Longitudinal cracks on the tunnel lining significantly influence the performance of tunnels in operation.In this study,we propose a semi-analytical method that provides a simple and effective way to calculate the inte...Longitudinal cracks on the tunnel lining significantly influence the performance of tunnels in operation.In this study,we propose a semi-analytical method that provides a simple and effective way to calculate the internal forces of tunnel linings with multiple cracks.The semi-analytical solution is obtained using structural analysis considering the flexural rigidity for the cracked longitudinal section of the tunnel lining.Then the proposed solution is verified numerically.Using the proposed method,the influences of the crack depth and the number of cracks on the bending moment and modified crack tip stress are investigated.With the increase in crack depth,the bending moment of lining scetion adjacent to the crack decreases,while the bending moment of lining scetion far away from the crack increases slightly.The more the number of cracks in a tunnel lining,the easier the new cracks initiated.展开更多
To investigate the longitudinal deformation profile(LDP)of a deep tunnel in non-hydrostatic condition,an analytical model is proposed in our study.In this model,the problem is considered as a superposition of two part...To investigate the longitudinal deformation profile(LDP)of a deep tunnel in non-hydrostatic condition,an analytical model is proposed in our study.In this model,the problem is considered as a superposition of two partial models,and the displacement field of the second partial model is the same as that of the concerned problem.Therefore,the problem can be solved by a model with simple boundary conditions.We obtain the solutions for the stress and displacement fields of an infinite body caused by arbitrary surface tractions on the boundary of the coming tunnel(zone inside the tunnel before excavation)by integrating the extended Kelvin solution over the boundary.The obtained stress solution is used to solve the specific surface tractions,which can satisfy the boundary conditions of the second partial model,on the boundary of the coming tunnel in an infinite body.Then,the specific surface tractions are substituted into the obtained displacement solution to solve the displacement on the wall and face of the tunnel.Therefore,the LDP can also be calculated.The proposed solution is verified by both numerical simulation and the LDP functions recommended by other researchers.The major advantage of our analytical model is that it can consider the effects of the axial and horizontal lateral pressure coefficients.It is revealed that the horizontal lateral pressure coefficient majorly affects the LDP behind the tunnel face,while the axial lateral pressure coefficient dominates the LDP ahead of the tunnel face.Furthermore,the deformation characteristics of the LDPs ahead of the face and the unexcavated core are investigated.The axial displacements of the excavation face can be used to predict the crown displacements ahead of the face.展开更多
DNA hypermethylation of tumor suppressor genes has been frequently observed in cancer patients, and therefore, may provide a valuable biomarker for cancer prevention and treatment. DNA hypermethylation may also provid...DNA hypermethylation of tumor suppressor genes has been frequently observed in cancer patients, and therefore, may provide a valuable biomarker for cancer prevention and treatment. DNA hypermethylation may also provide an important mechanism in cancer progression. Lung cancer is strongly associated with exposure to environmental carcinogens, especially tobacco smoke. DNA damage generated by tobacco smoke is believed to play an important role in lung cancer development. XPC is a DNA damage recognition protein required for DNA repair and other DNA damage responses and attenuated XPC protein levels have been detected in many lung cancer patients. We studied the role of XPC protein deficiency in tobacco smoke-caused DNA hypermethylation of important tumor suppressor genes. Using both normal human fibroblasts (NF) and XPC-deficient hu man fibroblasts (XPC), our DNA methylation studies demonstrated that the XPC deficiency caused elevated levels of DNA hypermethylation in both Brca1 and Mlh1 tumor suppressor genes following exposure to tobacco smoke condensate (TSC). The results of our ChIP studies revealed that the XPC deficiency led to an increased binding of DNA methyltransferase 3A (DNMT3A) at the promoter region CpG island-containing sequences of these genes under the TSC treatment;however, this increase was partially diminished with prior treatment with caffeine. The results of our immuno-precipitation (IP) studies demonstrated a protein-protein interaction of the ATR with DNMT3A. Our western blots revealed that the XPC deficiency caused an increase in TSC-induced ATR phosphorylation at serine 428, an indicator of ATR activation. All these results suggest that XPC deficiency causes an accelerated DNA hypermethylation in important tumor suppressor genes under tobacco smoke exposure and activation of the ATR signaling pathway is involved in this DNA hypermethylation process.展开更多
Majorana fermions have been predicted to exist at the edge states of a two-dimensional topological superconductor.We fabricated single quintuple layer(QL)Bi2Te3/FeTe heterostructure with the step-flow epitaxy method a...Majorana fermions have been predicted to exist at the edge states of a two-dimensional topological superconductor.We fabricated single quintuple layer(QL)Bi2Te3/FeTe heterostructure with the step-flow epitaxy method and studied the topological properties of this system by using angle-resolved photoemission spectroscopy and scanning tunneling microscopy/spectroscopy.We observed the coexistence of robust superconductivity and edge states on the single QL Bi2Te3 islands which can be potential evidence for topological superconductor.展开更多
Cross-talks (e.g., host-driven iron withdrawal and microbial iron uptake between host gastrointestinal tract and commensal microbes) regulate immunotolerance and intestinal homeostasis. However, underlying mechanisms ...Cross-talks (e.g., host-driven iron withdrawal and microbial iron uptake between host gastrointestinal tract and commensal microbes) regulate immunotolerance and intestinal homeostasis. However, underlying mechanisms that regulate the cross-talks remain poorly understood. Here, we show that bacterial products up-regulate iron-transporter transferrin and transferrin acts as an immunosuppressor by interacting with cluster of differentiation 14 (CD14) to inhibit pattern recognition receptor (PRR) signaling and induce host immunotolerance. Decreased intestinal transferrin is found in germ-free mice and human patients with ulcerative colitis, which are characterized by impaired intestinal immunotolerance. Intestinal transferrin and host immunotolerance are returned to normal when germ-free mice get normal microbial commensalism, suggesting an association between microbial commensalism, transferrin, and host immunotolerance. Mouse colitis models show that transferrin shortage impairs host’s tolerogenic responses, while its supplementation promotes immunotolerance. Designed peptide blocking transferrin–CD14 interaction inhibits immunosuppressive effects of transferrin. In monkeys with idiopathic chronic diarrhea, transferrin shows comparable or even better therapeutic effects than hydrocortisone. Our findings reveal that by up-regulating host transferrin to silence PRR signaling, commensal bacteria counteract immune activation induced by themselves to shape host immunity and contribute for intestinal tolerance.展开更多
Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain pro...Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.展开更多
State-of-the-art molecular electronics focus on the measurement of electrical properties of materials at the single-molecule level.Experimentally, molecular electronics face two primary challenges. One challenge is th...State-of-the-art molecular electronics focus on the measurement of electrical properties of materials at the single-molecule level.Experimentally, molecular electronics face two primary challenges. One challenge is the reliable construction of single-molecule junctions, and the second challenge is the arbitrary modulation of electron transport through these junctions. Over the past decades, electrochemistry has been widely adopted to meet these challenges, leading to a wealth of novel findings. This review starts from the application of electrochemical methods to the fabrication of nanogaps, which is an essential platform for the construction of single-molecule junctions. The utilization of electrochemistry for the modification of molecular junctions,including terminal groups and structural backbones, is introduced, and finally, recent progress in the electrochemical modulation of single-molecule electron transport is reviewed.展开更多
基金The authors gratefully acknowledge the financial support by the Key Project of High-speed Rail Joint Fund of National Natural Science Foundation of China(Grant No.U1934210)the Natural Science Foundation of Beijing,China(Grant No.8202037).
文摘Longitudinal cracks on the tunnel lining significantly influence the performance of tunnels in operation.In this study,we propose a semi-analytical method that provides a simple and effective way to calculate the internal forces of tunnel linings with multiple cracks.The semi-analytical solution is obtained using structural analysis considering the flexural rigidity for the cracked longitudinal section of the tunnel lining.Then the proposed solution is verified numerically.Using the proposed method,the influences of the crack depth and the number of cracks on the bending moment and modified crack tip stress are investigated.With the increase in crack depth,the bending moment of lining scetion adjacent to the crack decreases,while the bending moment of lining scetion far away from the crack increases slightly.The more the number of cracks in a tunnel lining,the easier the new cracks initiated.
基金the financial support by the Key Project of High-speed Rail Joint Fund of National Natural Science Foundation of China(Grant No.U1934210)the Natural Science Foundation of Beijing,China(Grant No.8202037)。
文摘To investigate the longitudinal deformation profile(LDP)of a deep tunnel in non-hydrostatic condition,an analytical model is proposed in our study.In this model,the problem is considered as a superposition of two partial models,and the displacement field of the second partial model is the same as that of the concerned problem.Therefore,the problem can be solved by a model with simple boundary conditions.We obtain the solutions for the stress and displacement fields of an infinite body caused by arbitrary surface tractions on the boundary of the coming tunnel(zone inside the tunnel before excavation)by integrating the extended Kelvin solution over the boundary.The obtained stress solution is used to solve the specific surface tractions,which can satisfy the boundary conditions of the second partial model,on the boundary of the coming tunnel in an infinite body.Then,the specific surface tractions are substituted into the obtained displacement solution to solve the displacement on the wall and face of the tunnel.Therefore,the LDP can also be calculated.The proposed solution is verified by both numerical simulation and the LDP functions recommended by other researchers.The major advantage of our analytical model is that it can consider the effects of the axial and horizontal lateral pressure coefficients.It is revealed that the horizontal lateral pressure coefficient majorly affects the LDP behind the tunnel face,while the axial lateral pressure coefficient dominates the LDP ahead of the tunnel face.Furthermore,the deformation characteristics of the LDPs ahead of the face and the unexcavated core are investigated.The axial displacements of the excavation face can be used to predict the crown displacements ahead of the face.
文摘DNA hypermethylation of tumor suppressor genes has been frequently observed in cancer patients, and therefore, may provide a valuable biomarker for cancer prevention and treatment. DNA hypermethylation may also provide an important mechanism in cancer progression. Lung cancer is strongly associated with exposure to environmental carcinogens, especially tobacco smoke. DNA damage generated by tobacco smoke is believed to play an important role in lung cancer development. XPC is a DNA damage recognition protein required for DNA repair and other DNA damage responses and attenuated XPC protein levels have been detected in many lung cancer patients. We studied the role of XPC protein deficiency in tobacco smoke-caused DNA hypermethylation of important tumor suppressor genes. Using both normal human fibroblasts (NF) and XPC-deficient hu man fibroblasts (XPC), our DNA methylation studies demonstrated that the XPC deficiency caused elevated levels of DNA hypermethylation in both Brca1 and Mlh1 tumor suppressor genes following exposure to tobacco smoke condensate (TSC). The results of our ChIP studies revealed that the XPC deficiency led to an increased binding of DNA methyltransferase 3A (DNMT3A) at the promoter region CpG island-containing sequences of these genes under the TSC treatment;however, this increase was partially diminished with prior treatment with caffeine. The results of our immuno-precipitation (IP) studies demonstrated a protein-protein interaction of the ATR with DNMT3A. Our western blots revealed that the XPC deficiency caused an increase in TSC-induced ATR phosphorylation at serine 428, an indicator of ATR activation. All these results suggest that XPC deficiency causes an accelerated DNA hypermethylation in important tumor suppressor genes under tobacco smoke exposure and activation of the ATR signaling pathway is involved in this DNA hypermethylation process.
基金Project supported by the National Natural Science Foundation of China(Grant Nos.61734008 and 11774143)the National Key Research and Development Program of China(Grant Nos.2018YFA0307100,2016YFA0301703,and 2016YFA0300300)+4 种基金the Natural Science Foundation of Guangdong Province,China(Grant Nos.2015A030313840 and 2017A030313033)the State Key Laboratory of Low-Dimensional Quantum Physics(Grant No.KF201602)Technology and Innovation Commission of Shenzhen Municipality,China(Grant Nos.ZDSYS20170303165926217 and JCYJ20170412152334605)Guangdong Provincial Key Laboratory,China(Grant No.2019B121203002)J.-W.M.was partially supported by the Program for Guangdong Introducing Innovative and Entrepreneurial Teams,China(Grant No.2017ZT07C062).
文摘Majorana fermions have been predicted to exist at the edge states of a two-dimensional topological superconductor.We fabricated single quintuple layer(QL)Bi2Te3/FeTe heterostructure with the step-flow epitaxy method and studied the topological properties of this system by using angle-resolved photoemission spectroscopy and scanning tunneling microscopy/spectroscopy.We observed the coexistence of robust superconductivity and edge states on the single QL Bi2Te3 islands which can be potential evidence for topological superconductor.
基金the National Key Research and Development Program of China(2022YFF1301601)the Ministry of Science and Technology of China(2018YFA0801403 and 2022YFC2105003)+6 种基金the National Science Foundation of China(31930015,32100907,U2002219,and 32371162)the Chinese Academy of Sciences(KFJ-BRP-008 and SAJC202103)Yunnan Province(202003AD150008,202202AA100002 and 202301AS070074)the Kunming Science and Technology Bureau(2022SCP007)the New Cornerstone Investigator Program from Shenzhen New Cornerstone Science Foundation,Excellent Young Scientists Foundation of Shandong Province(ZR2023YQ025)the Frontiers Medical Center,Tianfu Jincheng Laboratory Foundation(TFJC2023010007)the PI Project of Southern Marine Science and Engineering Guangdong Laboratory(Guangzhou)(GML2021GD0807).
文摘Cross-talks (e.g., host-driven iron withdrawal and microbial iron uptake between host gastrointestinal tract and commensal microbes) regulate immunotolerance and intestinal homeostasis. However, underlying mechanisms that regulate the cross-talks remain poorly understood. Here, we show that bacterial products up-regulate iron-transporter transferrin and transferrin acts as an immunosuppressor by interacting with cluster of differentiation 14 (CD14) to inhibit pattern recognition receptor (PRR) signaling and induce host immunotolerance. Decreased intestinal transferrin is found in germ-free mice and human patients with ulcerative colitis, which are characterized by impaired intestinal immunotolerance. Intestinal transferrin and host immunotolerance are returned to normal when germ-free mice get normal microbial commensalism, suggesting an association between microbial commensalism, transferrin, and host immunotolerance. Mouse colitis models show that transferrin shortage impairs host’s tolerogenic responses, while its supplementation promotes immunotolerance. Designed peptide blocking transferrin–CD14 interaction inhibits immunosuppressive effects of transferrin. In monkeys with idiopathic chronic diarrhea, transferrin shows comparable or even better therapeutic effects than hydrocortisone. Our findings reveal that by up-regulating host transferrin to silence PRR signaling, commensal bacteria counteract immune activation induced by themselves to shape host immunity and contribute for intestinal tolerance.
基金the National Natural Science Foundation of China(81903666 and 31930015)the Chinese Academy of Sciences(XDB31000000,KFJ-STS-SCYD-304,and K.C.Wong Education Foundation,China)+4 种基金the Science and Technology Department of Yunnan Province (202101AT070301,2019ZF003,202002AA100007,202003AD150008,and 2019FB103China)Project of Innovative Research Team of Yunnan Province(2019HC005China)the Department of Industry and Information Technology of Yunnan Province (2019-YT-053,China)。
文摘Unlike healthy, non-transformed cells, the proteostasis network of cancer cells is taxed to produce proteins involved in tumor development. Cancer cells have a higher dependency on molecular chaperones to maintain proteostasis. The chaperonin T-complex protein ring complex(TRiC) contains eight paralogous subunits(CCT1-8), and assists the folding of as many as 10% of cytosolic proteome.TRiC is essential for the progression of some cancers, but the roles of TRiC subunits in osteosarcoma remain to be explored. Here, we show that CCT4/TRiC is significantly correlated in human osteosarcoma,and plays a critical role in osteosarcoma cell survival. We identify a compound anticarin-β that can specifically bind to and inhibit CCT4. Anticarin-β shows higher selectivity in cancer cells than in normal cells. Mechanistically, anticarin-β potently impedes CCT4-mediated STAT3 maturation. Anticarin-β displays remarkable antitumor efficacy in orthotopic and patient-derived xenograft models of osteosarcoma.Collectively, our data uncover a key role of CCT4 in osteosarcoma, and propose a promising treatment strategy for osteosarcoma by disrupting CCT4 and proteostasis.
基金supported by the Fundamental Research Funds for the Central Universities in China (Xiamen University: 20720170035)the National Natural Science Foundation of China (21503179, 61573295, 21722305)the Nation Key R&D Program of China (2017YFA0204902)
文摘State-of-the-art molecular electronics focus on the measurement of electrical properties of materials at the single-molecule level.Experimentally, molecular electronics face two primary challenges. One challenge is the reliable construction of single-molecule junctions, and the second challenge is the arbitrary modulation of electron transport through these junctions. Over the past decades, electrochemistry has been widely adopted to meet these challenges, leading to a wealth of novel findings. This review starts from the application of electrochemical methods to the fabrication of nanogaps, which is an essential platform for the construction of single-molecule junctions. The utilization of electrochemistry for the modification of molecular junctions,including terminal groups and structural backbones, is introduced, and finally, recent progress in the electrochemical modulation of single-molecule electron transport is reviewed.