Strengthening interface bonding between boron nitride nanosheets(BNNS)and copper matrix is an essential prerequisite for exploiting a new generation of copper matrix composites(CMCs)with high strength and wear resista...Strengthening interface bonding between boron nitride nanosheets(BNNS)and copper matrix is an essential prerequisite for exploiting a new generation of copper matrix composites(CMCs)with high strength and wear resistance.Herein,BNNS/Cu composites were fabricated by the powder metallurgy route,matrix-alloying(adding 1.0 wt%Ti)strategy was adopted to improve the interfacial wettability and strengthen interface adhesion.A typical"sandwich"-like multiply interface structure involving TiN transition layers,BNNS and Cu matrix had been well constructed through the rational heat treatment(900℃ for 120 min).Additionally,nano-sized TiB whisker was in situ formed in the vicinity of the interface,it had linked the BNNS-Cu-TiN multiply interface,which played a role of"threading the needle"and significantly strengthened the multi-interfaces bonding.This specific interface structure was finely characterized,and the formation mechanism of solid-state interfacial reaction feature was proposed.The results demonstrated that the ultimate tensile strength(UTS)of BNNS/Cu-(Ti)-900℃ increased from 248 to 530 MPa(increased by 114%),and the coefficient of friction(COF)decreased from 0.51 to 0.28 than pure Cu.This work highlights the importance of interface configuration design,which contributes to the development of CMCs with prominent comprehensive properties.展开更多
Advanced pancreatic ductal adenocarcinoma(PDAC)has a dismal prognosis.Immunotherapy alone offers limited efficacy,but it is still unknown whether its combination with chemotherapy could offer synergistic anti-tumor ef...Advanced pancreatic ductal adenocarcinoma(PDAC)has a dismal prognosis.Immunotherapy alone offers limited efficacy,but it is still unknown whether its combination with chemotherapy could offer synergistic anti-tumor effects.This phase Ib/II study evaluated the safety and efficacy of combining toripalimab with the gemcitabine plus nab-paclitaxel(GnP)regimen as first-line treatment for locally advanced or metastatic PDAC and explored predictive biomarkers(ChiCTR2000032293).The primary endpoints were safety and overall survival(OS).The secondary outcomes were objective response rate(ORR),disease control rate(DCR),and progression-free survival(PFS).Immune-related biomarkers including programmed death-ligand 1(PD-L1)expression,genetic status,cytokine levels,and spatial features of the tumor immune microenviroment(TIME)were investigated.Neither serious treatment-related adverse events nor grade 4 immune-related adverse events were reported.Among the 72 patients,the median OS was 8.9 months,12-month OS rate was 31.9%,with median PFS of 5.6 months,ORR of 33.3%,and DCR of 90.3%.Higher PD-L1 expression,without liver metastases were associated with higher ORR,however these factors could not effectively distinguish responders and non-responders.Importantly,dendritic cells-T helper cells-cytotoxic T lymphocytes(DC-Th-CTL)enriched immune niche and their spatial interactions were dominant predictors of response based on TIME analysis using a cyclic multiplex tissue staining assay,with an area under the curve value of 0.8.Overall,GnP plus toripalimab exhibited good safety and differentiated efficacy in selected population,and the spatial interactions of DC-Th-CTL represent promising predictors to efficacy of immunochemotherapy in locally advanced or metastatic PDAC.展开更多
Chromosome karyotyping is a critical way to diagnose various hematological malignancies and genetic diseases,of which chromosome detection in raw metaphase cell images is the most critical and challenging step.In this...Chromosome karyotyping is a critical way to diagnose various hematological malignancies and genetic diseases,of which chromosome detection in raw metaphase cell images is the most critical and challenging step.In this work,focusing on the joint optimization of chromosome localization and classification,we propose ChromTR to accurately detect and classify 24 classes of chromosomes in raw metaphase cell images.ChromTR incorporates semantic feature learning and class distribution learning into a unified DETR-based detection framework.Specifically,we first propose a Semantic Feature Learning Network(SFLN)for semantic feature extraction and chromosome foreground region segmentation with object-wise supervision.Next,we construct a Semantic-Aware Transformer(SAT)with two parallel encoders and a Semantic-Aware decoder to integrate global visual and semantic features.To provide a prediction with a precise chromosome number and category distribution,a Category Distribution Reasoning Module(CDRM)is built for foreground-background objects and chromosome class distribution reasoning.We evaluate ChromTR on 1404 newly collected R-band metaphase images and the public G-band dataset AutoKary2022.Our proposed ChromTR outperforms all previous chromosome detection methods with an average precision of 92.56%in R-band chromosome detection,surpassing the baseline method by 3.02%.In a clinical test,ChromTR is also confident in tackling normal and numerically abnormal karyotypes.When extended to the chromosome enumeration task,ChromTR also demonstrates state-of-the-art performances on R-band and G-band two metaphase image datasets.Given these superior performances to other methods,our proposed method has been applied to assist clinical karyotype diagnosis.展开更多
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
基金financially supported by Yunnan Fundamental Research Projects(No.202301BE070001-007)。
文摘Strengthening interface bonding between boron nitride nanosheets(BNNS)and copper matrix is an essential prerequisite for exploiting a new generation of copper matrix composites(CMCs)with high strength and wear resistance.Herein,BNNS/Cu composites were fabricated by the powder metallurgy route,matrix-alloying(adding 1.0 wt%Ti)strategy was adopted to improve the interfacial wettability and strengthen interface adhesion.A typical"sandwich"-like multiply interface structure involving TiN transition layers,BNNS and Cu matrix had been well constructed through the rational heat treatment(900℃ for 120 min).Additionally,nano-sized TiB whisker was in situ formed in the vicinity of the interface,it had linked the BNNS-Cu-TiN multiply interface,which played a role of"threading the needle"and significantly strengthened the multi-interfaces bonding.This specific interface structure was finely characterized,and the formation mechanism of solid-state interfacial reaction feature was proposed.The results demonstrated that the ultimate tensile strength(UTS)of BNNS/Cu-(Ti)-900℃ increased from 248 to 530 MPa(increased by 114%),and the coefficient of friction(COF)decreased from 0.51 to 0.28 than pure Cu.This work highlights the importance of interface configuration design,which contributes to the development of CMCs with prominent comprehensive properties.
基金supported by the National Key Research and Development Program of China(2023YFB330850103)National Natural Science Foundation of China(No.82270542)Sichuan Science and Technology Department Key Research and Development Project(2022YFS0336).
文摘Advanced pancreatic ductal adenocarcinoma(PDAC)has a dismal prognosis.Immunotherapy alone offers limited efficacy,but it is still unknown whether its combination with chemotherapy could offer synergistic anti-tumor effects.This phase Ib/II study evaluated the safety and efficacy of combining toripalimab with the gemcitabine plus nab-paclitaxel(GnP)regimen as first-line treatment for locally advanced or metastatic PDAC and explored predictive biomarkers(ChiCTR2000032293).The primary endpoints were safety and overall survival(OS).The secondary outcomes were objective response rate(ORR),disease control rate(DCR),and progression-free survival(PFS).Immune-related biomarkers including programmed death-ligand 1(PD-L1)expression,genetic status,cytokine levels,and spatial features of the tumor immune microenviroment(TIME)were investigated.Neither serious treatment-related adverse events nor grade 4 immune-related adverse events were reported.Among the 72 patients,the median OS was 8.9 months,12-month OS rate was 31.9%,with median PFS of 5.6 months,ORR of 33.3%,and DCR of 90.3%.Higher PD-L1 expression,without liver metastases were associated with higher ORR,however these factors could not effectively distinguish responders and non-responders.Importantly,dendritic cells-T helper cells-cytotoxic T lymphocytes(DC-Th-CTL)enriched immune niche and their spatial interactions were dominant predictors of response based on TIME analysis using a cyclic multiplex tissue staining assay,with an area under the curve value of 0.8.Overall,GnP plus toripalimab exhibited good safety and differentiated efficacy in selected population,and the spatial interactions of DC-Th-CTL represent promising predictors to efficacy of immunochemotherapy in locally advanced or metastatic PDAC.
基金supported by the National Natural Science Foundation of China(No.81670137)SJTU Trans-med Awards Research(No.20220102)State Key Laboratory of Medical Genomics Support(No.201802)。
文摘Chromosome karyotyping is a critical way to diagnose various hematological malignancies and genetic diseases,of which chromosome detection in raw metaphase cell images is the most critical and challenging step.In this work,focusing on the joint optimization of chromosome localization and classification,we propose ChromTR to accurately detect and classify 24 classes of chromosomes in raw metaphase cell images.ChromTR incorporates semantic feature learning and class distribution learning into a unified DETR-based detection framework.Specifically,we first propose a Semantic Feature Learning Network(SFLN)for semantic feature extraction and chromosome foreground region segmentation with object-wise supervision.Next,we construct a Semantic-Aware Transformer(SAT)with two parallel encoders and a Semantic-Aware decoder to integrate global visual and semantic features.To provide a prediction with a precise chromosome number and category distribution,a Category Distribution Reasoning Module(CDRM)is built for foreground-background objects and chromosome class distribution reasoning.We evaluate ChromTR on 1404 newly collected R-band metaphase images and the public G-band dataset AutoKary2022.Our proposed ChromTR outperforms all previous chromosome detection methods with an average precision of 92.56%in R-band chromosome detection,surpassing the baseline method by 3.02%.In a clinical test,ChromTR is also confident in tackling normal and numerically abnormal karyotypes.When extended to the chromosome enumeration task,ChromTR also demonstrates state-of-the-art performances on R-band and G-band two metaphase image datasets.Given these superior performances to other methods,our proposed method has been applied to assist clinical karyotype diagnosis.
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.
