量子点活体追踪AD转基因鼠Aβ变化及GLP-1干预的保护作用
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摘要
研究背景：
阿尔茨海默病(AD)是一种原因不明,以进行性认知功能障碍、行为和人格障碍等为主要临床特征的中枢神经系统退行性疾病。Aβ是构成神经炎性斑的核心和血管沉积物的主要成分,被认为是AD最重要的致病物质之一。AD的病因和发病机制至今尚不清楚,越来越多的证据提示炎症反应在AD的病因和病理过程中具有重要作用,同时也是AD动物模型致病的一个主要原因。胰高血糖素样肽1(GLP-1)是由肠道内分泌L细胞分泌的肠促胰岛素,具有亲神经性,对神经元轴突的生长,神经元的营养有一定的调节作用,能防护谷氨酸诱导的凋亡和氧化应激损伤,可能成为具有潜在价值的治疗AD的新方法。量子点(QDs)是一种新型的荧光分子探针,具有荧光强度高、激发光谱连续而宽、光学稳定性好等优势。应用量子点探针活体成像观察Aβ的动态变化及药物对AD的疗效,对阿尔茨海默病的早期诊断与早期治疗具有十分重要的意义。
研究目的：
本研究通过水迷宫和分子生物学方法探讨GLP-1及衍生物对AD可能保护作用及机制,利用量子点-抗体探针活体追踪GLP-1干预前后AD转基因模型Aβ的变化,探讨GLP-1治疗AD的疗效及其神经保护作用机制。研究方法：1.将正常C57BL小鼠随机分3组：QDs组、QDs-Ap-Ab组、对照组,各组小鼠分别行量子点、量子点-Ap-Ab探针、PBS侧脑室注射后,采用组织形态学和动物行为学观察,应用石墨炉原子吸收光谱法检测血、尿中镉含量,全自动生化检测仪测定肝肾功能,系统考察量子点和制备的探针的生物毒性作用。
2.将饲养10月和16月的APP转基因鼠、正常C57BL小鼠随机分为：T10组、GLP-1A组、GLP-1±ExA组、正常组和T16组、GLP-1B组、GLP-1+ExB组、正常组,侧脑室连续注药后行水迷宫实验,并取材进行形态学观察,利用ELISA方法检测TNF-α和IL-1p蛋白含量,采用免疫组织化学和量子点荧光组织化学方法检测GFAP、Aβ、GLP-1R蛋白的表达,Real-time PCR检测GLP-1R mRNA基因的表达,Western blot检测p-p38MAPK蛋白含量的变化。
3.利用动物活体整体荧光成像系统和体视显微镜监测T10组、T16组、GLP-1A组和正常组量子点探针标记Aβ的变化,检测3天后断头取脑组织冰冻切片,荧光显微镜观察,验证Aβ的变化。
研究结果：
1、琼脂糖凝胶电泳检测到目的条带,证明量子点-Ap-Ab探针制备成功。毒性检测HE染色示QDs-Ap-Ab组海马CA1区细胞形态、结构与对照组相似；尼氏染色示探针组海马CA1区神经元形态正常,尼氏体清晰可见,与对照组无差异；石墨炉原子吸收光谱法检测示侧脑室QDs与QDs-Ap-Ab探针注射后12h,尿镉含量较对照组明显增加,1-7dQDs组、探针组的尿镉含量与对照组相比,差异无统计学意义；行为学观察7d,三组小鼠进食进水正常,二便正常,无举尾、皮肤毛发颜色改变,无步态异常、兴奋抑制反应,均无死亡；QDs组和QDs-Ap-Ab组血清ALT、AST、BUN和CRE水平与对照组无明显差异(P>0.05)。
2、T10组、T16组空间学习记忆能力、思考应变能力明显下降；海马神经元受损明显,线粒体结构不清；IL-1p、TNFα含量明显增多,GFAP、Aβ、GLP-1R蛋白表达明显增高,Aβ、GLP-1R蛋白表达区域部分重叠；GLP-1RmRNA水平增高明显；p-p38蛋白含量增多。侧脑室连续5d注射GLP-1后,GLPA组小鼠空间学习记忆能力、思考应变能力明显改善,GLPB组小鼠空间学习记忆能力、思考应变能力改善不明显；GLPA组L-1p、TNFα含量较T10组明显下降,GFAP、Aβ、GLP-1R蛋白表达明显减少,GLP-1RmRNA水平明显降低；p-p38蛋白含量减低。用GLP-1和Exendin Fragment9-39同时干预T10组,其空间学习记忆能力、IL-1p、TNFα含量、GFAP、Aβ、GLP-1R蛋白表达量、GLP-1RmRNA水平、p-p38蛋白含量与T10组无明显差异。
3、NH2-QDs-605脑内非特异性积聚较QDs-605明显NH2-QDs-605在脑脊液中光学特性稳定,生物相容性好。量子点-Ap-Ab探针标记16月和10月转基因鼠Ap,发现前者荧光范围较后者扩大,连续观测3天,量子点荧光强度没有衰减；GLP-1干预10月APP转基因鼠5天后,其荧光范围减小,荧光亮度降低；脑组织冰冻切片观测验证了上述结果。
研究结论：
1.成功构建了量子点-Ap-Ab探针,在一定的条件下,量子点及量子点-Ap-Ab探针对小鼠整体毒性作用小,生物相容性好。
2.GLP-1R在APP转基因模型海马组织、大脑皮层中表达增高,证实GLP-1可能通过与GLP-1R结合,参与减缓炎症反应、改善APP转基因鼠的学习和记忆能力。
3.GLP-1抑制脑组织中p38MAPK活化是减轻APP转基因鼠脑内的炎症反应的可能机制之一。
4.量子点-Ap-Ab探针可应用于活体动物脑内研究,并能有效识别APP转基因鼠脑内的Ap沉积。
5.量子点-Ap-Ab探针荧光成像可以应用于AD转基因模型抗p淀粉样蛋白斑块干预的疗效检测。
Objective:
Alzheimer's disease(AD) is a neurodegenerative disease of the nervous system which is characterized by irreversible memory impairment, continuous cognitive decline,and behavioral disturbances.Amyloid-βpeptide (Aβ)is the main component of blood-vessel and core part of neuritic plaques,which is regarded as one of the most important disease-causing material.The etiology and pathogensis of AD are still unknown to date, but a growing body of evidence suggests that neuroinflammation may play a significant role in etiology and pathogenesis of AD and it is also the main case in animal paradigms of the disease. Glucagon-like peptide 1 (GLP-1)is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells, in response to meal intake.It has been documented that GLP-1 can induce neurite outgrow, neurotropic properties, and can protect cells against excessive glutamate and other toxic insults.GLP-1 is probably a promising agent in the therapy of AD.Compared with traditional fluorescent dye, Quantum Dots(QDs)is a new fluorescence probe which has significant advantages in fluorescent intensity and ray stability.Thus, molecular imaging of A 0 in Vivo by Quantum Dot can provide not only highly sensitive monitoring of the course of AD at the early stage, which will be of great help in early diagnosis, and also evaluation of the curative effect of GLP-1 used in early treatment.
This study was designed to evaluate the biocompatibility and get the preliminary data of A in Vivo labeled by Quantum Dots-probe for real-time subsurface imaging in APP transgenic mice in Vivo, then to discuss the neuroprotective effect of intracerebroventricular injection of GLP-1 in APP transgenic mice, and revealed its probable mechanism.
Methods:
1.Normal C57BL mice were randomly divided into control-, QDs-Aβ-Ab-and QDs-group.Observing the response of injecting with respectively 5μL QDs, QDs-Aβ-Ab probe and saline in each group with behavioral comparison,HE staining, nissl staining, electron micrograph. Urine and blood cadmium levels were measured by HPLC.Hepatic and renal functions were detected by using automatic chemistry analyzer.
2.10-and 16-month old APP transgenic mice and normal C57BL mice were randomly divided into T10、GLP-1A、GLP-1+ExA、normal groups and T16、GLP-IB、GLP-1+ExB、normal groups, After intracerebroventricular injection of respectively 5μL GLP-1,GLP-1 and Exendin Fragment 9-39, saline,do the Morris water maze tests and use behavioral comparison on each group.The histomorphology of hippocampus were tested by micrograph. TNF-a and IL-1βlevels were measured by enzyme-linked immunosorbent assay (ELISA). The expression of GFAP、Aβand GLP-1R were tested by immuno-stochemistry. The distribution of Aβand GLP-1R were observed by Quantum Dots immunofluorescence double-labeling part.The variable expression of GLP-1 mRNA was detected by Real-time PCR. p-p38MAPK protein levels were investigated by western blot.
3.Monitoring the variation of Aβin T10、T16、GLP-1A and normal groups by using bio-imaging system and binocular stereomicroscope.After 3 days, using fluorescence microscope to detect the changes of the Aβin the frozen sections of the brain.
Results:
1. QDs-Aβ-Ab probe showed only one band as NH2-QDs-605 on the agarose gel electrophoresis.Cell morphology, ultrastructureand and nissl bodies in hippocampal CA1 of probe and QDs group mice are probably normal as control.After intracerebroventricular injecting with QDs and probes, t the urine cadmium levels were apparently higher than that in controls in 12 hours and down to normal as control in 1～7days. But there was little change in the blood cadmium level.The movements of all groups were normal.There was no significant difference in the content of serum ALT、AST、BUN and CRE among the three groups.
2.The learning and memory ability of APP transgenic mice was greatly declined, the ultrastructure in hippocampal CA1 shows neurons damage and is very vague. A part of distribution of Aβand GLP-1R were overlapped. The expression of IL-1β,TNFα, GFAP, Aβ,GLP-1R and p-p 38 are largely increased in APP transgenic mice, but the expressions are obviously decreased after GLP-1 treatment. GLP-1 had improved the spatial learning-memory in mices on a certain extent. GLP-1+ExA group had no significant change after treatment.
3.There were some non-specific deposits after NH2-QDs-605 injection in brain, but the optical properties of QDs and the probe remain stable. By using QDs-Aβ-Ab probe to bio-image the Aβ, the spatial width of fluorescence in T16 group were wider than T10.The spatial width of fluorescence in T10 group becomes less after GLP-1 treatment. The frozen section showed the same change as bio-imaging.
Conclusion:
1.The QDs-Aβ-Ab probe is successfully constructed, which had no toxic effects and good biocompatibility in brain.
2.GLP-1R are largely increased in APP transgenic mice. GLP-1 can improve the learning and memory ability combined with GLP-1R.
3.GLP-1 can play a part as an inhibitor of p38 MAPK phosphorylation, which might be a mechanism for the inhibition of neuroinflammation
4.The QDs-Aβ-Ab probe can be used in the investigation of the animal brain, and can effectively identify Aβ.
5.Bio-imaging with QDs can evaluate the curative effect of drugs in AD animal model.
阿尔茨海默病(AD)是一种原因不明,以进行性认知功能障碍、行为和人格障碍等为主要临床特征的中枢神经系统退行性疾病。Aβ是构成神经炎性斑的核心和血管沉积物的主要成分,被认为是AD最重要的致病物质之一。AD的病因和发病机制至今尚不清楚,越来越多的证据提示炎症反应在AD的病因和病理过程中具有重要作用,同时也是AD动物模型致病的一个主要原因。胰高血糖素样肽1(GLP-1)是由肠道内分泌L细胞分泌的肠促胰岛素,具有亲神经性,对神经元轴突的生长,神经元的营养有一定的调节作用,能防护谷氨酸诱导的凋亡和氧化应激损伤,可能成为具有潜在价值的治疗AD的新方法。量子点(QDs)是一种新型的荧光分子探针,具有荧光强度高、激发光谱连续而宽、光学稳定性好等优势。应用量子点探针活体成像观察Aβ的动态变化及药物对AD的疗效,对阿尔茨海默病的早期诊断与早期治疗具有十分重要的意义。
研究目的：
本研究通过水迷宫和分子生物学方法探讨GLP-1及衍生物对AD可能保护作用及机制,利用量子点-抗体探针活体追踪GLP-1干预前后AD转基因模型Aβ的变化,探讨GLP-1治疗AD的疗效及其神经保护作用机制。研究方法：1.将正常C57BL小鼠随机分3组：QDs组、QDs-Ap-Ab组、对照组,各组小鼠分别行量子点、量子点-Ap-Ab探针、PBS侧脑室注射后,采用组织形态学和动物行为学观察,应用石墨炉原子吸收光谱法检测血、尿中镉含量,全自动生化检测仪测定肝肾功能,系统考察量子点和制备的探针的生物毒性作用。
2.将饲养10月和16月的APP转基因鼠、正常C57BL小鼠随机分为：T10组、GLP-1A组、GLP-1±ExA组、正常组和T16组、GLP-1B组、GLP-1+ExB组、正常组,侧脑室连续注药后行水迷宫实验,并取材进行形态学观察,利用ELISA方法检测TNF-α和IL-1p蛋白含量,采用免疫组织化学和量子点荧光组织化学方法检测GFAP、Aβ、GLP-1R蛋白的表达,Real-time PCR检测GLP-1R mRNA基因的表达,Western blot检测p-p38MAPK蛋白含量的变化。
3.利用动物活体整体荧光成像系统和体视显微镜监测T10组、T16组、GLP-1A组和正常组量子点探针标记Aβ的变化,检测3天后断头取脑组织冰冻切片,荧光显微镜观察,验证Aβ的变化。
研究结果：
1、琼脂糖凝胶电泳检测到目的条带,证明量子点-Ap-Ab探针制备成功。毒性检测HE染色示QDs-Ap-Ab组海马CA1区细胞形态、结构与对照组相似；尼氏染色示探针组海马CA1区神经元形态正常,尼氏体清晰可见,与对照组无差异；石墨炉原子吸收光谱法检测示侧脑室QDs与QDs-Ap-Ab探针注射后12h,尿镉含量较对照组明显增加,1-7dQDs组、探针组的尿镉含量与对照组相比,差异无统计学意义；行为学观察7d,三组小鼠进食进水正常,二便正常,无举尾、皮肤毛发颜色改变,无步态异常、兴奋抑制反应,均无死亡；QDs组和QDs-Ap-Ab组血清ALT、AST、BUN和CRE水平与对照组无明显差异(P>0.05)。
2、T10组、T16组空间学习记忆能力、思考应变能力明显下降；海马神经元受损明显,线粒体结构不清；IL-1p、TNFα含量明显增多,GFAP、Aβ、GLP-1R蛋白表达明显增高,Aβ、GLP-1R蛋白表达区域部分重叠；GLP-1RmRNA水平增高明显；p-p38蛋白含量增多。侧脑室连续5d注射GLP-1后,GLPA组小鼠空间学习记忆能力、思考应变能力明显改善,GLPB组小鼠空间学习记忆能力、思考应变能力改善不明显；GLPA组L-1p、TNFα含量较T10组明显下降,GFAP、Aβ、GLP-1R蛋白表达明显减少,GLP-1RmRNA水平明显降低；p-p38蛋白含量减低。用GLP-1和Exendin Fragment9-39同时干预T10组,其空间学习记忆能力、IL-1p、TNFα含量、GFAP、Aβ、GLP-1R蛋白表达量、GLP-1RmRNA水平、p-p38蛋白含量与T10组无明显差异。
3、NH2-QDs-605脑内非特异性积聚较QDs-605明显NH2-QDs-605在脑脊液中光学特性稳定,生物相容性好。量子点-Ap-Ab探针标记16月和10月转基因鼠Ap,发现前者荧光范围较后者扩大,连续观测3天,量子点荧光强度没有衰减；GLP-1干预10月APP转基因鼠5天后,其荧光范围减小,荧光亮度降低；脑组织冰冻切片观测验证了上述结果。
研究结论：
1.成功构建了量子点-Ap-Ab探针,在一定的条件下,量子点及量子点-Ap-Ab探针对小鼠整体毒性作用小,生物相容性好。
2.GLP-1R在APP转基因模型海马组织、大脑皮层中表达增高,证实GLP-1可能通过与GLP-1R结合,参与减缓炎症反应、改善APP转基因鼠的学习和记忆能力。
3.GLP-1抑制脑组织中p38MAPK活化是减轻APP转基因鼠脑内的炎症反应的可能机制之一。
4.量子点-Ap-Ab探针可应用于活体动物脑内研究,并能有效识别APP转基因鼠脑内的Ap沉积。
5.量子点-Ap-Ab探针荧光成像可以应用于AD转基因模型抗p淀粉样蛋白斑块干预的疗效检测。
Objective:
Alzheimer's disease(AD) is a neurodegenerative disease of the nervous system which is characterized by irreversible memory impairment, continuous cognitive decline,and behavioral disturbances.Amyloid-βpeptide (Aβ)is the main component of blood-vessel and core part of neuritic plaques,which is regarded as one of the most important disease-causing material.The etiology and pathogensis of AD are still unknown to date, but a growing body of evidence suggests that neuroinflammation may play a significant role in etiology and pathogenesis of AD and it is also the main case in animal paradigms of the disease. Glucagon-like peptide 1 (GLP-1)is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells, in response to meal intake.It has been documented that GLP-1 can induce neurite outgrow, neurotropic properties, and can protect cells against excessive glutamate and other toxic insults.GLP-1 is probably a promising agent in the therapy of AD.Compared with traditional fluorescent dye, Quantum Dots(QDs)is a new fluorescence probe which has significant advantages in fluorescent intensity and ray stability.Thus, molecular imaging of A 0 in Vivo by Quantum Dot can provide not only highly sensitive monitoring of the course of AD at the early stage, which will be of great help in early diagnosis, and also evaluation of the curative effect of GLP-1 used in early treatment.
This study was designed to evaluate the biocompatibility and get the preliminary data of A in Vivo labeled by Quantum Dots-probe for real-time subsurface imaging in APP transgenic mice in Vivo, then to discuss the neuroprotective effect of intracerebroventricular injection of GLP-1 in APP transgenic mice, and revealed its probable mechanism.
Methods:
1.Normal C57BL mice were randomly divided into control-, QDs-Aβ-Ab-and QDs-group.Observing the response of injecting with respectively 5μL QDs, QDs-Aβ-Ab probe and saline in each group with behavioral comparison,HE staining, nissl staining, electron micrograph. Urine and blood cadmium levels were measured by HPLC.Hepatic and renal functions were detected by using automatic chemistry analyzer.
2.10-and 16-month old APP transgenic mice and normal C57BL mice were randomly divided into T10、GLP-1A、GLP-1+ExA、normal groups and T16、GLP-IB、GLP-1+ExB、normal groups, After intracerebroventricular injection of respectively 5μL GLP-1,GLP-1 and Exendin Fragment 9-39, saline,do the Morris water maze tests and use behavioral comparison on each group.The histomorphology of hippocampus were tested by micrograph. TNF-a and IL-1βlevels were measured by enzyme-linked immunosorbent assay (ELISA). The expression of GFAP、Aβand GLP-1R were tested by immuno-stochemistry. The distribution of Aβand GLP-1R were observed by Quantum Dots immunofluorescence double-labeling part.The variable expression of GLP-1 mRNA was detected by Real-time PCR. p-p38MAPK protein levels were investigated by western blot.
3.Monitoring the variation of Aβin T10、T16、GLP-1A and normal groups by using bio-imaging system and binocular stereomicroscope.After 3 days, using fluorescence microscope to detect the changes of the Aβin the frozen sections of the brain.
Results:
1. QDs-Aβ-Ab probe showed only one band as NH2-QDs-605 on the agarose gel electrophoresis.Cell morphology, ultrastructureand and nissl bodies in hippocampal CA1 of probe and QDs group mice are probably normal as control.After intracerebroventricular injecting with QDs and probes, t the urine cadmium levels were apparently higher than that in controls in 12 hours and down to normal as control in 1～7days. But there was little change in the blood cadmium level.The movements of all groups were normal.There was no significant difference in the content of serum ALT、AST、BUN and CRE among the three groups.
2.The learning and memory ability of APP transgenic mice was greatly declined, the ultrastructure in hippocampal CA1 shows neurons damage and is very vague. A part of distribution of Aβand GLP-1R were overlapped. The expression of IL-1β,TNFα, GFAP, Aβ,GLP-1R and p-p 38 are largely increased in APP transgenic mice, but the expressions are obviously decreased after GLP-1 treatment. GLP-1 had improved the spatial learning-memory in mices on a certain extent. GLP-1+ExA group had no significant change after treatment.
3.There were some non-specific deposits after NH2-QDs-605 injection in brain, but the optical properties of QDs and the probe remain stable. By using QDs-Aβ-Ab probe to bio-image the Aβ, the spatial width of fluorescence in T16 group were wider than T10.The spatial width of fluorescence in T10 group becomes less after GLP-1 treatment. The frozen section showed the same change as bio-imaging.
Conclusion:
1.The QDs-Aβ-Ab probe is successfully constructed, which had no toxic effects and good biocompatibility in brain.
2.GLP-1R are largely increased in APP transgenic mice. GLP-1 can improve the learning and memory ability combined with GLP-1R.
3.GLP-1 can play a part as an inhibitor of p38 MAPK phosphorylation, which might be a mechanism for the inhibition of neuroinflammation
4.The QDs-Aβ-Ab probe can be used in the investigation of the animal brain, and can effectively identify Aβ.
5.Bio-imaging with QDs can evaluate the curative effect of drugs in AD animal model.
引文
[1]Cummings JL. Alzheimer's disease. The New England journal of medicine, 2004,351(1):56-67.
[2]Cummings JL, Cole G. Alzheimer disease[J].Jama-Journal of the American Medical Association.2002,287(18):2335-2338.
[3]Anderson RN, Smith BL.Deaths:leading causes for 2001[J].Natl Vital Stat Rep.2003,52(9):1-85.
[4]Seiler N. Ammonia and Alzheimer's disease[J].Neurochemistry International. 2002,41(2-3):189-207.
[5]Wise J. Scientists call for more funding for research into Alzheimer's disease. BMJ (Clinical research ed.),2009,3:38.
[6]Checler F, Buee L.Fundamental data on the pathologies amyloid and Tau in Alzheimer's disease:Which therapeutic perspectives? Annales pharmaceutiques francaises,2009,67(2):136-53.
[7]Richner M, Bach G, West MJ. Over expression of amyloid beta-protein reduces the number of neurons in the striatum of APPswe/PS1DeltaE9. Brain research, 2009.
[8]van de Hoef DL, Hughes J, Livne-Bar I, et al. Identifying genes that interact with Drosophila presenilin and amyloid precursor protein. Genesis (New York, N.Y:2000),2009.
[9]Selkoe DJ. Biochemistry and Molecular Biology of Amyloid beta-Protein and the Mechanism of Alzheimer's Disease. Handbook of clinical neurology/edited by P.J. Vinken and G.W. Bruyn,2008,89:245-60.
[10]Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer's disease.Nature,2009,461(7266):916-22.
[11]Wirths O, Breyhan H,Marcello A, Cotel MC, Bruck W, Bayer TA. nflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiology Aging.2008,(25).
[12]Tuppo E E, Arias H R. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol,2005,37(2):289-305
[13]Schmidt R,Schmidth H,Curb D,et al. Earlyinflammation and dementia:a 5-year follow-up of theHonolulu Asia Aging Study. Ann Neurol,2002,5:168-174.
[14]Iadecola C,Zhang F,Niwa K et al.SODI rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein.Nat Neurnsci, 1999,2:157-161.
[15]Licastro F, Pedrini S, Caputo L, et al.Increased plasmalevels of interleukin-1, interleukin-6, and alpha-1-antichymotrypsin in patientswith Alzheimer's disease:peripheral inflammation or signals from the brain? JN euroim unol, 2000;103(1):97-102
[16]In'tveld BA,Ruitenberg A,Hofmn A,et al.Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. The New England journal of medicine,2001,345:1515-1521.
[17]Yip AG, Green RC, HuyckM, et al.Nonsteroidal anti-inflammatory drug use and Alzheimerps disease risk:the MIRAGE Study. BMC Geriatr,2005,12(5):2.
[18]Goto M, Kimura T, Hagio S,et al. Neuropathological anaysis of dementia in a Japanease leproarium.Dementia,1995,6(3):157-161.
[19]Blandino-Rosano M, Perez-Arana G, Mellado-Gil JM, et al. Anti-proliferative effect of pro-inflammatory cytokines in cultured beta cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition:protective role of glucagon-like peptide-1.J Mol Endocrinol.2008,41(1):35-44.
[20]Velasquez-Mieyer PA, Cowan PA, Perez-Faustinelli S, et al. Racial disparity in glucagon-like peptide 1 and inflammation markers among severely obese adolescents. Diabetes Care.2008,31(4):770-5.
[21]Dozier KC, Cureton EL, Kwan RO, et al.Glucagon-like peptide-1 protects mesenteric endothelium from injury during inflammation. Peptides.2009,30(9): 1735-1741
[22]Holst JJ. The physiology of glucagon-like peptide 1.Physiol Rev,2007,87(4): 1409-39.
[23]Kastin A J, Akerstrom V, Pan W. Interactions of glucagon-like peptide-1 (GLP-1)with the blood-brain barrier. J M ol N eurosci,2002,18(122):7-14.
[24]Perry T, Greig NH. A new Alzheimers disease interventive strategy:GLP-1. Current Drug Targets,2004,5:565-71.
[25]Perry T, Haughey NJ, Mattson MP, et al. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharm acol Exp Ther,2002,302(3):881-8.
[26]Qin Z, Sun Z, Huang J, et al.Mutated recombinant human glucagon-like peptide-1 protects SH-SY5Y cells from apoptosis induced by amyloid-beta peptide(1-42).Neurosci Lett.2008(3):217-21
[27]During MJ, Cao L, Zuzga D S, et al. Glucagon-like pep tide-1 receptor is involved in learning and neurop rotection. NatMed,2003,9(9):1173-9.
[28]Perry T, Greig NH.Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer's disease. Curr Alzheimer Res. 2005(3):377-85
[29]Perry T, LahiriD K, Sambamurti K, et al. Glucagon-like pep tide-1 decreases endogenous amyloid-beta peptide (Abeta)levels andp rotects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res,2003,72 (5): 603-12.
[30]Haute Autorite:de Santee (HAS). Diagnosis and management of Alzheimer's disease and related diseases. Revue neurologique,2008,164(8-9):754-74.
[31]Perneczky R, Kurz A. [Diagnosis and therapy of Alzheimer's disease:what's important for the family doctor?].MMW Fortschritte der Medizin,2008,150 (49-50):42-5;quiz 46.
[32]Blennow K, Zetterberg H. Use of CSF Biomarkers in Alzheimer's Disease Clinical Trials. The journal of nutrition, health & aging,2009,13(4):358-61.
[33]Higuchi M, Iwata N, Matsuba Y, et al.19F and 1H MRI detection of amyloid beta plaques in vivo. Nature neuroscience,2005,8(4):527-33.
[34]Klunk WE, Lopresti BJ, Ikonomovic MD, et al. Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer's disease brain but not in transgenic mouse brain. The Journal of neuroscience:the official journal of the Society for Neuroscience,2005,25(46):10598-606.
[35]Michalet X, Pinaud FF, Bentolila LA, et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science (New York, N.Y.),2005,307(5709):538-44.
[36]Xing Y, Xia Z, Rao J. Semiconductor Quantum Dots for Biosensing and In Vivo Imaging. IEEE transactions on nanobioscience,2009.
[37]Dahan M, Levi S,Luccardini, et al. Diffusion dynamics of Glycine Recptors revealed by signgle-Quantum Dot Tracking. Science,2003,302:442-445.
[38]Santra S,Yang H, Stanley JT, et al. Rapid and effective labeling of brain tissue using TAT-conjugated CdS:Mn/ZnS quantum dots.Chemical communications, 2005,7(25):3144-3146.
[39]Xiaohu G, Yuanyuan C, Richard ML,et al.In vivo cancer targeting and imaging with semiconductor quantum dots. Nature biotechology,2004, 22(8):969-976.
[40]Watson A, Wu X, Bruchez M. Lighting up cells with quantum dots. BioTechniques,2003,34(2):296-300,302-3.
[41]Tsay JM, Michalet X. New light on quantum dot cytotoxicity. Chemistry & biology,2005,12(11):1159-61.
[42]Lovric J,Bazzihs,Cuiey Y, et al.Differences in subcellular distribution and toxicity of green and red emitting CdTe quantum dots.J Mol Med,2005,83 (5):377-385.
[43]Dubertret B, Skourides P,Norris DJ,et al.In vivo imaging of quantum dots encapsulated in phospholipid micelles. Science,2002,298 (5599):1759-1762.
[44]Ryman-Rasmussen JP, Riviere JE, Monteiro-Riviere NA. Surface coatings determine cytotoxicity and irritation potential of quantum dot nanoparticles in epidermal keratinocytes. The Journal of investigative dermatology, 2007,127(1):143-53.
[45]Hoshino A, Manabe N, Fujioka K, et al.Use of fluorescent quantum dot bioconjugates for cellular imaging of immune cells, cell organelle labeling, and nanomedicine:surface modification regulates biological function, including cytotoxicity. Journal of artificial organs:the official journal of the Japanese Society for Artificial Organs,2007,10(3):149-57.
[46]Chen FQ,Gerion D. Noninvasive imaging ofdots in mice. Nano Lett,2004,4 (10):18-7.
[47]Jaiswal JK, Mattoussi H, Mauro JM, et al.Long term multiple color imaging of live cells using quantum dot bioconjugates. Nat Biotechnol,2003,21 (1):47.
[48]Chen LD, Liu J, Yu XF,et al.The biocomatibility of quantum dot probes used for the targeted imaging of hepatocellular carcinoma metastasis.biomaterials 29(2008):4170-4176.
[49]Dubertret B.Quantum dots in biology:recent progress. Medecine sciences: M/S,2004,20(8-9):737-40.
[50]Chan WH, Shiao NH, Lu PZ. CdSe quantum dots induce apoptosis in human neuroblastoma cells via mitochondrial2dependent pathways and inhibition of survival signals. Toxicol Lett,2006,167 (3):191-200.
[51]Eichenbaum H. Conscious awareness, memory and the hippocampus[J].Nat Neurosci.1999,2(9):775-776.
[52]Eichenbaum H. How does the hippocampus contribute to memory?[J].Trends Cogn Sci.2003,7(10):427-429.
[53]He Y, Lu HT, Sai LM, et al.Microwave synthesis of water-dispersed CdTe/CdS/ZnS core-shell-shell quantumdots with excellent photostability and biocompatibility. Adv. Mater.2008,20,3416-3421.
[54]Nellemann C, Dalgaard M, Lam HR, et al.The combined effects of vinclozolin and procymidone do not deviate from expected additivity in vitro and in vivo. Toxicological sciences:an official journal of the Society of Toxicology, 2003,71(2):251-62.
[55]Selkoe DJ. Alzheimer's disease:genes, proteins, and therapy. Physiological reviews,2001,81(2):741-66.
[56]Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. The New England journal of medicine,2003,348(14):1356-64.
[57]Jia JP, Jia JM, Zhou WD, et, al. Differential acetylcholine and choline concentrations in the cerebrospinal fluid of patients with Alzheimer's disease and vascular dementia.Chin Med,2004,117:1161-1164.
[58]Blennow K, de Leon MJ, Zetterberg H. Alzheimer'S disease. Lancet.2006,368 (9533):387-403.
[59]White JA, Manelli AM, Holmberg KH, et al.Differential effects of oligomeric and fibrillar amyloidbeta 1-42 on astrocyte-mediated inflammation. Neurobiol Dis.2005,18(3):459-465.
[60]Lindberg C, Selenica ML, Westlind DA, et al.Beta-amyloid protein strcture determines the nature of cytokine release from rat microglia. J Mol Neurosci. 2005,27(1):1-12.
[61]Guo JT, Yu J, Ca'ass D, et al.Inflammation-dependent cerebral deposition of ,serum amyloid a protein in a mouse model of amyloidosis. J Neurosci.2002, 22(14):5900-5909.
[62]Finch CE, Morgan TE. Systemic inflammation, infection, ApoE alleles, and Alzheimer disease:a position paper. Curr Alzheimer Res.2007,4(2):185-189.
[63]Tan ZS,Beiser AS,Vasan RS,et al.Inflammatory markers and the risk of Alzheimer disease:the Framingham Study. Neurology.2007,68(22): 1902-1908.
[64]Arai K, Matsuki N, Ikegaya Y, et al.Deterioration of spatial learning performances in lipopolysaccharide-treated mice. Jpn J Pharmacol.2001,87(3): 195-201.
[65]Tanzi RE, Bertam L. New frontiers in Alzheimer's disease genetics. Neuron. 2001,32:181-4.
[66]Halliday G, Robinson SR, Shepherd C, et al.Alzheimer's disease and inflammation:a review of cellular and therapeutic mechanisms. Clin Exp Pharmacol Physiol.2000,27:1.
[67]Heneka MT, O'Banion MK. Inflammatory processes in Alzheimer's disease. J Neuroimmunol.2007(1-2):69-91
[68]Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon contains the equence of glucagon and two related peptides. Nature.1983,302(5910):716-8.
[69]Moser MB, Moser El, Forrest E et al.Spatial learning with a minislab in the dorsal hippocampus[J].Proc Natl Acad Sci U S A.1995,92(21):9697-9701.
[70]Kucukatay V, Balkan S,Yaras N et al.The effect of pergolide on cognitive performance of young and middle-aged rats[J].Int J Neurosci.2002,112(9): 1027-1036.
[71]Thorens B.Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1.Proc Natl Acad Sci USA,1992, 89(18):8641-5.
[72]Drucker DJ, Nauck MA. The incretin sys tem:glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet.2006, 368(9548):1696-1705.
[73]Liu Y, Shepherd EG, Nelin LD.MAPK phosphatases-regulating the immune response. Nat Rev Immunol.2007,7(3):202-212.
[74]Kurnar S,Boehm J, Lee JC. p38 MAP kinases:key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov.2003,2(9): 717-726.
[75]McDonald DR, Bamberger ME, Combs CK, et al. Beta-Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 Monoeytes.J Neurosci.1998,18(12):4451-4460.
[76]Zhu X, Rottkamp CA, Boux H, et al. Activation of P38 kinase kinks tau phosphor-rylation, Oxidative stress and cell cycle-related events in Alzheimer's disease. J Neuropathol Exp Neurol.2000,59(10):880-8
[77]Blandino-Rosano M,Perez-Arana G,Mellado-Gil JM,,et al. Anti-proliferative effect of pro-inflammatory cytokines in cultured beta cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide-1.J Mol Endocrinol.2008(1):35-44.
[78]Li LX, MacDonald PE, Ahn DS,et al.Role of phosphatidylinositol 3-kinasegamma in the beta-cell:interactions with glucagon-like peptide-1. Endocrinology.2006,147(7):3318-3325.
[79]De T, Morrel IL, Stoub TR, et al.MRI-derived entorhinal volume is a good predictor of conversion from MCI to AD. Neurobiol Aging.2004,25: 1197-203.
[80]Patel T, Polikar R, Davatzikos C, et al.EEG and MRI data fusion for early diagnosis of Alzheimer's disease. Conference proceedings.Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference, 2008,2008:1757-60.
[81]Morris J, Price J. Pathologic correlates of nondemented aging, mild cognitive impairment, and early stage Alzheimer's disease. J Mol Neurosci.2001,17: 101-118.
[82]Selkoe DJ. Alzheimer'S disease:genotypes, phenotypes, and treatments. Science.1997,275:630-631.
[83]Hulette CM, Welsh-Bohmer KA, Murray MG, et al.Neuropathological and neuropsychological changes in"normal"aging:evidence for preclinical Alzheimer's disease in cognitively normal individuals. J Neuropathol Exp Neurol.1998,57:1168-1174.
[84]Ishiik. Amyloid imaging Rinsho Shinkeiqaku.2007,47(11):915-7.
[85]Herholz K. PET studies in denlentia. Ann Nucl Med.2003,17:79-89.
[86]Mielke R, Kessler J, Szelies B, et al. Nomal and pathological aging findings of positron-emission-tomography. J Neural Transm.1998,105:821-837.
[87]Minoshima S, Giordani B,Berent S, et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Annals of neurology,1997, 42(1):85-94.
[88]Killiany RJ, Gomez-Isla T, Moss M, et al.Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease.Annals of neurology, 2000,47(4):430-9.
[89]Rosenthel SJ. Bar-coding Biomolecules with Fluorescem Nanocrystals. Nature Biotechnology.2001,19(7):621-622.
[90]Walling MA, Novak JA, Shepard JR. Quantum dots for live cell and in vivo imaging. International journal of molecular sciences,2009,10(2):441-91.
[91]Rosenthal SJ, McBride JR. Quantum dots:putting the squeeze on nanocrystals. Nature nanotechnology,2009,4(1):16-7.
[92]Kricka LJ, Fortina P.Analytical ancestry:"firsts" in fluorescent labeling of nucleosides,nucleotides,and nucleic acids. Clin Chem.2009,55(4):670-83.
[93]Duyckaerts C, Panchal M, Delatour B, et al.Morphologic and molecular neuropathology of Alzheimer's disease. Annales pharmaceutiques francaises, 2009,67(2):127-35.
[94]Hampel H, Broich K. Enrichment of MCI and Early Alzheimer's Disease Treatment Trials Using Neurochemical and Imaging Candidate Biomarkers. The journal of nutrition, health & aging,2009,13(4):373-375.
[95]sbogbi-Jadid K, Small GW, Agdeppa ED, et al.Location of Neurofibrillary Tangles and Beta-Amyloid Plaques in the Brains of Living Patients with Alzheimer Disease. Am J Geriatr Psychiatry.2002,10(1):24-35.
[96]Nichols L, Pike VW, Cai L, et al. Imaging and in vivo quantitation of beta-amyloid:an exemplary biomarker for Alzheimer's disease? Biological psychiatry,2006,59(10):940-7.
[97]Voura EB, Jaiswal JK, Mattoussi H, et al.Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy. Nature medicine.2004,10:993.
[98]Morgan, NY, English S,Chen W, et al.Real time in vivo non-invasive optical imaging using near-infrared fluorescent quantum dots.Acad Radiol.2005,12: 313.
[99]Akerman ME, Chan WC, Laakkonen P, et al.Acad Sci.2008,99:12617.
[100]Larson DR, Zipfel WR, Williams RM, et al.Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science.2003,300(5624): 1434-1436.
[101]Kim S,Lim YT, Soltesz EG, et al.Near-infrared fluorescent type Ⅱ quantum dots for sentinel lymphnode mapping. NatBiotechnol.,2004,22:93-97.
[102]Uren RF. Cancer surgery joins the dots. Nat Biotechnol.2004,22(1):38-39.
[103]Jain RK, Stroh M. Zooming in and out with quantum dots. Nat Biotechnol. 2004,22:959-960.
[1]Stupp SI, Braun PV. Molecular manipulation of microstructures:biomaterials, ceramics,and semiconductors. Science.1997,277(5330):1242-8.
[2]Hall M, Kazakova I, Yao YM. High sensitivity immunoassays using particulate fluorescent labels. Analytical biochemistry.1999,272(2):165-70
[3]Alivisatos P.The use of nanocrystals in biological detection. Nature Biotechnology,2004,22(1):47-52.
[4]Bruchez MJ, Moronne M, Gin P, Weiss S,Alivisatos AP, et al.Semiconductor nanocrystals as fluorescent biological labels.Science,1998,281:2013-2016.
[5]Chan WC, Maxwell DJ, Gao X, et al. Luminescent quantum dots for multiplexed biological detection and imaging. Curr Opin Biotechnol.2002 Feb;13(1):40-6.Review
[6]Chan WC, Nie S.Quantum dot bioconjugates for ultrasensitive nonisotopic detection. Science 1998;281:2016-2018
[7]Ghoroghchian PP, Therien MJ, Hammer DA. In vivo fluorescence imaging:a personal perspective. Nanormedic and nanobiotechnology,2009,1(2):156-67.
[8]Kim S,Fisher B, Eisler HJ, et al. Type-Ⅱ quantum dots:CdTe/CdSe(core/shell) and CdSe/ZnTe(core/shell) heterostructures.Journal of the American Chemical Society,2003,125(38):11466-7.
[9]Farias PM,Santos BS,Thomaz AA,et al.Fluorescent Ⅱ-Ⅵ semiconductor quantum dots in living cells:nonlinear microspectroscopy in an optical tweezers system. The journal of physical chemistry. B,2008,112(9):2734-7.
[10]Guyot-Sionnest P. Quantum dots:a new quantum state?.Nature materials, 2005,4(9):653-4.
[11]Daneshvar H, Nelms J, Muhammad 0, et al. Imaging characteristics of zinc sulfide shell, cadmium telluride core quantum dots. Nanomedicine (London, England),2008,3(1):21-9.
[12]Li ZB, Cai W, Chen X. Semiconductor quantum dots for in vivo imaging. Journal of nanoscience and nanotechnology,2007,7(8):2567-81.
[13]Chen CY, Cheng CT, Lai CW, et al. Type-II CdSe/CdTe/ZnTe (core-shell-shell) quantum dots with cascade band edges:the separation of electron (at CdSe) and hole (at ZnTe) by the CdTe layer. Small (Weinheim an der Bergstrasse, Germany),2005,1(12):1215-20.
[14]Rogach AL, Franzl T, Klar TA, et al.Aqueous Synthesis of Thiol-Capped CdTe Nanocrystals:State-of-the-Art. Phys. Chem.2007,111(40),14628-14637.
[15]Whiteside MD, Treseder KK, Atsatt PR. The brighter side of soils:quantum dots track organic nitrogen through fungi and plants. Ecology,2009, 90(1):100-8.
[16]Chen C, Peng J, Xia HS,et al.Quantum dots-based immunofluorescence technology for the quantitative determination of HER2 expression in breast cancer. Biomaterials,2009,30(15):2912-8.
[17]Cao YW, Banin U. Synthesis and Characterization of InAs/InP and InAs/CdSe Core/Shell Nanocrystals. Angew Chem Int Edit.1999,38:3692-3694.
[18]Cao YW, Banin U. Growth and Properties of Semiconductor Core/Shell Nanocrystals with InAs Cores. J Chem Soc,2000,122:9692-9702.
[19]Qian HF, Dong CQ, Peng JL, et al.High-quality and water-soluble near-infrared photoluminescent CdHgTe/CdS quantum dots prepared by adjusting size and composition. J Phys Chem C.2007,111(45):16852-16857.
[20]Rosenthal SJ. Bar-coding biomolecules with fluorescent nanocrystals.Nature biotechnology,2001,19(7):621-2.
[21]Chen H, Gai H, Yeung ES.Inhibition of photobleaching and blue shift in quantum dots. Chemical communications (Cambridge, England), 2009,(13):1676-8.
[22]Bailey RE, Nie S M. Alloyed semiconductor quantum dots:tuning the optical properties without changing the particle size. J Am Chem Soc.2003,125(23): 7100-7106.
[23]Gao X, Cui Y, Levenson RM, et al.In vivo cancer targeting and imaging with semiconductor quantum dots. Nature Biotechnology.2004,22(8):969-976.
[24]Gao X, Yang L, Petros JA, et al.In vivo molecular and cellular imaging with quantum dots. Curr Opin Biotechnol.2005,16(1):63-72.
[25]Jiang W, Singhal A, Zheng JN, et al.Optimizing the synthesis of red-to near-IR-emitting CdS-capped CdTexSe1-x alloyed quantum dots for biomedical imaging. ChemMater,2006,18(20):4845-485.
[26]Wu XY, Liu HJ, Liu JQ, et al.Immunofuorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots. Nature Biotechnology,2003,21:41.
[27]Janiswal JK, Mattoussi H, Mauro JM, et al.Long-term multiple color imaging o live cells using quantum dot bioconjugates. Nature Biotechnology,2003,21(1): 47-51.
[28]Gao X, Nie S.Molecular profiling of single cells and tissue specimens with quantum dots. Trends in biotechnology,2003,21(9):371-3.
[29]Li JJ, Tsay JM, Michalet X, et al.Wavefunction engineering:From quantum weUs to near-infrared typeⅡ colloidal quantum dots synthesized by layer-by-layer colloidalepitaxy. Chem Phys,2005,318:82-90.
[30]True LD, Gao XH. Quantum Dots for Molecular Patology:Their Time Has Arrived. J Mol Diagn,2007,9(1):7.
[31]Klimov VI, Mikhailovsky AA, McBranch DW, et al. Quantization of multiparticle auger rates in semiconductor quantum dots. Science (New York, N.Y.),2000,287(5455):1011-3.
[32]Tsay J M, Plughoeft M, Bentolila LA, et al.Hybrid approach to the synthesis of highly luminescent CdTe/ZnS and CdHgTe/ZnS nanocrystals.J Am Ghem Soc, 2004,126(7):1926-1927.
[33]Bailey RE, Strausburg JB, Nie S.A new class of far-red and near-infrared biological labels based on alloyed semiconductor quantum dots. J Nanosci Nanotechnol,2004,4(6):569-574.
[34]Ganesh N, Zhang W, Mathias PC, et al.Enhanced fluorescence emission from quantum dots on a photonic crystal surface. Nature nanotechnology, 2007,2(8):515-20.
[35]Mancini MC, Kairdolf BA, Smith AM, et al.Oxidative quenching and degradation of polymer-encapsulated quantum dots:new insights into the long-term fate and toxicity of nanocrystals in vivo. Journal of the American Chemical Society,2008,130(33):10836-7.
[36]Mitchell GP, Mirkin CA, Letsinger RL.Programmed Assembly of DNA Functionalized Quantum Dots. Journal of the American Chemical Society,1999,121(35):8122-8123.
[37]Li QS, Zhang RQ, Lee ST, et al. Optimal surface functionalization of silicon quantum dots. The Journal of chemical physics,2008,128(24):244714.
[38]Dembski S,Graf C, Kruger T, et al.Photoactivation of CdSe/ZnS quantum dots embedded in silica colloids. Small (Weinheim an der Bergstrasse, Germany), 2008,4(9):1516-26.
[39]Uyeda HT, Medintz IL, Jaiswal JK, et al. Synthesis of Compact Multidentate Ligands to Prepare Stable Hydrophilic Quantum Dot Fluorophores. J Am Chem. Soc,2005,127(11),3870-3878.
[40]Chan WH, Shiao NH, Lu PZ. CdSe quantum dots induce apoptosis in human neuroblastoma cells via mitochondrial2dependent pathways and inhibition of survival signals. Toxicol Lett,2006,167 (3):191-200.
[41]Warnement MR, Tomlinson ID, Chang JC, et al.Controlling the reactivity of ampiphilic quantum dots in biological assays through hydrophobic assembly of custom PEG derivatives. Bioconjugate chemistry,2008,19(7):1404-13.
[42]Toita S,Hasegawa U, Koga H, et al.Protein-conjugated quantum dots effectively delivered into living cells by a cationic nanogel.Journal of nanoscience and nanotechnology,2008,8(5):2279-85.
[43]Hanaki K, Momo A, Oku T, et al. Semiconductor quantum dot/albumin complex is a long-life and highly photostable endosome marker. Biochem Biophys Res Commun,2003,302:496.
[44]Hoshino A,Hanakik,Suzuki K,et al.Applications of T-lymphoma labeled with fluorescent quantum dots to cell tracing markers in mouse body. Biochemcal and Biophysical Research Communications,2004,314:46-53.
[45]Chen FQ,Gerion D.Noninvasive imaging ofdots in mice. Nano Lett,2004,4 (10):18-7.
[46]Jaiswal JK, Mattoussi H, Mauro JM, et al.Long-term multiple color imaging of live cells using quantum dot bioconjugates. Nature biotechnology, 2003,21(1):47-51.
[47]Tokumasu F, Dvorak J. Development and application of quantum dots for immunocytochemistry of human erythrocytes. J Microsc,2003,211:256-261.
[48]Derfus A M, Chan C W, Bhatia S N. Probing the cytotoxicity of semiconductor quantum dots. Nano Lett,2004,4(1):11-18.
[49]Gao X, Chan WC, Nie S.Quantum-dot nanocrystals for ultrasensitive biological labeling and multicolor optical encoding. J Biomed Opt,2002,7:532
[50]Rozenzhak SM, Kadakia MP, Caserta TM, et al.Cellular internalization and targeting of semiconductor quantum dots. Chem Commun,2005,17:2217.
[51]Lidke DS,Nagy P, Heintzmann R, et al.Quantum dot ligands provide new insights into erbB/HER receptor-mediated signal transduction. Nat Biotechnol, 2004,22(2):198-203.
[52]Vu TQ, Maddipati R, Blute TA, et al.Peptide-conjugated quantum dots activate neuronal receptors and initiate downstream signaling of neurite growth. Nano letters,2005,5(4):603-7.
[53]Jiang W, Singhal A, Kim BY, et al.Assessing near-infrared quantum dots for deep tissue, organ, and animal imaging applications. JALA,2008,13(1):6-12.
[54]Binnig G, Rohrer H, Gerber C, et al.Surface studies by scanning tunneling microscopy. Phys Rev Lett,1982,49:57-61.
[55]Crawford S A, Higgins M J, Mulvaney P, et al. Nanostructure of the diatom frustule as revealed by atomic force and scanning elec-tron microscopy. J Phycol,2001,37:543-554.
[56]Camesano T A, Natan M J, Logan B E. Observation of changes in bacterial cell morphology using tapping mode atomic force mi-croscopy. Langmuir,2000,16: 4563～4572
[57]Bolshakova A V, Kiselyova O L, Filonov A S,et al. Comparative studies of bacteria with an atomic force microscopy operating in different modes. Ultramicroscopy,2001,86:121-128
[58]Micic M, Hu D, Suh Y D, et al.Correlated atomic force micros-copy and fluorescence lifetime imaging of live bacterial cells. Colloids and Surfaces B: Biointerfaces,2004,34:205-212.
[59]Dufrene YF, Bodnaert CJP, Gerin P A, et al.Direct probing of the surface ultrastructure and molecular interactions of dormant and germinating spores of Phanerochaete chrysosporium. J Bacte-riol,1999,181:5350-5354.
[60]Ahimou F, Touhami A, Dufrene Y F. Real-time imaging of the surface topography of living yeast cells by atomic force micros-copy. Yeast,2003,20: 25-30.
[61]van der Aa B C, Asther M, Dufrene Y F. Surface properties of Aspergillus oryzae spores investigated by atomic force micros-copy. Colloids Surf B Biointerfaces,2002,24:277-284.
[62]Larson DR, Zipfel WR, Williams RM, et al. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science.2003,300(5624): 1434-1436.
[63]Chen LD, Liu J, Yu XF,et al.The biocomatibility of quantum dot probes used for the targeted imaging of hepatocellular carcinoma metastasis.biomaterials 29(2008):4170-4176.
[64]Ballou B, Lagerholm B C, Ernst A L, Bruchez M P, Waggoner A S. Noninvasive imaging of quantum dots in mice. Bioconj. Chem,2004,15:79～ 86.
[65]Santra S, Yang H, Stanley JT, et al.Rapid and effective labeling of brain tissue using TAT-conjugated CdS:Mn/ZnS quantum dots. Chemical communications, 2005,7(25):3144-3146.
[66]Jiang W, Papa E, Fisher, H, et al.Semiconductor quantum dots as contrast agents for whole animal imaging. Trends Biotechnol,2004,22:607-609.
[67]Ballou B, Ernst L A, Waggoner AS.Fluorescence imaging of tumors in vivo. Curr Med Chem,2005,12(7):795-805.
[68]Akerman ME, Chan WC,Laakkonen P, et al.Nanocrystal targeting in vivo. Proc Natl Aead Sci USA,2002,99(20):12617-1262.
[69]Kim S,Lim YT,Soltesz EG,AM De Grand,J Lee.Near-infrared fluorescent type Ⅱ quantum dots for sentinel lymph node mapping. Nature Biotechnology, 2004,22(1):93-97.
[70]Sohesz EG, Kim S,Laurence RG, et al.Intraoperative sentinel lymph node mapping of the lung using nearinfrared fluorescent quantum dots. Ann Thorac Surg,2005,79(1):269-277.
[71]Hama Y, Koyama Y, Urano Y, et al.Simultaneous two colorspectral fluorescence lymphangiography with nelly infrared quantum dots to map two lymphatic flows from the breast and the upper extremity. Breast Cancer Res Treat,2007,103(1):23-28.
[72]Lim YT, Kim S,Nakayama A, et al.Selection of quantum dot wavelengths for biomedical assays and imaging. Mol Imaging,2003,2(1):50-64.
[73]Morgan NY, English S,Chen W, et al.Real time in vivo non-invasive optical imaging using near-infrared fluorescent quantum dots. Acad Radiol,2005,12(3): 313-323.
[74]Cai WB, Shin DW, Chen K, et al.Peptide-labeled nearinfrared quantum dots for imaging tumor vasculature in living subjects. Nano Lett,2006,6(4): 669-676.
[75]Michalet X, Pinaud FF, Bentolila LA, et al. Quantum Dots for Live Cells, in Vivo Imaging, and Diagnostics. Science,2005,307:538-544.
[2]Cummings JL, Cole G. Alzheimer disease[J].Jama-Journal of the American Medical Association.2002,287(18):2335-2338.
[3]Anderson RN, Smith BL.Deaths:leading causes for 2001[J].Natl Vital Stat Rep.2003,52(9):1-85.
[4]Seiler N. Ammonia and Alzheimer's disease[J].Neurochemistry International. 2002,41(2-3):189-207.
[5]Wise J. Scientists call for more funding for research into Alzheimer's disease. BMJ (Clinical research ed.),2009,3:38.
[6]Checler F, Buee L.Fundamental data on the pathologies amyloid and Tau in Alzheimer's disease:Which therapeutic perspectives? Annales pharmaceutiques francaises,2009,67(2):136-53.
[7]Richner M, Bach G, West MJ. Over expression of amyloid beta-protein reduces the number of neurons in the striatum of APPswe/PS1DeltaE9. Brain research, 2009.
[8]van de Hoef DL, Hughes J, Livne-Bar I, et al. Identifying genes that interact with Drosophila presenilin and amyloid precursor protein. Genesis (New York, N.Y:2000),2009.
[9]Selkoe DJ. Biochemistry and Molecular Biology of Amyloid beta-Protein and the Mechanism of Alzheimer's Disease. Handbook of clinical neurology/edited by P.J. Vinken and G.W. Bruyn,2008,89:245-60.
[10]Perrin RJ, Fagan AM, Holtzman DM. Multimodal techniques for diagnosis and prognosis of Alzheimer's disease.Nature,2009,461(7266):916-22.
[11]Wirths O, Breyhan H,Marcello A, Cotel MC, Bruck W, Bayer TA. nflammatory changes are tightly associated with neurodegeneration in the brain and spinal cord of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiology Aging.2008,(25).
[12]Tuppo E E, Arias H R. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol,2005,37(2):289-305
[13]Schmidt R,Schmidth H,Curb D,et al. Earlyinflammation and dementia:a 5-year follow-up of theHonolulu Asia Aging Study. Ann Neurol,2002,5:168-174.
[14]Iadecola C,Zhang F,Niwa K et al.SODI rescues cerebral endothelial dysfunction in mice overexpressing amyloid precursor protein.Nat Neurnsci, 1999,2:157-161.
[15]Licastro F, Pedrini S, Caputo L, et al.Increased plasmalevels of interleukin-1, interleukin-6, and alpha-1-antichymotrypsin in patientswith Alzheimer's disease:peripheral inflammation or signals from the brain? JN euroim unol, 2000;103(1):97-102
[16]In'tveld BA,Ruitenberg A,Hofmn A,et al.Nonsteroidal antiinflammatory drugs and the risk of Alzheimer's disease. The New England journal of medicine,2001,345:1515-1521.
[17]Yip AG, Green RC, HuyckM, et al.Nonsteroidal anti-inflammatory drug use and Alzheimerps disease risk:the MIRAGE Study. BMC Geriatr,2005,12(5):2.
[18]Goto M, Kimura T, Hagio S,et al. Neuropathological anaysis of dementia in a Japanease leproarium.Dementia,1995,6(3):157-161.
[19]Blandino-Rosano M, Perez-Arana G, Mellado-Gil JM, et al. Anti-proliferative effect of pro-inflammatory cytokines in cultured beta cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition:protective role of glucagon-like peptide-1.J Mol Endocrinol.2008,41(1):35-44.
[20]Velasquez-Mieyer PA, Cowan PA, Perez-Faustinelli S, et al. Racial disparity in glucagon-like peptide 1 and inflammation markers among severely obese adolescents. Diabetes Care.2008,31(4):770-5.
[21]Dozier KC, Cureton EL, Kwan RO, et al.Glucagon-like peptide-1 protects mesenteric endothelium from injury during inflammation. Peptides.2009,30(9): 1735-1741
[22]Holst JJ. The physiology of glucagon-like peptide 1.Physiol Rev,2007,87(4): 1409-39.
[23]Kastin A J, Akerstrom V, Pan W. Interactions of glucagon-like peptide-1 (GLP-1)with the blood-brain barrier. J M ol N eurosci,2002,18(122):7-14.
[24]Perry T, Greig NH. A new Alzheimers disease interventive strategy:GLP-1. Current Drug Targets,2004,5:565-71.
[25]Perry T, Haughey NJ, Mattson MP, et al. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharm acol Exp Ther,2002,302(3):881-8.
[26]Qin Z, Sun Z, Huang J, et al.Mutated recombinant human glucagon-like peptide-1 protects SH-SY5Y cells from apoptosis induced by amyloid-beta peptide(1-42).Neurosci Lett.2008(3):217-21
[27]During MJ, Cao L, Zuzga D S, et al. Glucagon-like pep tide-1 receptor is involved in learning and neurop rotection. NatMed,2003,9(9):1173-9.
[28]Perry T, Greig NH.Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer's disease. Curr Alzheimer Res. 2005(3):377-85
[29]Perry T, LahiriD K, Sambamurti K, et al. Glucagon-like pep tide-1 decreases endogenous amyloid-beta peptide (Abeta)levels andp rotects hippocampal neurons from death induced by Abeta and iron. J Neurosci Res,2003,72 (5): 603-12.
[30]Haute Autorite:de Santee (HAS). Diagnosis and management of Alzheimer's disease and related diseases. Revue neurologique,2008,164(8-9):754-74.
[31]Perneczky R, Kurz A. [Diagnosis and therapy of Alzheimer's disease:what's important for the family doctor?].MMW Fortschritte der Medizin,2008,150 (49-50):42-5;quiz 46.
[32]Blennow K, Zetterberg H. Use of CSF Biomarkers in Alzheimer's Disease Clinical Trials. The journal of nutrition, health & aging,2009,13(4):358-61.
[33]Higuchi M, Iwata N, Matsuba Y, et al.19F and 1H MRI detection of amyloid beta plaques in vivo. Nature neuroscience,2005,8(4):527-33.
[34]Klunk WE, Lopresti BJ, Ikonomovic MD, et al. Binding of the positron emission tomography tracer Pittsburgh compound-B reflects the amount of amyloid-beta in Alzheimer's disease brain but not in transgenic mouse brain. The Journal of neuroscience:the official journal of the Society for Neuroscience,2005,25(46):10598-606.
[35]Michalet X, Pinaud FF, Bentolila LA, et al. Quantum dots for live cells, in vivo imaging, and diagnostics. Science (New York, N.Y.),2005,307(5709):538-44.
[36]Xing Y, Xia Z, Rao J. Semiconductor Quantum Dots for Biosensing and In Vivo Imaging. IEEE transactions on nanobioscience,2009.
[37]Dahan M, Levi S,Luccardini, et al. Diffusion dynamics of Glycine Recptors revealed by signgle-Quantum Dot Tracking. Science,2003,302:442-445.
[38]Santra S,Yang H, Stanley JT, et al. Rapid and effective labeling of brain tissue using TAT-conjugated CdS:Mn/ZnS quantum dots.Chemical communications, 2005,7(25):3144-3146.
[39]Xiaohu G, Yuanyuan C, Richard ML,et al.In vivo cancer targeting and imaging with semiconductor quantum dots. Nature biotechology,2004, 22(8):969-976.
[40]Watson A, Wu X, Bruchez M. Lighting up cells with quantum dots. BioTechniques,2003,34(2):296-300,302-3.
[41]Tsay JM, Michalet X. New light on quantum dot cytotoxicity. Chemistry & biology,2005,12(11):1159-61.
[42]Lovric J,Bazzihs,Cuiey Y, et al.Differences in subcellular distribution and toxicity of green and red emitting CdTe quantum dots.J Mol Med,2005,83 (5):377-385.
[43]Dubertret B, Skourides P,Norris DJ,et al.In vivo imaging of quantum dots encapsulated in phospholipid micelles. Science,2002,298 (5599):1759-1762.
[44]Ryman-Rasmussen JP, Riviere JE, Monteiro-Riviere NA. Surface coatings determine cytotoxicity and irritation potential of quantum dot nanoparticles in epidermal keratinocytes. The Journal of investigative dermatology, 2007,127(1):143-53.
[45]Hoshino A, Manabe N, Fujioka K, et al.Use of fluorescent quantum dot bioconjugates for cellular imaging of immune cells, cell organelle labeling, and nanomedicine:surface modification regulates biological function, including cytotoxicity. Journal of artificial organs:the official journal of the Japanese Society for Artificial Organs,2007,10(3):149-57.
[46]Chen FQ,Gerion D. Noninvasive imaging ofdots in mice. Nano Lett,2004,4 (10):18-7.
[47]Jaiswal JK, Mattoussi H, Mauro JM, et al.Long term multiple color imaging of live cells using quantum dot bioconjugates. Nat Biotechnol,2003,21 (1):47.
[48]Chen LD, Liu J, Yu XF,et al.The biocomatibility of quantum dot probes used for the targeted imaging of hepatocellular carcinoma metastasis.biomaterials 29(2008):4170-4176.
[49]Dubertret B.Quantum dots in biology:recent progress. Medecine sciences: M/S,2004,20(8-9):737-40.
[50]Chan WH, Shiao NH, Lu PZ. CdSe quantum dots induce apoptosis in human neuroblastoma cells via mitochondrial2dependent pathways and inhibition of survival signals. Toxicol Lett,2006,167 (3):191-200.
[51]Eichenbaum H. Conscious awareness, memory and the hippocampus[J].Nat Neurosci.1999,2(9):775-776.
[52]Eichenbaum H. How does the hippocampus contribute to memory?[J].Trends Cogn Sci.2003,7(10):427-429.
[53]He Y, Lu HT, Sai LM, et al.Microwave synthesis of water-dispersed CdTe/CdS/ZnS core-shell-shell quantumdots with excellent photostability and biocompatibility. Adv. Mater.2008,20,3416-3421.
[54]Nellemann C, Dalgaard M, Lam HR, et al.The combined effects of vinclozolin and procymidone do not deviate from expected additivity in vitro and in vivo. Toxicological sciences:an official journal of the Society of Toxicology, 2003,71(2):251-62.
[55]Selkoe DJ. Alzheimer's disease:genes, proteins, and therapy. Physiological reviews,2001,81(2):741-66.
[56]Nussbaum RL, Ellis CE. Alzheimer's disease and Parkinson's disease. The New England journal of medicine,2003,348(14):1356-64.
[57]Jia JP, Jia JM, Zhou WD, et, al. Differential acetylcholine and choline concentrations in the cerebrospinal fluid of patients with Alzheimer's disease and vascular dementia.Chin Med,2004,117:1161-1164.
[58]Blennow K, de Leon MJ, Zetterberg H. Alzheimer'S disease. Lancet.2006,368 (9533):387-403.
[59]White JA, Manelli AM, Holmberg KH, et al.Differential effects of oligomeric and fibrillar amyloidbeta 1-42 on astrocyte-mediated inflammation. Neurobiol Dis.2005,18(3):459-465.
[60]Lindberg C, Selenica ML, Westlind DA, et al.Beta-amyloid protein strcture determines the nature of cytokine release from rat microglia. J Mol Neurosci. 2005,27(1):1-12.
[61]Guo JT, Yu J, Ca'ass D, et al.Inflammation-dependent cerebral deposition of ,serum amyloid a protein in a mouse model of amyloidosis. J Neurosci.2002, 22(14):5900-5909.
[62]Finch CE, Morgan TE. Systemic inflammation, infection, ApoE alleles, and Alzheimer disease:a position paper. Curr Alzheimer Res.2007,4(2):185-189.
[63]Tan ZS,Beiser AS,Vasan RS,et al.Inflammatory markers and the risk of Alzheimer disease:the Framingham Study. Neurology.2007,68(22): 1902-1908.
[64]Arai K, Matsuki N, Ikegaya Y, et al.Deterioration of spatial learning performances in lipopolysaccharide-treated mice. Jpn J Pharmacol.2001,87(3): 195-201.
[65]Tanzi RE, Bertam L. New frontiers in Alzheimer's disease genetics. Neuron. 2001,32:181-4.
[66]Halliday G, Robinson SR, Shepherd C, et al.Alzheimer's disease and inflammation:a review of cellular and therapeutic mechanisms. Clin Exp Pharmacol Physiol.2000,27:1.
[67]Heneka MT, O'Banion MK. Inflammatory processes in Alzheimer's disease. J Neuroimmunol.2007(1-2):69-91
[68]Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon contains the equence of glucagon and two related peptides. Nature.1983,302(5910):716-8.
[69]Moser MB, Moser El, Forrest E et al.Spatial learning with a minislab in the dorsal hippocampus[J].Proc Natl Acad Sci U S A.1995,92(21):9697-9701.
[70]Kucukatay V, Balkan S,Yaras N et al.The effect of pergolide on cognitive performance of young and middle-aged rats[J].Int J Neurosci.2002,112(9): 1027-1036.
[71]Thorens B.Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1.Proc Natl Acad Sci USA,1992, 89(18):8641-5.
[72]Drucker DJ, Nauck MA. The incretin sys tem:glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet.2006, 368(9548):1696-1705.
[73]Liu Y, Shepherd EG, Nelin LD.MAPK phosphatases-regulating the immune response. Nat Rev Immunol.2007,7(3):202-212.
[74]Kurnar S,Boehm J, Lee JC. p38 MAP kinases:key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov.2003,2(9): 717-726.
[75]McDonald DR, Bamberger ME, Combs CK, et al. Beta-Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 Monoeytes.J Neurosci.1998,18(12):4451-4460.
[76]Zhu X, Rottkamp CA, Boux H, et al. Activation of P38 kinase kinks tau phosphor-rylation, Oxidative stress and cell cycle-related events in Alzheimer's disease. J Neuropathol Exp Neurol.2000,59(10):880-8
[77]Blandino-Rosano M,Perez-Arana G,Mellado-Gil JM,,et al. Anti-proliferative effect of pro-inflammatory cytokines in cultured beta cells is associated with extracellular signal-regulated kinase 1/2 pathway inhibition: protective role of glucagon-like peptide-1.J Mol Endocrinol.2008(1):35-44.
[78]Li LX, MacDonald PE, Ahn DS,et al.Role of phosphatidylinositol 3-kinasegamma in the beta-cell:interactions with glucagon-like peptide-1. Endocrinology.2006,147(7):3318-3325.
[79]De T, Morrel IL, Stoub TR, et al.MRI-derived entorhinal volume is a good predictor of conversion from MCI to AD. Neurobiol Aging.2004,25: 1197-203.
[80]Patel T, Polikar R, Davatzikos C, et al.EEG and MRI data fusion for early diagnosis of Alzheimer's disease. Conference proceedings.Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference, 2008,2008:1757-60.
[81]Morris J, Price J. Pathologic correlates of nondemented aging, mild cognitive impairment, and early stage Alzheimer's disease. J Mol Neurosci.2001,17: 101-118.
[82]Selkoe DJ. Alzheimer'S disease:genotypes, phenotypes, and treatments. Science.1997,275:630-631.
[83]Hulette CM, Welsh-Bohmer KA, Murray MG, et al.Neuropathological and neuropsychological changes in"normal"aging:evidence for preclinical Alzheimer's disease in cognitively normal individuals. J Neuropathol Exp Neurol.1998,57:1168-1174.
[84]Ishiik. Amyloid imaging Rinsho Shinkeiqaku.2007,47(11):915-7.
[85]Herholz K. PET studies in denlentia. Ann Nucl Med.2003,17:79-89.
[86]Mielke R, Kessler J, Szelies B, et al. Nomal and pathological aging findings of positron-emission-tomography. J Neural Transm.1998,105:821-837.
[87]Minoshima S, Giordani B,Berent S, et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease. Annals of neurology,1997, 42(1):85-94.
[88]Killiany RJ, Gomez-Isla T, Moss M, et al.Use of structural magnetic resonance imaging to predict who will get Alzheimer's disease.Annals of neurology, 2000,47(4):430-9.
[89]Rosenthel SJ. Bar-coding Biomolecules with Fluorescem Nanocrystals. Nature Biotechnology.2001,19(7):621-622.
[90]Walling MA, Novak JA, Shepard JR. Quantum dots for live cell and in vivo imaging. International journal of molecular sciences,2009,10(2):441-91.
[91]Rosenthal SJ, McBride JR. Quantum dots:putting the squeeze on nanocrystals. Nature nanotechnology,2009,4(1):16-7.
[92]Kricka LJ, Fortina P.Analytical ancestry:"firsts" in fluorescent labeling of nucleosides,nucleotides,and nucleic acids. Clin Chem.2009,55(4):670-83.
[93]Duyckaerts C, Panchal M, Delatour B, et al.Morphologic and molecular neuropathology of Alzheimer's disease. Annales pharmaceutiques francaises, 2009,67(2):127-35.
[94]Hampel H, Broich K. Enrichment of MCI and Early Alzheimer's Disease Treatment Trials Using Neurochemical and Imaging Candidate Biomarkers. The journal of nutrition, health & aging,2009,13(4):373-375.
[95]sbogbi-Jadid K, Small GW, Agdeppa ED, et al.Location of Neurofibrillary Tangles and Beta-Amyloid Plaques in the Brains of Living Patients with Alzheimer Disease. Am J Geriatr Psychiatry.2002,10(1):24-35.
[96]Nichols L, Pike VW, Cai L, et al. Imaging and in vivo quantitation of beta-amyloid:an exemplary biomarker for Alzheimer's disease? Biological psychiatry,2006,59(10):940-7.
[97]Voura EB, Jaiswal JK, Mattoussi H, et al.Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy. Nature medicine.2004,10:993.
[98]Morgan, NY, English S,Chen W, et al.Real time in vivo non-invasive optical imaging using near-infrared fluorescent quantum dots.Acad Radiol.2005,12: 313.
[99]Akerman ME, Chan WC, Laakkonen P, et al.Acad Sci.2008,99:12617.
[100]Larson DR, Zipfel WR, Williams RM, et al.Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science.2003,300(5624): 1434-1436.
[101]Kim S,Lim YT, Soltesz EG, et al.Near-infrared fluorescent type Ⅱ quantum dots for sentinel lymphnode mapping. NatBiotechnol.,2004,22:93-97.
[102]Uren RF. Cancer surgery joins the dots. Nat Biotechnol.2004,22(1):38-39.
[103]Jain RK, Stroh M. Zooming in and out with quantum dots. Nat Biotechnol. 2004,22:959-960.
[1]Stupp SI, Braun PV. Molecular manipulation of microstructures:biomaterials, ceramics,and semiconductors. Science.1997,277(5330):1242-8.
[2]Hall M, Kazakova I, Yao YM. High sensitivity immunoassays using particulate fluorescent labels. Analytical biochemistry.1999,272(2):165-70
[3]Alivisatos P.The use of nanocrystals in biological detection. Nature Biotechnology,2004,22(1):47-52.
[4]Bruchez MJ, Moronne M, Gin P, Weiss S,Alivisatos AP, et al.Semiconductor nanocrystals as fluorescent biological labels.Science,1998,281:2013-2016.
[5]Chan WC, Maxwell DJ, Gao X, et al. Luminescent quantum dots for multiplexed biological detection and imaging. Curr Opin Biotechnol.2002 Feb;13(1):40-6.Review
[6]Chan WC, Nie S.Quantum dot bioconjugates for ultrasensitive nonisotopic detection. Science 1998;281:2016-2018
[7]Ghoroghchian PP, Therien MJ, Hammer DA. In vivo fluorescence imaging:a personal perspective. Nanormedic and nanobiotechnology,2009,1(2):156-67.
[8]Kim S,Fisher B, Eisler HJ, et al. Type-Ⅱ quantum dots:CdTe/CdSe(core/shell) and CdSe/ZnTe(core/shell) heterostructures.Journal of the American Chemical Society,2003,125(38):11466-7.
[9]Farias PM,Santos BS,Thomaz AA,et al.Fluorescent Ⅱ-Ⅵ semiconductor quantum dots in living cells:nonlinear microspectroscopy in an optical tweezers system. The journal of physical chemistry. B,2008,112(9):2734-7.
[10]Guyot-Sionnest P. Quantum dots:a new quantum state?.Nature materials, 2005,4(9):653-4.
[11]Daneshvar H, Nelms J, Muhammad 0, et al. Imaging characteristics of zinc sulfide shell, cadmium telluride core quantum dots. Nanomedicine (London, England),2008,3(1):21-9.
[12]Li ZB, Cai W, Chen X. Semiconductor quantum dots for in vivo imaging. Journal of nanoscience and nanotechnology,2007,7(8):2567-81.
[13]Chen CY, Cheng CT, Lai CW, et al. Type-II CdSe/CdTe/ZnTe (core-shell-shell) quantum dots with cascade band edges:the separation of electron (at CdSe) and hole (at ZnTe) by the CdTe layer. Small (Weinheim an der Bergstrasse, Germany),2005,1(12):1215-20.
[14]Rogach AL, Franzl T, Klar TA, et al.Aqueous Synthesis of Thiol-Capped CdTe Nanocrystals:State-of-the-Art. Phys. Chem.2007,111(40),14628-14637.
[15]Whiteside MD, Treseder KK, Atsatt PR. The brighter side of soils:quantum dots track organic nitrogen through fungi and plants. Ecology,2009, 90(1):100-8.
[16]Chen C, Peng J, Xia HS,et al.Quantum dots-based immunofluorescence technology for the quantitative determination of HER2 expression in breast cancer. Biomaterials,2009,30(15):2912-8.
[17]Cao YW, Banin U. Synthesis and Characterization of InAs/InP and InAs/CdSe Core/Shell Nanocrystals. Angew Chem Int Edit.1999,38:3692-3694.
[18]Cao YW, Banin U. Growth and Properties of Semiconductor Core/Shell Nanocrystals with InAs Cores. J Chem Soc,2000,122:9692-9702.
[19]Qian HF, Dong CQ, Peng JL, et al.High-quality and water-soluble near-infrared photoluminescent CdHgTe/CdS quantum dots prepared by adjusting size and composition. J Phys Chem C.2007,111(45):16852-16857.
[20]Rosenthal SJ. Bar-coding biomolecules with fluorescent nanocrystals.Nature biotechnology,2001,19(7):621-2.
[21]Chen H, Gai H, Yeung ES.Inhibition of photobleaching and blue shift in quantum dots. Chemical communications (Cambridge, England), 2009,(13):1676-8.
[22]Bailey RE, Nie S M. Alloyed semiconductor quantum dots:tuning the optical properties without changing the particle size. J Am Chem Soc.2003,125(23): 7100-7106.
[23]Gao X, Cui Y, Levenson RM, et al.In vivo cancer targeting and imaging with semiconductor quantum dots. Nature Biotechnology.2004,22(8):969-976.
[24]Gao X, Yang L, Petros JA, et al.In vivo molecular and cellular imaging with quantum dots. Curr Opin Biotechnol.2005,16(1):63-72.
[25]Jiang W, Singhal A, Zheng JN, et al.Optimizing the synthesis of red-to near-IR-emitting CdS-capped CdTexSe1-x alloyed quantum dots for biomedical imaging. ChemMater,2006,18(20):4845-485.
[26]Wu XY, Liu HJ, Liu JQ, et al.Immunofuorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots. Nature Biotechnology,2003,21:41.
[27]Janiswal JK, Mattoussi H, Mauro JM, et al.Long-term multiple color imaging o live cells using quantum dot bioconjugates. Nature Biotechnology,2003,21(1): 47-51.
[28]Gao X, Nie S.Molecular profiling of single cells and tissue specimens with quantum dots. Trends in biotechnology,2003,21(9):371-3.
[29]Li JJ, Tsay JM, Michalet X, et al.Wavefunction engineering:From quantum weUs to near-infrared typeⅡ colloidal quantum dots synthesized by layer-by-layer colloidalepitaxy. Chem Phys,2005,318:82-90.
[30]True LD, Gao XH. Quantum Dots for Molecular Patology:Their Time Has Arrived. J Mol Diagn,2007,9(1):7.
[31]Klimov VI, Mikhailovsky AA, McBranch DW, et al. Quantization of multiparticle auger rates in semiconductor quantum dots. Science (New York, N.Y.),2000,287(5455):1011-3.
[32]Tsay J M, Plughoeft M, Bentolila LA, et al.Hybrid approach to the synthesis of highly luminescent CdTe/ZnS and CdHgTe/ZnS nanocrystals.J Am Ghem Soc, 2004,126(7):1926-1927.
[33]Bailey RE, Strausburg JB, Nie S.A new class of far-red and near-infrared biological labels based on alloyed semiconductor quantum dots. J Nanosci Nanotechnol,2004,4(6):569-574.
[34]Ganesh N, Zhang W, Mathias PC, et al.Enhanced fluorescence emission from quantum dots on a photonic crystal surface. Nature nanotechnology, 2007,2(8):515-20.
[35]Mancini MC, Kairdolf BA, Smith AM, et al.Oxidative quenching and degradation of polymer-encapsulated quantum dots:new insights into the long-term fate and toxicity of nanocrystals in vivo. Journal of the American Chemical Society,2008,130(33):10836-7.
[36]Mitchell GP, Mirkin CA, Letsinger RL.Programmed Assembly of DNA Functionalized Quantum Dots. Journal of the American Chemical Society,1999,121(35):8122-8123.
[37]Li QS, Zhang RQ, Lee ST, et al. Optimal surface functionalization of silicon quantum dots. The Journal of chemical physics,2008,128(24):244714.
[38]Dembski S,Graf C, Kruger T, et al.Photoactivation of CdSe/ZnS quantum dots embedded in silica colloids. Small (Weinheim an der Bergstrasse, Germany), 2008,4(9):1516-26.
[39]Uyeda HT, Medintz IL, Jaiswal JK, et al. Synthesis of Compact Multidentate Ligands to Prepare Stable Hydrophilic Quantum Dot Fluorophores. J Am Chem. Soc,2005,127(11),3870-3878.
[40]Chan WH, Shiao NH, Lu PZ. CdSe quantum dots induce apoptosis in human neuroblastoma cells via mitochondrial2dependent pathways and inhibition of survival signals. Toxicol Lett,2006,167 (3):191-200.
[41]Warnement MR, Tomlinson ID, Chang JC, et al.Controlling the reactivity of ampiphilic quantum dots in biological assays through hydrophobic assembly of custom PEG derivatives. Bioconjugate chemistry,2008,19(7):1404-13.
[42]Toita S,Hasegawa U, Koga H, et al.Protein-conjugated quantum dots effectively delivered into living cells by a cationic nanogel.Journal of nanoscience and nanotechnology,2008,8(5):2279-85.
[43]Hanaki K, Momo A, Oku T, et al. Semiconductor quantum dot/albumin complex is a long-life and highly photostable endosome marker. Biochem Biophys Res Commun,2003,302:496.
[44]Hoshino A,Hanakik,Suzuki K,et al.Applications of T-lymphoma labeled with fluorescent quantum dots to cell tracing markers in mouse body. Biochemcal and Biophysical Research Communications,2004,314:46-53.
[45]Chen FQ,Gerion D.Noninvasive imaging ofdots in mice. Nano Lett,2004,4 (10):18-7.
[46]Jaiswal JK, Mattoussi H, Mauro JM, et al.Long-term multiple color imaging of live cells using quantum dot bioconjugates. Nature biotechnology, 2003,21(1):47-51.
[47]Tokumasu F, Dvorak J. Development and application of quantum dots for immunocytochemistry of human erythrocytes. J Microsc,2003,211:256-261.
[48]Derfus A M, Chan C W, Bhatia S N. Probing the cytotoxicity of semiconductor quantum dots. Nano Lett,2004,4(1):11-18.
[49]Gao X, Chan WC, Nie S.Quantum-dot nanocrystals for ultrasensitive biological labeling and multicolor optical encoding. J Biomed Opt,2002,7:532
[50]Rozenzhak SM, Kadakia MP, Caserta TM, et al.Cellular internalization and targeting of semiconductor quantum dots. Chem Commun,2005,17:2217.
[51]Lidke DS,Nagy P, Heintzmann R, et al.Quantum dot ligands provide new insights into erbB/HER receptor-mediated signal transduction. Nat Biotechnol, 2004,22(2):198-203.
[52]Vu TQ, Maddipati R, Blute TA, et al.Peptide-conjugated quantum dots activate neuronal receptors and initiate downstream signaling of neurite growth. Nano letters,2005,5(4):603-7.
[53]Jiang W, Singhal A, Kim BY, et al.Assessing near-infrared quantum dots for deep tissue, organ, and animal imaging applications. JALA,2008,13(1):6-12.
[54]Binnig G, Rohrer H, Gerber C, et al.Surface studies by scanning tunneling microscopy. Phys Rev Lett,1982,49:57-61.
[55]Crawford S A, Higgins M J, Mulvaney P, et al. Nanostructure of the diatom frustule as revealed by atomic force and scanning elec-tron microscopy. J Phycol,2001,37:543-554.
[56]Camesano T A, Natan M J, Logan B E. Observation of changes in bacterial cell morphology using tapping mode atomic force mi-croscopy. Langmuir,2000,16: 4563～4572
[57]Bolshakova A V, Kiselyova O L, Filonov A S,et al. Comparative studies of bacteria with an atomic force microscopy operating in different modes. Ultramicroscopy,2001,86:121-128
[58]Micic M, Hu D, Suh Y D, et al.Correlated atomic force micros-copy and fluorescence lifetime imaging of live bacterial cells. Colloids and Surfaces B: Biointerfaces,2004,34:205-212.
[59]Dufrene YF, Bodnaert CJP, Gerin P A, et al.Direct probing of the surface ultrastructure and molecular interactions of dormant and germinating spores of Phanerochaete chrysosporium. J Bacte-riol,1999,181:5350-5354.
[60]Ahimou F, Touhami A, Dufrene Y F. Real-time imaging of the surface topography of living yeast cells by atomic force micros-copy. Yeast,2003,20: 25-30.
[61]van der Aa B C, Asther M, Dufrene Y F. Surface properties of Aspergillus oryzae spores investigated by atomic force micros-copy. Colloids Surf B Biointerfaces,2002,24:277-284.
[62]Larson DR, Zipfel WR, Williams RM, et al. Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science.2003,300(5624): 1434-1436.
[63]Chen LD, Liu J, Yu XF,et al.The biocomatibility of quantum dot probes used for the targeted imaging of hepatocellular carcinoma metastasis.biomaterials 29(2008):4170-4176.
[64]Ballou B, Lagerholm B C, Ernst A L, Bruchez M P, Waggoner A S. Noninvasive imaging of quantum dots in mice. Bioconj. Chem,2004,15:79～ 86.
[65]Santra S, Yang H, Stanley JT, et al.Rapid and effective labeling of brain tissue using TAT-conjugated CdS:Mn/ZnS quantum dots. Chemical communications, 2005,7(25):3144-3146.
[66]Jiang W, Papa E, Fisher, H, et al.Semiconductor quantum dots as contrast agents for whole animal imaging. Trends Biotechnol,2004,22:607-609.
[67]Ballou B, Ernst L A, Waggoner AS.Fluorescence imaging of tumors in vivo. Curr Med Chem,2005,12(7):795-805.
[68]Akerman ME, Chan WC,Laakkonen P, et al.Nanocrystal targeting in vivo. Proc Natl Aead Sci USA,2002,99(20):12617-1262.
[69]Kim S,Lim YT,Soltesz EG,AM De Grand,J Lee.Near-infrared fluorescent type Ⅱ quantum dots for sentinel lymph node mapping. Nature Biotechnology, 2004,22(1):93-97.
[70]Sohesz EG, Kim S,Laurence RG, et al.Intraoperative sentinel lymph node mapping of the lung using nearinfrared fluorescent quantum dots. Ann Thorac Surg,2005,79(1):269-277.
[71]Hama Y, Koyama Y, Urano Y, et al.Simultaneous two colorspectral fluorescence lymphangiography with nelly infrared quantum dots to map two lymphatic flows from the breast and the upper extremity. Breast Cancer Res Treat,2007,103(1):23-28.
[72]Lim YT, Kim S,Nakayama A, et al.Selection of quantum dot wavelengths for biomedical assays and imaging. Mol Imaging,2003,2(1):50-64.
[73]Morgan NY, English S,Chen W, et al.Real time in vivo non-invasive optical imaging using near-infrared fluorescent quantum dots. Acad Radiol,2005,12(3): 313-323.
[74]Cai WB, Shin DW, Chen K, et al.Peptide-labeled nearinfrared quantum dots for imaging tumor vasculature in living subjects. Nano Lett,2006,6(4): 669-676.
[75]Michalet X, Pinaud FF, Bentolila LA, et al. Quantum Dots for Live Cells, in Vivo Imaging, and Diagnostics. Science,2005,307:538-544.