The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In ...The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In this study,based on a systematic survey and comparative genomic study of mouse and human LU domain-containing proteins,we identified a previously unannotated human gene encoding the candidate ortholog of mouse Ly-6A/Sca-1.This gene,hereby named LY6A,reversely overlaps with a lncRNA gene in the majority of exonic sequences.We found that LY6A is aberrantly expressed in pituitary tumors,but not in normal pituitary tissues,and may contribute to tumorigenesis.Similar to mouse Ly-6A/Sca-1,human LY6A is also upregulated by interferon,suggesting a conserved transcriptional regulatory mechanism between humans and mice.We cloned the full-length LY6A cDNA,whose encoded protein sequence,domain architecture,and exon‒intron structures are all well conserved with mouse Ly-6A/Sca-1.Ectopic expression of the LY6A protein in cells demonstrates that it acts the same as mouse Ly-6A/Sca-1 in their processing and glycosylphosphatidylinositol anchoring to the cell membrane.Collectively,these studies unveil a novel human gene encoding a candidate biomarker and provide an interesting model gene for studying gene regulatory and evolutionary mechanisms.展开更多
Self-healing hydrogel such as polyacrylic acid(PAA)hydrogel has attracted increasing attention based on its promising potential applications.However,it usually suffers from low strength especially as mechanical device...Self-healing hydrogel such as polyacrylic acid(PAA)hydrogel has attracted increasing attention based on its promising potential applications.However,it usually suffers from low strength especially as mechanical device.Herein,a commercial microcrystalline cellulose(MCC)was modified with acrylamide to graft polyacrylamide(PAM)chains on the particle surface.The acrylamide-modified MCC(AM-MCC)was then dispersed in monomer solution of acrylic acid to prepare composite hydrogel.The mechanical properties of the obtained composite hydrogels and the self-healed hydrogels were carefully measured by compressive and tensile tests,and by dynamic mechanical analysis.Our results demonstrate that introduction of a small amount of AM-MCC such as 3 wt%can not only reinforce the original hydrogel and the healed hydrogel markedly,but also improve self-healing efficiency obviously.The analyses indicate that in addition to the reversible multi-interactions such as hydrogen bonding and ionic interactions,the entanglements between the PAA chains of the hydrogel matrix and the PAM chains grafted on the MCC particles have also played an important role on the improvement in mechanical performances and the healing ability of the hydrogel.Moreover,the responsiveness to exterior ion has been tested to indicate potential application of the composite hydrogel as self-healable sensor.展开更多
Disabled homolog 2 (DAB2) is frequently deleted or epigenetically silenced in many human cancer cells' Therefore, DAB2 has always been regarded as a tumor suppressor gene. However, the role of DAB2 in tumor progres...Disabled homolog 2 (DAB2) is frequently deleted or epigenetically silenced in many human cancer cells' Therefore, DAB2 has always been regarded as a tumor suppressor gene. However, the role of DAB2 in tumor progression and metastasis remains unclear. In this study, DAB2 expression was upregulated along with human prostate cancer (PCa) progression. DAB2 overexpression or knockdown effects in LNCaP and PC3 cell lines were verified to address the biological functions of DAB2 in PCa progression and metastasis. LNCaP and PC3 cell lines were generated from human PCa cells with low and high metastatic potentials, respectively. The results showed that DAB2 shRNA knockdown can inhibit the migratory and invasive abilities of PC3 cells, as well as the tumorigenicity, whereas DAB2 overexpression enhanced LNCaP cell migration and invasion. Further investigation showed that DAB2 regulated the cell migration associated genes in PC3 cells, and the differential DAB2 expression between LNCaP and PC3 cells was partly regulated by histone 4 acetylation. Therefore, DAB2 may play an important role in PCa progression and metastasis.展开更多
voltage direct current(HVDC)transmission lines are being constructed throughout the world,aided by advancements in power electronics and the potential value to transfer power between distant areas and off-shore locati...voltage direct current(HVDC)transmission lines are being constructed throughout the world,aided by advancements in power electronics and the potential value to transfer power between distant areas and off-shore locations.Multiple HVDC lines within and across large AC interconnections could bring about economic benefits such as interregional capacity exchange and transfer of low-cost,distant electric energy directly to load centers.In addition,network configuration of HVDC lines could result in additional benefits that have not been deeply studied.This paper describes the modeling process for continentallevel power system interconnections with the addition of multiple HVDC lines configured as a macrogrid.The models used for study are based on industry-accepted power-flow and dynamic system models for the North American Eastern and Western Interconnections.The model provides insight on feasibility and initial steady-state and stability tests of the HVDC macrogrid and its interactions with the existing electricity infrastructure,opening the door to analysis of the technical value of such a macrogrid.展开更多
For critical infrastructure restoration planning,the real-time scheduling and coordination of system restoration efforts,the key in decision-making is to prioritize those critical components that are out of service du...For critical infrastructure restoration planning,the real-time scheduling and coordination of system restoration efforts,the key in decision-making is to prioritize those critical components that are out of service during the restoration.For this purpose,there is a need for component importance analysis.While it has been investigated extensively for individual systems,component importance considering interdependence among transmission,distribution and communication(T&D&C)systems has not been systematically analyzed and widely adopted.In this study,we propose a component importance assessment method in the context of interdependence between T&D&C networks.Analytic methods for multilayer networks and a set of metrics have been applied for assessing the component importance and interdependence between T&D&C networks based on their physical characteristics.The proposed methodology is further validated with integrated synthetic Illinois regional transmission,distribution,and communication(T&D&C)systems,the results reveal the unique characteristics of component/node importance,which may be strongly affected by the network topology and cross-domain node mapping.展开更多
Background:Heterogeneity of leukemia-initiating cells(LICs)is a major obstacle in acute myeloid leukemia(AML)therapy.Accumulated evidence indicates that the coexistence of multiple types of LICs with different pathoge...Background:Heterogeneity of leukemia-initiating cells(LICs)is a major obstacle in acute myeloid leukemia(AML)therapy.Accumulated evidence indicates that the coexistence of multiple types of LICs with different pathogenicity in the same individual is a common feature in AML.However,the functional heterogeneity including the drug response of coexistent LICs remains unclear.Therefore,this study aimed to clarify the intra-heterogeneity in LICs that can help predict leukemia behavior and develop more effective treatments.Methods:Spleen cells from the primary Setd2^(-/-)-AML mouse were transplanted into C57BL/6 recipient mice to generate a transplantable model.Flow cytometry was used to analyze the immunophenotype of the leukemic mice.Whole-genome sequencing was conducted to detect secondary hits responsible for leukemia transformation.A serial transplantation assay was used to determine the self-renewal potential of Setd2^(-/-)-AML cells.A limiting-dilution assay was performed to identify the LIC frequency in different subsets of leukemia cells.Bulk and single-cell RNA sequencing were performed to analyze the transcriptional heterogeneity of LICs.Small molecular inhibitor screening and in vivo drug treatment were employed to clarify the difference in drug response between the different subsets of LICs.Results:In this study,we observed an aged Setd2^(-/-)mouse developing AML with co-mutation of Nras^(G12S) and Braf^(K520E).Further investigation identified two types of LICs residing in the c-Kit^(+)B220^(+)Mac-1^(-)and c-Kit^(+)B220^(+)Mac-1^(+)subsets,respectively.In vivo transplantation assay disclosed the heterogeneity in differentiation between the coexistent LICs.Besides,an intrinsic doxorubicinresistant transcriptional signature was uncovered in c-Kit^(+)B220^(+)Mac-1^(+)cells.Indeed,doxorubicin plus cytarabine(DA),the standard chemotherapeutic regimen used in AML treatment,could specifically kill c-Kit^(+)B220^(+)Mac-1^(−)cells,but it hardly affected c-Kit^(+)B220^(+)Mac-1^(+)cells.Transcriptome analysis unveiled a higher activation of RAS downstream signaling pathways in c-Kit^(+)B220^(+)Mac-1^(+)cells than in c-Kit^(+)B220^(+)Mac-1^(-)cells.Combined treatmentwithDAand RAS pathway inhibitors killed both c-Kit^(+)B220^(+)Mac-1^(−)and c-Kit^(+)B220^(+)Mac-1^(+)cells and attenuated disease progression.Conclusions:This study identified two cell subsets enriched for LICs inmurine Setd2^(-/-)-AML and disclosed the transcriptional and functional heterogeneity of LICs,revealing that the coexistence of different types of LICs in thismodel brings about diverse drug response.展开更多
基金supported by the National Key Research and Development Plan of China(No.2018YFA0107802 to Xiaojian Sun,Nos.2018YFA0107200 and 2018YFA0800203 to Lan Wang)the General Program of the National Natural Science Foundation of China(Nos.81470316 and 81670094 to Xiaojian Sun,No.81972339 to Zhe Bao Wu,Nos.81570122 and 81770205 to Jinyan Huang,Nos.81670122 and 81970150 to Lan Wang)+5 种基金the National Research Center for Translational Medicine(Shanghai)grant(No.NRCTM(SH)-2019-05 to Zhe Bao Wu)the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant(No.20152506 to Xiaojian Sun)Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research(No.2019CXJQ01 to Saijuan Chen and Xiaojian Sun)Innovative Research Team of High-level Local Universities in Shanghai(to Weili Zhao and Xiaojian Sun)the Samuel Waxman Cancer Research Foundationthe Shanghai Guangci Translational Medical Research Development Foundation.
文摘The Ly-6 and uPAR(LU)domain-containing proteins represent a large family of cell-surface markers.In particular,mouse Ly-6A/Sca-1 is a widely used marker for various stem cells;however,its human ortholog is missing.In this study,based on a systematic survey and comparative genomic study of mouse and human LU domain-containing proteins,we identified a previously unannotated human gene encoding the candidate ortholog of mouse Ly-6A/Sca-1.This gene,hereby named LY6A,reversely overlaps with a lncRNA gene in the majority of exonic sequences.We found that LY6A is aberrantly expressed in pituitary tumors,but not in normal pituitary tissues,and may contribute to tumorigenesis.Similar to mouse Ly-6A/Sca-1,human LY6A is also upregulated by interferon,suggesting a conserved transcriptional regulatory mechanism between humans and mice.We cloned the full-length LY6A cDNA,whose encoded protein sequence,domain architecture,and exon‒intron structures are all well conserved with mouse Ly-6A/Sca-1.Ectopic expression of the LY6A protein in cells demonstrates that it acts the same as mouse Ly-6A/Sca-1 in their processing and glycosylphosphatidylinositol anchoring to the cell membrane.Collectively,these studies unveil a novel human gene encoding a candidate biomarker and provide an interesting model gene for studying gene regulatory and evolutionary mechanisms.
基金supports from the Natural Science Foundation of China(No.51273166)the Fundamental Research Funds for Xiamen University(No.20720172007).
文摘Self-healing hydrogel such as polyacrylic acid(PAA)hydrogel has attracted increasing attention based on its promising potential applications.However,it usually suffers from low strength especially as mechanical device.Herein,a commercial microcrystalline cellulose(MCC)was modified with acrylamide to graft polyacrylamide(PAM)chains on the particle surface.The acrylamide-modified MCC(AM-MCC)was then dispersed in monomer solution of acrylic acid to prepare composite hydrogel.The mechanical properties of the obtained composite hydrogels and the self-healed hydrogels were carefully measured by compressive and tensile tests,and by dynamic mechanical analysis.Our results demonstrate that introduction of a small amount of AM-MCC such as 3 wt%can not only reinforce the original hydrogel and the healed hydrogel markedly,but also improve self-healing efficiency obviously.The analyses indicate that in addition to the reversible multi-interactions such as hydrogen bonding and ionic interactions,the entanglements between the PAA chains of the hydrogel matrix and the PAM chains grafted on the MCC particles have also played an important role on the improvement in mechanical performances and the healing ability of the hydrogel.Moreover,the responsiveness to exterior ion has been tested to indicate potential application of the composite hydrogel as self-healable sensor.
文摘Disabled homolog 2 (DAB2) is frequently deleted or epigenetically silenced in many human cancer cells' Therefore, DAB2 has always been regarded as a tumor suppressor gene. However, the role of DAB2 in tumor progression and metastasis remains unclear. In this study, DAB2 expression was upregulated along with human prostate cancer (PCa) progression. DAB2 overexpression or knockdown effects in LNCaP and PC3 cell lines were verified to address the biological functions of DAB2 in PCa progression and metastasis. LNCaP and PC3 cell lines were generated from human PCa cells with low and high metastatic potentials, respectively. The results showed that DAB2 shRNA knockdown can inhibit the migratory and invasive abilities of PC3 cells, as well as the tumorigenicity, whereas DAB2 overexpression enhanced LNCaP cell migration and invasion. Further investigation showed that DAB2 regulated the cell migration associated genes in PC3 cells, and the differential DAB2 expression between LNCaP and PC3 cells was partly regulated by histone 4 acetylation. Therefore, DAB2 may play an important role in PCa progression and metastasis.
基金This work was supported by the Pacific Northwest National Laboratory operated by Battelle for the U.S.Department of Energy under contract DE-AC05-76RL01830.
文摘voltage direct current(HVDC)transmission lines are being constructed throughout the world,aided by advancements in power electronics and the potential value to transfer power between distant areas and off-shore locations.Multiple HVDC lines within and across large AC interconnections could bring about economic benefits such as interregional capacity exchange and transfer of low-cost,distant electric energy directly to load centers.In addition,network configuration of HVDC lines could result in additional benefits that have not been deeply studied.This paper describes the modeling process for continentallevel power system interconnections with the addition of multiple HVDC lines configured as a macrogrid.The models used for study are based on industry-accepted power-flow and dynamic system models for the North American Eastern and Western Interconnections.The model provides insight on feasibility and initial steady-state and stability tests of the HVDC macrogrid and its interactions with the existing electricity infrastructure,opening the door to analysis of the technical value of such a macrogrid.
基金This work was supported by DOE Office of Electricity,Advanced Grid Modeling(AGM)Program.
文摘For critical infrastructure restoration planning,the real-time scheduling and coordination of system restoration efforts,the key in decision-making is to prioritize those critical components that are out of service during the restoration.For this purpose,there is a need for component importance analysis.While it has been investigated extensively for individual systems,component importance considering interdependence among transmission,distribution and communication(T&D&C)systems has not been systematically analyzed and widely adopted.In this study,we propose a component importance assessment method in the context of interdependence between T&D&C networks.Analytic methods for multilayer networks and a set of metrics have been applied for assessing the component importance and interdependence between T&D&C networks based on their physical characteristics.The proposed methodology is further validated with integrated synthetic Illinois regional transmission,distribution,and communication(T&D&C)systems,the results reveal the unique characteristics of component/node importance,which may be strongly affected by the network topology and cross-domain node mapping.
基金National Natural Science Foundation of China,Grant/Award Numbers:81670149,81870102Samuel Waxman Cancer Research FoundationFoundation of Key Laboratory of Veterinary Biotechnology,Grant/Award Number:shklab202008。
文摘Background:Heterogeneity of leukemia-initiating cells(LICs)is a major obstacle in acute myeloid leukemia(AML)therapy.Accumulated evidence indicates that the coexistence of multiple types of LICs with different pathogenicity in the same individual is a common feature in AML.However,the functional heterogeneity including the drug response of coexistent LICs remains unclear.Therefore,this study aimed to clarify the intra-heterogeneity in LICs that can help predict leukemia behavior and develop more effective treatments.Methods:Spleen cells from the primary Setd2^(-/-)-AML mouse were transplanted into C57BL/6 recipient mice to generate a transplantable model.Flow cytometry was used to analyze the immunophenotype of the leukemic mice.Whole-genome sequencing was conducted to detect secondary hits responsible for leukemia transformation.A serial transplantation assay was used to determine the self-renewal potential of Setd2^(-/-)-AML cells.A limiting-dilution assay was performed to identify the LIC frequency in different subsets of leukemia cells.Bulk and single-cell RNA sequencing were performed to analyze the transcriptional heterogeneity of LICs.Small molecular inhibitor screening and in vivo drug treatment were employed to clarify the difference in drug response between the different subsets of LICs.Results:In this study,we observed an aged Setd2^(-/-)mouse developing AML with co-mutation of Nras^(G12S) and Braf^(K520E).Further investigation identified two types of LICs residing in the c-Kit^(+)B220^(+)Mac-1^(-)and c-Kit^(+)B220^(+)Mac-1^(+)subsets,respectively.In vivo transplantation assay disclosed the heterogeneity in differentiation between the coexistent LICs.Besides,an intrinsic doxorubicinresistant transcriptional signature was uncovered in c-Kit^(+)B220^(+)Mac-1^(+)cells.Indeed,doxorubicin plus cytarabine(DA),the standard chemotherapeutic regimen used in AML treatment,could specifically kill c-Kit^(+)B220^(+)Mac-1^(−)cells,but it hardly affected c-Kit^(+)B220^(+)Mac-1^(+)cells.Transcriptome analysis unveiled a higher activation of RAS downstream signaling pathways in c-Kit^(+)B220^(+)Mac-1^(+)cells than in c-Kit^(+)B220^(+)Mac-1^(-)cells.Combined treatmentwithDAand RAS pathway inhibitors killed both c-Kit^(+)B220^(+)Mac-1^(−)and c-Kit^(+)B220^(+)Mac-1^(+)cells and attenuated disease progression.Conclusions:This study identified two cell subsets enriched for LICs inmurine Setd2^(-/-)-AML and disclosed the transcriptional and functional heterogeneity of LICs,revealing that the coexistence of different types of LICs in thismodel brings about diverse drug response.