Abnormal aggregation and accumulation of pathological amyloid proteins such as amyloid-β,Tau,and𝛼α-synuclein play key pathological roles and serve as histological hallmarks in different neurodegenerative dis...Abnormal aggregation and accumulation of pathological amyloid proteins such as amyloid-β,Tau,and𝛼α-synuclein play key pathological roles and serve as histological hallmarks in different neurodegenerative diseases(NDs)such as Alzheimer’s disease(AD)and Parkinson’s disease(PD).In addition,various post-translational modifications(PTMs)have been identified on pathological amyloid proteins and are subjected to change during disease progression.Given the central role of amyloid proteins in NDs,tremendous efforts have been made to develop amyloid-targeting strategies for clinical diagnosis and molecular classification of NDs.In this review,we summarize two major strategies for targeting amyloid aggregates,with a focus on the trials in AD diagnosis.The first strategy is a positron emission tomography(PET)scan of protein aggregation in the brain.We mainly focus on introducing the development of small-molecule PET tracers for specifically recognizing pathological amyloid fibrils.The second strategy is the detection of PTM biomarkers on amyloid proteins in cerebrospinal fluid and plasma.We discuss the pathological roles of different PTMs in diseases and how we can use the PTM profile of amyloid proteins for clinical diagnosis.Finally,we point out the potential technical challenges of these two strategies,and outline other potential strategies,as well as a combination of multiple strategies,for molecular diagnosis of NDs.展开更多
Hair follicle dermal sheath(DS)harbors hair follicle dermal stem cells(hfDSCs),which can be recruited to replenish DS and dermal papilla(DP).Cultured DS cells can differentiate into various cell lineages in vitro.Howe...Hair follicle dermal sheath(DS)harbors hair follicle dermal stem cells(hfDSCs),which can be recruited to replenish DS and dermal papilla(DP).Cultured DS cells can differentiate into various cell lineages in vitro.However,it is unclear how its plasticity is modulated in vivo.Wnt/β-catenin signaling plays an important role in maintaining stem cells of various lineages and is required for HF development and regeneration.Here we report that activation ofβ-catenin in DS generates ectopic HF outgrowth(EF)by reprogramming HF epidermal cells and DS cells themselves,and endows DS cells with hair inducing ability.Epidermal homeostasis of pre-existing HFs is disrupted.Additionally,cell-autonomous progressive skin fibrosis is prominent in dermis,where the excessive fibroblasts largely originate from DS.Gene expression analysis of purified DS cells with activatedβ-catenin revealed significantly increased expression of Bmp,Fgf,and Notch ligands and administration of Bmp,Fgf,or Notch signaling inhibitor attenuates EF formation.In summary,our findings advance the current knowledge of high plasticity of DS cells and provide an insight into understanding how Wnt/β-catenin signaling controls DS cell behaviors.展开更多
The nucleocapsid(N)protein of SARS-CoV-2 has been reported to have a high ability of liquid-liquid phase separation,which enables its incorporation into stress granules(SGs)of host cells.However,whether SG invasion by...The nucleocapsid(N)protein of SARS-CoV-2 has been reported to have a high ability of liquid-liquid phase separation,which enables its incorporation into stress granules(SGs)of host cells.However,whether SG invasion by N protein occurs in the scenario of SARS-CoV-2 infection is unknow,neither do we know its con-sequence.Here,we used SARS-CoV-2 to infect mam-malian cells and observed the incorporation of N protein into SGs,which resulted in markedly impaired self-dis-assembly but stimulated cell cellular clearance of SGs.NMR experiments further showed that N protein binds to the SG-related amyloid proteins via non-specific tran-sient interactions,which not only expedites the phase transition of these proteins to aberrant amyloid aggre-gation in vitro,but also promotes the aggregation of FUS with ALS-associated P525L mutation in cells.In addition,we found that ACE2 is not necessary for the infection of SARS-CoV-2 to mammalian cells.Our work indicates that SARS-CoV-2 infection can impair the dis-assembly of host SGs and promote the aggregation of SG-related amyloid proteins,which may lead to an increased risk of neurodegeneration.展开更多
Navigation and recognition of disease lesions remain challenging during colorectal cancer diagnosis and treatment,given that the precision and capacity of using specific surface antigens as recognition sites are relat...Navigation and recognition of disease lesions remain challenging during colorectal cancer diagnosis and treatment,given that the precision and capacity of using specific surface antigens as recognition sites are relatively lacking.Moreover,the low penetration rate of noninvasive detection methods has delayed disease diagnosis in developing countries.We developed a bacterial device targeting the Thomsen-Friedenreich antigen,which is abundant on lesion tissue,and produced vesicles that serve as markers for ultrasonic detection.The device uses a bacterial cell surface display system and acoustic reporter gene to function as a screening device for colorectal cancer detection.The diagnostic efficiency of this device was determined by flow cytometry,immunohistochemistry,microfluidic chip-based assay,and ultrasonic examinations on both cellular and tissue scales.In all scales and experiments,our device showed great feasibility upon differentiating disease lesion and normal tissue,while foundation of the usage of vesicle reporter system as noninvasive method has also been laid.The application of this device provides insight into the practicability and prospect of bacterial detecting agents in the field of diagnostics.All animal studies were approved by the Institutional Animal Care and Use Committee of Shanghai Jiao Tong University,China(approval No.201801015)on February 23,2018.展开更多
Adenomatosis polyposis down-regulated 1(APCDD1) is a transmembrane glycoprotein that negatively regulates Wnt/β-catenin canonical signaling by binding with Wnt ligands and receptors. We analyzed the role of APCDD1 in...Adenomatosis polyposis down-regulated 1(APCDD1) is a transmembrane glycoprotein that negatively regulates Wnt/β-catenin canonical signaling by binding with Wnt ligands and receptors. We analyzed the role of APCDD1 in the Wnt5a/c-Jun non-canonical signaling pathway and demonstrated that APCDD1 can interact in vitro with Wnt5a, a classical ligand, and Ror2, a receptor of non-canonical Wnt signaling. Furthermore, we verified the binding of APCDD1 and Ror2 in primary cells of mouse skin. Moreover, APCDD1 seems to form a complex with Ror2 and Vangl2 in the cell, and complex formation can be improved by adding Wnt5a. In the presence of Wnt5a and Ror2, APCDD1 can induce the phosphorylation of c-Jun, a transcription factor of Wnt5a non-canonical signaling, and its phosphorylation level is a readout of Wnt5 a signaling. Wound-healing assay shows that APCDD1 accelerates polarized cell migration during Wnt5a-induced wound closure. Therefore,it is very likely that APCDD1 regulates Wnt5a/c-Jun non-canonical signaling as co-receptor binding with both Wnt5a and Ror2.展开更多
基金This work was supported by the National Natural Science Foundation of China(NSFC)(82188101,32171236,and 31872716 to C.L.,32170683 to D.L.)the Science and Technology Commission of Shanghai Municipality(STCSM)(20XD1425000 and 2019SHZDZX02 to C.L.)the Shanghai Pilot Program for Basic Research–Chinese Academy of Science,Shanghai Branch(CYJ-SHFY-2022-005)。
文摘Abnormal aggregation and accumulation of pathological amyloid proteins such as amyloid-β,Tau,and𝛼α-synuclein play key pathological roles and serve as histological hallmarks in different neurodegenerative diseases(NDs)such as Alzheimer’s disease(AD)and Parkinson’s disease(PD).In addition,various post-translational modifications(PTMs)have been identified on pathological amyloid proteins and are subjected to change during disease progression.Given the central role of amyloid proteins in NDs,tremendous efforts have been made to develop amyloid-targeting strategies for clinical diagnosis and molecular classification of NDs.In this review,we summarize two major strategies for targeting amyloid aggregates,with a focus on the trials in AD diagnosis.The first strategy is a positron emission tomography(PET)scan of protein aggregation in the brain.We mainly focus on introducing the development of small-molecule PET tracers for specifically recognizing pathological amyloid fibrils.The second strategy is the detection of PTM biomarkers on amyloid proteins in cerebrospinal fluid and plasma.We discuss the pathological roles of different PTMs in diseases and how we can use the PTM profile of amyloid proteins for clinical diagnosis.Finally,we point out the potential technical challenges of these two strategies,and outline other potential strategies,as well as a combination of multiple strategies,for molecular diagnosis of NDs.
基金the National Nature Scienee Foundation of China(31671504 and 81421061)the 973 Programs(2013CB967401)+1 种基金the Natural Science Foundation of Shanghai(13ZR1421100)the National Key Technology R&D Program(2012BAI01B09).
文摘Hair follicle dermal sheath(DS)harbors hair follicle dermal stem cells(hfDSCs),which can be recruited to replenish DS and dermal papilla(DP).Cultured DS cells can differentiate into various cell lineages in vitro.However,it is unclear how its plasticity is modulated in vivo.Wnt/β-catenin signaling plays an important role in maintaining stem cells of various lineages and is required for HF development and regeneration.Here we report that activation ofβ-catenin in DS generates ectopic HF outgrowth(EF)by reprogramming HF epidermal cells and DS cells themselves,and endows DS cells with hair inducing ability.Epidermal homeostasis of pre-existing HFs is disrupted.Additionally,cell-autonomous progressive skin fibrosis is prominent in dermis,where the excessive fibroblasts largely originate from DS.Gene expression analysis of purified DS cells with activatedβ-catenin revealed significantly increased expression of Bmp,Fgf,and Notch ligands and administration of Bmp,Fgf,or Notch signaling inhibitor attenuates EF formation.In summary,our findings advance the current knowledge of high plasticity of DS cells and provide an insight into understanding how Wnt/β-catenin signaling controls DS cell behaviors.
基金This work was supported by the National Natural Science Foundation(NSF)of China(32170683,82188101,32171236,31872716,32070049,82041016)the Major State Basic Research Development Program(2019YFE0120600)+5 种基金the Science and Technology Commission of Shanghai Municipality(STCSM)(20XD1425000 and 2019SHZDZX02)CAS project for Young Scientists in Basic research(YSBR-009)the Eastem Scholar project supported by Shanghai Municipal Education Commission,National Key R&D Program of China(2021YFC2301700,2021YFA1301900)Yunnan Key Research and Development project(202103AQ100001)CAMS Innovation Fund for Medical Sciences(2021-12M-1-038)special research fund on COVID-19 of Sichuan Province(2020YFS0010).
文摘The nucleocapsid(N)protein of SARS-CoV-2 has been reported to have a high ability of liquid-liquid phase separation,which enables its incorporation into stress granules(SGs)of host cells.However,whether SG invasion by N protein occurs in the scenario of SARS-CoV-2 infection is unknow,neither do we know its con-sequence.Here,we used SARS-CoV-2 to infect mam-malian cells and observed the incorporation of N protein into SGs,which resulted in markedly impaired self-dis-assembly but stimulated cell cellular clearance of SGs.NMR experiments further showed that N protein binds to the SG-related amyloid proteins via non-specific tran-sient interactions,which not only expedites the phase transition of these proteins to aberrant amyloid aggre-gation in vitro,but also promotes the aggregation of FUS with ALS-associated P525L mutation in cells.In addition,we found that ACE2 is not necessary for the infection of SARS-CoV-2 to mammalian cells.Our work indicates that SARS-CoV-2 infection can impair the dis-assembly of host SGs and promote the aggregation of SG-related amyloid proteins,which may lead to an increased risk of neurodegeneration.
基金This work was supported by the National Natural Science Foundation of China(No.31671504,31970775,and 19Z103150074)the Cross Research Fund of Biomedical Engineering of Shanghai Jiao Tong University,China(No.YG2016MS04).
文摘Navigation and recognition of disease lesions remain challenging during colorectal cancer diagnosis and treatment,given that the precision and capacity of using specific surface antigens as recognition sites are relatively lacking.Moreover,the low penetration rate of noninvasive detection methods has delayed disease diagnosis in developing countries.We developed a bacterial device targeting the Thomsen-Friedenreich antigen,which is abundant on lesion tissue,and produced vesicles that serve as markers for ultrasonic detection.The device uses a bacterial cell surface display system and acoustic reporter gene to function as a screening device for colorectal cancer detection.The diagnostic efficiency of this device was determined by flow cytometry,immunohistochemistry,microfluidic chip-based assay,and ultrasonic examinations on both cellular and tissue scales.In all scales and experiments,our device showed great feasibility upon differentiating disease lesion and normal tissue,while foundation of the usage of vesicle reporter system as noninvasive method has also been laid.The application of this device provides insight into the practicability and prospect of bacterial detecting agents in the field of diagnostics.All animal studies were approved by the Institutional Animal Care and Use Committee of Shanghai Jiao Tong University,China(approval No.201801015)on February 23,2018.
基金the National Natural Science Foundation of China(Nos.31671504 and 81421061)the Cross Research Fund of Biomedical Engineering of Shanghai Jiao Tong University(No.YG2016MS04)+1 种基金the Natural Science Foundation of Shanghai(No.13ZR1421100)the National Key Technology R&D Program of China(No.2012BAI01B09)
文摘Adenomatosis polyposis down-regulated 1(APCDD1) is a transmembrane glycoprotein that negatively regulates Wnt/β-catenin canonical signaling by binding with Wnt ligands and receptors. We analyzed the role of APCDD1 in the Wnt5a/c-Jun non-canonical signaling pathway and demonstrated that APCDD1 can interact in vitro with Wnt5a, a classical ligand, and Ror2, a receptor of non-canonical Wnt signaling. Furthermore, we verified the binding of APCDD1 and Ror2 in primary cells of mouse skin. Moreover, APCDD1 seems to form a complex with Ror2 and Vangl2 in the cell, and complex formation can be improved by adding Wnt5a. In the presence of Wnt5a and Ror2, APCDD1 can induce the phosphorylation of c-Jun, a transcription factor of Wnt5a non-canonical signaling, and its phosphorylation level is a readout of Wnt5 a signaling. Wound-healing assay shows that APCDD1 accelerates polarized cell migration during Wnt5a-induced wound closure. Therefore,it is very likely that APCDD1 regulates Wnt5a/c-Jun non-canonical signaling as co-receptor binding with both Wnt5a and Ror2.