Autophagy plays a pivotal role in diverse biological processes,including the maintenance and differentiation of neural stem cells(NSCs).Interestingly,while complete deletion of Fip200 severely impairs NSC maintenance ...Autophagy plays a pivotal role in diverse biological processes,including the maintenance and differentiation of neural stem cells(NSCs).Interestingly,while complete deletion of Fip200 severely impairs NSC maintenance and differentiation,inhibiting canonical autophagy via deletion of core genes,such as Atg5,Atg16l1,and Atg7,or blockade of canonical interactions between FIP200 and ATG13(designated as FIP200-4A mutant or FIP200 KI)does not produce comparable detrimental effects.This highlights the likely critical involvement of the non-canonical functions of FIP200,the mechanisms of which have remained elusive.Here,utilizing genetic mouse models,we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1,primarily via TAX1BP1 in NSCs.Conditional deletion of Tax1bp1 in fip200hGFAP conditional knock-in(cKI)mice led to NSC deficiency,resembling the fip200hGFAP conditional knockout(cKO)mouse phenotype.Notably,reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation.Conversely,a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration.Furthermore,conditional deletion of Tax1bp1 in fip200hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200hGFAP cKO mice.Collectively,these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function,presenting novel therapeutic targets for neurodegenerative diseases.展开更多
The integrity of the chromosomes for two WIL2-derived lymphoblastoid cell lines (TK6 and WTK1) in the presence and absence of ionizing radiation was analyzed by Multiplex Ligation-Dependent Probe Amplification (MLPA)....The integrity of the chromosomes for two WIL2-derived lymphoblastoid cell lines (TK6 and WTK1) in the presence and absence of ionizing radiation was analyzed by Multiplex Ligation-Dependent Probe Amplification (MLPA). The TK6 cell line has the native p53 tumor-suppressor gene, whereas WTK1 cells contain a p53 mutation. Each cell line was isolated pre- and post-irradiation (2 and 3 Gy) and analyzed by MLPA. The impact of irradiation on these two cell lines was investigated using probes that target specific regions on chromosomes associated with subtelomeric regions. Results indicate that WTK1 and TK6 are impacted differently after irradiation, and that each cell line presents its own unique MLPA profile. The most notable differences are the appearance of a number of probes in the post-irradiated MLPA profile that are not present in the controls, and two unique probe signals only seen in WTK1 cells. These results build on our previous studies that indicate how different human cell lines can be affected by radiation in significantly different ways depending on the presence or absence of wild type p53.展开更多
目的探讨中性粒细胞与淋巴细胞比值(neutrophil to lymphocyte ratio,NLR)与维持性血液透析(maintenance hemodialysis,MHD)患者全因死亡之间的关系。方法对九江市第一人民医院肾内科于2018年1月1日至2020年8月31日接受MHD治疗的患者进...目的探讨中性粒细胞与淋巴细胞比值(neutrophil to lymphocyte ratio,NLR)与维持性血液透析(maintenance hemodialysis,MHD)患者全因死亡之间的关系。方法对九江市第一人民医院肾内科于2018年1月1日至2020年8月31日接受MHD治疗的患者进行观察,所有患者均随访至死亡、失访或截至日期(2023年8月31日)。根据NLR四分位数分为四组,采用Kaplan-Meier法比较各组患者的生存率,利用Cox回归分析NLR与全因死亡之间的相关性,并采用Logistic回归分析高NLR水平的影响因素。结果共443例患者纳入研究,平均生存时间21.51个月,NLR水平的中位数(四分位数间距)为3.84(2.55,5.79);Kaplan-Meier生存曲线显示NLR>5.79的患者全因死亡率较高(χ2=19.824,P<0.001)。多因素校正后四组间的全因死亡风险差异有统计学意义(P<0.05)。多因素Logistic回归结果显示高血清白蛋白是NLR>5.79的保护因素(P<0.05)。结论NLR>5.79是MHD患者全因死亡的独立危险因素,可作为评估MHD患者死亡风险的指标之一。展开更多
基金National Natural Science Foundation of China(U2004138,81773132,81820108021)University Excellent Teaching Team of“Qinglan Project”in Jiangsu Province(2022-25)+1 种基金Henan Province Key Research and Development Project(232102521028)Excellent Youth Foundation of Henan Scientific Committee(21230040016)。
文摘Autophagy plays a pivotal role in diverse biological processes,including the maintenance and differentiation of neural stem cells(NSCs).Interestingly,while complete deletion of Fip200 severely impairs NSC maintenance and differentiation,inhibiting canonical autophagy via deletion of core genes,such as Atg5,Atg16l1,and Atg7,or blockade of canonical interactions between FIP200 and ATG13(designated as FIP200-4A mutant or FIP200 KI)does not produce comparable detrimental effects.This highlights the likely critical involvement of the non-canonical functions of FIP200,the mechanisms of which have remained elusive.Here,utilizing genetic mouse models,we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1,primarily via TAX1BP1 in NSCs.Conditional deletion of Tax1bp1 in fip200hGFAP conditional knock-in(cKI)mice led to NSC deficiency,resembling the fip200hGFAP conditional knockout(cKO)mouse phenotype.Notably,reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation.Conversely,a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration.Furthermore,conditional deletion of Tax1bp1 in fip200hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200hGFAP cKO mice.Collectively,these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function,presenting novel therapeutic targets for neurodegenerative diseases.
文摘The integrity of the chromosomes for two WIL2-derived lymphoblastoid cell lines (TK6 and WTK1) in the presence and absence of ionizing radiation was analyzed by Multiplex Ligation-Dependent Probe Amplification (MLPA). The TK6 cell line has the native p53 tumor-suppressor gene, whereas WTK1 cells contain a p53 mutation. Each cell line was isolated pre- and post-irradiation (2 and 3 Gy) and analyzed by MLPA. The impact of irradiation on these two cell lines was investigated using probes that target specific regions on chromosomes associated with subtelomeric regions. Results indicate that WTK1 and TK6 are impacted differently after irradiation, and that each cell line presents its own unique MLPA profile. The most notable differences are the appearance of a number of probes in the post-irradiated MLPA profile that are not present in the controls, and two unique probe signals only seen in WTK1 cells. These results build on our previous studies that indicate how different human cell lines can be affected by radiation in significantly different ways depending on the presence or absence of wild type p53.
文摘目的探讨中性粒细胞与淋巴细胞比值(neutrophil to lymphocyte ratio,NLR)与维持性血液透析(maintenance hemodialysis,MHD)患者全因死亡之间的关系。方法对九江市第一人民医院肾内科于2018年1月1日至2020年8月31日接受MHD治疗的患者进行观察,所有患者均随访至死亡、失访或截至日期(2023年8月31日)。根据NLR四分位数分为四组,采用Kaplan-Meier法比较各组患者的生存率,利用Cox回归分析NLR与全因死亡之间的相关性,并采用Logistic回归分析高NLR水平的影响因素。结果共443例患者纳入研究,平均生存时间21.51个月,NLR水平的中位数(四分位数间距)为3.84(2.55,5.79);Kaplan-Meier生存曲线显示NLR>5.79的患者全因死亡率较高(χ2=19.824,P<0.001)。多因素校正后四组间的全因死亡风险差异有统计学意义(P<0.05)。多因素Logistic回归结果显示高血清白蛋白是NLR>5.79的保护因素(P<0.05)。结论NLR>5.79是MHD患者全因死亡的独立危险因素,可作为评估MHD患者死亡风险的指标之一。
