Background:Oral squamous cell carcinoma(OSCC)is a common malignant tumor.Recently,Laminin Gamma 2(LAMC2)has been shown to be abnormally expressed in OSCC;however,how LAMC2 signaling contributes to the occurrence and d...Background:Oral squamous cell carcinoma(OSCC)is a common malignant tumor.Recently,Laminin Gamma 2(LAMC2)has been shown to be abnormally expressed in OSCC;however,how LAMC2 signaling contributes to the occurrence and development of OSCC and the role of autophagy in OSCC has not been fully explored.This study aimed to analyze the role and mechanism of LAMC2 signaling in OSCC and the involvement of autophagy in OSCC.Methods:To explore the mechanism by which LAMC2 is highly expressed in OSCC,we used small interfering RNA(siRNA)to knock down LAMC2 to further observe the changes in the signaling pathway.Furthermore,we used cell proliferation assays,Transwell invasion assays,and wound-healing assays to observe the changes in OSCC proliferation,invasion,and metastasis.RFP-LC3 was used to detect the level of autophagy intensity.A cell line-derived xenograft(CDX)model was used to detect the effect of LAMC2 on tumor growth in vivo.Results:This study found that the level of autophagy was correlated with the biological behavior of OSCC.The downregulation of LAMC2 activated autophagy and inhibited OSCC proliferation,invasion,and metastasis via inhibiting the PI3K/AKT/mTOR pathway.Moreover,autophagy has a dual effect on OSCC,and the synergistic downregulation of LAMC2 and autophagy can inhibit OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.Conclusions:LAMC2 interacts with autophagy to regulate OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.LAMC2 down-regulation can synergistically modulate autophagy to inhibit OSCC migration,invasion,and proliferation.展开更多
The dynamic traveling salesman problem(DTSP)is significant in logistics distribution in real-world applications in smart cities,but it is uncertain and difficult to solve.This paper proposes a scheme library-based ant...The dynamic traveling salesman problem(DTSP)is significant in logistics distribution in real-world applications in smart cities,but it is uncertain and difficult to solve.This paper proposes a scheme library-based ant colony optimization(ACO)with a two-optimization(2-opt)strategy to solve the DTSP efficiently.The work is novel and contributes to three aspects:problemmodel,optimization framework,and algorithmdesign.Firstly,in the problem model,traditional DTSP models often consider the change of travel distance between two nodes over time,while this paper focuses on a special DTSP model in that the node locations change dynamically over time.Secondly,in the optimization framework,the ACO algorithm is carried out in an offline optimization and online application framework to efficiently reuse the historical information to help fast respond to the dynamic environment.The framework of offline optimization and online application is proposed due to the fact that the environmental change inDTSPis caused by the change of node location,and therefore the newenvironment is somehowsimilar to certain previous environments.This way,in the offline optimization,the solutions for possible environmental changes are optimized in advance,and are stored in a mode scheme library.In the online application,when an environmental change is detected,the candidate solutions stored in the mode scheme library are reused via ACO to improve search efficiency and reduce computational complexity.Thirdly,in the algorithm design,the ACO cooperates with the 2-opt strategy to enhance search efficiency.To evaluate the performance of ACO with 2-opt,we design two challenging DTSP cases with up to 200 and 1379 nodes and compare them with other ACO and genetic algorithms.The experimental results show that ACO with 2-opt can solve the DTSPs effectively.展开更多
Tris(1,3-dichloro-2-propyl) phosphate(TDCIPP) is a commonly used organophosphatebased flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophospha...Tris(1,3-dichloro-2-propyl) phosphate(TDCIPP) is a commonly used organophosphatebased flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophosphate pesticides, the neurotoxicity of TDCIPP has raised widespread concerns. TDCIPP can increase neuronal apoptosis and induce autophagy.However, its regulatory mechanism remains unclear. In this study, we found that the expression upregulation of the DNA Damage-Inducible Transcript 4(DDIT4) protein, which might play essential roles in TDCIPP-induced neuronal autophagy and apoptosis, was observed in TDCIPP-treated differentiated rat PC12 cells. Furthermore, we determined the protective effect of the DDIT4 suppression on the autophagy and apoptosis induced by TDCIPP using Western blot(WB) and Flow cytometry(FACS) analysis. We observed that TDCIPP treatment increased the DDIT4, the autophagy marker Beclin-1, and the microtubule-associated protein light chain 3-II(LC_(3)II) expressions and decreased the mTOR phosphorylation levels. Conversely, the suppression of DDIT4 expression increased the p-mTOR expression and decreased cell autophagy and apoptosis. Collectively, our results revealed the function of DDIT4 in cell death mechanisms triggered by TDCIPP through the m TOR signaling axis in differentiated PC12 cells. Thus, this study provided vital evidence necessary to explain the mechanism of TDCIPP-induced neurotoxicity in differentiated PC12 cells.展开更多
The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells(OPCs) to differentiate, since OPCs and oligodendrocytelin...The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells(OPCs) to differentiate, since OPCs and oligodendrocytelineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid(SA) is mainly derived from star anise, and is reported to have antiinfluenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis(EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination.Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated m TOR. Taken together, our resultsdemonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.展开更多
The exacerbation of progressive multiple sclerosis(MS)is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells(OPCs).To discover novel therapeutic compounds for enhancing remye...The exacerbation of progressive multiple sclerosis(MS)is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells(OPCs).To discover novel therapeutic compounds for enhancing remyelination by endogenous OPCs,we screened for myelin basic protein expression using cultured rat OPCs and a library of small-molecule compounds.One of the most effective drugs was pinocembrin,which remarkably promoted OPC differentiation and maturation without affecting cell proliferation and survival.Based on these in vitro effects,we further assessed the therapeutic effects of pinocembrin in animal models of demyelinating diseases.We demonstrated that pinocembrin significantly ameliorated the progression of experimental autoimmune encephalomyelitis(EAE)and enhanced the repair of demyelination in lysolectin-induced lesions.Further studies indicated that pinocembrin increased the phosphorylation level of mammalian target of rapamycin(mTOR).Taken together,our results demonstrated that pinocembrin promotes OPC differentiation and remyelination through the phosphorylated mTOR pathway,and suggest a novel therapeutic prospect for this natural flavonoid product in treating demyelinating diseases.展开更多
Multiple sclerosis(MS) is a classical inflammatory demyelinating disease of the central nervous system(CNS). Microglia are the main resident immune cells in the CNS and are closely associated with the pathogenesis...Multiple sclerosis(MS) is a classical inflammatory demyelinating disease of the central nervous system(CNS). Microglia are the main resident immune cells in the CNS and are closely associated with the pathogenesis of MS.In the present study, we found that mi R-30 a was highly expressed in jellyfish-like microglia in chronic active lesions of MS patients, as well as in the microglia of mice with experimental autoimmune encephalomyelitis(EAE) at the chronic phase. In vitro, the conditioned supernatant of mouse microglia overexpressing miR-30 a promoted the apoptosis of oligodendrocyte precursor cells(OPCs), and inhibited OPC differentiation. In vivo, overexpressing miR-30 a in transplanted microglia exacerbated the progression of EAE.Overexpression and knock-down experiments in primary cultured mouse microglia showed that mi R-30 a increased the expression of IL-1 b and i NOS, which are pro-inflammatory, while inhibiting the expression of Ym-1 and CD206.Mechanistically, mi R-30 a inhibited the expression of Ppargc1 b, which is the co-activator of peroxisome proliferator-activated receptor gamma, resulting in pro-inflammatory effects. Our work shows that mi R-30 a is an important regulator of the inflammatory response in microglia, and may be a promising therapeutic target for inflammatory diseases like MS in the CNS.展开更多
Although phase change memory technology has developed drastically in the past two decades, the cognition of the key switching materials still ignores an important member, the face-centered cubic Sb2Te3. Apart from the...Although phase change memory technology has developed drastically in the past two decades, the cognition of the key switching materials still ignores an important member, the face-centered cubic Sb2Te3. Apart from the well-known equilibrium hexagonal Sb2Te3 crystal, we prove the metastable face-centered cubic Sb2Te3 phase does exist. Such a metastable crystal contains a large concentration of vacancies randomly occupying the cationic lattice sites. The face-centered cubic to hexagonal phase transformation of Sb2Te3, accompanied by vacancy aggregation, occurs at a quite lower temperature compared to that of Ge2Sb2Te5 alloy. We prove that the covalent-like bonds prevail in the metastable Sb2Te3 crystal, deviating from the ideal resonant features. If a proper doping technique is adopted, the metastable Sb2Te3 phase could be promising for realizing reversibly swift and low-energy phase change memory applications. Our study may offer a new insight into commercialized Ge-Sb-Te systems and help in the design of novel phase change materials to boost the performances of the phase change memorv device.展开更多
Leukocyte differentiation antigens (LDAs) play important roles in the immune system, by serving as surface markers and participating in multiple biological activities, such as recognizing pathogens, mediating membra...Leukocyte differentiation antigens (LDAs) play important roles in the immune system, by serving as surface markers and participating in multiple biological activities, such as recognizing pathogens, mediating membrane signals, interacting with other cells or systems, and regulating cell differentiation and activation. Data mining is a powerful tool used to identify novel LDAs from whole genome. LRRC25 (leucine rich repeat-containing 25) was predicted to have a role in the function of myeloid cells by a large-scale "omics" data analysis. Further experimental validation showed that LRRC25 is highly expressed in primary myeloid cells, such as granulocytes and monocytes, and lowly/intermediately expressed in B cells, but not in T cells and almost all NK cells. It was down-regulated in multiple acute myeloid leukemia (AML) cell lines and bone marrow cells of AML patients and up-regulated after all-trans retinoic acid (ATRA)-mediated granulocytic differentiation in AML cell lines and acute promyelocytic leukemia (APL; AML-M3, FAB classification) cells. Localization analysis showed that LRRC25 is a type I transmembrane molecule. Although ectopic LRRC25 did not promote spontaneous differentiation of NB4 cells, knockdown of LRRC25 by siRNA or shRNA and knockout of LRRC25 by the CRISPR-Cas9 system attenuated ATRA-induced termi- nal granulocytic differentiation, and restoration of LRRC25 in knockout cells could rescue ATRA-induced granulocytic differentiation. Therefore, LRRC25, a potential leukocyte differentiation antigen, is a key regulator of ATRA-induced granulocytic differentiation.展开更多
基金This work was supported by the National Natural Science Foundation of China(Grant Numbers 31971106,BWS21L013,21WS09002,JK20211A010213).
文摘Background:Oral squamous cell carcinoma(OSCC)is a common malignant tumor.Recently,Laminin Gamma 2(LAMC2)has been shown to be abnormally expressed in OSCC;however,how LAMC2 signaling contributes to the occurrence and development of OSCC and the role of autophagy in OSCC has not been fully explored.This study aimed to analyze the role and mechanism of LAMC2 signaling in OSCC and the involvement of autophagy in OSCC.Methods:To explore the mechanism by which LAMC2 is highly expressed in OSCC,we used small interfering RNA(siRNA)to knock down LAMC2 to further observe the changes in the signaling pathway.Furthermore,we used cell proliferation assays,Transwell invasion assays,and wound-healing assays to observe the changes in OSCC proliferation,invasion,and metastasis.RFP-LC3 was used to detect the level of autophagy intensity.A cell line-derived xenograft(CDX)model was used to detect the effect of LAMC2 on tumor growth in vivo.Results:This study found that the level of autophagy was correlated with the biological behavior of OSCC.The downregulation of LAMC2 activated autophagy and inhibited OSCC proliferation,invasion,and metastasis via inhibiting the PI3K/AKT/mTOR pathway.Moreover,autophagy has a dual effect on OSCC,and the synergistic downregulation of LAMC2 and autophagy can inhibit OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.Conclusions:LAMC2 interacts with autophagy to regulate OSCC metastasis,invasion,and proliferation via the PI3K/AKT/mTOR pathway.LAMC2 down-regulation can synergistically modulate autophagy to inhibit OSCC migration,invasion,and proliferation.
基金supported in part by the National Research Foundation of Korea (NRF-2021H1D3A2A01082705).
文摘The dynamic traveling salesman problem(DTSP)is significant in logistics distribution in real-world applications in smart cities,but it is uncertain and difficult to solve.This paper proposes a scheme library-based ant colony optimization(ACO)with a two-optimization(2-opt)strategy to solve the DTSP efficiently.The work is novel and contributes to three aspects:problemmodel,optimization framework,and algorithmdesign.Firstly,in the problem model,traditional DTSP models often consider the change of travel distance between two nodes over time,while this paper focuses on a special DTSP model in that the node locations change dynamically over time.Secondly,in the optimization framework,the ACO algorithm is carried out in an offline optimization and online application framework to efficiently reuse the historical information to help fast respond to the dynamic environment.The framework of offline optimization and online application is proposed due to the fact that the environmental change inDTSPis caused by the change of node location,and therefore the newenvironment is somehowsimilar to certain previous environments.This way,in the offline optimization,the solutions for possible environmental changes are optimized in advance,and are stored in a mode scheme library.In the online application,when an environmental change is detected,the candidate solutions stored in the mode scheme library are reused via ACO to improve search efficiency and reduce computational complexity.Thirdly,in the algorithm design,the ACO cooperates with the 2-opt strategy to enhance search efficiency.To evaluate the performance of ACO with 2-opt,we design two challenging DTSP cases with up to 200 and 1379 nodes and compare them with other ACO and genetic algorithms.The experimental results show that ACO with 2-opt can solve the DTSPs effectively.
基金supported by the National Key Research and Development Program of China (No. 2018YFC1603704)the Tianjin Natural Science Foundation (No. 20JCQNJC00860)。
文摘Tris(1,3-dichloro-2-propyl) phosphate(TDCIPP) is a commonly used organophosphatebased flame retardant and can bio-accumulate in human tissues and organs. As its structure is similar to that of neurotoxic organophosphate pesticides, the neurotoxicity of TDCIPP has raised widespread concerns. TDCIPP can increase neuronal apoptosis and induce autophagy.However, its regulatory mechanism remains unclear. In this study, we found that the expression upregulation of the DNA Damage-Inducible Transcript 4(DDIT4) protein, which might play essential roles in TDCIPP-induced neuronal autophagy and apoptosis, was observed in TDCIPP-treated differentiated rat PC12 cells. Furthermore, we determined the protective effect of the DDIT4 suppression on the autophagy and apoptosis induced by TDCIPP using Western blot(WB) and Flow cytometry(FACS) analysis. We observed that TDCIPP treatment increased the DDIT4, the autophagy marker Beclin-1, and the microtubule-associated protein light chain 3-II(LC_(3)II) expressions and decreased the mTOR phosphorylation levels. Conversely, the suppression of DDIT4 expression increased the p-mTOR expression and decreased cell autophagy and apoptosis. Collectively, our results revealed the function of DDIT4 in cell death mechanisms triggered by TDCIPP through the m TOR signaling axis in differentiated PC12 cells. Thus, this study provided vital evidence necessary to explain the mechanism of TDCIPP-induced neurotoxicity in differentiated PC12 cells.
基金supported by the National Natural Science Foundation of China(31571066 and 31771129)the National Basic Research Development Program of China(2016YFA0100802)
文摘The obstacle to successful remyelination in demyelinating diseases, such as multiple sclerosis, mainly lies in the inability of oligodendrocyte precursor cells(OPCs) to differentiate, since OPCs and oligodendrocytelineage cells that are unable to fully differentiate are found in the areas of demyelination. Thus, promoting the differentiation of OPCs is vital for the treatment of demyelinating diseases. Shikimic acid(SA) is mainly derived from star anise, and is reported to have antiinfluenza, anti-oxidation, and anti-tumor effects. In the present study, we found that SA significantly promoted the differentiation of cultured rat OPCs without affecting their proliferation and apoptosis. In mice, SA exerted therapeutic effects on experimental autoimmune encephalomyelitis(EAE), such as alleviating clinical EAE scores, inhibiting inflammation, and reducing demyelination in the CNS. SA also promoted the differentiation of OPCs as well as their remyelination after lysolecithin-induced demyelination.Furthermore, we showed that the promotion effect of SA on OPC differentiation was associated with the up-regulation of phosphorylated m TOR. Taken together, our resultsdemonstrated that SA could act as a potential drug candidate for the treatment of demyelinating diseases.
基金This work was supported by the National Natural Science Foundation of China(31771129).
文摘The exacerbation of progressive multiple sclerosis(MS)is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells(OPCs).To discover novel therapeutic compounds for enhancing remyelination by endogenous OPCs,we screened for myelin basic protein expression using cultured rat OPCs and a library of small-molecule compounds.One of the most effective drugs was pinocembrin,which remarkably promoted OPC differentiation and maturation without affecting cell proliferation and survival.Based on these in vitro effects,we further assessed the therapeutic effects of pinocembrin in animal models of demyelinating diseases.We demonstrated that pinocembrin significantly ameliorated the progression of experimental autoimmune encephalomyelitis(EAE)and enhanced the repair of demyelination in lysolectin-induced lesions.Further studies indicated that pinocembrin increased the phosphorylation level of mammalian target of rapamycin(mTOR).Taken together,our results demonstrated that pinocembrin promotes OPC differentiation and remyelination through the phosphorylated mTOR pathway,and suggest a novel therapeutic prospect for this natural flavonoid product in treating demyelinating diseases.
基金supported by the International Cooperation and Exchange of the National Natural Science Foundation of China(81461138035)the National Natural Science Foundation of China(81371326,31371068,and 31571066)the National Key Research and Development Program of China(2016YFA0100802)
文摘Multiple sclerosis(MS) is a classical inflammatory demyelinating disease of the central nervous system(CNS). Microglia are the main resident immune cells in the CNS and are closely associated with the pathogenesis of MS.In the present study, we found that mi R-30 a was highly expressed in jellyfish-like microglia in chronic active lesions of MS patients, as well as in the microglia of mice with experimental autoimmune encephalomyelitis(EAE) at the chronic phase. In vitro, the conditioned supernatant of mouse microglia overexpressing miR-30 a promoted the apoptosis of oligodendrocyte precursor cells(OPCs), and inhibited OPC differentiation. In vivo, overexpressing miR-30 a in transplanted microglia exacerbated the progression of EAE.Overexpression and knock-down experiments in primary cultured mouse microglia showed that mi R-30 a increased the expression of IL-1 b and i NOS, which are pro-inflammatory, while inhibiting the expression of Ym-1 and CD206.Mechanistically, mi R-30 a inhibited the expression of Ppargc1 b, which is the co-activator of peroxisome proliferator-activated receptor gamma, resulting in pro-inflammatory effects. Our work shows that mi R-30 a is an important regulator of the inflammatory response in microglia, and may be a promising therapeutic target for inflammatory diseases like MS in the CNS.
基金This work was supported by the Strategic Priority Research Program of Chinese Academy of Sciences (No. XDA09020402), National Integrate Circuit Research Program of China (No. 2009ZX02023-003), National Natural Science Foundation of China (Nos. 61076121, 61176122, 61106001, 61261160500, and 61376006), Science and Technology Council of Shanghai (Nos. 13ZR1447200 and 13DZ2295700). The supercomputer time was provided by the National Supercomputer Center in Tianjin, and the calculations were performed on TianHe-1 (A).
文摘Although phase change memory technology has developed drastically in the past two decades, the cognition of the key switching materials still ignores an important member, the face-centered cubic Sb2Te3. Apart from the well-known equilibrium hexagonal Sb2Te3 crystal, we prove the metastable face-centered cubic Sb2Te3 phase does exist. Such a metastable crystal contains a large concentration of vacancies randomly occupying the cationic lattice sites. The face-centered cubic to hexagonal phase transformation of Sb2Te3, accompanied by vacancy aggregation, occurs at a quite lower temperature compared to that of Ge2Sb2Te5 alloy. We prove that the covalent-like bonds prevail in the metastable Sb2Te3 crystal, deviating from the ideal resonant features. If a proper doping technique is adopted, the metastable Sb2Te3 phase could be promising for realizing reversibly swift and low-energy phase change memory applications. Our study may offer a new insight into commercialized Ge-Sb-Te systems and help in the design of novel phase change materials to boost the performances of the phase change memorv device.
基金We appreciate the assistance and advice from Professor Dalong Ma from the Department of Immunology, Peking University Health Science Center and thank Hounan Wu, a technician in the Analytic Center of Peking University Health Science Center, for her professional and skilled help in micro-well single cell sorting. This work was supported by the National Natural Science Foundation of China (Grant Nos. 31400736 and 31670947).
文摘Leukocyte differentiation antigens (LDAs) play important roles in the immune system, by serving as surface markers and participating in multiple biological activities, such as recognizing pathogens, mediating membrane signals, interacting with other cells or systems, and regulating cell differentiation and activation. Data mining is a powerful tool used to identify novel LDAs from whole genome. LRRC25 (leucine rich repeat-containing 25) was predicted to have a role in the function of myeloid cells by a large-scale "omics" data analysis. Further experimental validation showed that LRRC25 is highly expressed in primary myeloid cells, such as granulocytes and monocytes, and lowly/intermediately expressed in B cells, but not in T cells and almost all NK cells. It was down-regulated in multiple acute myeloid leukemia (AML) cell lines and bone marrow cells of AML patients and up-regulated after all-trans retinoic acid (ATRA)-mediated granulocytic differentiation in AML cell lines and acute promyelocytic leukemia (APL; AML-M3, FAB classification) cells. Localization analysis showed that LRRC25 is a type I transmembrane molecule. Although ectopic LRRC25 did not promote spontaneous differentiation of NB4 cells, knockdown of LRRC25 by siRNA or shRNA and knockout of LRRC25 by the CRISPR-Cas9 system attenuated ATRA-induced termi- nal granulocytic differentiation, and restoration of LRRC25 in knockout cells could rescue ATRA-induced granulocytic differentiation. Therefore, LRRC25, a potential leukocyte differentiation antigen, is a key regulator of ATRA-induced granulocytic differentiation.