This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of wood...This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, andfor the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.展开更多
The accuracy of nucleation parameter is a critical factor in the simulation of microstructural evolution during dynamic recrystallization(DRX).Based on the flow stress curve under hot deformation conditions,a new appr...The accuracy of nucleation parameter is a critical factor in the simulation of microstructural evolution during dynamic recrystallization(DRX).Based on the flow stress curve under hot deformation conditions,a new approach is proposed to identify the nucleation parameter during DRX.In this approach,a cellular automaton(CA) model is applied to quantitatively simulate the microstructural evolution and flow stress during hot deformation;and adaptive response surface method(ARSM) is applied as optimization model to provide input parameters to CA model and evaluate the outputs of the latter.By taking an oxygen-free high-conductivity(OFHC) copper as an example,the good agreement between the simulation results and the experimental observations demonstrates the availability of the proposed method.展开更多
Intercellular communication is an important means of molecular information transfer through exchange of membrane proteins from cells to cells. Advent of the latest analytical and imaging tools has allowed us to enhanc...Intercellular communication is an important means of molecular information transfer through exchange of membrane proteins from cells to cells. Advent of the latest analytical and imaging tools has allowed us to enhance our understanding of the cellular communication through the intercellular exchange of intact membrane patches, also called trogocytosis, which is a ubiquitous phenomenon. Immune responses against pathogens or any foreign antigens require fine immune regulation, where cellular communications are mediated by either soluble or cell surface molecules. It has been demonstrated that the membrane molecule transfer between immune cells such as dendritic and T cells can be derived through internalization/recycling pathway, dissociation-associated pathway, uptake of exosomes and membrane nanotube formations. Recent evidence implicates the trogocytosis as an important mechanism of the immune system to modulate immune responses. Exchange of membrane molecules/ antigens between immune cells has been observed for a long time, but the mechanisms and functional consequences of these transfers remain unclear. In this review, we discuss the possible mechanisms of trogocytosis and its physiological relevance to immune system, with special reference to T cells and the stimulatory or suppressive immune responses derived from T cells with acquired dendritic cell membrane molecules. Cellular ＆ Molecular Immunology. 2008;5（4）：261-269.展开更多
One-dimensional blast response of continuous-density graded cellular rods was investigated theoretically and numerically. Analytical model based on the rigid-plastic hardening(R-PH) model was used to predict the blast...One-dimensional blast response of continuous-density graded cellular rods was investigated theoretically and numerically. Analytical model based on the rigid-plastic hardening(R-PH) model was used to predict the blast response of density-graded cellular rods. Finite element(FE) analysis was performed using a new model based on the 3 D Voronoi technique. The FE results have a good agreement with the analytical predictions. The blast response and energy absorption of cellular rods with the same mass but different density distributions were examined under different blast loading. As a blast resistance structure, cellular materials with high energy absorption and low impulse transmit is attractive. However, high energy absorption and low impulse transmit cannot be achieved at the same time by changing the density distribution. The energy absorption capacity increases with the initial blast pressure and characteristic time of the exponentially decaying blast loading. By contract, when the blast loading exceeds the resistance capacity of cellular material, the transmitted stress will be enhanced which is detrimental to the structure being protected.展开更多
The flagellin component FliC of Salmonella typhimurium is capable of activating the innate immune system via specific interactions with TLR5 and can also act as a carrier of foreign antigen to elicit antigen-specific ...The flagellin component FliC of Salmonella typhimurium is capable of activating the innate immune system via specific interactions with TLR5 and can also act as a carrier of foreign antigen to elicit antigen-specific immune responses.Thus,we constructed an attenuated Salmonella strain SL5928(fliC/esat)expressing chimeric flagellin that contained the ESAT-6 antigen coding sequence of Mycobacterium tuberculosis inserted into the highly variable region of the Salmonella flagellin coding gene fliCi.The chimeric flagellin functioned normally,as demonstrated using a flagella swarming assay and electron microscopy.To analyze the effects of chimeric flagellin,the cell-mediated immune response and cytotoxic T lymphocyte(CTL)effects specific for ESAT-6 antigen were tested after intranasal immunization of mice with flagellated Salmonella SL5928(fliC/esat).The results showed that SL5928(fliC/esat)intranasal immunization can strongly elicit an ESAT-6-specific T helper(Th)1-type immune response in mucosal lymphoid tissues,such as nasopharynx-associated lymph nodes,lung and Peyer’s patches,and a Th1/Th2 response was elicited in spleen and mesenteric lymph nodes.Furthermore,intranasal immunization of SL5928(fliC/esat)produced efficient CTL effects,as demonstrated using a 5-and 6-carboxyfluorescein diacetate succinimidyl ester(CFSE)assay.Thus,our study revealed that Salmonella flagellin acts as a carrier for foreign antigen and triggers strong Th1 and CTL responses during intranasal immunization.Chimeric flagellin is potentially an effective strategy for the development of novel vaccines against tuberculosis in humans and animals.展开更多
基金Supported by contract N01-AI-05399 to the College of Veterinary Medicine, Cornell University from the National Institute of Allergy and Infectious Diseases. PC and SM also have been supported by contract N01-AI-95390 to the Georgetown University Medical Center, Georgetown University from the National Institute of Allergy and Infectious Diseases
文摘This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, andfor the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.
基金Project(2006CB705401) supported by the National Basic Research Program of China
文摘The accuracy of nucleation parameter is a critical factor in the simulation of microstructural evolution during dynamic recrystallization(DRX).Based on the flow stress curve under hot deformation conditions,a new approach is proposed to identify the nucleation parameter during DRX.In this approach,a cellular automaton(CA) model is applied to quantitatively simulate the microstructural evolution and flow stress during hot deformation;and adaptive response surface method(ARSM) is applied as optimization model to provide input parameters to CA model and evaluate the outputs of the latter.By taking an oxygen-free high-conductivity(OFHC) copper as an example,the good agreement between the simulation results and the experimental observations demonstrates the availability of the proposed method.
文摘Intercellular communication is an important means of molecular information transfer through exchange of membrane proteins from cells to cells. Advent of the latest analytical and imaging tools has allowed us to enhance our understanding of the cellular communication through the intercellular exchange of intact membrane patches, also called trogocytosis, which is a ubiquitous phenomenon. Immune responses against pathogens or any foreign antigens require fine immune regulation, where cellular communications are mediated by either soluble or cell surface molecules. It has been demonstrated that the membrane molecule transfer between immune cells such as dendritic and T cells can be derived through internalization/recycling pathway, dissociation-associated pathway, uptake of exosomes and membrane nanotube formations. Recent evidence implicates the trogocytosis as an important mechanism of the immune system to modulate immune responses. Exchange of membrane molecules/ antigens between immune cells has been observed for a long time, but the mechanisms and functional consequences of these transfers remain unclear. In this review, we discuss the possible mechanisms of trogocytosis and its physiological relevance to immune system, with special reference to T cells and the stimulatory or suppressive immune responses derived from T cells with acquired dendritic cell membrane molecules. Cellular ＆ Molecular Immunology. 2008;5（4）：261-269.
文摘One-dimensional blast response of continuous-density graded cellular rods was investigated theoretically and numerically. Analytical model based on the rigid-plastic hardening(R-PH) model was used to predict the blast response of density-graded cellular rods. Finite element(FE) analysis was performed using a new model based on the 3 D Voronoi technique. The FE results have a good agreement with the analytical predictions. The blast response and energy absorption of cellular rods with the same mass but different density distributions were examined under different blast loading. As a blast resistance structure, cellular materials with high energy absorption and low impulse transmit is attractive. However, high energy absorption and low impulse transmit cannot be achieved at the same time by changing the density distribution. The energy absorption capacity increases with the initial blast pressure and characteristic time of the exponentially decaying blast loading. By contract, when the blast loading exceeds the resistance capacity of cellular material, the transmitted stress will be enhanced which is detrimental to the structure being protected.
基金supported by grants from the Major State Basic Research Development Program of China(973 Program)the National S T Major Project(no.2008 ZX10003-010)+2 种基金the National Department Public Benefit Research Foundation(200903027)the Program for Changjiang Scholars and Innovative Research Team in University(PCSIRT)the Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.
文摘The flagellin component FliC of Salmonella typhimurium is capable of activating the innate immune system via specific interactions with TLR5 and can also act as a carrier of foreign antigen to elicit antigen-specific immune responses.Thus,we constructed an attenuated Salmonella strain SL5928(fliC/esat)expressing chimeric flagellin that contained the ESAT-6 antigen coding sequence of Mycobacterium tuberculosis inserted into the highly variable region of the Salmonella flagellin coding gene fliCi.The chimeric flagellin functioned normally,as demonstrated using a flagella swarming assay and electron microscopy.To analyze the effects of chimeric flagellin,the cell-mediated immune response and cytotoxic T lymphocyte(CTL)effects specific for ESAT-6 antigen were tested after intranasal immunization of mice with flagellated Salmonella SL5928(fliC/esat).The results showed that SL5928(fliC/esat)intranasal immunization can strongly elicit an ESAT-6-specific T helper(Th)1-type immune response in mucosal lymphoid tissues,such as nasopharynx-associated lymph nodes,lung and Peyer’s patches,and a Th1/Th2 response was elicited in spleen and mesenteric lymph nodes.Furthermore,intranasal immunization of SL5928(fliC/esat)produced efficient CTL effects,as demonstrated using a 5-and 6-carboxyfluorescein diacetate succinimidyl ester(CFSE)assay.Thus,our study revealed that Salmonella flagellin acts as a carrier for foreign antigen and triggers strong Th1 and CTL responses during intranasal immunization.Chimeric flagellin is potentially an effective strategy for the development of novel vaccines against tuberculosis in humans and animals.
