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公开(公告)号:US6063625A
公开(公告)日:2000-05-16
申请号:US156855
申请日:1998-09-16
申请人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Steffan N. Ho , Peter Belshaw
发明人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Steffan N. Ho , Peter Belshaw
IPC分类号: A61K38/00 , A61K47/48 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/725 , C12N15/62 , C12N15/63 , C12P15/00 , C12N15/00 , C12N15/85 , C12N15/86
CPC分类号: C07D498/18 , A61K47/48276 , C07F5/025 , C07H19/01 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K7/645 , C12N15/62 , C12N15/63 , C12P15/00 , A61K38/00 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90
摘要: Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active "dimerizers" or "de-dimerizers", respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve as "universal drugs". They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).
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公开(公告)号:US6046047A
公开(公告)日:2000-04-04
申请号:US157230
申请日:1998-09-16
申请人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw , Steffan N. Ho
发明人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw , Steffan N. Ho
IPC分类号: A61K38/00 , A61K47/48 , A61K48/00 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/715 , C07K14/725 , C12N15/12 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/18 , C12N15/13 , C12N15/85
CPC分类号: C07D498/18 , A61K47/48276 , A61K48/00 , C07F5/025 , C07H19/01 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K14/715 , C07K7/645 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/188 , A01K2217/05 , A61K38/00 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90
摘要: Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of tis invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active "dimerizers" or "de-dimerizers", respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve as "universal drugs". They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).
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公开(公告)号:US06011018A
公开(公告)日:2000-01-04
申请号:US87716
申请日:1998-05-29
申请人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
发明人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
IPC分类号: A61K38/00 , A61K47/48 , A61K48/00 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/715 , C07K14/725 , C12N15/12 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/18 , A61K31/70 , A61K38/13
CPC分类号: C07D498/18 , A61K47/48276 , A61K48/00 , C07F5/025 , C07H19/01 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K14/715 , C07K7/645 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/188 , A01K2217/05 , A61K38/00 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90
摘要: Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active "dimerizers" or "de-dimerizers", respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve as "universal drugs". They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).
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4.
公开(公告)号:US20090060888A1
公开(公告)日:2009-03-05
申请号:US11701239
申请日:2007-01-31
申请人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Steffan N. Ho , Peter Belshaw
发明人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Steffan N. Ho , Peter Belshaw
IPC分类号: A61K35/12 , C12N15/11 , C12N15/00 , C07K7/00 , A01H5/00 , A61P43/00 , A01K67/027 , C12N5/06 , C12N15/87 , A61K31/711
CPC分类号: C07K14/705 , A61K38/00 , A61K47/6425 , C07D498/18 , C07F5/025 , C07H19/01 , C07K7/645 , C07K14/395 , C07K14/7051 , C07K14/71 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90 , C12N15/1055 , C12N15/62 , C12N15/63 , C12N15/67 , C12P15/00
摘要: Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the ζ chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene.Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy.
摘要翻译: 蛋白质的二聚化和寡聚化是促进细胞膜受体,转录因子,囊泡融合蛋白和其他类型的细胞外和细胞外蛋白质的活化的一般生物学控制机制。 我们已经开发了细胞内蛋白质的调节(诱导型)二聚化或寡聚化的一般程序。 原则上,任何两种靶蛋白都可以通过用含有细胞可渗透的合成配体处理带有它们的细胞或生物来诱导相关联。 为了说明本发明的实践,我们已经诱导:(1)T细胞受体(TCR)-CD3复合物的Zeta链的细胞质尾巴的细胞内聚集,从而导致报告基因的信号传导和转录(2 )Fas受体的细胞质尾的同源二聚体,从而导致细胞特异性凋亡(程序性细胞死亡)和(3)DNA结合结构域(Gal4)和转录激活结构域(VP16)的异二聚化,从而导致 直接转录报告基因。 调节的细胞内蛋白与我们的细胞可渗透合成配体的关联提供了生物研究和医学,特别是基因治疗方面的新功能。
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5.
公开(公告)号:US06972193B1
公开(公告)日:2005-12-06
申请号:US09466568
申请日:1999-12-17
申请人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Steffan N. Ho , Peter Belshaw
发明人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Steffan N. Ho , Peter Belshaw
IPC分类号: A61K38/00 , A61K47/48 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/725 , C12N5/10 , C12N15/10 , C12N15/62 , C12N15/63 , C12P15/00
CPC分类号: C07K14/705 , A61K38/00 , A61K47/6425 , C07D498/18 , C07F5/025 , C07H19/01 , C07K7/645 , C07K14/395 , C07K14/7051 , C07K14/71 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90 , C12N15/1055 , C12N15/62 , C12N15/63 , C12N15/67 , C12P15/00
摘要: Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins.
摘要翻译: 蛋白质的二聚化和寡聚化是促进细胞膜受体,转录因子,囊泡融合蛋白和其他类型的细胞外和细胞外蛋白质的活化的一般生物学控制机制。 我们已经开发了细胞内蛋白质的调节(诱导型)二聚化或寡聚化的一般程序。
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公开(公告)号:US6054436A
公开(公告)日:2000-04-25
申请号:US87811
申请日:1998-05-29
申请人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
发明人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
IPC分类号: A61K38/00 , A61K47/48 , A61K48/00 , A61P43/00 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/715 , C07K14/725 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/18 , A61K31/70 , A61K38/12 , C12N5/10
CPC分类号: C07D498/18 , A61K47/48276 , A61K48/00 , C07F5/025 , C07H19/01 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K14/715 , C07K7/645 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/188 , A01K2217/05 , A61K38/00 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90
摘要: We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins and disclose methods and materials for using that procedure to regulatably initiate cell-specific apoptosis (programmed cell death) in genetically engineered cells.
摘要翻译: 我们已经开发了细胞内蛋白质的调节(诱导型)二聚化或寡聚化的一般程序,并且公开了使用该程序在基因工程细胞中调节启动细胞特异性凋亡(程序性细胞死亡)的方法和材料。
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公开(公告)号:US6165787A
公开(公告)日:2000-12-26
申请号:US087647
申请日:1998-05-29
申请人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
发明人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
IPC分类号: A61K38/00 , A61K47/48 , A61K48/00 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/715 , C07K14/725 , C12N5/08 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/18 , C12N5/10 , C12N5/06
CPC分类号: C07D498/18 , A01K2217/05 , A61K38/00 , A61K47/6425 , A61K48/00 , C07F5/025 , C07H19/01 , C07K7/645 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K14/715 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/188
摘要: Dimerization and oligomerization of proteins are general biological control mechanisms that contribute to the activation of cell membrane receptors, transcription factors, vesicle fusion proteins, and other classes of intra- and extracellular proteins. We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins. In principle, any two target proteins can be induced to associate by treating the cells or organisms that harbor them with cell permeable, synthetic ligands. To illustrate the practice of this invention, we have induced: (1) the intracellular aggregation of the cytoplasmic tail of the .zeta. chain of the T cell receptor (TCR)-CD3 complex thereby leading to signaling and transcription of a reporter gene, (2) the homodimerization of the cytoplasmic tail of the Fas receptor thereby leading to cell-specific apoptosis (programmed cell death) and (3) the heterodimerization of a DNA-binding domain (Gal4) and a transcription-activation domain (VP16) thereby leading to direct transcription of a reporter gene. Regulated intracellular protein association with our cell permeable, synthetic ligands offers new capabilities in biological research and medicine, in particular, in gene therapy. Using gene transfer techniques to introduce our artificial receptors, one can turn on or off the signaling pathways that lead to the overexpression of therapeutic proteins by administering orally active "dimerizers" or "de-dimerizers", respectively. Since cells from different recipients can be configured to have the pathway overexpress different therapeutic proteins for use in a variety of disorders, the dimerizers have the potential to serve as "universal drugs". They can also be viewed as cell permeable, organic replacements for therapeutic antisense agents or for proteins that would otherwise require intravenous injection or intracellular expression (e.g., the LDL receptor or the CFTR protein).
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公开(公告)号:US5834266A
公开(公告)日:1998-11-10
申请号:US292597
申请日:1994-08-18
申请人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
发明人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
IPC分类号: A61K38/00 , A61K47/48 , A61K48/00 , A61P43/00 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/715 , C07K14/725 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/18 , C12N5/10 , C12N15/79
CPC分类号: C07D498/18 , A61K47/48276 , A61K48/00 , C07F5/025 , C07H19/01 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K14/715 , C07K7/645 , C12N15/62 , C12N15/63 , C12P15/00 , C12P17/188 , A01K2217/05 , A61K38/00 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90
摘要: We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins and disclose methods and materials for using that procedure to regulatably initiate cell-specific apoptosis (programmed cell death) in genetically engineered cells.
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公开(公告)号:US08084596B2
公开(公告)日:2011-12-27
申请号:US12684064
申请日:2010-01-07
申请人: Gerald R. Crabtree , Peter Belshaw , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless
发明人: Gerald R. Crabtree , Peter Belshaw , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless
CPC分类号: C07D498/18 , A61K38/00 , A61K47/6425 , A61K48/00 , C07F5/025 , C07H19/01 , C07K7/645 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90 , C12N15/62 , C12N15/63 , C12P15/00
摘要: We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins and disclose methods and materials for using that procedure to regulatably initiate cell-specific apoptosis (programmed cell death) in genetically engineered cells.
摘要翻译: 我们已经开发了细胞内蛋白质的调节(诱导型)二聚化或寡聚化的一般程序,并且公开了使用该方法在基因工程细胞中调节启动细胞特异性凋亡(程序性细胞死亡)的方法和材料。
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公开(公告)号:US06891021B2
公开(公告)日:2005-05-10
申请号:US10054712
申请日:2001-11-13
申请人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
发明人: Gerald R. Crabtree , Stuart L. Schreiber , David M. Spencer , Thomas J. Wandless , Peter Belshaw
IPC分类号: A61K38/00 , A61K47/48 , C07D498/18 , C07F5/02 , C07H19/01 , C07K7/64 , C07K14/395 , C07K14/705 , C07K14/71 , C07K14/725 , C12N15/62 , C12N15/63 , C12P15/00 , C07K2/00 , C07K4/00
CPC分类号: C07D498/18 , A61K38/00 , A61K47/6425 , A61K48/00 , C07F5/025 , C07H19/01 , C07K7/645 , C07K14/395 , C07K14/705 , C07K14/7051 , C07K14/71 , C07K2319/00 , C07K2319/02 , C07K2319/03 , C07K2319/035 , C07K2319/09 , C07K2319/20 , C07K2319/32 , C07K2319/42 , C07K2319/43 , C07K2319/60 , C07K2319/71 , C07K2319/715 , C07K2319/81 , C07K2319/90 , C12N15/62 , C12N15/63 , C12P15/00
摘要: We have developed a general procedure for the regulated (inducible) dimerization or oligomerization of intracellular proteins and disclose methods and materials for using that procedure to regulatably initiate cell-specific apoptosis (programmed cell death) in genetically engineered cells
摘要翻译: 我们已经开发了细胞内蛋白质的调节(诱导型)二聚化或寡聚化的一般程序,并公开了使用该程序调节基因工程细胞中细胞特异性凋亡(程序性细胞死亡)的方法和材料
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