Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport ...Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.展开更多
Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal mus...Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal muscular atrophy-like clinical phenotype.The aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment strategies.Epithelial cells were isolated from urine samples from a spinal muscular atrophy(SMA)-like patient[MORC2 p.S87L),a CMT2Z patient[MORC2 p.Q400R),and a healthy control and induced to generate pluripotent stem cells,which were then differentiated into motor neuron precursor cells.Next-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAP K/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem cells.Reduced proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control.G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like patient.MORC2 p.S87Lspecific antisense oligonucleotides(p.S87L-ASO-targeting)showed significant efficacy in improving cell prolife ration and activating the PI3K/Akt and MAP K/ERK pathways in induced pluripotent stem cells.Howeve r,p.S87L-ASO-ta rgeting did not rescue prolife ration of motor neuron precursor cells.These findings suggest that downregulation of the PI3K/Akt and MAP K/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype.p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stage of pluripotent stem cell induction.展开更多
Objective:This study investigates the efficacy of analyzing fetal heart rate(FHR)signals based on Artificial Intelligence to obtain a baseline calculation and identify accelerations/decelerations in the FHR through el...Objective:This study investigates the efficacy of analyzing fetal heart rate(FHR)signals based on Artificial Intelligence to obtain a baseline calculation and identify accelerations/decelerations in the FHR through electronic fetal monitoring during labor.Methods:A total of 43,888 cardiotocograph(CTG)records of female patients in labor from January 2012 to December 2020 were collected from the NanFang Hospital of Southern Medical University.After filtering the data,2341 FHR records were used for the study.The ObVue fetal monitoring system,manufactured by Lian-Med Technology Co.Ltd.,was used to monitor the FHR signals for these pregnant women from the beginning of the first stage of labor to the end of delivery.Two obstetric experts together annotated the FHR signals in the system to determine the baseline as well as accelerations/decelerations of the FHR.Our cardiotocograph network(CTGNet)as well as traditional methods were then used to automatically analyze the baseline and acceleration/deceleration of the FHR signals.The results of calculations were compared with the annotations provided by the obstetric experts,and ten-fold cross-validation was applied to evaluate them.The root-mean-square difference(RMSD)between the baselines,acceleration F-measure(Acc.F-measure),deceleration F-measure(Dec.F-measure),coefficient of synthetic inconsistency(SI)and the morphological analysis discordance index(MADI)were used as evaluation metrics.The data were analyzed by using a pairedt-test.Results:The proposed CTGNet was superior to the best traditional method,proposed by Mantel,in terms of the RMSD.BL(1.7935±0.8099vs.2.0293±0.9267,t=-3.55,P=0.004),Acc.F-measure(86.8562±10.9422vs.72.2367±14.2096,t=12.43,P<0.001),Dec.F-measure(72.1038±33.2592vs.58.5040±38.0276,t=4.10,P<0.001),SI(34.8277±20.9595vs.54.8049±25.0265,t=-9.39,P<0.001),and MADI(3.1741±1.9901vs.3.7289±2.7253,t=-2.74,P=0.012).The proposed CTGNet thus had significant advantages over the best traditional method on all evaluation metrics.Conclusion:The proposed Artificial Intelligence-based method CTGNet delivers good performance in terms of the automatic analysis of FHR based on cardiotocograph data.It promises to be a key component of smart obstetrics systems of the future.展开更多
Dear Editor,Nowadays,two autologous CAR19-T drugs,Tisagenlecleucel(Kymriah^(TM))and axicabtagene ciloleucel(Yescarta^(TM)),have been approved for the treatment of B cell leukemia and lymphoma and achieved unprecedente...Dear Editor,Nowadays,two autologous CAR19-T drugs,Tisagenlecleucel(Kymriah^(TM))and axicabtagene ciloleucel(Yescarta^(TM)),have been approved for the treatment of B cell leukemia and lymphoma and achieved unprecedented successes.However,about 10-20%of B-ALL patients receiving CAR19-T drugs didn't achieve complete remission(CR),while 30~50%of patients achieved CR would relapse mainly within 1 year.Moreover,the high CR rate of CAR19-T therapy for B-ALL can't be recaptured in other B-NHLs,'such as Burkitt's lymphoma(BL).Therefore,there is an urgent need to improve the therapeutic efficacy of CAR19-T cells.3.展开更多
基金supported by the Community Development Office of Hunan Provincial Science and Technology DepartmentChina,Nos.2020SK53613(to DH),21JJ31006(to DH)the Fundamental Research Funds of Central South University,Nos.CX20220375(to TX),2023zzts215(to MZ)。
文摘Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.
基金supported by the National Natural Science Foundation of China,Nos.82171172(to RZ)and 81771366(to RZ)Fundamental Research Funds for the Central Universities of Central South University,Nos.2021zzts1095(to SZ)and 2022zzts0832(to HY)。
文摘Mutations in the microrchidia CW-type zinc finger protein 2(MORC2)gene are the causative agent of Charcot-Marie-Tooth disease type 2Z(CMT2Z),and the hotspot mutation p.S87L is associated with a more seve re spinal muscular atrophy-like clinical phenotype.The aims of this study were to determine the mechanism of the severe phenotype caused by the MORC2 p.S87L mutation and to explore potential treatment strategies.Epithelial cells were isolated from urine samples from a spinal muscular atrophy(SMA)-like patient[MORC2 p.S87L),a CMT2Z patient[MORC2 p.Q400R),and a healthy control and induced to generate pluripotent stem cells,which were then differentiated into motor neuron precursor cells.Next-generation RNA sequencing followed by KEGG pathway enrichment analysis revealed that differentially expressed genes involved in the PI3K/Akt and MAP K/ERK signaling pathways were enriched in the p.S87L SMA-like patient group and were significantly downregulated in induced pluripotent stem cells.Reduced proliferation was observed in the induced pluripotent stem cells and motor neuron precursor cells derived from the p.S87L SMA-like patient group compared with the CMT2Z patient group and the healthy control.G0/G1 phase cell cycle arrest was observed in induced pluripotent stem cells derived from the p.S87L SMA-like patient.MORC2 p.S87Lspecific antisense oligonucleotides(p.S87L-ASO-targeting)showed significant efficacy in improving cell prolife ration and activating the PI3K/Akt and MAP K/ERK pathways in induced pluripotent stem cells.Howeve r,p.S87L-ASO-ta rgeting did not rescue prolife ration of motor neuron precursor cells.These findings suggest that downregulation of the PI3K/Akt and MAP K/ERK signaling pathways leading to reduced cell proliferation and G0/G1 phase cell cycle arrest in induced pluripotent stem cells might be the underlying mechanism of the severe p.S87L SMA-like phenotype.p.S87L-ASO-targeting treatment can alleviate disordered cell proliferation in the early stage of pluripotent stem cell induction.
基金supported by National Key Research and Development Project(2019YFC0121907 and 2019YFC0120100)Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization(2021B1212040007)。
文摘Objective:This study investigates the efficacy of analyzing fetal heart rate(FHR)signals based on Artificial Intelligence to obtain a baseline calculation and identify accelerations/decelerations in the FHR through electronic fetal monitoring during labor.Methods:A total of 43,888 cardiotocograph(CTG)records of female patients in labor from January 2012 to December 2020 were collected from the NanFang Hospital of Southern Medical University.After filtering the data,2341 FHR records were used for the study.The ObVue fetal monitoring system,manufactured by Lian-Med Technology Co.Ltd.,was used to monitor the FHR signals for these pregnant women from the beginning of the first stage of labor to the end of delivery.Two obstetric experts together annotated the FHR signals in the system to determine the baseline as well as accelerations/decelerations of the FHR.Our cardiotocograph network(CTGNet)as well as traditional methods were then used to automatically analyze the baseline and acceleration/deceleration of the FHR signals.The results of calculations were compared with the annotations provided by the obstetric experts,and ten-fold cross-validation was applied to evaluate them.The root-mean-square difference(RMSD)between the baselines,acceleration F-measure(Acc.F-measure),deceleration F-measure(Dec.F-measure),coefficient of synthetic inconsistency(SI)and the morphological analysis discordance index(MADI)were used as evaluation metrics.The data were analyzed by using a pairedt-test.Results:The proposed CTGNet was superior to the best traditional method,proposed by Mantel,in terms of the RMSD.BL(1.7935±0.8099vs.2.0293±0.9267,t=-3.55,P=0.004),Acc.F-measure(86.8562±10.9422vs.72.2367±14.2096,t=12.43,P<0.001),Dec.F-measure(72.1038±33.2592vs.58.5040±38.0276,t=4.10,P<0.001),SI(34.8277±20.9595vs.54.8049±25.0265,t=-9.39,P<0.001),and MADI(3.1741±1.9901vs.3.7289±2.7253,t=-2.74,P=0.012).The proposed CTGNet thus had significant advantages over the best traditional method on all evaluation metrics.Conclusion:The proposed Artificial Intelligence-based method CTGNet delivers good performance in terms of the automatic analysis of FHR based on cardiotocograph data.It promises to be a key component of smart obstetrics systems of the future.
基金This work was supported by the National Key Research and Development Program of China(2016YFC0905100)the National Natural Science Foundation of China(81770200)the Major Scientifc and Technological Projects for Collaborative Prevention and Control of Birth Defects in Hunan Province(20195K1010).
文摘Dear Editor,Nowadays,two autologous CAR19-T drugs,Tisagenlecleucel(Kymriah^(TM))and axicabtagene ciloleucel(Yescarta^(TM)),have been approved for the treatment of B cell leukemia and lymphoma and achieved unprecedented successes.However,about 10-20%of B-ALL patients receiving CAR19-T drugs didn't achieve complete remission(CR),while 30~50%of patients achieved CR would relapse mainly within 1 year.Moreover,the high CR rate of CAR19-T therapy for B-ALL can't be recaptured in other B-NHLs,'such as Burkitt's lymphoma(BL).Therefore,there is an urgent need to improve the therapeutic efficacy of CAR19-T cells.3.