3 PI Stabilization of Delay-Free Linear Time-Invariant Systems
-细胞凋亡的检测方法-
细胞凋亡的检测方法细胞凋亡与坏死是两种完全不同的细胞凋亡形式,根据死亡细胞在形态学、生物化学和分子生物学上的差别,可以将二者区别开来。
细胞凋亡的检测方法有很多,下面介绍几种常用的测定方法。
一、细胞凋亡的形态学检测二、磷脂酰丝氨酸外翻分析(Annexin V法)磷脂酰丝氨酸(Phosphatidylserine, PS)正常位于细胞膜的内侧,但在细胞凋亡的早期,PS可从细胞膜的内侧翻转到细胞膜的表面,暴露在细胞外环境中(图3)。
Annexin-V是一种分子量为35~36KD的Ca2+依赖性磷脂结合蛋白,能与PS高亲和力特异性结合。
将Annexin-V进行荧光素(FITC、PE)或biotin标记,以标记了的Annexin-V作为荧光探针,利用流式细胞仪或荧光显微镜可检测细胞凋亡的发生。
碘化丙啶(propidine iodide, PI)是一种核酸染料,它不能透过完整的细胞膜,但在凋亡中晚期的细胞和死细胞,PI能够透过细胞膜而使细胞核红染。
因此将Annexin-V与PI匹配使用,就可以将凋亡早晚期的细胞以及死细胞区分开来。
方法1 悬浮细胞的染色:将正常培养和诱导凋亡的悬浮细胞(0.5~1×106)用PBS洗2次,加入100ul Binding Buffer和FITC标记的Annexin-V(20ug/ml)10ul,室温避光30min,再加入PI(50ug/ml)5ul,避光反应5min 后,加入400ul Binding Buffer,立即用FACScan进行流式细胞术定量检测(一般不超过1h),同时以不加AnnexinV-FITC及PI的一管作为阴性对照。
2 贴壁培养的细胞染色:先用0.25%的胰酶消化,洗涤、染色和分析同悬浮细胞。
3 爬片细胞染色:同上,最后用荧光显微镜和共聚焦激光扫描显微镜进行观察。
结果(图4、图5)注意事项1. 整个操作动作要尽量轻柔,勿用力吹打细胞。
2. 操作时注意避光,反应完毕后尽快在一小时内检测。
三磷酸腺苷生物发光法在卵巢癌细胞株药物敏感试验中的应用(精)
三磷酸腺苷生物发光法在卵巢癌细胞株药物敏感试验中的应用楼江燕彭芝兰刘珊玲王和1983年,Moyer等提出内源性三磷酸腺苷(ATP)的数量可以反映细胞的活性度。
随后Kangas等提出三磷酸腺苷生物发光 (ATP-CVA) 法这一新的药物敏感(药敏)试验方法。
ATP-CVA的原理为,内源性ATP是活体细胞最基本的能量来源,细胞死亡时,由于有ATP酶的存在,ATP迅速水解。
细胞内的ATP与荧光素-荧光素酶复合物作用产生可测定光,测定所产生的光,从而可获得ATP的数量。
通过测定已加入化疗药物的癌细胞中的ATP与对照组进行比较,可评价药物的敏感性。
本研究采用ATP-VCA法对卵巢癌细胞株SKOV3进行药敏检测,以探讨ATP-CVA法用于卵巢癌药敏试验的可行性。
一、材料与方法1. 研究对象:卵巢癌细胞株SKOV3购于美国Type CultureCollection(ATCC)公司。
2.试剂及仪器:试剂及仪器包括RPMI-1640培养基、胰岛素、胰酶、ATP 标准品,胎牛血清、荧光素、荧光素酶。
药物有顺氯胺铂 (cDDP)和拓扑特肯(topotecan)。
药物浓度的配制按其血浆峰浓度值(PPC)进行计算。
另外,还备有二氧化碳培养箱、超纯水器、F2105液闪计数仪、超净工作台及倒置生物显微镜等。
3.实验方法:(1)ATP标准品的检测:用培养基将ATP标准品配制成系列浓度:10-5、10-6、10-7、10-8、10-9mol/ml,加入等量的4%三氯醋酸溶液混匀,取100 μl进行测定,每种浓度做3个平行管。
(2)ATP生物荧光检测法:将样品100 μl加入闪烁瓶中,加200 μl中和液,调整pH为7.8,加入300 μl含荧光素-荧光素酶的反应混合液,轻轻摇匀,再加入4 ml反应缓冲液,于缓冲液闪计数仪中检测1 min,计算其累计计数值。
(3)卵巢癌细胞株SKOV3的培养及检测:将冻存的细胞株解冻复苏后,置于二氧化碳培养箱,于37℃、5%二氧化碳、95%湿度条件下进行培养。
JApplPhys_111_031301
Shujun Zhang and Fei Li Citation: J. Appl. Phys. 111, 031301 (2012); doi: 10.1063/1.3679521 View online: /10.1063/1.3679521 View Table of Contents: /resource/1/JAPIAU/v111/i3 Published by the AIP Publishing LLC.
Shls Research Institute, Pennsylvania State University, University Park, Pennsylvania 16802, USA Electronic Materials Research Laboratory and International Center for Dielectric Research, Xi’an Jiaotong University, Xi’an 710049, China
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苝酰亚胺衍生物金属离子荧光探针的研究进展
山 东 化 工 SHANDONGCHEMICALINDUSTRY 2019年第 48卷
酰亚胺衍生物金属离子荧光探针的研究进展
金 鑫,李林容,吴 超,郭嘉薇,楚 森,付丽娜
(黄河科技学院 医学院,河南 郑州 450063)
摘要:酰亚胺衍生物(perlenediimidederivatives,PDIs)是具有平面共轭大 π键的稠环大分子,光化学稳定性好,荧光发光性能强,是一类 性能优异的纳米分子材料,已在传感材料、太阳能电池等方面引起广泛关注。由于酰亚胺衍生物具有良好的光电性能和强化学可修 饰性,在医用荧光探针方面显示出良好的应用前景,例如可用作金属离子识别、药物载体、抗肿瘤药物、荧光示踪剂等用于疾病的诊断和 治疗,也可用于环境分析中各种不同分析物的检测。这种金属离子荧光探针灵敏度高、操作简便、荧光信号变化剧烈,能准确实现金属 离子识别。本文综述了近几年来国内外学者对酰亚胺衍生物作为金属离子荧光探针方面的研究,并对其发展做了展望。 关键词:酰亚胺衍生物;金属离子;荧光探针;结构修饰 中图分类号:TQ324.8 文献标识码:A 文章编号:1008-021X(2019)14-0084-03
Abstract:Perlenediimidederivatives(PDIs)wereakindofnanomolecularmaterialswithexcellentperformancewithlargeplanar conjugatedπ bonds,whichhavegoodphotochemicalstability,andstrongfluorescenceluminescenceperformance,whichhas attractedwideattentioninsensingmaterials,solarcellsandotheraspects.Asaperylenediimidederivativeswithgoodperformance ofphotoelectricperformanceandstrongchemicalmodifiability,itshowedapromisingapplicationprospectinthefieldofmedical fluorescentprobe.Forexample,itcanbeusedasrecognitionofmetalion,carrierofdrug,antitumordrugs,fluorescenttracerfor diseaseofdiagnosisandtreatment,aswellasforthedetectionofvariousanalytesinenvironmentalbiologicalanalysis.Thekindof metalionfluorescenceprobehashighsensitivity,simpleoperation,drasticchangeoffluorescencesignal,andcanaccurately realizemetalionrecognition.Inthisreview,theperformanceofperylenediimidederivativesasmetalionfluorescentprobeswas reviewed,andtheprospectoftheseaspectswasalsoincluded. Keywords:perylenediimidederivatives;metalions;fluorescentprobe;structuralIonsFluorescentProbes BasedonPerylenediimideDerivatives
2014年 苏州大学 三联吡啶钌电化学发光在药物分析中的应用研究
硕士学位论文论文题目三联吡啶钌电化学发光在药物分析中的应用研究研究生姓名饶海英指导教师姓名李建国专业名称分析化学研究方向分离科学与谱学分析论文提交日期2014年5月三联吡啶钌电化学发光在药物分析中的应用研究中文摘要三联吡啶钌电化学发光在药物分析中的应用研究中文摘要三联吡啶钌,一种新兴的发光试剂,具有良好的物理和化学性质。
近年来,已经广泛地应用于化学、生物、医学、材料、电子等学科领域。
而电致化学发光(ECL)技术集成了发光分析高灵敏度和电化学可控性好的优点,是一种有效的痕量分析技术。
将两者结合,三联吡啶钌电化学发光分析技术具有广阔的应用前景。
本论文以三联吡啶钌为发光试剂,构建了不同的三联吡啶钌电化学发光检测方法,分别对术前用药酚磺乙胺、阿托品、曲马多、利多卡因进行了检测。
本论文主要包括三个方面内容:1.阐述了三联吡啶钌的性质,三联吡啶钌电化学发光的原理,以及三联吡啶钌电化学发光在药物分析中的应用。
2.通过层层组装技术,制备了一种三联吡啶钌电化学发光传感器(Ru(bpy)32+ -Nafion-CPE),结合流动注射电致化学发光法对酚磺乙胺胺进行检测。
基于三联吡啶钌和酚磺乙胺在传感器表面的氧化反应,传感器的ECL信号与待测液酚磺乙胺的浓度成比例关系,由此建立了一种简单、灵敏测定酚磺乙胺的流动注射电致化学发光新方法,最低检出限为0.57ng/mL。
该方法可以减少昂贵试剂Ru(bpy)32+的使用,无试剂损耗,增强ECL信号和简化实验装置,大大拓宽了Ru(bpy)32+电化学发光的应用范围。
3.基于Ru(bpy)32+体系的阳极ECL信号,以β-环糊精(β-CD)为添加剂的毛细管电泳电致化学发光法实现对尿样中的阿托品,酚磺乙胺,曲马多和利多卡因的高灵敏,高选择性同时检测。
β-CD在一定浓度下,能使阿托品,酚磺乙胺,曲马多和利多卡因得到较好的分离效果,并且发光强度与四种药物的浓度在一定范围内呈线性关系,由此建立一种简单、快速、灵敏的同时检测术前用药的新方法。
paxalisib 结构式
paxalisib 结构式Paxalisib(INN名称:paxalisib,药物研发代号:GDC-0084)是一种新型的小分子靶向疗法,被广泛研究和应用于治疗神经胶质瘤(glioblastoma)等恶性脑肿瘤。
神经胶质瘤是一种高度侵袭性的脑肿瘤,具有高度异质性和抗药性。
传统的治疗手段如手术切除、放疗和化疗对于神经胶质瘤的治疗效果有限。
因此,研发新型的靶向治疗方法对于提高疗效显得尤为重要。
Paxalisib是一种小分子化合物,通过特异性抑制磷脂酰肌醇3-激酶(PI3K)信号通路,来阻断神经胶质瘤细胞的生长和扩散。
PI3K 信号通路在多种肿瘤中被发现高度异常激活,与细胞增殖、存活和侵袭能力密切相关。
Paxalisib通过选择性抑制PI3K信号通路的p110α亚型,阻断了细胞内PI3K/AKT/mTOR信号传导通路的活性。
这一信号通路的抑制可以抑制神经胶质瘤细胞的增殖、诱导细胞凋亡,并抑制血管生成。
此外,Paxalisib还通过调节肿瘤微环境和免疫系统的功能,增强抗肿瘤免疫应答,对神经胶质瘤的治疗具有潜在的协同作用。
临床试验显示,Paxalisib在治疗复发性神经胶质瘤中显示出了良好的疗效和安全性。
一项III期临床试验结果显示,与化疗相比,Paxalisib显著延长了患者的无进展生存期。
此外,Paxalisib还显示出了改善患者神经系统功能和生活质量的潜力。
尽管Paxalisib在治疗神经胶质瘤方面取得了一定的成功,但其仍面临一些挑战和限制。
首先,Paxalisib的长期疗效和生存率尚不清楚,需要进一步的研究来验证其疗效。
其次,Paxalisib的副作用需要加以重视和管理,如疲劳、恶心、呕吐等不良反应。
此外,Paxalisib的耐药性也是一个需要关注的问题,进一步的研究需要解决这一问题。
Paxalisib作为一种新型的靶向疗法,显示出了治疗神经胶质瘤的潜力。
它通过选择性抑制PI3K信号通路,抑制神经胶质瘤细胞的增殖和扩散,从而延长了患者的无进展生存期。
自噬流的检测方法
自噬流的检测方法一、本文概述自噬流是一种细胞自我消化和再生的过程,对于维持细胞稳态和适应环境变化具有重要意义。
随着生物学研究的深入,自噬流的检测已成为研究细胞自噬机制的重要手段。
本文旨在综述自噬流的检测方法,包括常用的生物化学方法、显微成像技术以及基于流式细胞仪的分析等。
我们将详细介绍这些方法的原理、操作步骤、优缺点以及应用实例,以期为自噬流研究提供全面的技术支持和参考。
通过本文的阅读,读者可以深入了解自噬流检测的原理和方法,掌握自噬流研究的最新进展,为相关研究提供有益的借鉴和指导。
二、自噬流的基本概念和机制自噬流(Autophagic Flux)是细胞自噬过程的一个核心概念,它描述了从自噬体的形成、自噬底物的降解,到降解产物的再利用这一连续过程。
自噬是一种细胞内的降解途径,通过这一过程,细胞可以将受损的细胞器、错误折叠的蛋白质或其他细胞内组分包裹在双层膜结构的自噬体中,并运送到溶酶体进行降解,从而实现物质的循环利用和细胞的稳态维持。
自噬流的基本机制涉及多个关键步骤。
细胞在感受到饥饿、缺氧或其他压力信号时,会启动自噬过程。
随后,自噬相关基因(Autophagy-related genes, ATGs)及其产物会参与自噬体的形成。
这些自噬体通过膜延伸和闭合,将待降解的底物包裹在内。
形成成熟的自噬体后,它们会与溶酶体融合,形成自噬溶酶体。
在自噬溶酶体中,自噬体的内膜及其包裹的底物会被溶酶体中的水解酶降解,释放出氨基酸、脂肪酸等小分子物质。
这些降解产物随后会被细胞重新利用,以支持细胞的生存和代谢活动。
自噬流的顺畅进行对于细胞的正常生理功能至关重要。
它不仅可以清除细胞内的有害物质和受损组分,还可以为细胞提供能量和营养物质,以应对各种环境压力。
因此,研究自噬流的检测方法对于理解自噬的生理和病理作用,以及开发相关疾病的治疗策略具有重要意义。
三、自噬流检测方法的分类与特点自噬流的检测是理解自噬过程的关键环节,其方法多种多样,各具特点。
Peters (2010) Episodic Future Thinking Reduces Reward Delay Discounting
NeuronArticleEpisodic Future Thinking ReducesReward Delay Discounting through an Enhancement of Prefrontal-Mediotemporal InteractionsJan Peters1,*and Christian Bu¨chel11NeuroimageNord,Department of Systems Neuroscience,University Medical Center Hamburg-Eppendorf,Hamburg20246,Germany*Correspondence:j.peters@uke.uni-hamburg.deDOI10.1016/j.neuron.2010.03.026SUMMARYHumans discount the value of future rewards over time.Here we show using functional magnetic reso-nance imaging(fMRI)and neural coupling analyses that episodic future thinking reduces the rate of delay discounting through a modulation of neural decision-making and episodic future thinking networks.In addition to a standard control condition,real subject-specific episodic event cues were presented during a delay discounting task.Spontaneous episodic imagery during cue processing predicted how much subjects changed their preferences toward more future-minded choice behavior.Neural valuation signals in the anterior cingulate cortex and functional coupling of this region with hippo-campus and amygdala predicted the degree to which future thinking modulated individual preference functions.A second experiment replicated the behavioral effects and ruled out alternative explana-tions such as date-based processing and temporal focus.The present data reveal a mechanism through which neural decision-making and prospection networks can interact to generate future-minded choice behavior.INTRODUCTIONThe consequences of choices are often delayed in time,and in many cases it pays off to wait.While agents normally prefer larger over smaller rewards,this situation changes when rewards are associated with costs,such as delays,uncertainties,or effort requirements.Agents integrate such costs into a value function in an individual manner.In the hyperbolic model of delay dis-counting(also referred to as intertemporal choice),for example, a subject-specific discount parameter accurately describes how individuals discount delayed rewards in value(Green and Myer-son,2004;Mazur,1987).Although the degree of delay discount-ing varies considerably between individuals,humans in general have a particularly pronounced ability to delay gratification, and many of our choices only pay off after months or even years. It has been speculated that the capacity for episodic future thought(also referred to as mental time travel or prospective thinking)(Bar,2009;Schacter et al.,2007;Szpunar et al.,2007) may underlie the human ability to make choices with high long-term benefits(Boyer,2008),yielding higher evolutionaryfitness of our species.At the neural level,a number of models have been proposed for intertemporal decision-making in humans.In the so-called b-d model(McClure et al.,2004,2007),a limbic system(b)is thought to place special weight on immediate rewards,whereas a more cognitive,prefrontal-cortex-based system(d)is more involved in patient choices.In an alternative model,the values of both immediate and delayed rewards are thought to be repre-sented in a unitary system encompassing medial prefrontal cortex(mPFC),posterior cingulate cortex(PCC),and ventral striatum(VS)(Kable and Glimcher,2007;Kable and Glimcher, 2010;Peters and Bu¨chel,2009).Finally,in the self-control model, values are assumed to be represented in structures such as the ventromedial prefrontal cortex(vmPFC)but are subject to top-down modulation by prefrontal control regions such as the lateral PFC(Figner et al.,2010;Hare et al.,2009).Both the b-d model and the self-control model predict that reduced impulsivity in in-tertemporal choice,induced for example by episodic future thought,would involve prefrontal cortex regions implicated in cognitive control,such as the lateral PFC or the anterior cingulate cortex(ACC).Lesion studies,on the other hand,also implicated medial temporal lobe regions in decision-making and delay discounting. In rodents,damage to the basolateral amygdala(BLA)increases delay discounting(Winstanley et al.,2004),effort discounting (Floresco and Ghods-Sharifi,2007;Ghods-Sharifiet al.,2009), and probability discounting(Ghods-Sharifiet al.,2009).Interac-tions between the ACC and the BLA in particular have been proposed to regulate behavior in order to allow organisms to overcome a variety of different decision costs,including delays (Floresco and Ghods-Sharifi,2007).In line with thesefindings, impairments in decision-making are also observed in humans with damage to the ACC or amygdala(Bechara et al.,1994, 1999;Manes et al.,2002;Naccache et al.,2005).Along similar lines,hippocampal damage affects decision-making.Disadvantageous choice behavior has recently been documented in patients suffering from amnesia due to hippo-campal lesions(Gupta et al.,2009),and rats with hippocampal damage show increased delay discounting(Cheung and Cardinal,2005;Mariano et al.,2009;Rawlins et al.,1985).These observations are of particular interest given that hippocampal138Neuron66,138–148,April15,2010ª2010Elsevier Inc.damage impairs the ability to imagine novel experiences (Hassa-bis et al.,2007).Based on this and a range of other studies,it has recently been proposed that hippocampus and parahippocam-pal cortex play a crucial role in the formation of vivid event repre-sentations,regardless of whether they lie in the past,present,or future (Schacter and Addis,2009).The hippocampus may thus contribute to decision-making through its role in self-projection into the future (Bar,2009;Schacter et al.,2007),allowing an organism to evaluate future payoffs through mental simulation (Johnson and Redish,2007;Johnson et al.,2007).Future thinking may thus affect intertemporal choice through hippo-campal involvement.Here we used model-based fMRI,analyses of functional coupling,and extensive behavioral procedures to investigate how episodic future thinking affects delay discounting.In Exper-iment 1,subjects performed a classical delay discounting task(Kable and Glimcher,2007;Peters and Bu¨chel,2009)that involved a series of choices between smaller immediate and larger delayed rewards,while brain activity was measured using fMRI.Critically,we introduced a novel episodic condition that involved the presentation of episodic cue words (tags )obtained during an extensive prescan interview,referring to real,subject-specific future events planned for the respective day of reward delivery.This design allowed us to assess individual discount rates separately for the two experimental conditions,allowing us to investigate neural mechanisms mediating changes in delay discounting associated with episodic thinking.In a second behavioral study,we replicated the behavioral effects of Exper-iment 1and addressed a number of alternative explanations for the observed effects of episodic tags on discount rates.RESULTSExperiment 1:Prescan InterviewOn day 1,healthy young volunteers (n =30,mean age =25,15male)completed a computer-based delay discounting proce-dure to estimate their individual discount rate (Peters and Bu ¨-chel,2009).This discount rate was used solely for the purpose of constructing subject-specific trials for the fMRI session (see Experimental Procedures ).Furthermore,participants compiled a list of events that they had planned in the next 7months (e.g.,vacations,weddings,parties,courses,and so forth)andrated them on scales from 1to 6with respect to personal rele-vance,arousal,and valence.For each participant,seven subject-specific events were selected such that the spacing between events increased with increasing delay to the episode,and that events were roughly matched based on personal rele-vance,arousal,and valence.Multiple regression analysis of these ratings across the different delays showed no linear effects (relevance:p =0.867,arousal:p =0.120,valence:p =0.977,see Figure S1available online).For each subject,a separate set of seven delays was computed that was later used as delays in the control condition.Median and range for the delays used in each condition are listed in Table S1(available online).For each event,a label was selected that would serve as a verbal tag for the fMRI session.Experiment 1:fMRI Behavioral ResultsOn day 2,volunteers performed two sessions of a delay dis-counting procedure while fMRI was measured using a 3T Siemens Scanner with a 32-channel head-coil.In each session,subjects made a total of 118choices between 20V available immediately and larger but delayed amounts.Subjects were told that one of their choices would be randomly selected and paid out following scanning,with the respective delay.Critically,in half the trials,an additional subject-specific episodic tag (see above,e.g.,‘‘vacation paris’’or ‘‘birthday john’’)was displayed based on the prescan interview (see Figure 1)indicating which event they had planned on the particular day (episodic condi-tion),whereas in the remaining trials,no episodic tag was pre-sented (control condition).Amount and waiting time were thus displayed in both conditions,but only the episodic condition involved the presentation of an additional subject-specific event tag.Importantly,nonoverlapping sets of delays were used in the two conditions.Following scanning,subjects rated for each episodic tag how often it evoked episodic associations during scanning (frequency of associations:1,never;to 6,always)and how vivid these associations were (vividness of associa-tions:1,not vivid at all;to 6,highly vivid;see Figure S1).Addition-ally,written reports were obtained (see Supplemental Informa-tion ).Multiple regression revealed no significant linear effects of delay on postscan ratings (frequency:p =0.224,vividness:p =0.770).We averaged the postscan ratings acrosseventsFigure 1.Behavioral TaskDuring fMRI,subjects made repeated choices between a fixed immediate reward of 20V and larger but delayed amounts.In the control condi-tion,amounts were paired with a waiting time only,whereas in the episodic condition,amounts were paired with a waiting time and a subject-specific verbal episodic tag indicating to the subjects which event they had planned at the respective day of reward delivery.Events were real and collected in a separate testing session prior to the day of scanning.NeuronEpisodic Modulation of Delay DiscountingNeuron 66,138–148,April 15,2010ª2010Elsevier Inc.139and the frequency/vividness dimensions,yielding an‘‘imagery score’’for each subject.Individual participants’choice data from the fMRI session were then analyzed byfitting hyperbolic discount functions to subject-specific indifference points to obtain discount rates (k-parameters),separately for the episodic and control condi-tions(see Experimental Procedures).Subjective preferences were well-characterized by hyperbolic functions(median R2 episodic condition=0.81,control condition=0.85).Discount functions of four exemplary subjects are shown in Figure2A. For both conditions,considerable variability in the discount rate was observed(median[range]of discount rates:control condition=0.014[0.003–0.19],episodic condition=0.013 [0.002–0.18]).To account for the skewed distribution of discount rates,all further analyses were conducted on the log-trans-formed k-parameters.Across subjects,log-transformed discount rates were significantly lower in the episodic condition compared with the control condition(t(29)=2.27,p=0.016),indi-cating that participants’choice behavior was less impulsive in the episodic condition.The difference in log-discount rates between conditions is henceforth referred to as the episodic tag effect.Fitting hyperbolic functions to the median indifference points across subjects also showed reduced discounting in the episodic condition(discount rate control condition=0.0099, episodic condition=0.0077).The size of the tag effect was not related to the discount rate in the control condition(p=0.56). We next hypothesized that the tag effect would be positively correlated with postscan ratings of episodic thought(imagery scores,see above).Robust regression revealed an increase in the size of the tag effect with increasing imagery scores (t=2.08,p=0.023,see Figure2B),suggesting that the effect of the tags on preferences was stronger the more vividly subjects imagined the episodes.Examples of written postscan reports are provided in the Supplemental Results for participants from the entire range of imagination ratings.We also correlated the tag effect with standard neuropsychological measures,the Sensation Seeking Scale(SSS)V(Beauducel et al.,2003;Zuck-erman,1996)and the Behavioral Inhibition Scale/Behavioral Approach Scale(BIS/BAS)(Carver and White,1994).The tag effect was positively correlated with the experience-seeking subscale of the SSS(p=0.026)and inversely correlated with the reward-responsiveness subscale of the BIS/BAS scales (p<0.005).Repeated-measures ANOVA of reaction times(RTs)as a func-tion of option value(lower,similar,or higher relative to the refer-ence option;see Experimental Procedures and Figure2C)did not show a main effect of condition(p=0.712)or a condition 3value interaction(p=0.220),but revealed a main effect of value(F(1.8,53.9)=16.740,p<0.001).Post hoc comparisons revealed faster RTs for higher-valued options relative to similarly (p=0.002)or lower valued options(p<0.001)but no difference between lower and similarly valued options(p=0.081).FMRI DataFMRI data were modeled using the general linear model(GLM) as implemented in SPM5.Subjective value of each decision option was calculated by multiplying the objective amount of each delayed reward with the discount fraction estimated behaviorally based on the choices during scanning,and included as a parametric regressor in the GLM.Note that discount rates were estimated separately for the control and episodic conditions(see above and Figure2),and we thus used condition-specific k-parameters for calculation of the subjective value regressor.Additional parametric regressors for inverse delay-to-reward and absolute reward magnitude, orthogonalized with respect to subjective value,were included in theGLM.Figure2.Behavioral Data from Experiment1Shown are experimentally derived discount func-tions from the fMRI session for four exemplaryparticipants(A),correlation with imagery scores(B),and reaction times(RTs)(C).(A)Hyperbolicfunctions werefit to the indifference points sepa-rately for the control(dashed lines)and episodic(solid lines,filled circles)conditions,and thebest-fitting k-parameters(discount rates)and R2values are shown for each subject.The log-trans-formed difference between discount rates wastaken as a measure of the effect of the episodictags on choice preferences.(B)Robust regressionrevealed an association between log-differences indiscount rates and imagery scores obtained frompostscan ratings(see text).(C)RTs were signifi-cantly modulated by option value(main effectvalue p<0.001)with faster responses in trialswith a value of the delayed reward higher thanthe20V reference amount.Note that althoughseven delays were used for each condition,somedata points are missing,e.g.,onlyfive delay indif-ference points for the episodic condition areplotted for sub20.This indicates that,for the twolongest delays,this subject never chose the de-layed reward.***p<0.005.Error bars=SEM.Neuron Episodic Modulation of Delay Discounting140Neuron66,138–148,April15,2010ª2010Elsevier Inc.Episodic Tags Activate the Future Thinking NetworkWe first analyzed differences in the condition regressors without parametric pared to those of the control condi-tion,BOLD responses to the presentation of the delayed reward in the episodic condition yielded highly significant activations (corrected for whole-brain volume)in an extensive network of brain regions previously implicated in episodic future thinking (Addis et al.,2007;Schacter et al.,2007;Szpunar et al.,2007)(see Figure 3and Table S2),including retrosplenial cortex (RSC)/PCC (peak MNI coordinates:À6,À54,14,peak z value =6.26),left lateral parietal cortex (LPC,À44,À66,32,z value =5.35),and vmPFC (À8,34,À12,z value =5.50).Distributed Neural Coding of Subjective ValueWe then replicated previous findings (Kable and Glimcher,2007;Kable and Glimcher,2010;Peters and Bu¨chel,2009)using a conjunction analysis (Nichols et al.,2005)searching for regions showing a positive correlation between the height of the BOLD response and subjective value in the control and episodic condi-tions in a parametric analysis (Figure 4A and Table S3).Note that this is a conservative analysis that requires that a given voxel exceed the statistical threshold in both contrasts separately.This analysis revealed clusters in the lateral orbitofrontal cortex (OFC,À36,50,À10,z value =4.50)and central OFC (À18,12,À14,z value =4.05),bilateral VS (right:10,8,0,z value =4.22;left:À10,8,À6,z value =3.51),mPFC (6,26,16,z value =3.72),and PCC (À2,À28,24,z value =4.09),representing subjective (discounted)value in both conditions.We next analyzed the neural tag effect,i.e.,regions in which the subjective value correlation was greater for the episodic condi-tion as compared with the control condition (Figure 4B and Table S4).This analysis revealed clusters in the left LPC (À66,À42,32,z value =4.96,),ACC (À2,16,36,z value =4.76),left dorsolateral prefrontal cortex (DLPFC,À38,36,36,z value =4.81),and right amygdala (24,2,À24,z value =3.75).Finally,we performed a triple-conjunction analysis,testing for regions that were correlated with subjective value in both conditions,but in which the value correlation increased in the episodic condition.Only left LPC showed this pattern (À66,À42,30,z value =3.55,see Figure 4C and Table S5),the same region that we previously identified as delay-specific in valuation (Petersand Bu¨chel,2009).There were no regions in which the subjective value correlation was greater in the control condition when compared with the episodic condition at p <0.001uncorrected.ACC Valuation Signals and Functional Connectivity Predict Interindividual Differences in Discount Function ShiftsWe next correlated differences in the neural tag effect with inter-individual differences in the size of the behavioral tag effect.To this end,we performed a simple regression analysis in SPM5on the single-subject contrast images of the neural tag effect (i.e.,subjective value correlation episodic >control)using the behavioral tag effect [log(k control )–log(k episodic )]as an explana-tory variable.This analysis revealed clusters in the bilateral ACC (right:18,34,18,z value =3.95,p =0.021corrected,left:À20,34,20,z value =3.52,Figure 5,see Table S6for a complete list).Coronal sections (Figure 5C)clearly show that both ACC clusters are located in gray matter of the cingulate sulcus.Because ACC-limbic interactions have previously been impli-cated in the control of choice behavior (Floresco and Ghods-Sharifi,2007;Roiser et al.,2009),we next analyzed functional coupling with the right ACC from the above regression contrast (coordinates 18,34,18,see Figure 6A)using a psychophysiolog-ical interaction analysis (PPI)(Friston et al.,1997).Note that this analysis was conducted on a separate first-level GLM in which control and episodic trials were modeled as 10s miniblocks (see Experimental Procedures for details).We first identified regions in which coupling with the ACC changed in the episodic condition compared with the control condition (see Table S7)and then performed a simple regression analysis on these coupling parameters using the behavioral tag effect as an explanatory variable.The tag effect was associated with increased coupling between ACC and hippocampus (À32,À18,À16,z value =3.18,p =0.031corrected,Figure 6B)and ACC and left amygdala (À26,À4,À26,z value =2.95,p =0.051corrected,Figure 6B,see Table S8for a complete list of activa-tions).The same regression analysis in a second PPI with the seed voxel placed in the contralateral ACC region from the same regression contrast (À20,34,22,see above)yielded qual-itatively similar,though subthreshold,results in these same structures (hippocampus:À28,À32,À6,z value =1.96,amyg-dala:À28,À6,À16,z value =1.97).Experiment 2We conducted an additional behavioral experiment to address a number of alternative explanations for the observed effects of tags on choice behavior.First,it could be argued thatepisodicFigure 3.Categorical Effect of Episodic Tags on Brain ActivityGreater activity in lateral parietal cortex (left)and posterior cingulate/retrosplenial and ventro-medial prefrontal cortex (right)was observed in the episodic condition compared with the control condition.p <0.05,FWE-corrected for whole-brain volume.NeuronEpisodic Modulation of Delay DiscountingNeuron 66,138–148,April 15,2010ª2010Elsevier Inc.141tags increase subjective certainty that a reward would be forth-coming.In Experiment 2,we therefore collected postscan ratings of reward confidence.Second,it could be argued that events,always being associated with a particular date,may have shifted temporal focus from delay-based to more date-based processing.This would represent a potential confound,because date-associated rewards are discounted less than delay-associated rewards (Read et al.,2005).We therefore now collected postscan ratings of temporal focus (date-based versus delay-based).Finally,Experiment 1left open the question of whether the tag effect depends on the temporal specificity of the episodic cues.We therefore introduced an additional exper-imental condition that involved the presentation of subject-specific temporally unspecific future event cues.These tags (henceforth referred to as unspecific tags)were obtained by asking subjects to imagine events that could realistically happen to them in the next couple of months,but that were not directly tied to a particular point in time (see Experimental Procedures ).Episodic Imagery,Not Temporal Specificity,Reward Confidence,or Temporal Focus,Predicts the Size of the Tag EffectIn total,data from 16participants (9female)are included.Anal-ysis of pretest ratings confirmed that temporally unspecific and specific tags were matched in terms of personal relevance,arousal,valence,and preexisting associations (all p >0.15).Choice preferences were again well described by hyperbolic functions (median R 2control =0.84,unspecific =0.81,specific =0.80).We replicated the parametric tag effect (i.e.,increasing effect of tags on discount rates with increasing posttest imagery scores)in this independent sample for both temporally specific (p =0.047,Figure 7A)and temporally unspecific (p =0.022,Figure 7A)tags,showing that the effect depends on future thinking,rather than being specifically tied to the temporal spec-ificity of the event cues.Following testing,subjects rated how certain they were that a particular reward would actually be forth-coming.Overall,confidence in the payment procedure washighFigure 4.Neural Representation of Subjective Value (Parametric Analysis)(A)Regions in which the correlation with subjective value (parametric analysis)was significant in both the control and the episodic conditions (conjunction analysis)included central and lateral orbitofrontal cortex (OFC),bilateral ventral striatum (VS),medial prefrontal cortex (mPFC),and posterior cingulate cortex(PCC),replicating previous studies (Kable and Glimcher,2007;Peters and Bu¨chel,2009).(B)Regions in which the subjective value correlation was greater for the episodic compared with the control condition included lateral parietal cortex (LPC),ante-rior cingulate cortex (ACC),dorsolateral prefrontal cortex (DLPFC),and the right amygdala (Amy).(C)A conjunction analysis revealed that only LPC activity was positively correlated with subjective value in both conditions,but showed a greater regression slope in the episodic condition.No regions showed a better correlation with subjective value in the control condition.Error bars =SEM.All peaks are significant at p <0.001,uncorrected;(A)and (B)are thresholded at p <0.001uncorrected and (C)is thresholded at p <0.005,uncorrected for display purposes.NeuronEpisodic Modulation of Delay Discounting142Neuron 66,138–148,April 15,2010ª2010Elsevier Inc.(Figure 7B),and neither unspecific nor specific tags altered these subjective certainty estimates (one-way ANOVA:F (2,45)=0.113,p =0.894).Subjects also rated their temporal focus as either delay-based or date-based (see Experimental Procedures ),i.e.,whether they based their decisions on the delay-to-reward that was actually displayed,or whether they attempted to convert delays into the corresponding dates and then made their choices based on these dates.There was no overall significant effect of condition on temporal focus (one-way ANOVA:F (2,45)=1.485,p =0.237,Figure 7C),but a direct comparison between the control and the temporally specific condition showed a significant difference (t (15)=3.18,p =0.006).We there-fore correlated the differences in temporal focus ratings between conditions (control:unspecific and control:specific)with the respective tag effects (Figure 7D).There were no correlations (unspecific:p =0.71,specific:p =0.94),suggesting that the observed differences in discounting cannot be attributed to differences in temporal focus.High-Imagery,but Not Low-Imagery,Subjects Adjust Their Discount Function in an Episodic ContextFor a final analysis,we pooled the samples of Experiments 1and 2(n =46subjects in total),using only the temporally specific tag data from Experiment 2.We performed a median split into low-and high-imagery participants according to posttest imagery scores (low-imagery subjects:n =23[15/8Exp1/Exp2],imagery range =1.5–3.4,high-imagery subjects:n =23[15/8Exp1/Exp2],imagery range =3.5–5).The tag effect was significantly greater than 0in the high-imagery group (t (22)=2.6,p =0.0085,see Figure 7D),where subjects reduced their discount rate by onaverage 16%in the presence of episodic tags.In the low-imagery group,on the other hand,the tag effect was not different from zero (t (22)=0.573,p =0.286),yielding a significant group difference (t (44)=2.40,p =0.011).DISCUSSIONWe investigated the interactions between episodic future thought and intertemporal decision-making using behavioral testing and fMRI.Experiment 1shows that reward delay dis-counting is modulated by episodic future event cues,and the extent of this modulation is predicted by the degree of sponta-neous episodic imagery during decision-making,an effect that we replicated in Experiment 2(episodic tag effect).The neuroi-maging data (Experiment 1)highlight two mechanisms that support this effect:(1)valuation signals in the lateral ACC and (2)neural coupling between ACC and hippocampus/amygdala,both predicting the size of the tag effect.The size of the tag effect was directly related to posttest imagery scores,strongly suggesting that future thinking signifi-cantly contributed to this effect.Pooling subjects across both experiments revealed that high-imagery subjects reduced their discount rate by on average 16%in the episodic condition,whereas low-imagery subjects did not.Experiment 2addressed a number of alternative accounts for this effect.First,reward confidence was comparable for all conditions,arguing against the possibility that the tags may have somehow altered subjec-tive certainty that a reward would be forthcoming.Second,differences in temporal focus between conditions(date-basedFigure 5.Correlation between the Neural and Behavioral Tag Effect(A)Glass brain and (B and C)anatomical projection of the correlation between the neural tag effect (subjective value correlation episodic >control)and the behav-ioral tag effect (log difference between discount rates)in the bilateral ACC (p =0.021,FWE-corrected across an anatomical mask of bilateral ACC).(C)Coronal sections of the same contrast at a liberal threshold of p <0.01show that both left and right ACC clusters encompass gray matter of the cingulate gyrus.(D)Scatter-plot depicting the linear relationship between the neural and the behavioral tag effect in the right ACC.(A)and (B)are thresholded at p <0.001with 10contiguous voxels,whereas (C)is thresholded at p <0.01with 10contiguousvoxels.Figure 6.Results of the Psychophysiolog-ical Interaction Analysis(A)The seed for the psychophysiological interac-tion (PPI)analysis was placed in the right ACC (18,34,18).(B)The tag effect was associated with increased ACC-hippocampal coupling (p =0.031,corrected across bilateral hippocampus)and ACC-amyg-dala coupling (p =0.051,corrected across bilateral amygdala).Maps are thresholded at p <0.005,uncorrected for display purposes and projected onto the mean structural scan of all participants;HC,hippocampus;Amy,Amygdala;rACC,right anterior cingulate cortex.NeuronEpisodic Modulation of Delay DiscountingNeuron 66,138–148,April 15,2010ª2010Elsevier Inc.143。
改进单神经元PI_的三相PWM整流器电压控制
ELECTRIC DRIVE2024Vol.54No.5电气传动2024年第54卷第5期改进单神经元PI的三相PWM整流器电压控制夏涛1,刘亮1,张仰飞1,2,刘海涛1,2,孟高军1,2(1.南京工程学院电力工程学院,江苏南京211167;2.江苏省配电网智能技术与装备协同创新中心,江苏南京211167)摘要:针对三相脉宽调制(PWM)整流器在负载变化时输出电压波动大且恢复时间长的问题,提出一种改进单神经元梯度学习控制策略。
由于传统的PI控制器参数在负载变化时适应性差,在电压外环采用单神经元PI控制,利用梯度下降法在线调整权值参数。
为了避免求解过程中落入局部最优解,采用带有重启功能的随机梯度下降算法(SGDR),利用余弦退火改变权值的学习速率,提升算法的收敛性能。
通过Matlab及半实物仿真实验,比较分析三相PWM整流器电压外环采用不同控制算法下的动态响应性能,结果表明:改进单神经元PI算法控制下的三相PWM整流器在负载变化时具有更小的电压波动、更快的动态响应以及更加稳定的运行状态。
关键词:整流器;电压外环;单神经元;梯度学习;余弦退火;负载扰动中图分类号:TM461文献标识码:A DOI:10.19457/j.1001-2095.dqcd24368Three-phase PWM Rectifier Voltage Control Based on Improved Single Neuron PIXIA Tao1,LIU Liang1,ZHANG Yangfei1,2,LIU Haitao1,2,MENG Gaojun1,2(1.School of Electric Power Engineering,Nanjing Institute of Technology,Nanjing211167,Jiangsu,China;2.Jiangsu Collaborative Innovation Center for Smart Distribution Network,Nanjing211167,Jiangsu,China)Abstract:Aiming at the problem of large output voltage fluctuation and long recovery time of three-phase pulse-width modulation(PWM)rectifiers when the load changes,an improved single-neuron gradient learning control strategy was proposed.Due to the poor adaptability of the traditional PI controller parameters when the load changes,a single neuron PI control was adopted in the voltage outer loop,and the gradient descent method was used to adjust the weight parameters online.In order to avoid falling into a local optimal solution during the solution process,a stochastic gradient descent algorithm with restart function(SGDR)was used,and cosine annealing was used to change the learning rate of the weights to improve the convergence performance of the algorithm.Through Matlab and hardware-in-the-loop simulation experiments,the dynamic response performance of the voltage outer loop of the three-phase PWM rectifier under different control algorithms was compared and analyzed.The results show that the three-phase PWM rectifier controlled by the improved single neuron PI algorithm has smaller voltage fluctuation,faster dynamic response and more stable operating state when the load changes.Key words:rectifier;voltage outer loop;single neuron;gradient learning;cosine annealing;load perturbation三相脉宽调制(pulse-width modulation,PWM)整流器既能整流又可实现逆变,且凭借整流输出电压可调、引起的网侧电流谐波含量少、稳定单位功率因数运行等优点[1],在电动汽车充电领域得到广泛应用,满足了汽车储能元件与电网间电能的互补利用[2]。
胶质瘤中STAT3通路及其负调控因子PIAS3活化状态和生物学效应的分析
胶质瘤中STAT3通路及其负调控因子PIAS3活化状态和生物学效应的分析张朋;孙铮;刘哲宇;李阳【摘要】目的:探讨STAT3信号通路及其负调控因子PIAS3在胶质瘤细胞中的活化状态及生物学效应。
方法采用免疫组织化学方法检测胶质瘤中p⁃STAT3及PIAS3的活化状态;STAT3通路抑制剂60μmol/L AG490作用胶质瘤U118、U87细胞24、48 h, MTT法观察U118、U87细胞增殖能力的变化;免疫荧光检测AG490作用前后细胞p⁃STAT3及PIAS3蛋白表达的变化。
结果 p⁃STAT3及PIAS3在不同级别胶质瘤细胞胞质和胞核内的表达无统计学差异,但在细胞核内p⁃STAT3和PIAS3的表达呈负相关;AG490处理细胞后,U118细胞数量无明显改变,U87细胞则表现为生长抑制。
免疫荧光结果显示,AG490处理后,U118细胞p⁃STAT3和PIAS3表达水平均无显著改变,U87细胞p⁃STAT3核内表达下调,PIAS3出现明显核易位。
结论 PIAS3通过核易位调控STAT3信号通路的活性,抑制胶质瘤细胞生长。
%Objective To discuss the activation and biological effects of STAT3 signaling pathway and its negative regulator PIAS3 in glioma cells. Methods Immunohistochemistry(IHC)was used to test the expression of p⁃STAT3 and PIAS3 in gliomas. AG490(60μmol/L),the in⁃hibitor of STAT3 signaling pathway,was used to treat U118 and U87 cells for 24/48 h,and the method of MTT assay was taken to evaluate the pro⁃liferation after AG490 treatment. The expression of p⁃STAT3 and PIAS3 was also examined by immunofluorescence(IF). Results There was no obvious significance between p⁃STAT3 and PIAS3 in nuclei or cytoplasm at different grades of gliomas. Whereas,p⁃STAT3 and PIAS3 were nega⁃tivelycorrelated in the nuclei of vary grades malignancy gliomas. After AG490 treatment,U118 cells showed no obvious quantitative changes.How⁃ever,U87 cells showed obvious growth inhibition. IF results showed that there was no significant change at the levels of p⁃STAT3 and PIAS3 after AG490 treatment in U118 cells. However,the expression of p⁃STAT3 in the nuclei was down⁃regulated,and PIAS3 showed obvious nuclear translo⁃cation in U87 cells. Conclusion Nuclear translocation of PIAS3 plays the key role in modulating JAK/STAT signaling activation and inhibiting glioma cells proliferation.【期刊名称】《中国医科大学学报》【年(卷),期】2016(045)008【总页数】5页(P719-722,727)【关键词】胶质瘤;STAT3信号通路;PIAS3;AG490【作者】张朋;孙铮;刘哲宇;李阳【作者单位】大连医科大学基础医学院细胞生物学教研室,辽宁大连 116044;大连医科大学中西医结合基础研究所,辽宁大连 116044;大连医科大学中西医结合基础研究所,辽宁大连 116044;附属第一医院神经外科,辽宁大连 116011【正文语种】中文【中图分类】R739.4网络出版地址胶质瘤是神经间质细胞,即神经胶质前体细胞,向成熟方向分化时受阻所致。
过氧化物酶体增殖物激活受体
过氧化物酶体增殖物激活受体(PPAR) 是一类由配体激活的核转录因子,属Ⅱ型核受体超家族成员, 存在3种亚型,即PPARα、PPARδ、PPARγ,这三种亚型在结构上有一定的相似性,均含DNA结合区和配体结合区等。
PPAR与配体结合后被激活,与9-顺视黄酸类受体形成异二聚体,然后与靶基因的启动子上游的过氧化物酶体增殖物反应元件(peroxisome proliferator response element,PPRE)结合而发挥转录调控作用。
PPRE 由含相隔一个或两个核苷酸的重复序列AGGTCA组成。
与配体结合后,PPAR在DNA结合区发生变构,进而影响PPAR刺激靶基因转录的能力。
PPARδ几乎在所有组织中表达,浓度低于PPARα及PPARγ,直至最近以前尚未找到此一核受体的选择性配基。
PPARδ是代谢综合征(肥胖、胰岛素抵抗、高血压是与脂质紊乱有关的共同的病态表现)的一个新靶点。
有不少的研究表明:GW501516可作为PPARδ的特异激动剂用于研究。
参考网址:/cjh/2003/shownews.asp?id=156/conference/preview.php?kind_id=03&cat_name=ADA2001&title_id=59219 Regulation of Muscle Fiber Type and Running Endurance by PPARδplos biology,Volume 2 | Issue 10 | October 2004/plosonline/?request=get-document&doi=10.1371%2Fjournal.pbio.0020294NF-KB通路中的抑制剂好像有1.PDTC(pyrrolidine dithiocarbamate),是一种抗氧化剂,主要作用于IκB降解的上游环节(IκBα的磷酸化或IKK的活性水平),2.Gliotoxin 是一种免疫抑制剂,机制可能从多个环节阻断NF-KB的激活,如IκB的降解,NF-KB的核移位和与DNA的结合。
三联吡啶
4'-(2-吡啶基)-2,2':6',2"-三联吡啶的合成作者:孟维玲指导老师:杨浩摘要:本文以2乙酰吡啶、2吡啶甲醛、吡啶及碘为原料经过3步反应,合成了4'-(2-吡啶基)-2,2':6',2"-三联吡啶,并用IR和UV对此化合物及中间体1-(2'-吡啶基)-3-(2'-吡啶基)-2-丙烯-1-酮和1-(2'-吡啶基)羰甲基吡啶碘盐的结构进行了表征,初步探讨了反应的合成机理, 并优化了反应温度和溶剂, 使其更加具体和高效。
关键词:合成、配体、碘盐、三联吡啶、表征0 引言光信息材料作为信息社会的技术支撑,受到广泛关注,光致发光材料成为当今研究领域的重要课题之一。
金属配合物的性质介于有机与无机物之间,既具有有机物的高荧光量子效率的优点,又有无机物的稳定性好的特点,被认为是最有应用前景的一类发光材料,激起化学界对这类配合物的合成及研究热潮,以期得到发光效率高,电子传输性能好的发光材料。
在配位聚合物的合成研究中,配体是影响结构特征的决定性因素之一。
配体的配位能力、配体的齿数、配体配位点间的间距、以及配体异构等诸多因素都可能对配位聚合物的最终结构产生影响[10]。
所以,设计和合成配体成为定向合成配位聚合物中至关重要的一个环节。
多吡啶配体及其衍生物具有σ给电子能力及∏受电子能力,能够与多种金属形成稳定的配合物,具有十分丰富的配位化学内容,而成为经典体系之一,三联吡啶是这类体系的重要成员之一[7。
8.10.11]。
4'吡啶取代基团有弱的吸电子作用,同时又扩张了2,2':6',2"-三联吡啶的π体系,使得三联吡啶类配体含有大的共轭π电子结构和刚性多吡啶基团,可以用来稳定较低的氧化态,从而构筑更丰富的配合物,所以三联吡啶类配位聚合物也显示出优异的光致发光性质。
三联吡啶是在20世纪30年代由Morgan和Burstall[2]首次分离得到的. 三联吡啶及其衍生物具有R给电子能力及P受电子能力[5], 能与多种金属离子形成稳定的配合物, 是现代配位化学中应用较为广泛的螯合配体[3]。
罗氏(英文版)-TUNEL-细胞凋亡原位检测试剂盒-POD
In Situ Cell Death Detection Kit, POD
y Version 14
Content version: July 2012
Kit for immunohistochemical detection and quantification of apoptosis (programmed cell death) at single cell level, based on labeling of DNA strand breaks (TUNEL technology): Analysis by light microscopy.
Cat. No. 11 684 817 910
Store the kit at Ϫ15 to Ϫ25°C
1 Kit (50 tests)
1. 1.1 1. 1.1 1.2 2. 2.1 2.2 3. 3.1 3.2
Preface Table of contents Preface .............................................................................................................................2 Table of contents ..................................................................................................................................... 2 Kit contents ................................................................................................................................................ 3 Introduction .....................................................................................................................5 Product overview ..................................................................................................................................... 5 Background information ....................................................................................................................... 8 Procedures and required materials ...........................................................................9 Flow chart .................................................................................................................................................10 Preparation of sample material ........................................................................................................10 3.2.1 Adherent cells, cell smears and cytospin preparations ..............................................11 3.2.2 Tissue sections ...........................................................................................................................11 3.2.2.1 Treatment of paraffin-embedded tissue ............................................................11 3.2.2.2 Treatment of cryopreserved tissue ......................................................................12 Labeling protocol ...................................................................................................................................13 3.3.1 Before you begin .......................................................................................................................13 3.3.2 Labeling protocol for adherent cells, cell smears, cytospin preparations and tissues ........................................................................................................14 3.3.3 Labeling protocol for difficult tissue ..................................................................................15 Signal conversion ..................................................................................................................................16 Appendix ....................................................................................................................... 17 Troubleshooting .....................................................................................................................................17 References ...............................................................................................................................................20 Ordering guide .......................................................................................................................................21
甘油002高效液相色谱法检测发酵液中二羟基丙酮和甘油的含量
高效液相色谱法检测发酵液中二羟基丙酮和甘油的含量陈 菁,陈建华,周怡雯,周长林(中国药科大学生命科学与技术学院,江苏南京210009)摘 要:目的建立二羟基丙酮(DHA)发酵过程中产物和残余甘油底物的高效液相色谱检测方法。
方法流动相为乙腈 水(90:10),色谱柱为Lichrospher 5 NH 2( 4.6mm 250mm),用紫外检测器在271nm 处检测DHA ,用示差折光检测器检测甘油。
结果DHA 的线性范围为2.00~12.00mg/mL,最低检出限(LOD)和最低定量限(LOQ)分别为0.30和1.20mg/mL 。
甘油的线性范围为1.00~10.00mg/mL,LOD 和LOQ 分别为0.22和0.50mg /mL 。
结论此文建立的D HA 和甘油的检测方法精密度好,准确性高,不受发酵液中其他杂质的影响,可以应用于DHA 发酵过程中底物和产物的检测。
关键词:二羟基丙酮;甘油;高效液相色谱法;含量测定中图分类号:TQ460.7 文献标识码:A 文章编号:1005 1678(2007)03 0170 03Quantitative determination of dihydroxyacetone and glycerolin the fermentation broth by HPLCCHEN Jing,C HE N Jian hua,ZHOU Yi wen,ZHOU Chang lin(School o f Li f e Science and Technology ,China Pharmaceutical University ,Nanjing 210009,China ) Abstract:Purpose To develop high performance liquid chromatographic (HPLC)methods for the quanti tative determination of dihydroxyacetone (D HA)and glycerol in the fermentation broth.Methods The analytes were separated on a Lichrospher 5 NH 2column(4.6mm 250mm)with the mobile phase of acetonitrile wa ter (90 10)at a flow rate of 1mL/min.D HA was detected by UV detector at 271nm and glycerol was detec t ed by refractometer.Validation parameters such as linearity,precision,accuracy,specificity,limit of detec tion (LOD)and limit of quantitation (LOQ)were determined.Results The linearity range for the determina tion of D HA was 2.00~12.00mg/mL with a correlation coefficient (r )of 0.9994.The LOD and LOQ were 0.30and 1.20mg/mL respectively.The linearity range for the determination of glycerol was 1.00~10.00mg/mL with a correlation coefficient of 0.9998.The LOD and LOQ were 0.22and 0.50mg/m L respective ly.Conclusion The established methods in this paper were simple and rapid and there is no interference from other constitutes in the fermentation broth on using the methods.The methods were applicable for DHA and glycerol determination in the fermentation process.Key words:dihydroxyacetone;glycerol;HPLC;quantitative determination收稿日期:2006 11 01;修回日期:2006 12 01作者简介:陈菁(1982 ),女,山西霍州人,在读硕士研究生,主要研究方向为微生物转化;陈建华,通信作者,Tel:025 ********,E mail:jhchen@ 。
自噬过程中磷脂酰肌醇信号通路的调节研究
自噬过程中磷脂酰肌醇信号通路的调节研究自噬是细胞通过溶酶体分解和回收细胞内垃圾物质的过程。
近年来,自噬被发现对于维持细胞的稳态、减缓衰老和对抗疾病等重要作用。
磷脂酰肌醇(PI)信号通路是自噬调节中的一个重要组成部分,因此,研究PI信号通路的调节对于深入了解自噬过程具有重要意义。
自噬是一种高度保守的生物学现象,大多数生物种的细胞都能进行自噬。
在自噬过程中,先通过形成一个隔离膜,把特定的细胞器或物质包裹进去,形成一个内腔,随后这个内腔会融合到溶酶体中,并通过溶酶体内各种水解酶对内腔中的物质进行降解,最终释放出营养物质和废物。
磷脂酰肌醇(PI)信号通路包括PI3K-Akt-mTOR和PI3K-Beclin1-Atg14L/Vps34等两个分支,分别参与自噬的运行机制。
如果PI3K信号通路持续激活,细胞会抑制自噬过程;而如果PI3K信号通路被抑制,细胞将会引发自噬。
因此,调节PI信号通路的活性是自噬过程一个非常重要的调控机制。
PI3K-Akt-mTOR信号通路通过磷酸化和抑制ULK1(Autophagy-related protein 1)来抑制自噬过程。
ULK1是自噬发生的早期事件,其磷酸化会抑制其自身激酶活性。
这一机制能够通过调节IRS-1/Akt/mTOR信号通路来发挥作用。
当IRS-1/Akt/mTOR信号通路被激活的时候,细胞将会抑制自噬与ULK1的磷酸化,因此阻止自噬发生。
相反的,当细胞发生紧急情况、糖葡萄糖原储备枯竭和氧/营养不足时,细胞会被迫通过自噬来进行细胞垃圾清理和提供能量的需求。
这时,PI3K信号通路被抑制,Beclin1和Atg14L结合后的复合物会增强Vps34的活性,从而诱导自噬泡形成。
此外,PI信号通路中的另一个分支PI3K-Beclin1-Atg14L/Vps34也参与了自噬的形成。
在这个过程中,Vps34活性的明显增加,会导致自噬囊泡的形成和发展。
而Beclin1和Atg14L会通过协同作用来调节Vps34的激活。
阿托伐他汀钙片最新美国药典标准
阿托伐他汀钙⽚最新美国药典标准B RIEFINGAtorvastatin Calcium Tablets. Because there is no existing USP monograph for this dosage form, a new monograph, based on validated methods of analyses, is proposed. The HPLC procedures in the Assay and in the test for Organic Impurities are based on analysesperformed with the Ultremex C18 brand of L1 column. The typical retention time foratorvastatin is about 9 min.(SM3: E. Gonikberg, L. Santos, M. Marques.)Correspondence Number—C97231Comment deadline: November 30, 2011Add the following:Atorvastatin Calcium TabletsDEFINITIONAtorvastatin Calcium Tablets contain an amount of atorvastatin calcium (C33H34FN2O5)2Ca equivalent to NLT 94.5% and NMT 105.0% of the labeled amount of atorvastatin.IDENTIFICATIONA.The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.ASSAYP ROCEDUREBuffer: 0.05 M ammonium citrate buffer pH 4.0 prepared as follows. Dissolve 9.62 g ofanhydrous citric acid in 950 mL of water, adjust with ammonium hydroxide to a pH of 4.0, and dilute with water to 1000 mL.Mobile phase: Acetonitrile, stabilizer-free tetrahydrofuran, and Buffer (27:20:53)Diluent: Dissolve 9.62 g of anhydrous citric acid in 900 mL of water, adjust with ammonium hydroxide to a pH of 7.4, and dilute with water to 1000 mL. Mix 1000 mL of this solution with 1000 mL of acetonitrile.System suitability solution: 0.1 mg/mL of USP Atorvastatin Calcium RS and 0.01 mg/mL of USP Atorvastatin Related Compound H RS in Diluent. Shake mechanically for 30 min or until dissolved.Standard solution: 0.1 mg/mL of USP Atorvastatin Calcium RS in Diluent. Shake mechanically for 15 min or until dissolved.Sample solution: Transfer 10 Tablets into an appropriate volumetric flask. Add Diluent to about 50% of the final volume of the flask, and shake the mixture mechanically for 15 min or until completely dissolved. Dilute with Diluent to volume. Further dilute the solution with Diluent to obtain a solution containing 0.1 mg/mL of atorvastatin based on the label claim, and pass the solution through a suitable filter.Chromatographic system(See Chromatography 621, System Suitability.)Mode: LCDetector: UV 244 nmColumn: 4.6-mm × 25-cm; 5-µm packing L1Flow rate: 1.5 mL/minInjection size: 20 µLSystem suitabilitySamples: System suitability solution and Standard solutionSuitability requirementsResolution: NLT 5.0 between atorvastatin and atorvastatin related compound H, System suitability solutionTailing factor: NMT 1.2 for atorvastatin, System suitability solutionRelative standard deviation: NMT 1.0%, Standard solutionAnalysisSamples: Standard solution and Sample solutionCalculate the percentage of the labeled amount of atorvastatin (C33H35FN2O5) in the portion of Tablets taken:Result = (r U/r S) × (C S/C U) × (2 ×M r1/M r2) × 100r U= peak response from the Sample solutionr S= peak response from the Standard solutionC S= concentration of USP Atorvastatin Calcium RS in the Standard solution(mg/mL)C U = nominal concentration of atorvastatin in the Sample solution (mg/mL) M r1 = molecular weight of atorvastatin, 558.64 M r2 = molecular weight of atorvastatin calcium, 1155.34 Acceptance criteria: 94.5.0%–105.0% PERFORMANCE TESTSD ISSOLUTION 711:Medium: pH 6.8, 0.05 M phosphate buffer; 900 mL Apparatus 2: 75 rpm Time: 15 minDiluent: Acetonitrile and water (50:50)Standard stock solution: 1.0 mg/mL of USP Atorvastatin Calcium RS in Diluent . Shake mechanically for 10 min or until dissolved.Standard solution: Dilute the Standard stock solution with Medium to obtain a final concentration of (L /900) mg/mL, where L is the label claim in mg/Tablet. Sample solution: Pass a portion of the solution under test through a suitable filter. Instrumental conditions(See Spectrophotometry and Light-Scattering 851.) Analytical wavelength: 244 nm Cell path: See Table 1.Table 1Label Claim (mg/Tablet) Cell Path (cm)10 1.0 20 and 400.5 800.2Blank: Medium AnalysisSamples: Standard solution and Sample solutionCalculate the percentage of the labeled amount of atorvastatin (C 33H 35FN 2O 5) dissolved:(A U /A S ) × (C S /L ) × (2 × M r1/M r2) × V × 100A U = absorbance of the Sample solutionA S= absorbance of the Standard solutionC S= concentration of the Standard solution (mg/mL)L= label claim (mg/Tablet)M r1 = molecular weight of atorvastatin, 558.64M r2 = molecular weight of atorvastatin calcium, 1155.34V= volume of Medium, 900 mLTolerances: NLT 80% (Q) of the labeled amount of atorvastatin (C33H35FN2O5) is dissolved.U NIFORMITY OF D OSAGE U NITS 905:Diluent: Acetonitrile and water (50:50)Standard solution: 0.1 mg/mL of USP Atorvastatin Calcium RS in Diluent. Shakemechanically for 15 min or until dissolved.Sample solution: Place each Tablet into a separate appropriately sized volumetric flask.Add Diluent to about 50% of the final volume of the flask, and shake the mixturemechanically for 15 min or until completely dissolved. Dilute with Diluent to volume. Further dilute the solution with Diluent to obtain a solution containing 0.1 mg/mL of atorvastatin based on the label claim, and pass the solution through a suitable filter.Instrumental conditions(See Spectrophotometry and Light-Scattering 851.)Mode: UVCell: 0.1 cmAbsorbance: 244 nmBlank: DiluentAnalysisSamples: Standard solution and Sample solutionCalculate the percentage of the labeled amount of atorvastatin (C33H35FN2O5) in the Tablet taken:Result = (A U/A S) × (C S/C U) × (2 ×M r1/M r2) × 100A U= absorbance of the Sample solutionA S= absorbance of the Standard solutionC S= concentration of USP Atorvastatin Calcium RS in the Standard solution(mg/mL)C U= nominal concentration of atorvastatin in the Sample solution (mg/mL)M r1 = molecular weight of atorvastatin, 558.64M r2 = molecular weight of atorvastatin calcium, 1155.34Acceptance criteria: Meets the requirementsIMPURITIESO RGANIC I MPURITIESBuffer, Mobile phase, Diluent, System suitability solution, Standard solution, and Sample solution: Proceed as directed in the Assay.Chromatographic system: Proceed as directed in the Assay, except record thechromatograms for at least three times the retention time of atorvastatin.System suitabilitySample: System suitability solutionSuitability requirementsResolution: NLT 5.0 between atorvastatin and atorvastatin related compound HTailing factor: NMT 1.2 for the atorvastatin peak and less than 1.5 for the atorvastatin related compound H peakRelative standard deviation: NMT 2.0% for atorvastatin related compound HAnalysisSample: Sample solutionCalculate the percentage of any individual impurity in the portion of Tablets taken:Result = (r U/r T) × 100r U = peak response for each impurityr T = sum of all the peak responsesAcceptance criteria: See Table 2.Table 2NameRelativeRetentionTimeAcceptanceCriteria,NMT (%)Atorvastatin pyrrolidone analog a0.85 0.5 Atorvastatin 1.00 —Atorvastatin related compound H b 1.35 0.5 Atorvastatin epoxy pyrrolooxazin analog c 1.74 0.5NameRelative Retention TimeAcceptance Criteria, NMT (%)Atorvastatin epoxy pyrrolooxazin tricyclic analog d1.92 0.5 Atorvastatin related compound D e2.72 0.5 Any other individual impurity — 0.2 Total impurities—2.0a(3R ,5R )-7-[5-(4-Fluorophenyl)-3-isopropyl-2-oxo-4-phenyl-3-(phenylcarba moyl)-2,3-dihydro-1H -pyrrol-1-yl]-3,5-dihydroxyheptanoic acid. bLactone impurity. c4-{6-(4-Fluorophenyl)-7,8-epoxy-6-hydroxy-8a-isopropyl-7-phenyl-8-(phen ylcarbamoyl)hexahydro-2H -pyrrolo[2,1-b] [1,3]oxazin-2-yl}-3-hydroxybutanoic acid. d2,6-(2-Carboxymethyl-3-oxapropano)-7,8-epoxy-8a-(4-fluorophenyl)-6-isop ropyl-N ,8-diphenylhexahydro-2H -pyrrolo[2,1-b] [1,3]oxazine-7-carboxamide. eEpoxide impurity, or3-(4-fluorobenzoyl)-2-isobutyryl-3-phenyloxirane-2-carboxylic acidphenylamide.ADDITIONAL REQUIREMENTSP ACKAGING AND S TORAGE : Preserve in tight containers, and store at controlled roomtemperature.USP R EFERENCE S TANDARDS 11USP Atorvastatin Calcium RSUSP Atorvastatin Related Compound H RS (lactone impurity)5-(4-Fluorophenyl)-1-{2-[(2R ,4R )-4-hydroxy-6-oxotetrahydro-2H -pyran-2-yl]ethyl}-2-isoprop yl-N ,4-diphenyl-1H -pyrrole-3-carboxamide. C 33H 33FN 2O 4 540.622S (USP35)。
E3泛素连接酶LRSAM1的自缔结和活性调控
目录硕士学位论文 (1)摘要 (I)ABSTRACT (III)第一章文献综述 (1)1.1 E3泛素连接酶LRSAM1 (1)1.1.1蛋白质翻译后修饰——泛素化 (1)1.1.2 E3泛素连接酶 (3)1.1.3 LRSAM1的研究进展 (4)1.1.4 E3泛素连接酶的活性调控 (5)1.1.5 E3泛素连接酶的结构域研究 (6)1.2多克隆抗体 (8)1.2.1多克隆抗体的定义 (8)1.2.2多克隆抗体的制备原则 (8)1.2.3多克隆抗体的质量鉴定 (9)1.2.4多克隆抗体的科研价值 (10)第二章引言 (11)2.1选题背景 (11)2.2研究目的和意义 (11)第三章LRSAM1的纯化和多克隆抗体的制备 (13)3.1前言 (13)3.2实验材料、试剂与仪器 (13)3.2.1实验材料和试剂 (13)3.2.2实验仪器 (13)3.3实验方法 (14)3.3.1无标签LRSAM1的表达和变性纯化 (14)3.4实验结果 (16)3.5分析与讨论 (17)第四章LRSAM1多克隆抗体的纯化和效价鉴定 (19)4.1前言 (19)4.2实验材料、试剂与仪器 (19)4.2.1实验材料和试剂 (19)4.2.2实验仪器 (19)4.3试验方法 (19)4.3.1溴化氰活化Sepharose Beads的制备 (19)4.3.2重组抗原与活化Sepharose Beads的交联 (20)4.3.3 LRSAM1多克隆抗体的亲和纯化 (20)4.3.4 LRSAM1多克隆抗体的质量鉴定 (20)4.4实验结果 (21)4.5分析与讨论 (22)第五章LRSAM1 N端结构域对E3活性的调控 (25)5.1前言 (25)5.2实验材料、试剂与仪器 (25)5.2.1实验材料和试剂 (25)5.2.2实验仪器 (25)5.3试验方法 (25)5.3.1泛素化系统相关蛋白纯化与活性检测 (25)5.3.2 LRSAM1突变体的构建和纯化 (27)5.3.3体外泛素化反应 (28)5.4实验结果 (29)5.5分析与讨论 (32)第六章LRSAM1的自缔结和分子间泛素化 (35)6.1前言 (35)6.2实验材料、试剂和仪器 (35)6.2.1实验材料和试剂 (35)6.2.2实验仪器 (35)6.3试验方法 (35)6.3.1 LRSAM1蛋白的自缔结 (35)6.3.2 LRSAM1蛋白分子间泛素化 (37)6.4实验结果 (37)6.5讨论与分析 (38)第七章LRSAM1调控分子间泛素化类型 (41)7.1前言 (41)7.2实验材料、试剂与仪器 (41)7.2.1实验材料和试剂 (41)7.2.2实验仪器 (41)7.3试验方法 (41)7.3.1 LRSAM1蛋白C端删除突变体的构建和纯化 (41)7.3.2 LRSAM1蛋白C端删除突变体的体外泛素化重组 (41)7.4实验结果 (42)7.5讨论与分析 (44)第八章CC1拮抗CC2-SAM1对LRSAM1活性的抑制 (47)8.1前言 (47)8.2实验材料、试剂和仪器 (47)8.2.1实验材料和试剂 (47)8.2.2实验仪器 (47)8.3试验方法 (47)8.3.1 LRSAM1结构域突变体的构建和纯化 (47)8.3.2体外研究LRSAM1各结构域对活性的影响 (48)8.3.3细胞内TSG101的泛素化实验 (48)8.4实验结果 (48)8.5讨论与分析 (51)第九章结论与展望 (53)参考文献 (55)附录 (63)致谢 (65)在校期间发表论文 (67)。
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Multiplying S{s^ k) by N*{s) we obtain the following result. L e m m a 3.1 5(s, k) is Hurwitz if and only if ai{5{s,k)N*{s)) = n-{l{Nis))-r{N{s))). (3.2)
CONTROLLER
PLANT
FIGURE 3.1. Feedback control system. To this end, consider the feedback system shown in Fig. 3.1. Here r is the command signal, y is the output. G(s) = Njs)
then, (3.1) can be rewritten as 6{s, k) - [kNe{s^) + De{s^)] + s[kNo{s^) + Dois^)] .
3.2 A Characterization of All Stabilizing Feedback Gains
41
It is clear from this expression that both the even as well as the odd parts of 6{s, k) depend on k. This creates difficulties when trying to use Lemma 2.1 to ensure the Hurwitz stability of 5{s, k). To overcome this problem, we will now construct a polynomial for which only the even part depends on fc, and to which Theorem 2.4 is applicable. Suppose that the degree of D{s) is n while the degree of N{s) is m and m < n. Define iV*(5) : - N{-s) = Ne{s^) sNois^).
•
In order to solve our stabilization problem, we need to determine those values of k, if any, for which (3.2) holds. Notice that in this expression, the values of n and l{N{s)) — r{N{s)) are known and fixed. Using the even-odd decompositions of N{s) and D{s) we have S{s, k)N*{s) where
Our objective is to determine those values of /c, if any, for which the closedloop system is stable, that is, 5{s^ k) is Hurwitz. If we now consider the even-odd decompositions of N{s) and D{s) N{s) D{s) = = Ne{s^) + sNois^) De{s^) + sDo{s^)
Now, 6{s^k) of degree n is Hurwitz if and only if l{5{s,k)) r{S{s, k)) = 0. Furthermore, from Theorem 2.4 ai{S{s,k)N''{s)) Thus ai{5{s,k)N^s)) = n{l{N{s)) - r{N{s))) . = l{5{s,k)N*{s)) r{5{s,k)N''{s)).
Dis)
is the plant to be controlled, N{s) and D{s) are coprime polynomials, and C{s) is the controller to be designed. In the case of constant gain stabilization, C{s) = k so that the closed-loop characteristic polynomial 6{s^ k) is given by 5{s,k) = D{s)-VkN{s). (3.1)
PI Stabilization of Delay-Pree Linear Time-Invariant Systems
In this chapter we utilize the Generalized Her mite-Biehler Theorem presented in the previous chapter to give a solution to the problem of feedback stabilization of a given finite-dimensional linear-time invariant plant by a constant gain controller and by a PI controller. In each case the complete set of stabilizing solutions is found.
Proof. Since l{a{s) • b{s)) = l{a{s)) + l{b{s)) and r{a{s) • b{s)) = r{a{s)) + r(6(s)), we have li5is,k)N''{s))-r{S{s,k)N*{s)) = = = l{6{s,k)) - r{6{s,k)) +l{N*{s))-r{N*is)) li6is,k))-r{Sis,k)) +l{N{-s)) r{N{-s)) ms,k))-r{5{s,k)) -{l{N{s))-r{N{s))). = n and
/ll(s2) /l2(s') = = i?e(s')iVe(s') s'-Do(5')iV<,(s2)
=
hi{s^) -f kh2(s^) + sgi{s^)
Ne{s^)Ne{s^)-S^No{s^)No{s^)
51 (s^)
=
Ne{s^)Do{s^)-D,{s^)No{s'').
42
3. PI Stabilization of Delay-Free Linear Time-Invariant Systems
Substituting s = juj, we obtain S{JL^,k)N*{ju;) where p{uj,k) Pi(a;) = pi{oo)+ kp2{u) = [D,{-u;^)Ne{~u;^)+u;^Do{-u;^)No{-u;^)] [Ne{-u;^)Ne(~u;^)+uj^No{-uj^)No{-uJ^)] - De{-u;^)No{-u^)] . (3.4) (3.5) (3.6) (3.7) = p{uj,k)+jq(ij) (3.3)
P2{uj) =
q{uj) = u;[Ne{'u;^)Do{~u^) Also, define Pf{u),k) Qfiuj) = =
Note that the zeros of the imaginary part ^^(0;) are independent of A;. For clarity of presentation, we first introduce some definitions before formally stating the main result of this section. Definition 3.1 Let the integers m, n and the function qf{uj) he as already defined. Let 0 = uo < uji < uj2 < • • • < uji-i be the real, non-negative, distinct finite zeros of qf{uj) with odd multiplicities. Define a sequence of numbers ^o, ^1, ^2, * • • 5 ^z cis follows:
40
பைடு நூலகம்
3. PI Stabilization of Delay-Free Linear Time-Invariant Systems
3.2 A Characterization of All Stabilizing Feedback Gains
In this section we utilize the Generalized Hermite-Biehler Theorem to give a solution to the problem of feedback stabilization of a given linear timeinvariant plant by a constant gain controller. Even though this problem can be solved using classical approaches such as the Nyquist stability criterion and the Routh-Hurwitz criterion, it is not clear how to extend these methods to the more complicated cases where PI or PID controllers are involved. By using the Generalized Hermite-Biehler Theorem, an elegant procedure is developed that can be extended to the aforementioned cases.