根据“预模式假说(Prepattern Hypothesis)”,黑腹果蝇(Drosophila melanogaster)背部感觉器官前体(sensory organ precursors,SOP)的发育依赖于预模式基因、原神经基因和神经源性基因的依次调控。大多数情况下,单一调控基因的功能失常...根据“预模式假说(Prepattern Hypothesis)”,黑腹果蝇(Drosophila melanogaster)背部感觉器官前体(sensory organ precursors,SOP)的发育依赖于预模式基因、原神经基因和神经源性基因的依次调控。大多数情况下,单一调控基因的功能失常引起的异位SOP形成,或表现为空间不连续,或仅限于原神经簇内。而fred基因的敲低会造成一种异位SOP发生的新型表型,这些异位SOP在空间上是连续的,且不局限于原神经簇区域。本研究发现,由敲减fred所诱导的异位SOP形成不依赖于原神经簇,表明几乎所有翅成虫盘细胞都具有潜在的神经发生潜力。并且,本研究还发现预模式基因pannier(pnr)与fred协同作用,以两种截然不同的方式调控SOP细胞的命运:一方面,pnr和fred在背板中部对于内源性SOP的形成是必需的;但另一方面,它们在原神经簇外协同抑制SOP发生。本研究结果打破了“预模式假说”中SOP形成依赖于原神经簇形成的论断,为该假说提供了一项重要补充。展开更多
目的:观察弱内向整流相关及花生四烯酸激活的弱内向整流相关双孔钾离子通道(tandem of pore domains in a weak inward rectifying related-tandem of pore domains in a weak inward rectifying related arachidonic acid activated tw...目的:观察弱内向整流相关及花生四烯酸激活的弱内向整流相关双孔钾离子通道(tandem of pore domains in a weak inward rectifying related-tandem of pore domains in a weak inward rectifying related arachidonic acid activated two pore-domain potassium channels, TREK-TRAAK K2P)激活对氧化损伤的人视网膜色素上皮(retinal pigment epithelial, RPE)细胞吞噬功能的影响。方法:免疫荧光法检测TREK-1、TREK-2及TRAAK通道蛋白在人RPE细胞的表达,以不同时间和浓度梯度的叔丁基过氧化氢(tertbutyl hydroperoxide, t-BHP)诱导人RPE细胞氧化损伤。分对照组、t-BHP组、利鲁唑加t-BHP组,利鲁唑组,向各组加入2×107/mL的荧光微球或FITC标记猪感光细胞外节膜盘孵育6 h,固定染色后荧光显微镜拍照,Image-Pro Plus 6.0软件分析计算RPE细胞吞噬率和吞噬指数。结果:TREK-1、TREK-2、TREEK通道蛋白亚型在人RPE细胞质中均高表达。人RPE细胞在t-BHP干预后存活率呈浓度和时间依赖性,200μmol/L t-BHP干预6 h与对照组存活率比较差异无统计学意义(P>0.05),400μmol/L t-BHP干预6 h致半数死亡。特异性吞噬指数:t-BHP组低于其他各组(P<0.001),而利鲁唑组高于对照组,差异无统计学意义(P>0.05)。特异性吞噬率:t-BHP组低于其他各组,差异无统计学意义(P>0.05)。非特异性吞噬指数:t-BHP组低于其他各组(P<0.001);非特异性吞噬率:t-BHP组低于利鲁唑加t-BHP组,差异无统计学意义(P>0.05),两两比较,仅利鲁唑组高于t-BHP组(P<0.05)。结论:激活TREK-TRAAK K2P通道可保护氧化损伤人RPE细胞的吞噬功能。展开更多
多发性骨髓瘤(multiple myeloma,MM)是一种不可治愈的血液系统恶性肿瘤,尽管新型蛋白酶体抑制剂、免疫调节剂及CD38单抗等药物的应用显著延长了患者的生存时间,但复发耐药仍难以避免。细胞免疫治疗,特别是嵌合抗原受体(chimeric antigen...多发性骨髓瘤(multiple myeloma,MM)是一种不可治愈的血液系统恶性肿瘤,尽管新型蛋白酶体抑制剂、免疫调节剂及CD38单抗等药物的应用显著延长了患者的生存时间,但复发耐药仍难以避免。细胞免疫治疗,特别是嵌合抗原受体(chimeric antigen receptor,CAR)T细胞疗法的快速发展,极大程度的改变了复发/难治性(relapsed/refractory,R/R)MM患者的治疗现状。FDA目前已批准了2款靶向B细胞成熟抗原(B cell maturation antigen,BCMA)的CAR-T细胞产品,使其用于既往接受过4线及以上治疗的R/R MM患者。随着临床研究的不断深入,靶向GPRC5D(G protein-coupled receptor C class Group 5 member D,G蛋白偶联受体C类第5组成员D)的CAR-T细胞治疗也显示出其独特的优势。除了应用于难治复发的患者,多项临床试验支持CAR-T在MM中治疗线数的前移。本文就CAR-T细胞治疗在MM中开展的关键性临床研究展开综述,旨在为临床应用提供参考。展开更多
Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community.A classical model is the removal of polarity-deficient clones,such as the p...Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community.A classical model is the removal of polarity-deficient clones,such as the precancerous scribble(scrib)mutant clones,in Drosophila imaginal discs.The activation of Ras,Yki,or Notch signaling robustly reverses the scrib mutant clonal fate from elimination to tumorous growth.Whether these signals converge to adopt a common mechanism to overcome the elimination pressure posed by cell competition remains unclear.Using single-cell transcriptomics,we find that a critical converging point downstream of Ras,Yki,and Notch signals is the upregulation of Upd2,an IL-6 family cytokine.Overexpression of Upd2 is sufficient to rescue the scrib mutant clones from elimination.Depletion of Upd2 blocks the growth of the scrib mutant clones with active Ras,Yki,and Notch signals.Moreover,Upd2 overexpression promotes robust intestinal stem cell(ISC)proliferation,while Upd2 is intrinsically required in ISCs for the growth of the adult intestine.Together,these results identify Upd2 as a crucial cell fitness factor that sustains tissue growth but can potentiate tumorigenesis when deregulated.展开更多
Signal transduction in a cell is mostly mediated with biochemical reactions which are noisy and often modeled with chemical master equations or Langevin type of dynamics.Thus stochastic simulation constitutes a major ...Signal transduction in a cell is mostly mediated with biochemical reactions which are noisy and often modeled with chemical master equations or Langevin type of dynamics.Thus stochastic simulation constitutes a major part of computation in cell signaling.Nevertheless,the presence of a wide span of time scales or molecular numbers in various pathways may lead to trouble in computation efficiency or accuracy.To avoid this problem,the commonly employed variational method evolves the whole probability distribution and reduces the stochastic equations to deterministic ones of only a few parameters.However,the design of the left variational basis is essential for its successful application,especially to large networks.In this paper,we extend the conventional polynomial basis to the Fourier and further the Gaussian basis,much facilitating description of multi-peaked or localized non-Gaussian distributions and at the same time avoiding numerical instability and computational complexity frequently encountered with conventional basis.The extension here is demonstrated in several typical biochemical signaling networks and achieves similar accuracy as the benchmark Gillespie algorithm,but with much less running time,which seems to open new opportunities in the variational approach to efficient analysis of noisy dynamics.展开更多
文摘根据“预模式假说(Prepattern Hypothesis)”,黑腹果蝇(Drosophila melanogaster)背部感觉器官前体(sensory organ precursors,SOP)的发育依赖于预模式基因、原神经基因和神经源性基因的依次调控。大多数情况下,单一调控基因的功能失常引起的异位SOP形成,或表现为空间不连续,或仅限于原神经簇内。而fred基因的敲低会造成一种异位SOP发生的新型表型,这些异位SOP在空间上是连续的,且不局限于原神经簇区域。本研究发现,由敲减fred所诱导的异位SOP形成不依赖于原神经簇,表明几乎所有翅成虫盘细胞都具有潜在的神经发生潜力。并且,本研究还发现预模式基因pannier(pnr)与fred协同作用,以两种截然不同的方式调控SOP细胞的命运:一方面,pnr和fred在背板中部对于内源性SOP的形成是必需的;但另一方面,它们在原神经簇外协同抑制SOP发生。本研究结果打破了“预模式假说”中SOP形成依赖于原神经簇形成的论断,为该假说提供了一项重要补充。
文摘目的:观察弱内向整流相关及花生四烯酸激活的弱内向整流相关双孔钾离子通道(tandem of pore domains in a weak inward rectifying related-tandem of pore domains in a weak inward rectifying related arachidonic acid activated two pore-domain potassium channels, TREK-TRAAK K2P)激活对氧化损伤的人视网膜色素上皮(retinal pigment epithelial, RPE)细胞吞噬功能的影响。方法:免疫荧光法检测TREK-1、TREK-2及TRAAK通道蛋白在人RPE细胞的表达,以不同时间和浓度梯度的叔丁基过氧化氢(tertbutyl hydroperoxide, t-BHP)诱导人RPE细胞氧化损伤。分对照组、t-BHP组、利鲁唑加t-BHP组,利鲁唑组,向各组加入2×107/mL的荧光微球或FITC标记猪感光细胞外节膜盘孵育6 h,固定染色后荧光显微镜拍照,Image-Pro Plus 6.0软件分析计算RPE细胞吞噬率和吞噬指数。结果:TREK-1、TREK-2、TREEK通道蛋白亚型在人RPE细胞质中均高表达。人RPE细胞在t-BHP干预后存活率呈浓度和时间依赖性,200μmol/L t-BHP干预6 h与对照组存活率比较差异无统计学意义(P>0.05),400μmol/L t-BHP干预6 h致半数死亡。特异性吞噬指数:t-BHP组低于其他各组(P<0.001),而利鲁唑组高于对照组,差异无统计学意义(P>0.05)。特异性吞噬率:t-BHP组低于其他各组,差异无统计学意义(P>0.05)。非特异性吞噬指数:t-BHP组低于其他各组(P<0.001);非特异性吞噬率:t-BHP组低于利鲁唑加t-BHP组,差异无统计学意义(P>0.05),两两比较,仅利鲁唑组高于t-BHP组(P<0.05)。结论:激活TREK-TRAAK K2P通道可保护氧化损伤人RPE细胞的吞噬功能。
文摘多发性骨髓瘤(multiple myeloma,MM)是一种不可治愈的血液系统恶性肿瘤,尽管新型蛋白酶体抑制剂、免疫调节剂及CD38单抗等药物的应用显著延长了患者的生存时间,但复发耐药仍难以避免。细胞免疫治疗,特别是嵌合抗原受体(chimeric antigen receptor,CAR)T细胞疗法的快速发展,极大程度的改变了复发/难治性(relapsed/refractory,R/R)MM患者的治疗现状。FDA目前已批准了2款靶向B细胞成熟抗原(B cell maturation antigen,BCMA)的CAR-T细胞产品,使其用于既往接受过4线及以上治疗的R/R MM患者。随着临床研究的不断深入,靶向GPRC5D(G protein-coupled receptor C class Group 5 member D,G蛋白偶联受体C类第5组成员D)的CAR-T细胞治疗也显示出其独特的优势。除了应用于难治复发的患者,多项临床试验支持CAR-T在MM中治疗线数的前移。本文就CAR-T细胞治疗在MM中开展的关键性临床研究展开综述,旨在为临床应用提供参考。
基金supported by grants to Yan Yan from the Research Grants Council of the Hong Kong Special Administrative Region(GRF16103620,GRF16104324,T13-602/21N)from Shenzhen Science and Technology Innovation Commission(JCYJ20200109140201722)+1 种基金to Toyotaka Ishibashi from the National Natural Science Foundation of China(32170548)to Zongzhao Zhai from the National Natural Science Foundation of China(32170509 and 31871469).
文摘Cell competition is an evolutionarily ancient mechanism that functions to remove unfit or dangerous clonal cells in a multicellular community.A classical model is the removal of polarity-deficient clones,such as the precancerous scribble(scrib)mutant clones,in Drosophila imaginal discs.The activation of Ras,Yki,or Notch signaling robustly reverses the scrib mutant clonal fate from elimination to tumorous growth.Whether these signals converge to adopt a common mechanism to overcome the elimination pressure posed by cell competition remains unclear.Using single-cell transcriptomics,we find that a critical converging point downstream of Ras,Yki,and Notch signals is the upregulation of Upd2,an IL-6 family cytokine.Overexpression of Upd2 is sufficient to rescue the scrib mutant clones from elimination.Depletion of Upd2 blocks the growth of the scrib mutant clones with active Ras,Yki,and Notch signals.Moreover,Upd2 overexpression promotes robust intestinal stem cell(ISC)proliferation,while Upd2 is intrinsically required in ISCs for the growth of the adult intestine.Together,these results identify Upd2 as a crucial cell fitness factor that sustains tissue growth but can potentiate tumorigenesis when deregulated.
基金supported by the National Natural Science Foundation of China under Grants No.12375030。
文摘Signal transduction in a cell is mostly mediated with biochemical reactions which are noisy and often modeled with chemical master equations or Langevin type of dynamics.Thus stochastic simulation constitutes a major part of computation in cell signaling.Nevertheless,the presence of a wide span of time scales or molecular numbers in various pathways may lead to trouble in computation efficiency or accuracy.To avoid this problem,the commonly employed variational method evolves the whole probability distribution and reduces the stochastic equations to deterministic ones of only a few parameters.However,the design of the left variational basis is essential for its successful application,especially to large networks.In this paper,we extend the conventional polynomial basis to the Fourier and further the Gaussian basis,much facilitating description of multi-peaked or localized non-Gaussian distributions and at the same time avoiding numerical instability and computational complexity frequently encountered with conventional basis.The extension here is demonstrated in several typical biochemical signaling networks and achieves similar accuracy as the benchmark Gillespie algorithm,but with much less running time,which seems to open new opportunities in the variational approach to efficient analysis of noisy dynamics.
