日：
20030430
专利内容由知识产权出版社提供
摘要：在此提供式(I)化合物，其中R－R如文中所述，R为芳基或杂芳基。

此类化合物特别用于治疗一种疾病，所述疾病由5－羟色胺、去甲肾上腺素或多巴胺的可利用性降低引起或取决于5－羟色胺、去甲肾上腺素或多巴胺的可利用性降低。

申请人：阿尔巴尼分子研究公司
地址：美国纽约州
国籍：US
代理机构：中国专利代理(香港)有限公司
代理人：姜建成
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Hirsch Teil1. What are chemical sensors?- Definition !!!2. Selectivity- Definition- Equilibrium based selectivity: free energy, dielectric constant and distance,- Kinetic based selectivity: steady-state regime3. Recognition Methods- Ion recognition: recognition-electric charge, selectivity-size,transduction-potentiometric, optical methodse.g. PH electrode ----> part 3- Recognition by affinity interactions: reversible, non-covalent bonds-ionic bonds, hydrogen bonds, van der Waals interaction => result in a molecular assiciation complex; also respect to shape and chemical reactivity; indicated by stability constant (very stable)- antibody - antigen interaction => immunochemical reactionantibody: glycoprotein produced by immune system to identify and neutralizepathogen microorganisms.antigen: the part of the pathogen that reactions with the antibody.use specific antibody receptor => identify pathogenuse antigen receptor => identify antibody (the detection of infection byparticular pathogen)- lectin proteins recognize caborhydrates (agglutinins, hemagglutinin)carbohydrate-binding modules link to the catalytic part of glycosidehydrolases => result in degradation of cell wall, storage of polysaccharide- A Molecularly Imprinted Polymer (MIP) is a polymer that has been processed usingthe molecular imprinting technique which leaves cavities in polymer matrix withaffinity to a chosen "template" molecule.In chemistry, molecular imprinting is a technique to create template-shaped cavities in polymer matrices with memory of the template molecules to be used in molecular recognition.-Nucleic acid aptamers are nucleic acid species that have been engineered throughrepeated rounds of in vitro selection to bind to various molecular targets such assmall molecules, proteins, nucleic acids, and even cells, tissues and organisms.Aptamers are useful in biotechnological and therapeutic a pplications as they offer molecular recognition properties that rival that of the commonly used bimolecular antibodies.- Recognition by nucleic acids: hydrogen bonds between two distinct pairs of nucleobases => two complementary nucleic acids form a double strand association complex => called hybridizationnucleic acid sensors: short single strand NA as receptor to recognize a particular NA sequence in the analyte NA => detection of genetic anomalies and pathogen mircoorganism- Recognition by enzyme: dynamic processEnzyme: protein compound that function as catalysts in chemical reaction occurring in living system.- Recognition by cells and tissues: advantages of enzyme incorporated in biological materials => in their natural environmentsee part 3, Wegener - Recognition by gases and vapors: based on sorption at solid material => surface-adsorption, inner-absorption; purely physical phenomenon or chemical reaction.4. Transduction MetohdosChemical transduction: monitoring the change of chemical composition of the sensing element in response to the recognition process. => change in concentration/amount is measured => detect primary product -> secondary product or coreagent -> labeling productLABEL can be a simple molecular species or nanoparticals that can be detected by available physiochemical methods => enzyme, fluorescent dyes, luminescent dyes, electroactive compoundsPhysical transduction: a specific physical property of the sensing element that is affected by its interaction with the analyte is monitored. => mass, reflective index, dielectric properties, electrical resistivity => LABEL-FREE- Thermometric transductionRecognition of the analyte leads to change in temperature => only catalytical processes generate sufficient heat to the measurement => application: combustible gases react with O2 at the surface of a catalyst.- Transduction based on mechanical effectsRecognition leads to change in mass of the sensing element => monitored by mass tranducer based on quartz crystal microbalance (QCM)----------------------------------------------------------------------------------------------------------------- QCM, correct name: Thickness shear modePiezoelectric effect:generation of electrical charges on the surface of a solid by strain, pressure or torsion (mechanical deformation of solid) =>electricity resulting from pressureI nverse piezoelectric effect:application of charges to surfaces of piezoelectricsolid generates mechanical deformation (elongation, contraction, torsion)QCM is based on Inverse piezoelectric effect!# AT cut => 35`15`=> minimum temperature coefficient at 50~70 CIt makes the AT-cut well suited to applications requiring high degree of frequency stability over wide temperature ranges.## Electrodes are applied on both sides, and AC voltage applied.DC cannot flow across the crystal because it consists of an insulator material;however the crystal somewhat behaves as capacitor and allow an AC current to f low along the left-hand loop.AC voltage applied => leads to shear oscillation of crystal => when the voltage frequency matches the intrinsic vibration frequency of the crystal => the vibration amplitude is at maximal => the resonant => resonant frequency (f0) => depend on crystal thickness (e.g. d q= 330 um, f0= 5MHZ), density and elasticity of piezoelectric material### AT-cut resonator: thickness: ~0.2 mm, diameter of the active area: 5~20 mm #### Deposition of a homogenous mass film (a rigid overlay)Sauerbrey equation:Cf indicate sensitivity of QCMcondition of this equation: rigid deposited mass; △m<2% of crystal mass;operated in vacuum or in gaseous atmopphereIn liquid: the liquid breaks the vibration by friction => lessen f0Thickness of the layer must be greater than the wave decay lengththat is of 250 nm of 5 MHz resonator at water. ----> part 2!!!##### QCM in practice => see p.41----------------------------------------------------------------------------------------------------------------- - Resistive and capacitive transductionRecognition leads to changes in the electrical property of this materialResistive transduction: gases interact with MOS => change in electrical resistivity Capactive transduction => dielectric constant- Electrochemical transductionsee part 2, Matysik - Optical transductionOptical transduction can be based on light emission or light absorption, also by physical quantity (reflective index) and light scattering.5. Sensor Configuration and Fabrication- Lateral flow assayA typical test strip consists of the following components:1. Sample pad – an absorbent pad onto which the test sample is applied2. Conjugate pad –this contains antibodies specific to the target analyte;conjugated to coloured particles (e.g. gold nanoparticles)3. Reaction membrane –typically a hydrophobic nitrocellulose or celluloseacetate membrane onto which anti-target analyte antibodies are immobilized in a line across the membrane as a capture zone or test line, and a control zonecontaining antibodies specific for the conjugate antibodies.4. Wicking pad –a further absorbent pad designed to draw the sample acrossthe reaction membrane by capillary action and collect it.Double antibody sandwich assays: the sample migrates from the sample pad through the conjugate pad where any target analyte present will bind to the c onjugate.=> The sample then continues to migrate across the membrane until it reaches the test line where the target or conjugate complex will bind to the immobilized antibodies producing a visible line on the membrane. => The sample then migrates further along the strip until it reaches the control line, where excess conjugate will bind and producea second visible line on the membrane.This control line indicates that the sample has migrated across the membrane as intended. Two clear lines on the membrane is a positive result. A single line in the control zone is a negative result. Double antibody sandwich assays are most suitable for larger analytes, such as bacterial pathogens and viruses, with multiple antigenic sites. 6. Methods and Material in Sensor Preparation- Immobilization at solid surface => integration of a transducer with the receptor Physical adsorption at a solid supportNon covalent immobilization at solid surface => hydrophobic interaction, hydrogen bonding, electrostatic attraction; monolayer; no restrict access; not stable; Langmuir isotherm -> equilibrium interactionSupport material: silica, cellulose acetate, PVCCovalent bonding to the solid supportCovalent conjugation => stable, covalent bond, time consuming, expensiveCommon reactive group: -OH, -NH2, -C=O, -SH- Carboxylic acid with DCC- Glutaraldehyde reacts with the a.a. of lysine in protein => widely used Support: porous material => high specific area, high density of immobilized compounds => hydrogel: immobilized by entrapment/covalent corsslink - Natural polymers: Cellulose, Dextran- Synthetic polymers: Polystyrene- Active polymers: Epoxide (without preliminary activation) -->DNA array !!!- Inactive Polymers: Vicinal hydroxyls actived by CNBr- Inorganic support: Silica, AL2O3, TiO2 => stable at extreme PH- Metal support: noble metals, thiols on golds --> self assembled monolayers!Affinity reaction: avidin-biotin !!!Thin molecular layers: one or several molecular layers in solid support - Self-assembly of amphiphilic compounds: preparation of liposome andmicelles; liposome can be used of entrapment of molecular- Bilipid layer membranes: Langmuir-Blodgett technique- Layer by Layer assembly- Sol-Gel chemistry methods: silica gel => -O-Si-O-- Hydrogels: Xerogel, aerogel- Conducting polymers: Polyacetylene, polyaniline --> gas senor based on CP (----> part 3 !!!); also as entrapment matrix for biological receptors- Mesoporous materials: porous materials with pore (diameter: 2-50 nm,close to protein) => enzyme immobilization by entrapment (crosslinking withglutaraldehyde)- Deposition of polymers onto solid surfaces: dip coating, drop coating, spin coating ----> part 2 !!!Perm-selective memberanes: Nafin ----> Clark oxygen electrode Support-free crosslinkingEntrapment in a polymer networkEncapsulation7. Microfabrication Methodes- Spot Arraying: Contact-based & Noncontact-based; DNA microarray !!!!!Pros & Cons- Thick-film Technology: screen-printing technique (5-50 um thick layer)- Thin-film Technology: Photolithography (2 um)- Softlithography ----> experiment !!!!- Microcontact printing ----> experiment !!!!8. Optical Sensors- Electromagnetic RadiationOptical sensor => interaction of electromagnetic radiation with sensor layer - frequency; wavelength; photon energy (definition)- Structure: integration with wavelength-selection (optical filters) device and light sources (lasers), light detectors (phototransistors)- Optical Waveguides- Optical FibersOptical fibers' structuretotal internal reflection => evanescent wave- Spectrochemical Transduction MethodsSpectrochemical method analysis => light absorption or emission by sample => optical label performs absorption or emission (organic dye or metal complexes) - Light absorption: absorbance => concentration; sensitivity => thickness, absorpyivity, absorptivity => wavelength- Diffuse reflectance spectrometry: refelctance => concentration; suitable forsolid in near IR- Luminescence: Fluorescence spectromerty => fluorophore (label, organic dye or metal complexes, luminescent nanparticle ); steady-statefluorescence measurement, Time-resolved fluormetry; fluorescencequenching; resonance energy transfer (FRET); chemical- andbioluminescence => luminol; electrochemicaluminescence; Ramanspetrometry- Surface Plasmon Resonance Spectroscopy (SPR)。

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曲霉属assimilation同化 ; 同化作用associated virus伴随病毒asteraceae菊科astigmatism散光asymmetric PCR不对称PCR[引物用量不对称的PCR] ATCC ATCCatmospheric pollution大气污染atopy过敏症attenuation减毒作用auditory canal听道Aurelia海月水母属auricle(1) 心耳, (2) 叶耳aurora kinases极光激酶authentic真的，真实的，真正的Autoanalyzer[商]自动分析仪[Technicon公司商标] autoclave高压灭菌器; 消毒蒸锅autofluorescence自体荧光autogamy自体受精; 自核交配autograft自体组织移植片automaticity自动节律性autophagy自噬autoregulatory自调控Autosis自死亡autotic自死亡的avian鸟类的avifauna区系avirulent strain减毒株，无毒株axillary region腋区axons神经轴突Axygen爱思进azoospermia无精症azospirillum巴西固氮b cell epitope b细胞抗原决定基B cell lymphoma B细胞淋巴瘤Bacillus subtillis枯草芽胞杆菌backbone脊柱bacteria culture细菌培养bacterial motility细菌运动性bacterial virulence细菌毒力bacteriochlorophyll细菌叶绿素; 菌绿素bacteriocin细菌素bacteriophage噬菌体bacterioplankton异养浮游细菌bacteriostasis抑菌作用bacteroid类菌体balance of nature自然平衡balanced diet均衡膳食band centrifugation method层带离心法bar chart条线图 ; 棒形图 ; 条形图barbate具毛的barbiturate巴比妥酸盐barbituric acid巴比妥酸bark树皮baroreceptor reflex压力感受拼射Barr body巴氏体 ; 巴尔氏小体 ; 性染色质小体barren不孕baseplate基片basic ingredient基础成分basic number基数Basidiomycetes担子菌纲Basidiomycotina担子菌亚门basonuclin碱性核蛋白，碱核蛋白basophilic嗜碱的bast fiber韧皮纤维batch process分批工艺，分批法bathochromically红移bats蝙蝠Bdellovibrio bacteriovorus蛭弧菌beclin苄氯素bee venom蜂毒benign良性benzimidazoles苯甲亚胺醇benzyl alcohol苯甲醇bile胆bile duct胆管biliary duct胆管binding energy结合能binocular vision双眼视觉bioburden微生物量Bioceramics生物陶瓷biochip生物芯片biodegradable生物可降解的biodegradation生物降解 ; 生物降解作用Bio-energizer生物促生剂bioenergy生物能量biofeedback生物反馈biofilm生物薄膜,生物膜,生物被膜,微生物膜biogenesis生源说biogeographic region生物地理区biogeography生物地理bioinformatics生物信息学biolistic technology生物弹道技术biological glucoside生物甙Biological invasion生物入侵biological nitrogen fixation生物固氮酌biological products生物制品biological rhythm生物节律bioluminescence生物发光biomarker生物标志物Biomass Energy生物质能源biomimetic synthesis仿生合成biomimetics生体模仿学biomolecular生物大分子bionics仿生学biophysics生物物理学Bio-rad伯乐生物biosecurity生物安全biosensor生物传感器biostratigraphical生物地层的biotechnology生物技术 ; 生物科技biotelemetry生物遥测学biotic community生物群落群biotinylation生物素化biotransformation生物转化biotype(1) 生物型 ; 生物类型, (2)同型小种 ; biovar生物变型bird migration鸟迁移bird of prey猛禽类bird ringing鸟类环子birdsong鸟鸣birth出产bisexual flower两性花biting insect咬虫bitopic membrane proteins双顶膜蛋白bivalent(1) 二价的 , (2) 二价染色体blastospore芽生孢子bleaching agent漂白剂blight疫病blind spot盲点blinded study参加者不知情的研究blood circulation血循环blood flow血量blood group antigen血型抗原blood screening血液筛查blood type血型blunt end钝圆末端Bohr effect波尔效应boletus牛肝菌属bone骨，骨骼bone age骨龄bone ash骨灰bone lamella骨层板bone marrow transplantation骨髓移植bone meal骨粉bone tissue骨组织boron deficiency硼缺乏botulinum肉毒菌botulism肉毒中毒bound water结合水bract苞片brain cortex大脑皮质brainstem脑干branch point分支点[如见于RNA剪接]branchial鳃的BRAND普兰特breadths宽度breeding season繁殖期brefeldin布雷菲（尔）德菌素Brief Introduction简介broad leaved forest落叶林bromophenol blue溴酚蓝bromothymol blue溴百里酚蓝; 溴百里香酚蓝, 溴麝香草酚蓝bronchitis支气管炎bronchus支气管brown alga褐藻brownian motion布朗运动bryophyte苔藓植物 ; 苔藓类bryophytes苔藓Buchner funnel布氏漏斗buffer缓冲剂bulldog clamp动脉夹bullous大疱bupleurum柴胡属buster大体butterflies蝴蝶butyrylcholinesterase丁酰胆碱脂酶by product副产物C. elegans；Caenorhabditis e线虫，秀丽隐杆线虫cache缓冲cadherin钙粘着蛋白calciferol钙化醇calcification钙化 ; 钙化作用calcineurin钙调磷酸酶calcitonin降血钙蛋白calcium binding protein钙结合蛋白（质）calculating machine计算器calcyclin钙周期蛋白，钙（细胞）周期蛋白calibration curve校准曲线callose胼胝质，愈伤葡聚糖callosum胼胝质callus differentiation愈伤组织分化calmodulin钙调蛋白，钙调节蛋白，钙调素calnexin钙联结蛋白calpain钙蛋白酶camalexin一种植物保护素cambrian period寒武纪campaniform钟状的cancer cell癌细胞cane sugar甘蔗糖cannabinoid大麻成分capillary毛细管capping加帽，加帽反应；封闭反应；帽化，成帽反应capping protein加帽蛋白，戴帽蛋白caproyl己酸基capsid（病毒）衣壳，（病毒）壳体capsule(1) 荚膜, (2) 孢蒴, (3) 蒴果captivity笼养caragana锦鸡儿属carbamate氨基甲酸脂carbohydrate糖carbon balance碳平衡carbon dioxide fixation碳酸气固定carbonyl羰基carboxykinase羧激酶carboxylate羧酸cardiac glycoside强心苷cardiovascular心血管cardiovascular disease心血管疾病carex苔草属cargo笼carotenoid类胡萝卜素; 类叶红素carrying capacity(1) 携带力 ; 负载力 , (2) 容纳量cascade级联caspase胱冬酶caste阶级; 级castor bean蓖麻籽castration去势catabolite分解代谢物catalytic center催化中心catalytic constant催化常数，转换数[符号Kcat]catalytic mechanism催化机理catalytic subunit催化亚基catalyzer催化剂catenation链状排列catenin连环蛋白cathelicidin组织蛋白酶抑制素catheter导管cave洞穴caveolae(复）陷窝，小窝，小凹cavity腔cecropin蚕素cell adhesion molecule细胞粘着分子，细胞粘附分子cell biology细胞生物学cell fusion细胞融合 ; 细胞并合cell line细胞株cell membrance细胞膜cell membrane（细）胞膜cell migration细胞迁移cell nucleus细胞核cell polarity细胞极性cell protein细胞蛋白质cell respiration细胞呼吸cell strain细胞株cell theory,theory of cell细胞学说Cell-map proteomics细胞器蛋白质组学,细胞图谱蛋白质组学cellular respiration细胞呼吸 ; 细胞呼吸作用cellulase纤维素cellulose decomposing fungi纤维素分解真菌类cement gland黏腺center中心center of origin起源中心centrifugal separation离心分离（法）centrifuge离心机centrifuge tube离心管centriole中心粒centrum椎体cephalopod头足动物 ; 头足类cephalosporin头孢菌素cercaria摇尾幼虫; 尾蚴cereals谷粒cerebral cortex大脑皮质cerebrospinal fluid脑脊液降钙素基因相关肽CGRP，calcitonin gene related peptidechalaza(1)卵带; 卵黄系带, (2) 合点chalazal合点端chalone抑素，抑制素channel管道channel theory经络学说chaperone protein伴侣蛋白质，伴娘蛋白chara轮藻character字符characteristic性状charged particle带电粒子charophyte轮藻植物chemokine趋化因子chemotaxis趋化性chemotaxonomic分类学chenopodiaceae藜科植物Chest PA & LAT胸部正侧位chi square test检验chiasma frequency交叉频率chilling injury寒害chimeric嵌合的chimeric gene嵌合基因chimeric protein嵌合体蛋白质chiral手性的chitinase几丁酶chloral氯醛chloramphenicol氯霉素; 氯霉素chloramphenicol acetyltransf氯霉素乙酰转移酶Chlorella绿藻属; 绿球藻属chlorenchyma绿色组织chlorogenic acid绿原酸chlorophyllbody叶绿体chlorophyll-protein叶绿素蛋白chlorophyta绿藻chlorophyte绿色植物chlorpyrifos毒死蜱,氯吡硫磷cholecystokinin缩胆囊素; 胆囊收缩素cholera toxin霍乱毒素[分A、B亚基]cholesterol胆固醇cholesterol oxidase胆固醇氧化酶cholic acid胆酸choline esterase胆碱酯酶cholinesterase胆碱脂chondroitin软骨蛋白chondrosarcoma软骨瘤chorda tympani鼓索chorionic绒膜chromatin染色质chromatin condensation染色质凝聚chromatographic column层析柱chromophore生色团chromosomal aberration染色体畸变; 染色体异常chromosome mapping染色体作图，染色体定位chromosome polymorphism染色体多态性chromosome segregation染色体分离chronic慢性的chukar石鸡chymotrypsinogen胰凝乳蛋白 原cilium纤毛circadian生理节律circadian rhythm（近）昼夜节律circulation循环怜circulation of blood血循环circulatory system循环系统cisplatin[商]顺式铂氨，顺氯氨铂[一种抗癌药] citric acid柠檬酸cladistic分支系统学clasper交合突; 鳍脚class纲clavulanic acid棒酸clay粘土cleavage site切割位点climate气候climax community顶极群落clinical microbiology临床微生物学clinical trial临床实验clonal activation克隆活化clonal expansion克隆扩充clone克隆cloning无性繁殖系化closure闭合clot凝块clumped distribution丛生分布Cluster of Orthologous Group蛋白相邻类的聚簇CMP CMPcnidoblast刺细胞CNQX CNQXCNTF CNTFCoA CoAcoat protein外壳蛋白; 病毒蛋白外壳;病毒蛋白外壳;(病毒)外壳蛋白coating antigen包被抗原cocarboxylase辅羧酶coccus球菌cochlea耳蜗coding sequence编码序列codominant共显性种codon密码子codon bias密码子偏倚（性）coeliac artery腹腔动脉coenzyme辅cohesin黏连蛋白colchicine秋水仙碱colinearity共线性collagen胶原collagenase胶原酶collar襟collum颈colonization定居colony菌落color reaction呈色反应colouration着色coma昏迷commitment定型comparative morphology比较形态学Comparative proteomics analy比较蛋白质组学研究compartmentalization区域化compartmentation区域化compensation补偿compensation depth补偿深度compensation point补偿点competence感受态competent活性的，有能力的，（处于）感受态的competitive capacity竞争能力competitive inhibition竞争性抑制作用complement补体[补体系统包括C1-C9等多种成分]complementation互补（作用）complete response完全有效conazole唑类;一般是后缀中使用concatemer多联体,串联体,连环体;噬菌体]串联体concatenation连环酌concentration浓度concentration gradient浓度梯度concerted model齐变模式concretion结石condensation(1) 缩合, (2)凝聚; 凝结condiments刀conditional gene条件基因conductivity传导性conductivity detector电导率检测器cone(1) 视锥, (2) 球果 ; 球花configuration构形confluent culture铺满培养物，铺满培养congestion充血conglomerate聚块conidium分生孢子conifer针叶树; 松柏类植物conjugated bile acid结合胆汁酸conjugated protein缀合朊; 结合蛋白质;结合蛋白质;结合蛋白(质)conjugation接合connectomes连接组Connectomics连接组学consanguineous marriage血亲联婚consecutive连串的，相连续的conserved domain保存区段consortium聚生体[一种以上细菌聚集在一起，具有相对固定的依存关系] constipation便秘constriction狭窄construction构建，组建contamination污染Content of Heavy Metal重金属含量contig重叠群，毗连（序列）群[一组从基因组中克隆的毗连DNA序列] contiguity邻接continental shelf大陆架continuous passage culture连续传代培养（物）continuous variation连续变异contour line等高线contour map等高线图，等值线图control对照control gene第基因control plot对照小区conus芋螺convergence会聚[用于神经系统]；趋同conzyme辅酶cooling jacket冷却套cooling tower冷却塔cooperative协同的cooperative behavior协同行为cooperative effect协同效应，合作效应coordination协调coordination bond配位键copepod桡足类copulation(1) 接合, (2) 交配cordycepin3'-脱氧腺苷；蛹虫草菌素cormorant鸬鹚Corn Straw玉米秸杆Corning康宁coronary heart disease冠心病correlation coefficient相关系数corrosion protection防腐cortex皮层corticoid类皮质激素cortin皮质激素cortisol皮质醇cortisone可的松cosmid黏粒cosmopolitan广布种costus lactone木香内酯cosurfactant助表面活性剂cotranslational integration共翻译整合cotranslational secretion共翻译分泌cotton棉花counter electrode对电极counterstaining对染（法），复染（法）[一种对比染色法] coupled偶联的coupled reaction偶联反应coupled transport偶联输送cover degree覆盖度cover glass盖玻片CpG island CpG岛cramp痉挛cre表达crecricetulus仓鼠cricket蟋蟀crickets蟋蟀CRO,contract research orgniz合同研究组织crops罪cross protection交叉保护cross section横切面crosstalk串华，通讯cruciferae十字花科植物crust地壳土壤crustacea甲壳动物cryogen冷冻剂，制冷剂cryopreservation深低温保藏[法]cryoprotectant冷冻保护剂cryptobiosis隐生cryptorchidism隐睾crystal structure晶体结构crystallization结晶（作用）cucumber黄瓜culm空心秆cultivar培养变种culture培养; 培养物culture collection培养物保藏culture tube培养（试）管cupule(1) 杯形托, (2) 胞芽杯, 93) 杯形器, (4) 壳斗current density电流密度cushion垫层cuticle角质膜cutis皮肤cuvette比色皿cyan氰cyanobacteria蓝细菌cyanobacterial蓝藻cyanobacterial toxins藻毒素cyanobacterium蓝细菌cybrid胞质杂种cycas苏铁属cycle循环cyclin细胞周期蛋白cyclophilin亲环蛋白，亲环素,环孢素A结合蛋白cymbidium兰属cystathionine胱硫醚cystoma囊瘤cytochemistry细胞化学cytochrome c oxidase细胞色素c氧化酶cytochrome oxidase细胞色素氧化酶cytokine细胞因子cytokine network细胞因子网络cytokinesis胞质分裂 ; 细胞质分裂cytokinin细胞分裂素; 细胞激动素cytological细胞学的cytomegalovirus巨细胞病毒cytometer血球计数器血球计cytometric[医] 细胞计数的;cytoneme胞管cytopathic effect（致）细胞病变（效应）cytopenia细胞减少（症）cytoplasmic membrane细胞质膜cytoplasmic tail胞质尾区[如指跨膜蛋白的胞内小区]cytosol细胞溶质cytotaxonomy细胞分类学cytotoxic T lymphocyte细胞毒性T淋巴细胞cytotrophoblast细胞滋养层dairy cow乳牛de novo n. 重新, 更始，【生物学】从头dead space无效空间decane癸烷decomposer分解者[可指具有分解动植物残体或其排泄物能力的微生物] defective缺损的，缺陷的defective virus缺损病毒，缺陷病毒defensin防卫素，防御素defined medium确定成分培养基，已知成分培养液deforestation滥伐 ; 滥伐林木deformation变形degenerate简并的degradation退化dehiscent fruit裂果dehydration脱水（作用）dehydrogenase脱氢dehydrogenation脱氢（作用）deiodinase脱碘酶deionized water去离子水delayed fluorescence迟延荧光delayed hypersensitivity迟发过敏性delayed recovery恢复延迟deletion mutagenesis缺失诱变delphinium翠雀属deme同类群 ; 混交群体demethylation脱甲基化denaturants变性剂dendron树突denitrification反硝化作用density gradient密度梯度dental齿骨dental caries龋齿dentine齿质deoxycytidine脱氧胞苷deoxysugar脱氧糖depletion排除depressed脱阻抑的deprived除去的，丧失的derivate衍生物dermatan皮层dermatitis皮炎dermatoglyphics肤纹desaturase去饱和酶desaturases去饱和酶descendants后代descent谱系description描述desertification沙漠化desmin结蛋白desmocollin桥粒（芯）胶（粘）蛋白desquamation脱鳞desulfurization脱硫（作用）detention滞留determination测定detritus碎屑; 腐质developmental genetics发生遗传学device仪器devonian period泥盆纪dextran葡聚糖，右旋糖酐dextran sulfate葡聚糖硫酸酯dextrin糊精dhamotil复方地芬诺酯片,芬诺酯和阿托品diabetes insipidus尿崩症diagnostic procedure诊断程序，诊断手续dianthus石竹属diapause(1) 滞育, (2) 休眠期diarrhea腹泻diastolic pressure舒张压; 心舒压dichotomy双歧分枝Dickkopf-1Wnt通路抑制因子dielectrophoresis介电（电）泳diester二酯differential centrifugation差速离心differential expression差异表达Differential-Display PCR, DD差别显示聚合酶链反应diffusion扩散dihybrid双基因杂种dihydrofolate二氢叶酸dihydrotestosterone二氢睾酮dihydroxyacetone二羟丙酮dihydroxyvitamin二羟维生素diluent稀释剂，稀释液dimethylarginine二甲基精氨酸dinitrophenol二硝基苯酚dinoflagellate腰鞭毛虫; 甲藻; 涡鞭藻dioecious雌雄异体的dioecism雌雄异体，雌雄异株dioxygenase双加氧酶diphtheria白候dipterocarpaceae龙脑香科discontinuous variation不连续变异dish平皿Dishevelled，Dsh或Dvl蓬乱蛋白disinfection消毒dislocation转换位置dispersal散布displacement位移disproportionation岐化（反应）disturbance of consciousness意识障碍disulfide bond二硫键disulfide linkage二硫键dna binding protein dna 结合蛋白质DNA ligase DNA 连接DNA typing DNA分型docking protein船坞蛋白，停靠蛋白，停泊蛋白dodecane十二烷dolphins海豚domain域，区域，结构域，功能域dominance显性；优势（度）dominant allele显性等位基因dominant gene显性基因dominant lethal显性致死dosimeter剂量计double chin二重颊double-reciprocal plot双倒数作图，Lineweaver_Burk作图dove鸠dragonflies蜻蜓drebrin脑发育蛋白drift漂变drosophila果蝇属drug abuse&dependence毒品滥用和依赖drug resistant strain抗药性菌株dry weight干重duality二重性duct管duplication复制dynamic balance动态平衡dynamin发动蛋白，缢断蛋白dynein动力蛋白dyslipidemia血脂异常dysregulation调节异常early gene早期基因eating habits饮食习惯ecdysis蜕皮ecdysone蜕皮素；蜕皮激素ecg心电图echinoderm棘皮类Echinodermata棘皮动物门echinoderms棘皮动物eclampsia子癫症ecological factor生态因素ecotone群落交错区；群落过渡带ecotope生态区ectoblast外胚层ectodomain胞外域ectoplasm外质effect of gene基因剂量效应elaioplast油质体elasticity弹性elastoma高弹性electric focusing电子聚焦electrofusion电融合electrolyte solution电解质溶液electromotive force电动势electron diffraction电子衍射electron microscope电（子显微）镜electron transfer电子传递，电子转移electrophoresis pattern电泳图谱electrophysiological propert电生理特性electrophysiology电生理学electroporated电穿孔electroporation电转化electrospinning电纺丝，静电纺丝electrotransformation电转化（法）element元素elevational海拔elfin矮人elicitins激发素elicitor诱导子elimination消去，消除；弃置elongated spermatids精子细胞elongation延伸eluant洗脱液eluate洗脱物，洗出液Eluted[医] 被洗脱的，被洗提的; embedding medium包埋剂embryo culture胚胎培养embryogenesis胚形成embryoid胚状体embryonal胚的emetine吐根碱[属异喹啉类生物碱] emotional reaction情写应emphysema肺气肿encephalon脑髓encephalopathy脑病变endangering濒危endemic特有种，特有的，地方性的，地方的endemic disease地方病endocrine内分泌endocuticle内表皮endocytosis胞吞endoderm内胚层endodermis内皮endogenous内源（性）的endogenous opioid peptide内源性阿片样肽endogenous protective system内生保护系统endomembrane system内膜系统endometrioid子宫内膜endopeptidase内 ； 键内切endoplasmic reticulum (ER)内质网endosymbiont内共生体endothecium药室内壁energetics能量学energy band能量带energy charge能荷energy conservation能量守恒energy crop能源作物energy transduction能量转移entomological昆虫entomophily虫媒entropy熵enucleation去核environmental conditions环境条件environmental pollution环境污染environmentalist环境问题专家enzymatically adv.enzymatically modified lecit酶改性磷脂enzyme kinetics酶动力学enzyme system酶系统eosinophilia嗜伊红粒细胞增多症eosinophils嗜伊红粒细胞ephedra麻黄属ephemeral短命ephrin蝶素epidemic流行病epidemic hemorrhagic fever流行性出血热epidemiology流行病学epidermis表皮epigenetics发育遗传学,表观遗传学epigenome表观基因组epinasty偏上性episome附加体，游离体episperm种皮epistatic gene上位基因epithelium上皮细胞epitope mapping表位作图，表位定位epitope tagging表位附加，表位追加[把附加的抗原表位融合到目的蛋白上] epoxide hydrolase环氧化物酶epoxygenase环氧化酶Eppendorf tube[商]Eppendorf离心管，微量离心管eppin细粒蛋白Equisetum木贼属equivalence等价equivalent当量ergosterol麦角固醇；麦角甾醇error correction错误校正erythroid网织红细胞erythroid differentiation fa红细胞分化因子erythropoiesis红血球生成；红血细胞生成；造红血球；造红血细胞ester酯estival夏季的estrogen雌激素estrous cycle动情周期estrus动情期ethnobotanical民族植物学ethological行为学的ethyl alcohol乙醇ethylenimine氮杂环丙烷etiolation黄化；黄化现象etoposide鬼臼亚乙苷eudicot双子叶植物;eukaryon真核eukaryotic真核生物的eutrophic lake富营养湖evolutionarily进化上exchange group可交换组[比较相似并常可互换的氨基酸残基]excimer受激子excitatory postsynaptic pote兴奋性突触后电位excreted排泄; 排出; 分泌; 排除( excrete的过去式和过去分词 ); Exendin-4唾液素4［暂名］exocyst泡外exocytosis胞吐酌exon shuffling外显子改组exonuclease核酸外切酶exosmosis外渗exosome外切体expiration呼explantation外植exponential growth指数生长expressed sequence tag序列表达标签Expression proteomics表达蛋白质组学expression vector表达载体external外的extine外壁extracellular胞外的；细胞外的extracellular fluid胞外液；细胞外液exudate渗出液eyebrow眉face shield面罩factor因子falciform镰刀状的Fallopian tube法类皮欧氏管；输卵管familial adenomatous polypos家族性多发性腺癌fang长牙fatal dose致死量fatty liver脂肪肝fatty substance脂肪物质favus白癣fecundity生育力；生殖力felling采伐female flower雌花ferment酶fermentation发酵fern蕨类ferns蕨类fertility受精能力fertilized已受精的fertilizer肥料ferulic acid阿魏酸fiber plant纤维植物fibrinogen纤维蛋白原fibrinolysis（血）纤（蛋白）溶（解）fibroblast成纤维细胞fibroblastic tumor纤维母细胞瘤fibronectin纤连蛋白fibrosis纤维化fibrous protein纤维状蛋白; 纤维状蛋白质; 纤维状朊;纤维状蛋白质;....field study实地考察;野外考察filamentous丝状的filter press压榨滤净器filtering过滤fin ray条finch雀fingerprint指纹，指纹结构[例如核酸或蛋白质的酶切消化物在双向电泳中显示的特征first leaf第一叶fish protein concentrate鱼粉; 浓缩鱼蛋的;浓缩鱼蛋的;鱼蛋白浓缩物flagellin鞭毛蛋白flanking sequence侧面序列flat bone扁平骨flats平原flavone黄酮flavonoid类黄酮flesh果肉flexion屈曲flexor muscle屈肌floor plate底板flora植物区系；植物相floral植物的floras区系florigen成花素flow瘤flow cell流动池flow cytometer流式细胞仪flower color gene花色基因flowering plant有花植物fluid mosaic model[膜的]流动镶嵌模型，流体镶嵌模型fluorescence microscopy荧光显微镜检术fluorescence recovery after 光脱色荧光恢复技术fluoroacetate氟乙酸；氟乙酸盐、酯、根fluorochrome荧光燃料flurbiprofen氟比洛芬foam cells泡沫细胞focal adhesion焦点粘连focal distance焦距focus聚焦foetus胎儿food protein食用蛋白forelimb前肢对称性formyl甲酸基formyltransferase甲酰转移酶fossa窝fractalkine曲动蛋白fraction分段fragmentation断裂frame rate帧率freeze冻结Freon[商]氟利昂frequency频度frequency index频率指数friction摩擦friction coefficient摩擦系数frizzled，Frz卷曲蛋白frontal analysis迎头（分析）法fru果糖fructofuranosidase呋喃果糖苷酶fructosamine果糖胺fructose果糖fucan岩藻多糖fucose岩藻糖fucosyltransferase岩藻糖转移酶fuel cell燃料电池fumarase延胡索酸酶fumarate延胡索酸fumaric acid反丁烯二酸Funaria葫芦藓属functional differentiation机能分化functional gene功能基团functional group官能团functional localization功能定位functional protein功能蛋白functional redundancy功能性丰余，功能丰余性functional response机能反应fundus眼底fungi真菌fungicide杀霉菌剂funiculus菌丝索furry毛皮fusion融合；并合G1 Phase G1期gadfly牛虻gain增益gait步态galactosyltransferase半乳糖基转移酶galea外叶gallbladder胆galliformes鸡形目galvanometer电疗gametogenesis配子发生ganglioside神经节苷脂garlic大蒜gastritis胃炎gastrointestinal cancer胃肠癌gastrulation原肠胚形成Gaucher disease戈谢病，高雪病gazelle羚GC content GC含量gel mobility shift assay凝胶迁移率变动分析，凝胶移位分析gelation凝胶作用gelsolin凝溶胶蛋白gena颊gene action基因作用gene analysis基因分析gene bank基因库; 基因文库;基因文库gene carrier基因携带者gene clone基因克隆gene cloning基因克隆化;基因无性繁殖gene cluster基因簇gene combination基因组合gene complex基因综合体gene content基因含量gene conversion基因转变gene copy基因复制; 基因拷贝;基因拷贝gene deletion基因缺失gene dosage基因剂量;基因量;基因数量; 基因剂量gene engineering遗传工程;基因工程gene flow基因怜;基因流; 基因流动;基因流动; &n....gene frequency基因频率;等位基因频率gene fusion基因融合gene information基因信息gene interaction基因互作; 基因相互作用;基因相互酌;基因相互作用gene location基因定位gene loci基因位点gene locus基因位点;基因座位gene map基因图;基因图谱gene mapping基因定位; 基因定位; 基因图;基因图; &....gene order基因序列gene pairs基因对gene pool基因储备;基因库; 基因文库gene recombination基因重组gene theory基因论;基因学说gene therapy基因疗法;基因治疗; 基因治疗general anesthesia全身麻醉genetic遗传的genetic distance遗传距离genetic engineering基因工程，遗传工程，遗传工程学genetic immunization基因免疫接种[采用基因疫苗进行接种]genetic screening遗传筛选genetic transformation遗传转化[例如一个品系的生物吸收另一品系生物的遗传物质，并获得后一genetic variance遗传方差genetics遗传学Genistein’,5,7三羟基异黄酮genome基因组,染色体组Genome Mismatch Scanning基因组错配扫描genomic imprinting基因组印记[配子发生过程中基因的选择性差异表达]genomics基因组学genophore基因线，基因带gentamicin艮他霉素gentianaceae龙胆科geranium老鹳草属geranylgeranyl香叶酰香叶酰germ cell胚细胞germ plasm种质, 生殖质germinal center发芽中心germination萌发；萌发作用germline生殖细胞系ghost菌蜕gibberellic acid赤霉酸；赤霉酸gibberellin赤霉素；赤霉素glacial period冰川时代glaciation冰河酌gland腺体glandular epithelium腺上皮glass beads玻璃念珠gley horizon潜育层glia胶质Global Proteomics整体蛋白质组学glomerulosclerosis肾小球硬化症glottis声门glucocorticoid糖皮质（激）素glucomannan葡甘露聚糖glucosamine葡糖胺，氨基葡糖glucose oxidase葡萄糖氧化酶glucosidase葡糖苷酶glucuronyl葡糖醛酸基glutaminase谷酰胺酶glutelin谷蛋白glycinebetaine甘氨酸甜菜碱glycoconjugates糖缀合物,糖复合物glycophorin血型糖蛋白glycoprotein糖蛋白glycosphingolipid鞘糖脂Glyoxal Oxidase乙二醛氧化酶glyoxylate cycle乙醛酸循环GM-CSF GM-CSFGMP GMPgneiss片麻岩GnRH GnRHgoblet cell杯形细胞gonads生殖腺grain protein content籽粒蛋白含量Gram stain革兰氏染液gramicidin A短杆菌肽Agramineae禾本科植物granulation tissue肉芽组织granuloma肉芽肿granulose细菌淀粉粒granzyme颗粒酶grape procyanidins葡多酚green plant绿色植物groundwater level地下水位grove林growth curve生长曲线growth promoter生长促进剂grus鹤GTP-Binding Proteins GTP结合蛋白质类guanosine鸟尿环核甙guild种群guinea pig豚鼠gull鸥gus gus酶habitat栖所haemagglutinin血球凝集素hail霰hail damage雹害hair follicle毛囊halophilic嗜盐菌halophilic bacteria嗜盐菌halosere盐生演替系列hamamelidaceae金缕梅科Hantaan virus汉坦病毒,汉滩病毒,汉他病毒harder哈德Hardy-Weinberg equilibrium哈迪-温伯格平衡hazard ratio风险比HBAg HBAgHBcAg乙型肝炎核心抗原HBeAg HBeAgHBsAg HBsAg。

生物技术进展２０１６年㊀第６卷㊀第４期㊀２３９~２４３ＣｕｒｒｅｎｔＢｉｏｔｅｃｈｎｏｌｏｇｙ㊀ＩＳＳＮ２０９５￣２３４１进展评述Ｒｅｖｉｅｗｓ㊀收稿日期:２０１６￣０２￣２２ꎻ接受日期:２０１６￣０４￣０４㊀作者简介:郑惠惠ꎬ技术员ꎬ主要从事真核重组抗原研发研究ꎮＥ￣ｍａｉｌ:ｓｈａｎｊｖｑｉｕｍｉｎｇ＠１６３.ｃｏｍꎮ∗通信作者:江洪ꎬ工程师ꎬ主要从事重组抗原研发研究ꎮＥ￣ｍａｉｌ:ｊｉａｎｇ＠ｗｏｎｄｅｒｇｅｎ.ｃｏｍＣＨＯ细胞表达系统研究进展郑惠惠ꎬ㊀江㊀洪∗北京万达因生物医学技术有限责任公司ꎬ北京１４１０１７摘㊀要:ＣＨＯ细胞表达系统是目前重组糖蛋白生产的首选系统ꎮ随着无血清悬浮培养技术㊁基因工程技术和大规模培养技术的应用和不断发展ꎬＣＨＯ细胞表达系统已经成为生物技术药物最重要的表达或生产系统ꎬ并被广泛应用于抗体㊁重组蛋白药物和疫苗等产品的研发和生产中ꎮ近年来ꎬ针对ＣＨＯ细胞表达系统在某些重组蛋白的表达和大规模生产中存在的不足ꎬ研究者们通过利用基因工程技术手段ꎬ结合重组蛋白表达机制的研究成果ꎬ为优化和应用ＣＨＯ细胞表达系统做出了不懈努力ꎮ从培养基的优化㊁高产重组ＣＨＯ细胞株的构建㊁大规模培养三个方面综述了ＣＨＯ细胞表达系统的最近研究进展ꎬ以期为ＣＨＯ细胞表达系统的研究与应用提供参考ꎮ关键词:ＣＨＯ细胞培养ꎻ细胞改造ꎻ重组抗原表达ＤＯＩ:１０.３９６９/ｊ.ｉｓｓｎ.２０９５￣２３４１.２０１６.０４.０３ＰｒｏｇｒｅｓｓｏｆＣＨＯＥｘｐｒｅｓｓｉｏｎＳｙｓｔｅｍＺＨＥＮＧＨｕｉ￣ｈｕｉꎬＪＩＡＮＧＨｏｎｇ∗ＢｅｉｊｉｎｇＷｏｎｄｅｒｇｅｎＢｉｏ￣ｍｅｄｉｃｉｎｅＴｅｃｈｎｏｌｏｇｙＣｏ.Ｌｔｄ.ꎬＢｅｉｊｉｎｇ１４１０１７ꎬＣｈｉｎａＡｂｓｔｒａｃｔ:ＣＨＯｃｅｌｌｅｘｐｒｅｓｓｉｏｎｓｙｓｔｅｍｉｓｔｈｅｐｒｅｆｅｒｒｅｄｓｙｓｔｅｍｆｏｒｒｅｃｏｍｂｉｎａｎｔｇｌｙｃｏｐｒｏｔｅｉｎｐｒｏｄｕｃｔｉｏｎ.Ｗｉｔｈｔｈｅｅｖｏｌｖｉｎｇｄｅｖｅｌｏｐｍｅｎｔａｎｄａｐｐｌｉｃａｔｉｏｎｓｏｆｓｅｒｕｍ￣ｆｒｅｅｓｕｓｐｅｎｓｉｏｎｃｕｌｔｕｒｅｔｅｃｈｎｏｌｏｇｙꎬｇｅｎｅｔｉｃｅｎｇｉｎｅｅｒｉｎｇａｎｄｔｈｅｌａｒｇｅ￣ｓｃａｌｅｃｕｌｔｕｒｅｔｅｃｈｎｏｌｏｇｉｅｓꎬＣＨＯｃｅｌｌｅｘｐｒｅｓｓｉｏｎｓｙｓｔｅｍｈａｓｂｅｃｏｍｅｔｈｅｍｏｓｔｉｍｐｏｒｔａｎｔｅｘｐｒｅｓｓｉｏｎｏｒｐｒｏｄｕｃｔｉｏｎｓｙｓｔｅｍｏｆｂｉｏｔｅｃｈｎｏｌｏｇｙｐｒｏｄｕｃｔｓ.Ｔｈｉｓｓｙｓｔｅｍｉｓｗｉｄｅｌｙｕｓｅｄｉｎｔｈｅｒｅｓｅａｒｃｈａｎｄｐｒｏｄｕｃｔｉｏｎｏｆａｎｔｉｂｏｄｉｅｓꎬｒｅｃｏｍｂｉｎａｎｔｐｒｏｔｅｉｎｓａｎｄｖａｃｃｉｎｅｓ.Ｉｎｒｅｃｅｎｔｙｅａｒｓꎬｒｅｓｅａｒｃｈｅｒｓｈａｖｅｍａｄｅｇｒｅａｔｅｆｆｏｒｔｓｔｏｉｍｐｒｏｖｅｔｈｅｅｘｐｒｅｓｓｉｏｎａｎｄｌａｒｇｅ￣ｓｃａｌｅｐｒｏｄｕｃｔｉｏｎｏｆｒｅｃｏｍｂｉｎａｎｔｐｒｏｔｅｉｎｓｂｙｕｓｉｎｇｌａｔｅｓｔｂｉｏｅｎｇｉｎｅｅｒｉｎｇｔｅｃｈｎｏｌｏｇｙａｎｄｔｈｅｄｅｖｅｌｏｐｍｅｎｔｏｆｔｈｅｒｅｃｏｍｂｉｎａｎｔｐｒｏｔｅｉｎｅｘｐｒｅｓｓｉｏｎｍｅｃｈａｎｉｓｍ.ＴｈｉｓａｒｔｉｃｌｅｂｒｉｅｆｌｙｒｅｖｉｅｗｅｄｔｈｅｒｅｃｅｎｔｄｅｖｅｌｏｐｍｅｎｔｏｆｔｈｅＣＨＯｃｅｌｌｅｘｐｒｅｓｓｉｏｎｓｙｓｔｅｍｉｎｔｈｒｅｅａｓｐｅｃｔｓ:ｔｈｅｏｐｔｉｍｉｚａｔｉｏｎｏｆｔｈｅｃｕｌｔｕｒｅｍｅｄｉｕｍꎬｃｏｎｓｔｒｕｃｔｉｏｎｏｆｅｎｇｉｎｅｅｒｅｄＣＨＯｓｔｒａｉｎｓｆｏｒｈｉｇｈ￣ｌｅｖｅｌｐｒｏｄｕｃｔｉｏｎａｎｄｌａｒｇｅ￣ｓｃａｌｅｃｕｌｔｕｒｅｒｅｓｅａｒｃｈꎬｗｈｉｃｈｗａｓｅｘｐｅｃｔｅｄｔｏｐｒｏｖｉｄｅｒｅｆｅｒｅｎｃｅｆｏｒｒｅｓｅａｒｃｈａｎｄａｐｐｌｉｃａｔｉｏｎｏｆＣＨＯｃｅｌｌｅｘｐｒｅｓｓｉｏｎｓｙｓｔｅｍ.Ｋｅｙｗｏｒｄｓ:ＣＨＯｃｅｌｌｃｕｌｔｕｒｅꎻｃｅｌｌｅｎｇｉｎｅｅｒｉｎｇꎻｒｅｃｏｍｂｉｎａｎｔａｎｔｉｇｅｎｅｘｐｒｅｓｓｉｏｎ㊀㊀ＣＨＯ细胞是由Ｐｕｃｋ于１９５７年建成的中国仓鼠卵巢成纤维细胞系ꎮ发展至今ꎬＣＨＯ细胞已成为生物技术药物最重要的表达或生产系统ꎮ随着无血清悬浮培养技术㊁基因工程技术㊁生物反应器设计放大与强化技术㊁大规模高密度流加和连续灌注培养技术等的发展ꎬＣＨＯ细胞系统被广泛应用于抗体㊁基因重组蛋白质药物㊁病毒疫苗等生物技术产品的研究开发和工业化生产中ꎮＣＨＯ细胞是目前重组糖基蛋白生产的首选体系ꎮ因为它具有准确的转录后修饰功能ꎬ表达的蛋白在分子结构㊁理化特性和生物学功能方面更接近于天然蛋白分子ꎮ但ＣＨＯ细胞在无血清培养基中会出现活力差㊁分泌外源蛋白能力弱等问题ꎮ所以建立稳定㊁高产的重组ＣＨＯ细胞成为很多研究者的目标ꎮ近年来ꎬ研究者从细胞营养㊁代谢㊁凋亡㊁信号传导等角度ꎬ结合蛋白表达机制等研究成果ꎬ对这一目标的实现做出了很多努力ꎮ本文从培养基优化㊁高产重组ＣＨＯ细胞株的构. All Rights Reserved.建㊁大规模培养三个方面综述了ＣＨＯ细胞表达系统的最新研究进展ꎬ以期为ＣＨＯ细胞表达系统的应用提供参考ꎮ１㊀培养基的优化研究发现ꎬ不同的细胞株甚至克隆对营养成分的需求都有差别ꎮ通过筛选比较不同培养基成分对重组抗原生产的影响ꎬ并开发适用于不同重组ＣＨＯ细胞株的培养基ꎬ成为很多研究者提高ＣＨＯ细胞表达系统产量的重要方式ꎮ为了维持细胞在无血清培养基中的正常生长ꎬ需要在基础培养基中添加很多其他因子ꎬ如激素㊁生长因子㊁蛋白水解物等ꎮ蛋白质水解物含有丰富的营养成分ꎬ可有效缩短细胞对无血清培养基的适应过程ꎮＤａｖａｍｉ等[１]通过组合比较不同来源的蛋白水解物对细胞密度及表达产量的影响ꎬ优化得到更适于ＤＧ４４的培养基ꎮ酵母水解物作为一种成本较低的非动物源蛋白水解物ꎬ可以使细胞密度增加的同时ꎬ使重组表达抗体的表达量大幅提高[２]ꎮ大豆水解物等都可以被添加到基础培养基中[１ꎬ３ꎬ４]ꎮ由于蛋白水解物的构成复杂ꎬ且批间差异大ꎬ因此蛋白水解物的添加会影响细胞培养基批次间的稳定性ꎮ如果去除培养基中的蛋白质水解物ꎬ需要添加氨基酸或微量元素等ꎬ通过优化调整其比例ꎬ仍能支持高密度的ＣＨＯ细胞培养[５]ꎮ刘兴茂等[６]采用Ｐｌａｃｋｅｔｔ￣Ｂｕｒｍａｎ实验对影响细胞生长的培养添加成分进行了考察ꎬ确定了腐胺㊁胰岛素及转铁蛋白对１１Ｇ￣Ｓ细胞的悬浮培养有明显的生长促进作用ꎮ设计的培养基可以使细胞最大生长密度达到４.１２ˑ１０６ｃｅｌｌｓ/ｍＬꎮＸｕ等[７]采用Ｐｌａｃｋｅｔｔ￣Ｂｕｒｍａｎ设计与支持向量机(ＳＶＭ)预测并实验确定了硫酸锌㊁转铁蛋白及ＢＳＡ对ＣＨＯ￣Ｋ１细胞的生长有促进作用ꎮ另有研究表明ꎬ使用柠檬酸铁作为转铁蛋白的替代物ꎬ可以使细胞的密度达到７.０ˑ１０６ｃｅｌｌｓ/ｍＬꎬ但是会降低转染效率[８]ꎮＭｉｋｉ等[９]研究发现ꎬ添加生长因子ＩＧＦ￣１和脂类信号分子溶血磷脂酸(ＬＰＡ)也可以有效加速ＣＨＯ细胞生长ꎮ优化培养基能有效提高重组ＣＨＯ细胞的培养密度ꎮ高密度的ＣＨＯ细胞培养是ＣＨＯ细胞表达系统实现工业化生产应用的必要条件之一ꎮ与大肠杆菌和酵母表达系统相比ꎬＣＨＯ细胞有生长较慢㊁培养周期较长㊁产量较低等缺点ꎮ为了提高重组蛋白产量㊁扩大ＣＨＯ细胞表达系统的生产应用范围ꎬ研究者们在优化培养基的实验基础上ꎬ构建高产的重组ＣＨＯ细胞系ꎬ为大规模的重组蛋白生产提供基础ꎮ２㊀高产重组ＣＨＯ细胞株的构建研究者们利用发展迅速的基因编辑技术对ＣＨＯ细胞进行筛选和改造ꎬ得到高产的重组细胞株ꎮ研究者们通过过量表达或敲除某个基因ꎬ调整代谢途径㊁延缓细胞凋亡㊁增强转录表达效率ꎬ有效的增加了重组蛋白产量ꎮ通过结合全基因组测序和基因敲除技术的研究成果ꎬ研究者们为得到反应性更好的糖基化重组蛋白做出了不懈努力ꎮ２.１㊀调整代谢途径乳酸作为糖酵解产生的代谢产物会影响细胞生长ꎮＺｈｏｕ等[１０]使用ｓｉＲＮＡ技术降低乳酸脱氢酶Ａ(ＬＤＨａ)和丙铜酸脱氢酶激酶(ＰＤＨＫｓ)基因的表达ꎬ使乳酸的产生降低了９０％ꎬ并增加了单抗的产量ꎮＴｏｕｓｓａｉｎｔ等[１１]通过在ｒＣＨＯ中表达酵母丙酮酸羧化酶(ＰＹＣ２)ꎬ改变了流加培养方式中葡萄糖的代谢速率ꎬ增长了细胞的对数生长期ꎬ从而增加了细胞密度及产量ꎮ２.２㊀延缓细胞凋亡为了延长细胞培养的时间从而增加产量ꎬ有研究者建立了能表达抗凋亡基因的ＣＨＯ细胞系ꎮＭａｊｏｓ等[１２]通过在ＣＨＯ中表达１个Ａｓｐ２９Ａｓｎ突变的抑制凋亡基因ꎬ有效延缓了细胞凋亡ꎮ也有研究者通过敲除细胞中的促凋亡基因来延缓细胞凋亡ꎬ如Ｃｏｓｔ等[１３]敲除了ＢＣＬ２相关蛋白Ｘ(ＢＡＸ)和ＢＡＫ的基因ꎬ使单克隆抗体产量增加了５倍ꎮＲｉｔｔｅｒ等[１４]发现８号染色体端粒区的缺失也可以使产物产量成倍增加ꎮ２.３㊀增强转录表达效率有研究者在细胞信号通路研究成果的基础上ꎬ通过表达转录及翻译过程中的相关蛋白ꎬ增强转录和表达效率ꎬ以增加目的重组蛋白的产量ꎮＬｅＦｏｕｒｎ等[１５]通过在ＣＨＯ中表达人信号受体蛋白ＳＲＰ１４ꎬ成功增加了分泌表达的重组蛋白的产０４２生物技术进展ＣｕｒｒｅｎｔＢｉｏｔｅｃｈｎｏｌｏｇｙ. All Rights Reserved.量ꎮＰｅｎｇ等[１６]通过表达转录翻译相关蛋白ＳＬＹ１㊁ＭＵＮＣ１８Ｃ和ＸＢＰ１ꎬ使ＩｇＧ的产量提高了２０倍ꎻＲａｈｉｍｐｏｕｒ等[１７]在ＣＨＯ细胞中表达神经酰胺转移蛋白(ＣＥＲＴ)的突变基因使ｔ￣ＰＡ的产量增加了３５％ꎮ２.４㊀表达糖基化酶能产生糖基化的重组蛋白是ＣＨＯ细胞表达系统重要的优势ꎬ研究者们通过建立能表达Ｎ￣糖基化途径中不同酶类的细胞系以增加糖基化重组蛋白的反应性ꎮ如Ｇｏｈ[１８]建立的一个含有Ｎ￣乙酰氨基葡萄糖转移酶Ｉ基因的突变体ＣＨＯ￣ｇｍｔ４细胞系ꎬ其表达的重组葡萄糖脑苷脂酶将不需要多糖重构可直接用于治疗戈谢病患者ꎮＺｈａｎｇ等[１９]通过ＣＨＯ￣ｇｍｔ５细胞株表达的重组抗体ꎬ其Ｆｃ的Ｎ￣多糖缺少岩藻糖和唾液酸能增强ＡＤＣＣ的作用ꎮ根据ＣＨＯ￣Ｋ１的基因组信息ꎬＹａｎｇ等[２０]通过锌指核酸酶(ＺＦＮｓ)基因敲除的方法ꎬ研究了１９种包括作用于Ｎ￣糖基链分支㊁半乳糖基㊁聚ＬａｃＮＡｃ延伸㊁唾液酸化加盖的Ｎ￣糖基转移酶对Ｎ￣糖基化作用的影响ꎬ为更准确的表达特定糖基化方式的重组蛋白提供了重要参考ꎮ重组ＣＨＯ细胞表达重组蛋白能力的高低ꎬ不能简单的归结为某些关键基因的作用ꎮ为了得到高产的重组细胞株ꎬ需要研究者们综合考虑细胞的代谢情况㊁培养条件㊁蛋白表达效率和蛋白加工修饰能力等诸多因素ꎮ３㊀大规模培养研究基因工程技术㊁细胞融合技术及抗体类药物的迅速发展ꎬ推进了生物反应器培养技术在生物制药中的应用ꎮ由于ＣＨＯ细胞能以悬浮培养的方式高密度培养ꎬ培养体积可达１０００Ｌ以上ꎬ所以在大规模培养和重组蛋白的高产量生产中ꎬＣＨＯ细胞表达系统拥有广阔的发展前景ꎮ在大规模生产中ꎬ通常采用流加培养方式ꎬ通过添加营养物质来延长培养时间ꎬ增加细胞密度和目的产品的浓度ꎮ为了更大程度的提高重组蛋白的生产效率ꎬ研究者们需要根据不同细胞株的生长代谢特点ꎬ选择和优化起始培养基㊁补料培养基及补料策略ꎮ现代计算机技术㊁数学算法及理论的应用ꎬ也为研究者对细胞流加培养的优化提供了很大帮助ꎮ３.１㊀优化培养参数选择合适的培养基㊁优化细胞培养的参数(如温度㊁ｐＨ㊁溶氧㊁ＣＯ２浓度㊁渗透压等)对生产至关重要ꎮ同时ꎬ流加工艺参数(如流加培养基成分㊁流加时间等)均需根据不同的细胞株及反应器的特点来设计优化ꎮＦａｎ等[２１]采用分批补料方式培养ＣＨＯ细胞ꎬ实验显示培养基中的氨基酸和葡萄糖浓度对细胞的生长㊁ＩｇＧ浓度和Ｎ￣糖基化生成都很重要ꎮＫｉｍ等[２２]使用分批补料培养使ＩｇＧ的产量达到２.３ｇ/Ｌꎮ通过用小麦蛋白水解物(ＷＧＨ)代替补料中的谷氨酰胺可以使ｔ￣ＰＡ的产量达到４２２ｍｇ/Ｌ[２３]ꎮ３.２㊀应用新的培养技术微载体培养是一种动物细胞大规模培养技术ꎮ培养液中大量的微载体为细胞提供了极大的附着表面ꎬ从而可实现细胞的高密度培养ꎮ胡显文等[２４]在搅拌式反应器中无血清培养分泌ｕ￣ＰＡ的ＤＮＡ重组ＣＨＯ细胞ꎬ通过部分更换Ｃｙｔｏｐｏｒｅ多孔微载体ꎬ解决了大规模细胞培养中细胞凋亡的问题ꎮ并使用周期变压刺激技术使ｕ￣ＰＡ的产量提高了１０倍ꎬ且可以降低葡萄糖厌氧代谢产生乳酸的转化率ꎮＶｅｎｔｉｎｉ等[２５]通过Ｃｙｔｏｄｅｘ微载体培养ＣＨＯ￣ｈＴＳＨ细胞的实验表明ꎬ培养基中微载体的数量及在ｒｈＴＳＨ合成期开始时的细胞浓度是提高目的蛋白产量的重要参数ꎮ李智等[２６]利用ＣＨＯ细胞能在培养过程中自然结团的特性ꎬ采用超声沉降柱二合一灌流系统促进细胞结团和加强截留的特性ꎬ用无血清培养基连续灌流培养基因重组ＣＨＯ细胞ＭＫ３￣Ａ２株ꎬ分泌表达的ｒｈＴＮＫ￣ｔＰＡ生产率平均为８９ｍｇ/Ｌ ｄꎮ３.３㊀添加保护剂聚醚Ｆ６８可以有效减少生物反应器中搅拌对细胞产生的机械损伤ꎮ针对Ｆ６８对某些细胞株的生长及产量降低的情况ꎬ研究者发现０.０５％或０.０７５％的５００ｋＤａ的γＰＧＡ可以替代Ｆ６８应用于ＣＨＯＤＧ４４细胞的培养中[２７]ꎮ在细胞培养工艺逐级放大的过程中ꎬ每一步都需要研究者们监控细胞在生长和表达方面的相关指标ꎮ生物反应器在线监控ｐＨ㊁溶氧等参数的功能㊁色谱和在线蛋白分解监测等技术为大规模培养的过程控制提供了帮助ꎮ１４２郑惠惠ꎬ等:ＣＨＯ细胞表达系统研究进展. All Rights Reserved.４　展望ＣＨＯ细胞是表达外源蛋白最多也是最成功的一类细胞ꎬ有其不可比拟的优点ꎬ同时也存在现行技术手段不能弥补的不足之处ꎮ结合生物信息学㊁细胞生物学㊁基因工程技术和生物反应器技术的研究成果ꎬ研究者们可以通过综合考虑细胞代谢特性㊁蛋白表达特性等影响因素ꎬ通过研发个性化培养条件及培养工艺ꎬ构建高表达载体ꎬ筛选稳定高产的重组细胞株ꎬ改造宿主细胞等角度继续优化ＣＨＯ细胞表达系统ꎬ为产业化生产重组蛋白提供基础ꎮ用于产业化生产的重组ＣＨＯ细胞ꎬ需要具备生长特性良好㊁能在无血清培养基中高密度培养㊁表达重组蛋白能力强㊁能正确的进行翻译后修饰等特点ꎮ糖基化是蛋白翻译后最重要的修饰之一ꎬ直接影响重组蛋白的空间结构㊁生物活性㊁稳定性㊁免疫原性和生物反应性等ꎮ对重组蛋白的糖基化研究一直是研发和生产真核重组蛋白的热点课题ꎮ随着基因编辑技术的发展ꎬ研究者们通过表达特定糖基化相关酶从而得到完整㊁准确的特定形式的糖链结构ꎬ为糖基化蛋白在免疫诊断㊁临床治疗等领域的持续发展奠定了基础ꎮ随着基因技术的不断发展ꎬ对细胞代谢㊁信号传导等方面研究的持续深入ꎬ构建能表达准确修饰的糖基化重组蛋白的高产重组ＣＨＯ细胞株仍将成为研究热点ꎮ参㊀考㊀文㊀献[１]㊀ＤａｖａｍｉＦꎬＥｇｈｂａｌｐｏｕｒＦꎬＮｅｍａｔｏｌｌａｈｉＬꎬｅｔａｌ..ＥｆｆｅｃｔｓｏｆｐｅｐｔｏｎｅｓｕｐｐｌｅｍｅｎｔａｔｉｏｎｉｎｄｉｆｆｅｒｅｎｔｃｕｌｔｕｒｅｍｅｄｉａｏｎｇｒｏｗｔｈꎬｍｅｔａｂｏｌｉｃｐａｔｈｗａｙａｎｄｐｒｏｄｕｃｔｉｖｉｔｙｏｆＣＨＯＤＧ４４ｃｅｌｌｓ:ａｎｅｗｉｎｓｉｇｈｔｉｎｔｏａｍｉｎｏａｃｉｄｐｒｏｆｉｌｅｓ[Ｊ].Ｉｒａｎ.Ｂｉｏｍｅｄ.Ｊ.ꎬ２０１５ꎬ１９(４):１９４－２０５.[２]㊀ＳｕｎｇＹＨꎬＬｉｍＳＷꎬＣｈｕｎｇＪＹꎬｅｔａｌ..Ｙｅａｓｔｈｙｄｒｏｌｙｓａｔｅａｓａｌｏｗ￣ｃｏｓｔａｄｄｉｔｉｖｅｔｏｓｅｒｕｍ￣ｆｒｅｅｍｅｄｉｕｍｆｏｒｔｈｅｐｒｏｄｕｃｔｉｏｎｏｆｈｕｍａｎｔｈｒｏｍｂｏｐｏｉｅｔｉｎｉｎｓｕｓｐｅｎｓｉｏｎｃｕｌｔｕｒｅｓｏｆＣｈｉｎｅｓｅｈａｍｓｔｅｒｏｖａｒｙｃｅｌｌｓ[Ｊ].Ａｐｐｌ.Ｍｉｃｒｏｂｉｏｌ.Ｂｉｏｔｅｃｈｎｏｌ.ꎬ２００４ꎬ６３(５):５２７－５３６.[３]㊀ＤａｖａｍｉＦꎬＢａｌｄｉＬꎬＲａｊｅｎｄｒａＹꎬｅｔａｌ..ＰｅｐｔｏｎｅｓｕｐｐｌｅｍｅｎｔａｔｉｏｎｏｆｃｕｌｔｕｒｅｍｅｄｉｕｍｈａｓｖａｒｉａｂｌｅｅｆｆｅｃｔｓｏｎｔｈｅｐｒｏｄｕｃｔｉｖｉｔｙｏｆＣＨＯｃｅｌｌｓ[Ｊ].Ｉｎｔ.Ｊ.Ｍｏｌ.ＣｅｌｌＭｅｄ.ꎬ２０１４ꎬ３(３):１４６－１５６.[４]㊀ＣｈｕｎＢＨꎬＫｉｍＪＨꎬＬｅｅＨＪꎬｅｔａｌ..Ｕｓａｂｉｌｉｔｙｏｆｓｉｚｅ￣ｅｘｃｌｕｄｅｄｆｒａｃｔｉｏｎｓｏｆｓｏｙｐｒｏｔｅｉｎｈｙｄｒｏｌｙｓａｔｅｓｆｏｒｇｒｏｗｔｈａｎｄｖｉａｂｉｌｉｔｙｏｆＣｈｉｎｅｓｅｈａｍｓｔｅｒｏｖａｒｙｃｅｌｌｓｉｎｐｒｏｔｅｉｎ￣ｆｒｅｅｓｕｓｐｅｎｓｉｏｎｃｕｌｔｕｒｅ[Ｊ].Ｂｉｏｒｅｓｏｕｒ.Ｔｅｃｈｎｏｌ.ꎬ２００７ꎬ９８(５):１０００－１００５.[５]㊀张大鹤ꎬ易小萍ꎬ张元兴ꎬ等ꎬ适于重组ＣＨＯ细胞培养的无血清培养基的制备[Ｊ].中国生物制品学杂志ꎬ２０１１(１０):１１５２－１１５６.[６]㊀刘兴茂ꎬ刘红ꎬ叶玲玲ꎬ等ꎬＣＨＯ工程细胞无血清悬浮分批培养的生长代谢特征及动力学模型[Ｊ].生物工程学报ꎬ２０１０ꎬ(１):８５－９２.[７]㊀ＸｕＪꎬＹａｎＦＲꎬＬｉＺＨꎬｅｔａｌ..Ｓｅｒｕｍ￣ｆｒｅｅｍｅｄｉｕｍｏｐｔｉｍｉｚａｔｉｏｎｂａｓｅｄｏｎｔｒｉａｌｄｅｓｉｇｎａｎｄｓｕｐｐｏｒｔｖｅｃｔｏｒｒｅｇｒｅｓｓｉｏｎ[Ｊ].Ｂｉｏｍｅｄ.Ｒｅｓ.Ｉｎｔ.ꎬ２０１４ꎬｄｏｉ:１０.１１５５/２０１４/２６９３０５. [８]㊀ＥｂｅｒｈａｒｄｙＳＲꎬＲａｄｚｎｉａｋＬꎬＬｉｕＺ.Ｉｒｏｎ(ＩＩＩ)ｃｉｔｒａｔｅｉｎｈｉｂｉｔｓｐｏｌｙｅｔｈｙｌｅｎｉｍｉｎｅ￣ｍｅｄｉａｔｅｄｔｒａｎｓｉｅｎｔｔｒａｎｓｆｅｃｔｉｏｎｏｆＣｈｉｎｅｓｅｈａｍｓｔｅｒｏｖａｒｙｃｅｌｌｓｉｎｓｅｒｕｍ￣ｆｒｅｅｍｅｄｉｕｍ[Ｊ].Ｃｙｔｏｔｅｃｈｎｏｌｏｇｙꎬ２００９ꎬ６０:１－９.[９]㊀ＭｉｋｉＨꎬＴａｋａｇｉＭ.Ｄｅｓｉｇｎｏｆｓｅｒｕｍ￣ｆｒｅｅｍｅｄｉｕｍｆｏｒｓｕｓｐｅｎｓｉｏｎｃｕｌｔｕｒｅｏｆＣＨＯｃｅｌｌｓｏｎｔｈｅｂａｓｉｓｏｆｇｅｎｅｒａｌｃｏｍｍｅｒｃｉａｌｍｅｄｉａ[Ｊ].Ｃｙｔｏｔｅｃｈｎｏｌｏｇｙꎬ２０１５ꎬ６７(４):６８９－６９７.[１０]㊀ＺｈｏｕＭꎬＣｒａｗｆｏｒｄＹꎬＮｇＤꎬｅｔａｌ..ＤｅｃｒｅａｓｉｎｇｌａｃｔａｔｅｌｅｖｅｌａｎｄｉｎｃｒｅａｓｉｎｇａｎｔｉｂｏｄｙｐｒｏｄｕｃｔｉｏｎｉｎＣｈｉｎｅｓｅＨａｍｓｔｅｒＯｖａｒｙｃｅｌｌｓ(ＣＨＯ)ｂｙｒｅｄｕｃｉｎｇｔｈｅｅｘｐｒｅｓｓｉｏｎｏｆｌａｃｔａｔｅｄｅｈｙｄｒｏｇｅｎａｓｅａｎｄｐｙｒｕｖａｔｅｄｅｈｙｄｒｏｇｅｎａｓｅｋｉｎａｓｅｓ[Ｊ].Ｊ.Ｂｉｏｔｅｃｈｎｏｌ.ꎬ２０１１ꎬ１５３(１－２):２７－３４.[１１]㊀ＴｏｕｓｓａｉｎｔＣꎬＨｅｎｒｙＯꎬＤｕｒｏｃｈｅｒＹ.ＭｅｔａｂｏｌｉｃｅｎｇｉｎｅｅｒｉｎｇｏｆＣＨＯｃｅｌｌｓｔｏａｌｔｅｒｌａｃｔａｔｅｍｅｔａｂｏｌｉｓｍｄｕｒｉｎｇｆｅｄ￣ｂａｔｃｈｃｕｌｔｕｒｅｓ[Ｊ].Ｊ.Ｂｉｏｔｅｃｈｎｏｌ.ꎬ２０１５ꎬ２１７:１２２－１３１.[１２]㊀ＭａｊｏｒｓＢＳꎬＣｈｉａｎｇＧＧꎬＰｅｄｅｒｓｏｎＮＥꎬｅｔａｌ..Ｄｉｒｅｃｔｅｄｅｖｏｌｕｔｉｏｎｏｆｍａｍｍａｌｉａｎａｎｔｉ￣ａｐｏｐｔｏｓｉｓｐｒｏｔｅｉｎｓｂｙｓｏｍａｔｉｃｈｙｐｅｒｍｕｔａｔｉｏｎ[Ｊ].ＰｒｏｔｅｉｎＥｎｇ.Ｄｅｓ.Ｓｅｌ.ꎬ２０１２ꎬ２５(１):２７－３８.[１３]㊀ＣｏｓｔＧＪꎬＦｒｅｙｖｅｒｔＹꎬＶａｆｉａｄｉｓＡꎬｅｔａｌ..ＢＡＫａｎｄＢＡＸｄｅｌｅｔｉｏｎｕｓｉｎｇｚｉｎｃ￣ｆｉｎｇｅｒｎｕｃｌｅａｓｅｓｙｉｅｌｄｓａｐｏｐｔｏｓｉｓ￣ｒｅｓｉｓｔａｎｔＣＨＯｃｅｌｌｓ[Ｊ].Ｂｉｏｔｅｃｈｎｏｌ.Ｂｉｏｅｎｇ.ꎬ２０１０ꎬ１０５(２):３３０－４０. [１４]㊀ＲｉｔｔｅｒＡꎬＶｏｅｄｉｓｃｈＢꎬＷｉｅｎｂｅｒｇＪꎬｅｔａｌ..Ｄｅｌｅｔｉｏｎｏｆａｔｅｌｏｍｅｒｉｃｒｅｇｉｏｎｏｎｃｈｒｏｍｏｓｏｍｅ８ｃｏｒｒｅｌａｔｅｓｗｉｔｈｈｉｇｈｅｒｐｒｏｄｕｃｔｉｖｉｔｙａｎｄｓｔａｂｉｌｉｔｙｏｆＣＨＯｃｅｌｌｌｉｎｅｓ[Ｊ].Ｂｉｏｔｅｃｈｎｏｌ.Ｂｉｏｅｎｇ.ꎬ２０１６ꎬ１１３(５):１０８４－１０９３.[１５]㊀ＬｅＦｏｕｒｎＶꎬＧｉｒｏｄＰＡꎬＢｕｃｅｔａＭꎬｅｔａｌ..ＣＨＯｃｅｌｌｅｎｇｉｎｅｅｒｉｎｇｔｏｐｒｅｖｅｎｔｐｏｌｙｐｅｐｔｉｄｅａｇｇｒｅｇａｔｉｏｎａｎｄｉｍｐｒｏｖｅｔｈｅｒａｐｅｕｔｉｃｐｒｏｔｅｉｎｓｅｃｒｅｔｉｏｎ[Ｊ].Ｍｅｔａｂ.Ｅｎｇ.ꎬ２０１４ꎬ２１:９１－１０２.[１６]㊀ＰｅｎｇＲＷꎬＦｕｓｓｅｎｅｇｇｅｒＭ.ＭｏｌｅｃｕｌａｒｅｎｇｉｎｅｅｒｉｎｇｏｆｅｘｏｃｙｔｉｃｖｅｓｉｃｌｅｔｒａｆｆｉｃｅｎｈａｎｃｅｓｔｈｅｐｒｏｄｕｃｔｉｖｉｔｙｏｆＣｈｉｎｅｓｅｈａｍｓｔｅｒｏｖａｒｙｃｅｌｌｓ[Ｊ].Ｂｉｏｔｅｃｈｎｏｌ.Ｂｉｏｅｎｇ.ꎬ２００９ꎬ１０２(４):１１７０－１１８１.[１７]㊀ＲａｈｉｍｐｏｕｒＡꎬＶａｚｉｒｉＢꎬＭｏａｚｚａｍｉＲꎬｅｔａｌ..ＥｎｇｉｎｅｅｒｉｎｇｔｈｅｃｅｌｌｕｌａｒｐｒｏｔｅｉｎｓｅｃｒｅｔｏｒｙｐａｔｈｗａｙｆｏｒｅｎｈａｎｃｅｍｅｎｔｏｆｒｅｃｏｍｂｉｎａｎｔｔｉｓｓｕｅｐｌａｓｍｉｎｏｇｅｎａｃｔｉｖａｔｏｒｅｘｐｒｅｓｓｉｏｎｉｎＣｈｉｎｅｓｅｈａｍｓｔｅｒｏｖａｒｙｃｅｌｌｓ:ｅｆｆｅｃｔｓｏｆＣＥＲＴａｎｄＸＢＰ１ｓｇｅｎｅｓ[Ｊ].Ｊ.Ｍｉｃｒｏｂｉｏｌ.Ｂｉｏｔｅｃｈｎｏｌ.ꎬ２０１３ꎬ２３(８):１１１６－１１２２. [１８]㊀ＧｏｈＪＳꎬＬｉｕＹꎬＣｈａｎＫＦꎬｅｔａｌ..ＰｒｏｄｕｃｉｎｇｒｅｃｏｍｂｉｎａｎｔｔｈｅｒａｐｅｕｔｉｃｇｌｙｃｏｐｒｏｔｅｉｎｓｗｉｔｈｅｎｈａｎｃｅｄｓｉａｌｙｌａｔｉｏｎｕｓｉｎｇＣＨＯ￣ｇｍｔ４ｇｌｙｃｏｓｙｌａｔｉｏｎｍｕｔａｎｔｃｅｌｌｓ[Ｊ].Ｂｉｏｅｎｇｉｎｅｅｒｅｄꎬ２０１４ꎬ５２４２生物技术进展ＣｕｒｒｅｎｔＢｉｏｔｅｃｈｎｏｌｏｇｙ. All Rights Reserved.(４):２６９－２７３.[１９]㊀ＺｈａｎｇＰꎬＨａｒｙａｄｉＲꎬＣｈａｎＫＦꎬｅｔａｌ..ＩｄｅｎｔｉｆｉｃａｔｉｏｎｏｆｆｕｎｃｔｉｏｎａｌｅｌｅｍｅｎｔｓｏｆｔｈｅＧＤＰ￣ｆｕｃｏｓｅｔｒａｎｓｐｏｒｔｅｒＳＬＣ３５Ｃ１ｕｓｉｎｇａｎｏｖｅｌＣｈｉｎｅｓｅｈａｍｓｔｅｒｏｖａｒｙｍｕｔａｎｔ[Ｊ].Ｇｌｙｃｏｂｉｏｌｏｇｙꎬ２０１２ꎬ２２(７):８９７－９１１.[２０]㊀ＹａｎｇＺꎬＷａｎｇＳꎬＨａｌｉｍＡꎬｅｔａｌ..ＥｎｇｉｎｅｅｒｅｄＣＨＯｃｅｌｌｓｆｏｒｐｒｏｄｕｃｔｉｏｎｏｆｄｉｖｅｒｓｅꎬｈｏｍｏｇｅｎｅｏｕｓｇｌｙｃｏｐｒｏｔｅｉｎｓ[Ｊ].Ｎａｔ.Ｂｉｏｔｅｃｈｎｏｌ.ꎬ２０１５ꎬ３３(８):８４２－８４４.[２１]㊀ＦａｎＹꎬＪｉｍｅｎｅｚＤｅｌＶａｌＩꎬＭｕｌｌｅｒＣꎬｅｔａｌ..Ａｍｉｎｏａｃｉｄａｎｄｇｌｕｃｏｓｅｍｅｔａｂｏｌｉｓｍｉｎｆｅｄ￣ｂａｔｃｈＣＨＯｃｅｌｌｃｕｌｔｕｒｅａｆｆｅｃｔｓａｎｔｉｂｏｄｙｐｒｏｄｕｃｔｉｏｎａｎｄｇｌｙｃｏｓｙｌａｔｉｏｎ[Ｊ].Ｂｉｏｔｅｃｈｎｏｌ.Ｂｉｏｅｎｇ.ꎬ２０１５ꎬ１１２(３):５２１－５３５.[２２]㊀ＫｉｍＢＪꎬＺｈａｏＴꎬＹｏｕｎｇＬꎬｅｔａｌ..Ｂａｔｃｈꎬｆｅｄ￣ｂａｔｃｈꎬａｎｄｍｉｃｒｏｃａｒｒｉｅｒｃｕｌｔｕｒｅｓｗｉｔｈＣＨＯｃｅｌｌｌｉｎｅｓｉｎａｐｒｅｓｓｕｒｅ￣ｃｙｃｌｅｄｒｉｖｅｎｍｉｎｉａｔｕｒｉｚｅｄｂｉｏｒｅａｃｔｏｒ[Ｊ].Ｂｉｏｔｅｃｈｎｏｌ.Ｂｉｏｅｎｇ.ꎬ２０１２ꎬ１０９(１):１３７－１４５.[２３]㊀ＫｉｍｄｏＹꎬＣｈａｕｄｈｒｙＭＡꎬＫｅｎｎａｒｄＭＬꎬｅｔａｌ..Ｆｅｄ￣ｂａｔｃｈＣＨＯｃｅｌｌｔ￣ＰＡｐｒｏｄｕｃｔｉｏｎａｎｄｆｅｅｄｇｌｕｔａｍｉｎｅｒｅｐｌａｃｅｍｅｎｔｔｏｒｅｄｕｃｅａｍｍｏｎｉａｐｒｏｄｕｃｔｉｏｎ[Ｊ].Ｂｉｏｔｅｃｈｎｏｌ.Ｐｒｏｇ.ꎬ２０１３ꎬ２９(１):１６５－１７５.[２４]㊀胡显文ꎬ肖成祖ꎬ高丽华ꎬ等.用多孔微载体大规模长期培养动物细胞的方法[Ｊ].生物技术通报ꎬ２００１ꎬ(１):４５－４８. [２５]㊀ＶｅｎｔｉｎｉＤＣꎬＤａｍｉａｎｉＲꎬＳｏｕｓａＡＰꎬｅｔａｌ..ＩｍｐｒｏｖｅｄｂｉｏｐｒｏｃｅｓｓｗｉｔｈＣＨＯ￣ｈＴＳＨｃｅｌｌｓｏｎｈｉｇｈｅｒｍｉｃｒｏｃａｒｒｉｅｒｃｏｎｃｅｎｔｒａｔｉｏｎｐｒｏｖｉｄｅｓｈｉｇｈｅｒｏｖｅｒａｌｌｂｉｏｍａｓｓａｎｄｐｒｏｄｕｃｔｉｖｉｔｙｆｏｒｒｈＴＳＨ[Ｊ].Ａｐｐｌ.Ｂｉｏｃｈｅｍ.Ｂｉｏｔｅｃｈｎｏｌ.ꎬ２０１１ꎬ１６４(４):４０１－４０９.[２６]㊀李智ꎬ肖成祖ꎬ杨琴ꎬ等.ＣＨＯ细胞无血清结团灌流培养:超声－沉降柱二合一灌流系统[Ｊ].中国生物工程杂志ꎬ２００８ꎬ(４):５３－５８.[２７]㊀ＣｈｕｎＢＨꎬＬｅｅＹＫꎬＣｈｕｎｇＮ.Ｐｏｌｙ￣ｇａｍｍａ￣ｇｌｕｔａｍｉｃａｃｉｄｅｎｈａｎｃｅｓｔｈｅｇｒｏｗｔｈａｎｄｖｉａｂｉｌｉｔｙｏｆＣｈｉｎｅｓｅｈａｍｓｔｅｒｏｖａｒｙｃｅｌｌｓｉｎｓｅｒｕｍ￣ｆｒｅｅｍｅｄｉｕｍ[Ｊ].Ｂｉｏｔｅｃｈｎｏｌ.Ｌｅｔｔ.ꎬ２０１２ꎬ３４(１０):１８０７－１８１０.３４２郑惠惠ꎬ等:ＣＨＯ细胞表达系统研究进展. All Rights Reserved.。

β环糊精英国药品标准-回复β环糊精是一种常见的药用辅料，广泛应用于制药工业中。

该物质由一系列葡萄糖单元组成，呈现出一种环状的结构。

它可以与药物分子相互作用，改善药物的溶解性、稳定性和生物利用度。

β环糊精在很多国家都有药品标准，其中包括英国药品标准。

本文将一步一步回答关于β环糊精英国药品标准的相关问题。

第一步：了解β环糊精β环糊精是一种天然产物，由7个葡萄糖分子通过β-(1,4) 糖苷键连接而成的环状结构。

其化学名为糠酊，分子式为（C6H10O5）7，分子量为1134.98g/mol。

它具有良好的生物相容性和生物可降解性，在制药工业中被广泛应用。

第二步：了解英国药品标准英国药品标准是英国药典（British Pharmacopoeia，BP）制定的药品规范，旨在确保药品的质量、安全性和疗效。

BP是英国国家药典委员会指导下的独立组织，负责制定和更新英国药品标准。

该标准适用于英国的药品生产商和药品配方师。

第三步：了解β环糊精在英国药品标准中的应用β环糊精在药品制造中起到了至关重要的作用，它可以与药物分子形成包合物，从而改善药物的溶解性和稳定性，提高其生物利用度。

在英国药品标准中，β环糊精被定义为一种辅料，用于改善药物的制剂特性。

第四步：了解β环糊精的质量标准根据英国药品标准，β环糊精需要符合一系列质量标准。

这些标准包括外观、固体含量、重金属残留物、微生物限度、pH值等。

例如，β环糊精的外观应该是白色至类白色粉末，固体含量应不低于95，重金属残留物应符合规定的限量要求，微生物限度应符合规定的要求，pH值应在5.0至8.0之间。

第五步：验证β环糊精的质量为确保β环糊精的质量符合英国药品标准，药品生产商需要进行质量控制测试。

这些测试包括物质鉴定、外观检查、固体含量测定、重金属检测、微生物检测以及pH值测试等。

只有通过这些测试并满足英国药品标准中的要求，才能确保β环糊精质量符合标准。

综上所述，β环糊精是一种常见的药用辅料，在英国药品标准中有明确的规定。

分析检测食品中牛、羊、猪、马源性成分鉴定能力验证及测量审核结果分析徐新龙，杨　丽，彭国刚，李子帆，李军霞，李　兰（阿拉山口海关技术中心，动植食品纺织实验室，新疆阿拉山口 833418）摘 要：目的：分析食品中牛源性成分鉴定能力验证结果偏离的原因，总结经验教训以提高实验室对食品中4种动物源性成分鉴定的准确性，确保能力维持。

方法：对两次参试肉糜样品分别提取DNA，依据SN/T 2051—2008及SN/T 3730.5—2013进行牛、羊、猪、马源性成分单体系实时荧光PCR检测，同时设立阳性对照、阴性对照及空白对照进行质量控制。

结果：能力验证样品19-J109检出牛、猪源性成分，未检出羊、马源性成分；样品19-Y826检出牛、羊、猪、马源性成分；中期报告显示样品19-J109牛源性成分鉴定结果为假阳性，结果不满意；测量审核样品19-B316检出牛源性成分，19-B223未检出牛源性成分，结果满意。

结论：通过对能力验证不满意结果进行原因分析，并对过程加以改进，测量审核结果满意，证明实验室具备食品中牛、羊、猪、马源性成分定性检测的能力，可满足进出口食品中肉类掺假检测的需求。

关键词：食品；动物源性成分；能力验证；测量审核；实时荧光PCRAnalysis of the Results of Proficiency Testing and Measurement Audit for the Identification of Bovine, Ovine, Porcine and Equine-Derived Ingredients in Food ProductsXU Xinlong, YANG Li, PENG Guogang, LI Zifan, LI Junxia, LI Lan(Alashankou Customs Technology Center, Animal and Plant Food and Textile Laboratory, Alashankou 833418, China) Abstract: Objective: In order to improve the accuracy of the laboratory’s identification of four animal-derived ingredients in food and ensure the ability’s maintenance, it is necessary to analyze the reasons behind the deviation of the results of the proficiency testing of bovine-derived ingredients in food. Additionally, the experience and lessons learned should be summarized. Method: DNA was isolated from the two test’s minced meat samples, and SN/T 2051—2008 and SN/T 3730.5—2013 were followed in the single-system real-time fluorescence PCR detection of components produced from sheep, pigs, horses, and cows. For quality control, blank, negative, and positive controls were set up simultaneously. Result: Sheep and horses were not discovered in the proficiency testing sample 19-J109, however components derived from cattle and pigs were. Sample 19-Y826 contained components originated from sheep, cattle, pigs, and horses. The mid-term assessment revealed that sample 19-J109’s bovine-derived component identification results were false positives and unsatisfactory. Test sample 19-B316 had components produced from cows, whereas test sample 19-B223 contained no such components, with satisfactory findings. Conclusion: The results of the measurement audit are satisfactory after the procedure was improved and the reasons for the ability verification’s bad results were examined. It has been demonstrated that a laboratory can qualitatively identify the presence of pigs, horses, sheep, and cattle in food, which satisfies the requirement for detecting meat adulteration in both imported and exported food.Keywords: food; animal derived ingredients; proficiency testing; measurement audit; real-time fluorescent PCR 作者简介：徐新龙（1986—），男，新疆呼图壁人，硕士，兽医师。

尚旭珂，朱斯亮，郑宝东，等. 体外模拟消化环境中消化酶对κ-卡拉胶/酪蛋白复合体系流变学特性及微观结构的影响[J]. 食品工业科技，2024，45（4）：33−41. doi: 10.13386/j.issn1002-0306.2023030008SHANG Xuke, ZHU Siliang, ZHENG Baodong, et al. Effects of Digestive Enzymes on Rheological Properties and Microstructure of κ-Carrageenan/Casein Composite Systems in vitro Simulated Digestion Environment[J]. Science and Technology of Food Industry, 2024,45(4): 33−41. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2023030008· 研究与探讨 ·体外模拟消化环境中消化酶对κ-卡拉胶/酪蛋白复合体系流变学特性及微观结构的影响尚旭珂1,2，朱斯亮1,2，郑宝东1，郭娟娟1,2,*（1.福建农林大学食品科学学院，福建福州 350000；2.泉州师范学院海洋与食品学院，福建泉州 362000）摘　要：卡拉胶与酪蛋白的结合对肠道屏障具有一定的保护作用，为研究两者在体外消化模拟中消化酶是否是影响多糖或多糖-蛋白复合体系构象转变的主要因素，本文以κ-卡拉胶为研究对象，选择酪蛋白为基质，探究体外模拟消化环境中消化酶对κ-卡拉胶/酪蛋白复合体系结合稳定性的影响。

结果表明，消化酶对κ-卡拉胶与酪蛋白的结合影响不大，但可以使体系硫酸基团暴露量显著增加，不利于κ-卡拉胶的构型。

体系中的酪蛋白被分解为低分子量的蛋白质或肽段，使得复合体系的特征长度增加，相互作用减弱，粘弹性下降，双螺旋结构稳定性降低。

专利名称：一种携载β-胡萝卜素的亲水性纳米药物及其在制备治疗脑缺血再灌注损伤的药物中应用
专利类型：发明专利
发明人：李士勇,罗军,王晔,袁真
申请号：CN201911077427.0
申请日：20191106
公开号：CN110755406A
公开日：
20200207
专利内容由知识产权出版社提供
摘要：本发明属于医药技术领域，尤其涉及一种携载β‑胡萝卜素的亲水性纳米药物及其在制备治疗脑缺血再灌注损伤的药物中应用。

本发明利用高分子DSPE‑PEG携载β‑胡萝卜素，增加其水溶性和稳定性；利用鞘内注射的方法增加该纳米药物在脑内的聚集；利用β‑胡萝卜素清除活性氧，有效减少缺血‑再灌注脑后的氧化应激损伤，对开发β‑胡萝卜素的医学应用具有重要价值，对于治疗和减轻脑的缺血再灌注损伤具有重要的意义。

申请人：南昌大学第二附属医院
地址：330006 江西省南昌市民德路1号南昌大学第二附属医院
国籍：CN
代理机构：北京金智普华知识产权代理有限公司
代理人：杨采良
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专利名称：一种肽的固相合成方法及其合成的肽专利类型：发明专利
发明人：王宇恩,陈永汉,刘剑,马亚平,袁建成
申请号：CN201210364825.2
申请日：20120926
公开号：CN102875639A
公开日：
20130116
专利内容由知识产权出版社提供
摘要：本发明提供了一种含不对称二硫键的肽的固相合成方法，以及由此方法合成的肽。

申请人：深圳翰宇药业股份有限公司
地址：518057 广东省深圳市南山区高新技术工业园中区翰宇生物医药园办公大楼四层国籍：CN
代理机构：北京北翔知识产权代理有限公司
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