目的研究程序性细胞死亡蛋白4(programmed cell death protein 4,PDCD4)在脓毒症诱导的急性肾损伤(acute kidney injury,AKI)中的作用机制,以及调控PDCD4表达通过丝裂原活化蛋白激酶3(mitogen-activated protein kinase 3,MAP2K3)和p38...目的研究程序性细胞死亡蛋白4(programmed cell death protein 4,PDCD4)在脓毒症诱导的急性肾损伤(acute kidney injury,AKI)中的作用机制,以及调控PDCD4表达通过丝裂原活化蛋白激酶3(mitogen-activated protein kinase 3,MAP2K3)和p38蛋白激酶(p38 mitogen-activated protein kinase,p38 MAPK)对脓毒症AKI起到潜在治疗作用。方法用脂多糖(lipopolysaccharide,LPS)刺激人肾小管上皮细胞(HK-2)构建脓毒症AKI细胞模型。进一步用腺病毒介导siRNA和过表达载体抑制和上调AKI细胞模型中PDCD4的表达;CCK-8法检测细胞增殖;用DCFH-DA及激光共聚焦显微镜检测细胞中ROS水平,用总SOD活性检测试剂和MDA检测试剂盒检测细胞中SOD和MDA水平;免疫共沉淀验证PDCD4和MAP2K3之间的蛋白相互作用;TUNEL染色法检测细胞凋亡;RT-qPCR和Western blot检测PDCD4及相关基因的mRNA和蛋白表达水平;ELISA法检测患者血清中炎症相关因子水平。结果LPS诱导可以促进HK-2细胞中PDCD4表达,下调PDCD4可抑制LPS诱导的HK-2细胞的炎症、氧化应激及细胞凋亡。数据库预测及免疫共沉淀证实PDCD4可以与MAP2K3相互作用,且在LPS诱导的HK-2细胞中,MAP2K3表达水平显著增强。MAP2K3过表达和p38 MAPK激动剂可以减轻PDCD4下调对LPS诱导的细胞炎症和氧化应激的影响并抑制细胞凋亡。结论下调PDCD4可以通过抑制MAP2K3和p38 MAPK从而抑制LPS诱导的肾小管上皮细胞的炎症和凋亡。展开更多
Herein,the catalysts of ultrathin g-C_(3)N_(4)surface-modified hollow spherical Bi2MoO6(g-C_(3)N_(4)/Bi2MoO6,abbreviated as CN/BMO)were fabricated by the co-solvothermal method.The variable valence Mo^(5+)/Mo^(6+)ioni...Herein,the catalysts of ultrathin g-C_(3)N_(4)surface-modified hollow spherical Bi2MoO6(g-C_(3)N_(4)/Bi2MoO6,abbreviated as CN/BMO)were fabricated by the co-solvothermal method.The variable valence Mo^(5+)/Mo^(6+)ionic bridge in CN/BMO catalysts can boost the rapid transfer of photogenerated electrons from Bi2MoO6to g-C_(3)N_(4).And the synergy effect of g-C_(3)N_(4)and Bi2MoO6components remarkably enhance CO_(2)adsorption capability.CN/BMO-2 catalyst has the best performances for visible light-driven CO_(2)reduction compared with single Bi2MoO6and g-C_(3)N_(4),i.e.,its amount and selectivity of CO product are 139.50μmol g-1and 96.88%for 9 h,respectively.Based on the results of characterizations and density functional theory calculation,the photocatalytic mechanism for CO_(2)reduction is proposed.The high-efficient separation efficiency of photogenerated electron-hole pairs,induced by variable valence Mo^(5+)/Mo^(6+)ionic bridge,can boost the rate-limiting steps(COOH*-to-CO*and CO*desorption)of selective visible light-driven CO_(2)conversion into CO.It inspires the establishment of efficient photocatalysts for CO_(2)conversion.展开更多
BACKGROUND Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and T cell immunoglobulin and mucin domain-containing protein 3(TIM-3)are beneficial to the resumption of anti-tumor immunity...BACKGROUND Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and T cell immunoglobulin and mucin domain-containing protein 3(TIM-3)are beneficial to the resumption of anti-tumor immunity response and hold extreme potential as efficient therapies for certain malignancies.However,ICIs with a single target exhibit poor overall response rate in hepatocellular carcinoma(HCC)patients due to the complex pathological mechanisms of HCC.AIM To investigate the effects of combined TIM-3 and PD-1 blockade on tumor development in an HCC mouse model,aiming to identify more effective immunotherapies and provide more treatment options for HCC patients.METHODS The levels of PD-1 and TIM-3 on CD4+and CD8+T cells from tumor tissues,ascites,and matched adjacent tissues from HCC patients were determined with flow cytometry.An HCC xenograft mouse model was established and treated with anti-TIM-3 monoclonal antibody(mAb)and/or anti-PD-1 mAb.Tumor growth in each group was measured.Hematoxylin and eosin staining and immunohistochemical staining were used to evaluate T cell infiltration in tumors.The percentage of CD4+and CD8+T cells in tissue samples from mice was tested with flow cytometry.The percentages of PD-1+CD8+,TIM-3+CD8+,and PD-1+TIM-3+CD8+T cells was accessed by flow cytometry.The levels of the cytokines including tumor necrosis factor alpha(TNF-α),interferon-γ(IFN-γ),interleukin(IL)-6,and IL-10 in tumor tissues were gauged with enzyme-linked immunosorbent assay kits.RESULTS We confirmed that PD-1 and TIM-3 expression was substantially upregulated in CD4+and CD8+T cells isolated from tumor tissues and ascites of HCC patients.TIM-3 mAb and PD-1 mAb treatment both reduced tumor volume and weight,while combined blockade had more substantial anti-tumor effects than individual treatment.Then we showed that combined therapy increased T cell infiltration into tumor tissues,and downregulated PD-1 and TIM-3 expression on CD8+T cells in tumor tissues.Moreover,combined treatment facilitated the production of T cell effector cytokines TNF-α and IFN-γ,and reduced the production of immunosuppressive cytokines IL-10 and IL-6 in tumor tissues.Thus,we implicated that combined blockade could ameliorate T cell exhaustion in HCC mouse model.CONCLUSION Combined TIM-3 and PD-1 blockade restrains HCC development by facilitating CD4+ and CD8+T cell-mediated antitumor immune responses.展开更多
The AEC (Architecture, Engineering, and Construction) industry is gradually shifting away from 2D CAD drawings and toward Building Information Modeling as a result of the fast development of science and technology (BI...The AEC (Architecture, Engineering, and Construction) industry is gradually shifting away from 2D CAD drawings and toward Building Information Modeling as a result of the fast development of science and technology (BIM). The BIM idea’s introduction emphasizes the need to specify a building in a single building model with adequate information to suit its different needs rather than defining it in fragmented documents. This research work aims to use the BIM 4D for the simulation of the construction sequence of a Swivel Bridge. For that, the software Revit was used to make the 3D model of the bridge, and the software Navisworks was used for the 4D construction simulation of the project. The results demonstrated that BIM technology could help reduce delays and problems with the schedule and improve communication among stakeholders, and BIM visualization and simulation features were very useful compared to traditional planning methods.展开更多
Histone H3 lysine 4 trimethylation(H3K4me3)is a canonical chromatin modification associated with active gene transcription,playing a pivotal role in regulating various cellular functions.Components of the H3K4me3 meth...Histone H3 lysine 4 trimethylation(H3K4me3)is a canonical chromatin modification associated with active gene transcription,playing a pivotal role in regulating various cellular functions.Components of the H3K4me3 methyltransferase complex,known as the proteins associated with SET1(COMPASS),have been implicated in exerting cancer-protective or cancer-inhibitory effects through inducive H3K4me3 modification.However,the role of the indispensable non-catalytic component of COMPASS CXXC-type zinc finger protein 1(CFP1)in malignant progression remains unclear.展开更多
Four novel bridged dianilines containing fluorine were synthesized using 4-chloro-3, 5-dinitrobenzotrifluoride and diamine by two step condensation and reduction. The structures of corresponding compounds were determi...Four novel bridged dianilines containing fluorine were synthesized using 4-chloro-3, 5-dinitrobenzotrifluoride and diamine by two step condensation and reduction. The structures of corresponding compounds were determined by means of IR, NMR and elemental analysis.展开更多
文摘目的研究程序性细胞死亡蛋白4(programmed cell death protein 4,PDCD4)在脓毒症诱导的急性肾损伤(acute kidney injury,AKI)中的作用机制,以及调控PDCD4表达通过丝裂原活化蛋白激酶3(mitogen-activated protein kinase 3,MAP2K3)和p38蛋白激酶(p38 mitogen-activated protein kinase,p38 MAPK)对脓毒症AKI起到潜在治疗作用。方法用脂多糖(lipopolysaccharide,LPS)刺激人肾小管上皮细胞(HK-2)构建脓毒症AKI细胞模型。进一步用腺病毒介导siRNA和过表达载体抑制和上调AKI细胞模型中PDCD4的表达;CCK-8法检测细胞增殖;用DCFH-DA及激光共聚焦显微镜检测细胞中ROS水平,用总SOD活性检测试剂和MDA检测试剂盒检测细胞中SOD和MDA水平;免疫共沉淀验证PDCD4和MAP2K3之间的蛋白相互作用;TUNEL染色法检测细胞凋亡;RT-qPCR和Western blot检测PDCD4及相关基因的mRNA和蛋白表达水平;ELISA法检测患者血清中炎症相关因子水平。结果LPS诱导可以促进HK-2细胞中PDCD4表达,下调PDCD4可抑制LPS诱导的HK-2细胞的炎症、氧化应激及细胞凋亡。数据库预测及免疫共沉淀证实PDCD4可以与MAP2K3相互作用,且在LPS诱导的HK-2细胞中,MAP2K3表达水平显著增强。MAP2K3过表达和p38 MAPK激动剂可以减轻PDCD4下调对LPS诱导的细胞炎症和氧化应激的影响并抑制细胞凋亡。结论下调PDCD4可以通过抑制MAP2K3和p38 MAPK从而抑制LPS诱导的肾小管上皮细胞的炎症和凋亡。
基金supported by the National Natural Science Foundation of China(21972166)the Beijing Natural Science Foundation(2202045)the National Key Research and Development Program of China(2019YFC1907600)。
文摘Herein,the catalysts of ultrathin g-C_(3)N_(4)surface-modified hollow spherical Bi2MoO6(g-C_(3)N_(4)/Bi2MoO6,abbreviated as CN/BMO)were fabricated by the co-solvothermal method.The variable valence Mo^(5+)/Mo^(6+)ionic bridge in CN/BMO catalysts can boost the rapid transfer of photogenerated electrons from Bi2MoO6to g-C_(3)N_(4).And the synergy effect of g-C_(3)N_(4)and Bi2MoO6components remarkably enhance CO_(2)adsorption capability.CN/BMO-2 catalyst has the best performances for visible light-driven CO_(2)reduction compared with single Bi2MoO6and g-C_(3)N_(4),i.e.,its amount and selectivity of CO product are 139.50μmol g-1and 96.88%for 9 h,respectively.Based on the results of characterizations and density functional theory calculation,the photocatalytic mechanism for CO_(2)reduction is proposed.The high-efficient separation efficiency of photogenerated electron-hole pairs,induced by variable valence Mo^(5+)/Mo^(6+)ionic bridge,can boost the rate-limiting steps(COOH*-to-CO*and CO*desorption)of selective visible light-driven CO_(2)conversion into CO.It inspires the establishment of efficient photocatalysts for CO_(2)conversion.
基金Supported by the First-Class Discipline Construction Founded Project of Ningxia Medical University and the School of Clinical Medicine,No.2020008.
文摘BACKGROUND Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and T cell immunoglobulin and mucin domain-containing protein 3(TIM-3)are beneficial to the resumption of anti-tumor immunity response and hold extreme potential as efficient therapies for certain malignancies.However,ICIs with a single target exhibit poor overall response rate in hepatocellular carcinoma(HCC)patients due to the complex pathological mechanisms of HCC.AIM To investigate the effects of combined TIM-3 and PD-1 blockade on tumor development in an HCC mouse model,aiming to identify more effective immunotherapies and provide more treatment options for HCC patients.METHODS The levels of PD-1 and TIM-3 on CD4+and CD8+T cells from tumor tissues,ascites,and matched adjacent tissues from HCC patients were determined with flow cytometry.An HCC xenograft mouse model was established and treated with anti-TIM-3 monoclonal antibody(mAb)and/or anti-PD-1 mAb.Tumor growth in each group was measured.Hematoxylin and eosin staining and immunohistochemical staining were used to evaluate T cell infiltration in tumors.The percentage of CD4+and CD8+T cells in tissue samples from mice was tested with flow cytometry.The percentages of PD-1+CD8+,TIM-3+CD8+,and PD-1+TIM-3+CD8+T cells was accessed by flow cytometry.The levels of the cytokines including tumor necrosis factor alpha(TNF-α),interferon-γ(IFN-γ),interleukin(IL)-6,and IL-10 in tumor tissues were gauged with enzyme-linked immunosorbent assay kits.RESULTS We confirmed that PD-1 and TIM-3 expression was substantially upregulated in CD4+and CD8+T cells isolated from tumor tissues and ascites of HCC patients.TIM-3 mAb and PD-1 mAb treatment both reduced tumor volume and weight,while combined blockade had more substantial anti-tumor effects than individual treatment.Then we showed that combined therapy increased T cell infiltration into tumor tissues,and downregulated PD-1 and TIM-3 expression on CD8+T cells in tumor tissues.Moreover,combined treatment facilitated the production of T cell effector cytokines TNF-α and IFN-γ,and reduced the production of immunosuppressive cytokines IL-10 and IL-6 in tumor tissues.Thus,we implicated that combined blockade could ameliorate T cell exhaustion in HCC mouse model.CONCLUSION Combined TIM-3 and PD-1 blockade restrains HCC development by facilitating CD4+ and CD8+T cell-mediated antitumor immune responses.
文摘The AEC (Architecture, Engineering, and Construction) industry is gradually shifting away from 2D CAD drawings and toward Building Information Modeling as a result of the fast development of science and technology (BIM). The BIM idea’s introduction emphasizes the need to specify a building in a single building model with adequate information to suit its different needs rather than defining it in fragmented documents. This research work aims to use the BIM 4D for the simulation of the construction sequence of a Swivel Bridge. For that, the software Revit was used to make the 3D model of the bridge, and the software Navisworks was used for the 4D construction simulation of the project. The results demonstrated that BIM technology could help reduce delays and problems with the schedule and improve communication among stakeholders, and BIM visualization and simulation features were very useful compared to traditional planning methods.
基金This work was supported by the National Key R&D Program of China(2021YFF1201303)the National Natural Science Foundation of China(81972196)+1 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-1-12M-012)the R&D Program of Beijing Municipal Education Commission(KJZD20191002302).
文摘Histone H3 lysine 4 trimethylation(H3K4me3)is a canonical chromatin modification associated with active gene transcription,playing a pivotal role in regulating various cellular functions.Components of the H3K4me3 methyltransferase complex,known as the proteins associated with SET1(COMPASS),have been implicated in exerting cancer-protective or cancer-inhibitory effects through inducive H3K4me3 modification.However,the role of the indispensable non-catalytic component of COMPASS CXXC-type zinc finger protein 1(CFP1)in malignant progression remains unclear.
文摘淋巴细胞活化基因3(lymphocyte-activation gene 3,LAG-3)又称CD223,是一种由LAG-3基因编码的含有498个氨基酸的I型穿膜蛋白,由胞外区、穿膜区和胞内区三部分组成。LAG-3主要通过胞外区与配体结合,负向调控T淋巴细胞,避免T细胞过度激活引发自身免疫。与程序性死亡蛋白-1(programmed cell death 1,PD-1)和细胞毒性T淋巴细胞抗原4(cytotoxic T lymphocyte antigen 4,CTLA-4)一样,LAG-3是体内重要的免疫检查点,对人体免疫系统起到平衡调控作用。肿瘤细胞通过高表达LAG-3配体逃避机体免疫系统的监视。随着免疫检查点的研究逐渐深入,LAG-3成为继PD-1和CTLA-4之后新一代的免疫治疗靶点。本文主要对LAG-3的结构、功能及其抑制剂在肿瘤免疫治疗中的应用进行综述,以期为LAG-3的进一步研究提供参考。
基金Supported by the Key Scientific Research Founda-tion of Education Development of Hunan Province (02A036)Sci-ence and Technology Program Foundation of Hunan Province(03JZY3042)
文摘Four novel bridged dianilines containing fluorine were synthesized using 4-chloro-3, 5-dinitrobenzotrifluoride and diamine by two step condensation and reduction. The structures of corresponding compounds were determined by means of IR, NMR and elemental analysis.
