Background：Myocarditis is an uncommon but serious manifestation of systemic lupus erythematosus （SLE）.This study aimed to investigate clinical characteristics and outcomes of lupus myocarditis （LM） and to determi...Background：Myocarditis is an uncommon but serious manifestation of systemic lupus erythematosus （SLE）.This study aimed to investigate clinical characteristics and outcomes of lupus myocarditis （LM） and to determine risk factors of LM in hospitalized Chinese patients with SLE.Methods：We conducted a retrospective case-control study.A total of 25 patients with LM from 2001 to 2012 were enrolled as the study group,and 1 O0 patients with SLE but without LM were randomly pooled as the control group.Univariable analysis was performed using Chi-square tests for categorical variables,and the Student＇s t-test or Mann-Whitney U-test was performed for continuous variables according to the normality.Results：LM presented as the initial manifestation of SLE in 7 patients （28％） and occurred mostly at earlier stages compared to the controls （20.88 ± 35.73 vs.44.08 ± 61.56 months,P =0.008）.Twenty-one patients （84％） experienced episodes of symptomatic heart failure.Echocardiography showed that 23 patients （92％） had decreased left ventricular ejection fraction （＜50％） and all patients had wall motion abnormalities.A high SLE Disease Activity Index was the independent risk factor in the development of LM （odds ratio =1.322,P ＜ 0.001）.With aggressive immunosuppressive therapies,most patients achieved satisfactory outcome.The in-hospital mortality was not significantly higher in the LM group than in the controls （4％ vs.2％,P =0.491）.Conclusions：LM could result in cardiac dysfunction and even sudden death.High SLE disease activity might potentially predict the occurrence of LM at the early stage of SLE.Characteristic echocardiographic findings could confirm the diagnosis of LM.Early aggressive immunosuppressive therapy could improve the cardiac outcome of LM.展开更多
Background:Internal tandem duplications(ITD)within the juxtamembrane domain of FMS-like tyrosine kinase 3(FLT3)represent a poor prognostic indicator in acute myeloid leukemia(AML).Therapeutic benefits of tyrosine kina...Background:Internal tandem duplications(ITD)within the juxtamembrane domain of FMS-like tyrosine kinase 3(FLT3)represent a poor prognostic indicator in acute myeloid leukemia(AML).Therapeutic benefits of tyrosine kinase inhibitors,such as sorafenib,are limited due to the emergence of drug resistance.While investigations have been con-ducted to improve the understanding of the molecular mechanisms underlying the resistance to this FLT3 inhibitor,a profile of cell functioning at the metabolite level and crosstalk between metabolic pathways has yet to be created.This study aimed to elucidate the alteration of metabolomic profile of leukemia cells resistant to the FLT3 inhibitor.Methods:We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations,namely the murine BaF3/ITD-R and the human MV4-11-R cell lines.We performed a global untargeted metabolomics and stable isotope-labe-ling mass spectrometry analysis to identify the metabolic alterations relevant to the therapeutic resistance.Results:The resistant cells displayed fundamentally rewired metabolic profiles,characterized by a higher demand for glucose,accompanied by a reduction in glucose flux into the pentose phosphate pathway(PPP);and by an increase in oxidative stress,accompanied by an enhanced glutathione synthesis.We demonstrated that the highest scoring network of altered metabolites in resistant cells was related to nucleotide degradation.A stable isotope tracing experiment was performed and the results indicated a decrease in the quantity of glucose entering the PPP in resistant cells.Further experiment suggested that the inhibition of major enzymes in the PPP consist of glucose-6-phosphate dehydrogenase deficiency(G6PD)in the oxidative arm and transketolase(TKT)in the non-oxidative arm.In addition,we observed that chronic treatment with sorafenib resulted in an increased oxidative stress in FLT3/ITD-positive leu-kemia cells,which was accompanied by decreased cell proliferation and an enhanced antioxidant response.Conclusions:Our data regarding comparative metabolomics characterized a distinct metabolic and redox adaptation that may contribute to sorafenib resistance in FLT3/ITD-mutated leukemia cells.展开更多
The cryo-electron microscopy(cryo-EM)is one of the most powerful technologies available today for structural biology.The RELION(Regularized Likelihood Optimization)implements a Bayesian algorithm for cryo-EM structure...The cryo-electron microscopy(cryo-EM)is one of the most powerful technologies available today for structural biology.The RELION(Regularized Likelihood Optimization)implements a Bayesian algorithm for cryo-EM structure determination,which is one of the most widely used software in this field.Many researchers have devoted effort to improve the performance of RELION to satisfy the analysis for the ever-increasing volume of datasets.In this paper,we focus on performance analysis of the most time-consuming computation steps in RELION and identify their performance bottlenecks for specific optimizations.We propose several performance optimization strategies to improve the overall performance of RELION,including optimization of expectation step,parallelization of maximization step,accelerating the computation of symmetries,and memory affinity optimization.The experiment results show that our proposed optimizations achieve significant speedups of RELION across representative datasets.In addition,we perform roofline model analysis to understand the effectiveness of our optimizations.展开更多
文摘Background：Myocarditis is an uncommon but serious manifestation of systemic lupus erythematosus （SLE）.This study aimed to investigate clinical characteristics and outcomes of lupus myocarditis （LM） and to determine risk factors of LM in hospitalized Chinese patients with SLE.Methods：We conducted a retrospective case-control study.A total of 25 patients with LM from 2001 to 2012 were enrolled as the study group,and 1 O0 patients with SLE but without LM were randomly pooled as the control group.Univariable analysis was performed using Chi-square tests for categorical variables,and the Student＇s t-test or Mann-Whitney U-test was performed for continuous variables according to the normality.Results：LM presented as the initial manifestation of SLE in 7 patients （28％） and occurred mostly at earlier stages compared to the controls （20.88 ± 35.73 vs.44.08 ± 61.56 months,P =0.008）.Twenty-one patients （84％） experienced episodes of symptomatic heart failure.Echocardiography showed that 23 patients （92％） had decreased left ventricular ejection fraction （＜50％） and all patients had wall motion abnormalities.A high SLE Disease Activity Index was the independent risk factor in the development of LM （odds ratio =1.322,P ＜ 0.001）.With aggressive immunosuppressive therapies,most patients achieved satisfactory outcome.The in-hospital mortality was not significantly higher in the LM group than in the controls （4％ vs.2％,P =0.491）.Conclusions：LM could result in cardiac dysfunction and even sudden death.High SLE disease activity might potentially predict the occurrence of LM at the early stage of SLE.Characteristic echocardiographic findings could confirm the diagnosis of LM.Early aggressive immunosuppressive therapy could improve the cardiac outcome of LM.
基金This study was supported by the research grant from National Key R&D Program of China(2018YFC0910203)
文摘Background:Internal tandem duplications(ITD)within the juxtamembrane domain of FMS-like tyrosine kinase 3(FLT3)represent a poor prognostic indicator in acute myeloid leukemia(AML).Therapeutic benefits of tyrosine kinase inhibitors,such as sorafenib,are limited due to the emergence of drug resistance.While investigations have been con-ducted to improve the understanding of the molecular mechanisms underlying the resistance to this FLT3 inhibitor,a profile of cell functioning at the metabolite level and crosstalk between metabolic pathways has yet to be created.This study aimed to elucidate the alteration of metabolomic profile of leukemia cells resistant to the FLT3 inhibitor.Methods:We established two sorafenib-resistant cell lines carrying FLT3/ITD mutations,namely the murine BaF3/ITD-R and the human MV4-11-R cell lines.We performed a global untargeted metabolomics and stable isotope-labe-ling mass spectrometry analysis to identify the metabolic alterations relevant to the therapeutic resistance.Results:The resistant cells displayed fundamentally rewired metabolic profiles,characterized by a higher demand for glucose,accompanied by a reduction in glucose flux into the pentose phosphate pathway(PPP);and by an increase in oxidative stress,accompanied by an enhanced glutathione synthesis.We demonstrated that the highest scoring network of altered metabolites in resistant cells was related to nucleotide degradation.A stable isotope tracing experiment was performed and the results indicated a decrease in the quantity of glucose entering the PPP in resistant cells.Further experiment suggested that the inhibition of major enzymes in the PPP consist of glucose-6-phosphate dehydrogenase deficiency(G6PD)in the oxidative arm and transketolase(TKT)in the non-oxidative arm.In addition,we observed that chronic treatment with sorafenib resulted in an increased oxidative stress in FLT3/ITD-positive leu-kemia cells,which was accompanied by decreased cell proliferation and an enhanced antioxidant response.Conclusions:Our data regarding comparative metabolomics characterized a distinct metabolic and redox adaptation that may contribute to sorafenib resistance in FLT3/ITD-mutated leukemia cells.
基金the National Key R&D Program of China(2020YFB1506703)the National Natural Science Foundation of China(Grant No.62072018)the Open Project Program of the State Key Laboratory of Mathematical Engineering and Advanced Computing(2019A12).
文摘The cryo-electron microscopy(cryo-EM)is one of the most powerful technologies available today for structural biology.The RELION(Regularized Likelihood Optimization)implements a Bayesian algorithm for cryo-EM structure determination,which is one of the most widely used software in this field.Many researchers have devoted effort to improve the performance of RELION to satisfy the analysis for the ever-increasing volume of datasets.In this paper,we focus on performance analysis of the most time-consuming computation steps in RELION and identify their performance bottlenecks for specific optimizations.We propose several performance optimization strategies to improve the overall performance of RELION,including optimization of expectation step,parallelization of maximization step,accelerating the computation of symmetries,and memory affinity optimization.The experiment results show that our proposed optimizations achieve significant speedups of RELION across representative datasets.In addition,we perform roofline model analysis to understand the effectiveness of our optimizations.
