Mammalian target of rapamycin(mTOR),a serine/threonine kinase orchestrating cellular metabolism,is a crucial immune system regulator.However,it remains unclear how mTOR regulates dendritic cell(DC) function in vivo,es...Mammalian target of rapamycin(mTOR),a serine/threonine kinase orchestrating cellular metabolism,is a crucial immune system regulator.However,it remains unclear how mTOR regulates dendritic cell(DC) function in vivo,especially DC-T cell encounters,a critical step for initiating adaptive immune responses.We dynamically visualized DC-T contacts in mouse lymph node using confocal microscopy and established an encounter model to characterize the effect of mTOR inhibition on DC-T cell encounters using DC morphology.Quantitative data showed mTOR inhibition via rapamycin altered DC shape,with an increased form factor(30.17%) and decreased cellular surface area(20.36%) and perimeter(22.43%),which were associated with Cdc42 protein downregulation(52.71%).Additionally,DCs adopted a similar morphological change with Cdc42 inhibition via ZCL278 as that observed with mTOR inhibition.These morphologically altered DCs displayed low encounter rates with T cells.Time-lapse imaging data of T cell motility supported the simulated result of the encounter model,where antigen-specific T cells appeared to reduce arrest in the lymph nodes of rapamycin-pretreated mice relative to the untreated group.Therefore,mTOR inhibition altered DC morphology in vivo and decreased the DC-T cell encounter rate,as well as Cdc42 inhibition.By establishing an encounter model,our study provides an intuitive approach for the early prediction of DC function through morphological quantification of form factor and area.展开更多
To enhance the computational efficiency of spatio-temporally discretized phase-field models,we present a high-speed solver specifically designed for the Poisson equations,a component frequently used in the numerical c...To enhance the computational efficiency of spatio-temporally discretized phase-field models,we present a high-speed solver specifically designed for the Poisson equations,a component frequently used in the numerical computation of such models.This efficient solver employs algorithms based on discrete cosine transformations(DCT)or discrete sine transformations(DST)and is not restricted by any spatio-temporal schemes.Our proposed methodology is appropriate for a variety of phase-field models and is especially efficient when combined with flow field systems.Meanwhile,this study has conducted an extensive numerical comparison and found that employing DCT and DST techniques not only yields results comparable to those obtained via the Multigrid(MG)method,a conventional approach used in the resolution of the Poisson equations,but also enhances computational efficiency by over 90%.展开更多
针对带基数约束凸优化问题,提出了一个基于非线性DC(Difference of two convex functions)逼近函数的序列凸优化算法,并证明了该算法收敛到DC逼近问题的KKT(Karush-Kuhn-Tucker)点。数值实验结果表明:基于非线性DC逼近函数的序列凸优化...针对带基数约束凸优化问题,提出了一个基于非线性DC(Difference of two convex functions)逼近函数的序列凸优化算法,并证明了该算法收敛到DC逼近问题的KKT(Karush-Kuhn-Tucker)点。数值实验结果表明:基于非线性DC逼近函数的序列凸优化算法能有效找到带基数约束凸优化问题的稀疏解,且得到解的质量优于已有算法。展开更多
Objective： To investigate the antitumor effect of endostatin combined with tumor antigen-pulsed dendritic cell （DC）-T cell therapy on lung cancer. Methods： Transplanted Lewis lung cancer （LLC） models of C57BL/6 ...Objective： To investigate the antitumor effect of endostatin combined with tumor antigen-pulsed dendritic cell （DC）-T cell therapy on lung cancer. Methods： Transplanted Lewis lung cancer （LLC） models of C57BL/6 mice were established by subcutaneous injection of LLC cells in left extremity axillary. Tumor antigen-pulsed DC-T cells from spleen cells and bone of mice were cultured in vitro. Tumor-bearing mice were randomly divided into three groups, including DC- T＋endostatin group, DC-T group, and phosphate-buffered saline （PBS） control group. Microvessel density （MVD） of tumor tissue in tumor-bearing mice was determined by immunohistochemistry （IHC）. The expressions of vascular endothelial growth factor （VEGF） and hypoxia-inducible factor-1α （HIF-1α） were determined by Western blotting and IHC staining. The proportions of CD8＋ T cells, mature dendritic cells （mDC）, tumor-associated macrophages [TAM （M1/M2）], and myeloid-derived suppressor cells （MDSC） in suspended cells of tumor tissue were determined by flow cytometry. The expressions of inter｜eukin （IL）-6, IL-10, IL-17, transforming growth factor-β（TGF-β） and interferon-γ （IFN-γ） in suspended cells of tumor tissue were detected by enzyme-linked immune sorbent assay （ELISA）. Results： DC-T cells combined with endostatin remarkably suppressed tumor growth. MVD of mice in DC- T＋endostatin group was significantly lower than that of the control group and DC-T monotherapy group. The expressions of VEGF, IL-6 and IL-17 in tumors were markedly decreased, but IFN-γ, and HIF-1α increased after treating with DC-T cells combined with endostatin, compared to control group and DC-T group. In the DC- T＋endostatin group, the proportions of MDSC and TAM （M2 type） were significantly decreased, mDC and TAM （Nil type） were up-regulated, and CD8＋ T cells were recruited to infiltrate tumors, in contrast to PBS control and DC-T monotherapy. DC-T cells combined with endostatin potently reduced the expressions of IL-6, IL-10, TGF-β and IL-17 in tumor tissue, and enhanced the expression of IFN-γ. Conclusions： The study indicated the synergic antitumor effects between endostatin and tumor antigen-pulsed DC-T cells, which may be a prospective therapy strategy to achieve potent antitumor effects on lung cancer.展开更多
基金supported by the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (61721092)the Major Research Plan of the National Natural Science Foundation of China (91542000, 91442201)+2 种基金National Science Fund for Distinguished Young Scholars (81625012)National Natural Science Foundation of China (81501593)the Director Fund of WNLO
文摘Mammalian target of rapamycin(mTOR),a serine/threonine kinase orchestrating cellular metabolism,is a crucial immune system regulator.However,it remains unclear how mTOR regulates dendritic cell(DC) function in vivo,especially DC-T cell encounters,a critical step for initiating adaptive immune responses.We dynamically visualized DC-T contacts in mouse lymph node using confocal microscopy and established an encounter model to characterize the effect of mTOR inhibition on DC-T cell encounters using DC morphology.Quantitative data showed mTOR inhibition via rapamycin altered DC shape,with an increased form factor(30.17%) and decreased cellular surface area(20.36%) and perimeter(22.43%),which were associated with Cdc42 protein downregulation(52.71%).Additionally,DCs adopted a similar morphological change with Cdc42 inhibition via ZCL278 as that observed with mTOR inhibition.These morphologically altered DCs displayed low encounter rates with T cells.Time-lapse imaging data of T cell motility supported the simulated result of the encounter model,where antigen-specific T cells appeared to reduce arrest in the lymph nodes of rapamycin-pretreated mice relative to the untreated group.Therefore,mTOR inhibition altered DC morphology in vivo and decreased the DC-T cell encounter rate,as well as Cdc42 inhibition.By establishing an encounter model,our study provides an intuitive approach for the early prediction of DC function through morphological quantification of form factor and area.
基金Supported by Shanxi Province Natural Science Research(202203021212249)Special/Youth Foundation of Taiyuan University of Technology(2022QN101)+3 种基金National Natural Science Foundation of China(12301556)Research Project Supported by Shanxi Scholarship Council of China(2021-029)International Cooperation Base and Platform Project of Shanxi Province(202104041101019)Basic Research Plan of Shanxi Province(202203021211129)。
文摘To enhance the computational efficiency of spatio-temporally discretized phase-field models,we present a high-speed solver specifically designed for the Poisson equations,a component frequently used in the numerical computation of such models.This efficient solver employs algorithms based on discrete cosine transformations(DCT)or discrete sine transformations(DST)and is not restricted by any spatio-temporal schemes.Our proposed methodology is appropriate for a variety of phase-field models and is especially efficient when combined with flow field systems.Meanwhile,this study has conducted an extensive numerical comparison and found that employing DCT and DST techniques not only yields results comparable to those obtained via the Multigrid(MG)method,a conventional approach used in the resolution of the Poisson equations,but also enhances computational efficiency by over 90%.
文摘针对带基数约束凸优化问题,提出了一个基于非线性DC(Difference of two convex functions)逼近函数的序列凸优化算法,并证明了该算法收敛到DC逼近问题的KKT(Karush-Kuhn-Tucker)点。数值实验结果表明:基于非线性DC逼近函数的序列凸优化算法能有效找到带基数约束凸优化问题的稀疏解,且得到解的质量优于已有算法。
基金supported by Natural Science Foundation of Shandong province,China(No.ZR2010HL015)Natural Science Youth Foundation of Shandong province,China(No.ZR2013HQ017)
文摘Objective： To investigate the antitumor effect of endostatin combined with tumor antigen-pulsed dendritic cell （DC）-T cell therapy on lung cancer. Methods： Transplanted Lewis lung cancer （LLC） models of C57BL/6 mice were established by subcutaneous injection of LLC cells in left extremity axillary. Tumor antigen-pulsed DC-T cells from spleen cells and bone of mice were cultured in vitro. Tumor-bearing mice were randomly divided into three groups, including DC- T＋endostatin group, DC-T group, and phosphate-buffered saline （PBS） control group. Microvessel density （MVD） of tumor tissue in tumor-bearing mice was determined by immunohistochemistry （IHC）. The expressions of vascular endothelial growth factor （VEGF） and hypoxia-inducible factor-1α （HIF-1α） were determined by Western blotting and IHC staining. The proportions of CD8＋ T cells, mature dendritic cells （mDC）, tumor-associated macrophages [TAM （M1/M2）], and myeloid-derived suppressor cells （MDSC） in suspended cells of tumor tissue were determined by flow cytometry. The expressions of inter｜eukin （IL）-6, IL-10, IL-17, transforming growth factor-β（TGF-β） and interferon-γ （IFN-γ） in suspended cells of tumor tissue were detected by enzyme-linked immune sorbent assay （ELISA）. Results： DC-T cells combined with endostatin remarkably suppressed tumor growth. MVD of mice in DC- T＋endostatin group was significantly lower than that of the control group and DC-T monotherapy group. The expressions of VEGF, IL-6 and IL-17 in tumors were markedly decreased, but IFN-γ, and HIF-1α increased after treating with DC-T cells combined with endostatin, compared to control group and DC-T group. In the DC- T＋endostatin group, the proportions of MDSC and TAM （M2 type） were significantly decreased, mDC and TAM （Nil type） were up-regulated, and CD8＋ T cells were recruited to infiltrate tumors, in contrast to PBS control and DC-T monotherapy. DC-T cells combined with endostatin potently reduced the expressions of IL-6, IL-10, TGF-β and IL-17 in tumor tissue, and enhanced the expression of IFN-γ. Conclusions： The study indicated the synergic antitumor effects between endostatin and tumor antigen-pulsed DC-T cells, which may be a prospective therapy strategy to achieve potent antitumor effects on lung cancer.
