Incorporation of synthetic heme(FeP) into recombinant human serum albumin(rHSA) provides an artificial hemoprotein(rHSA-FeP) which can bind and release oxygen reversibly under physiological conditions(in aqueous media...Incorporation of synthetic heme(FeP) into recombinant human serum albumin(rHSA) provides an artificial hemoprotein(rHSA-FeP) which can bind and release oxygen reversibly under physiological conditions(in aqueous media, pH 7.3, 37 ℃) like hemoglobin(Hb) and myoglobin. An rHSA host absorbs maximally eight FeP molecules, and the solution properties are almost identical to those of rHSA itself. The second-order structure and surface charge distribution of rHSA were always constant independent of the binding numbers of FeP. Its O 2-binding ability satisfies the initial clinical requirements for red cell substitute. Although the NO-binding affinity is 8-fold high compared to the Hbs, administration of this fluid into rats showed negligible change in the blood pressure. Physiological responses to exchange transfusion with this rHSA-FeP into anaesthetized rats have also been evaluated.展开更多
Any linear stage of machine tool has inherent six-degree-of-freedom(6-DOF)geometric errors.Its motion control system,however,has only the position feedback.Moreover,the feedback point is not the commanded cutting poin...Any linear stage of machine tool has inherent six-degree-of-freedom(6-DOF)geometric errors.Its motion control system,however,has only the position feedback.Moreover,the feedback point is not the commanded cutting point.This is the main reason why the positioning error along each axis and the volumetric error in the working space are inevitable.This paper presents a compact 5-DOF sensor system that can be embedded in each axis of motion as additional feedback sensors of the machine tool for the detection of three angular errors and two straightness errors.Using the derived volumetric error model,the feedback point can be transferred to the cutting point.The design principle of the developed 5-DOF sensor system is described.An in-depth study of systematic error compensation due to crosstalk of straightness error and angular error is analyzed.A prototype has been built into a three-axis NC milling machine.The results of a series of the comparison experiments demonstrate the feasibility of the developed sensor system.展开更多
In the visual pathway, optic nerve(ON) injury may cause secondary degeneration of neurons in distal regions, such as the visual cortex. However, the role of the neuroinflammatory response in regulating secondary impai...In the visual pathway, optic nerve(ON) injury may cause secondary degeneration of neurons in distal regions, such as the visual cortex. However, the role of the neuroinflammatory response in regulating secondary impairment in the visual cortex after ON injury remains unclear. The NOD-like receptor family pyrin domain containing 3(NLRP3) is an important regulator of neuroinflammation. In this study, we established a mouse model of unilateral ON crush(ONC) and showed that the expression of NLRP3 was significantly increased in the primary visual cortex(V1) as a response to ONC and that the NLRP3 inflammasome was activated in the contralateral V1 1 days–14 days after ONC. Ablation of the NLRP3 gene significantly decreased the trans-neuronal degeneration within 14 days. Visual electrophysiological function was improved in NLRP3-/- mice. Taken together, these findings suggest that NLRP3 is a potential therapeutic target for protecting visual cortical neurons against degeneration after ON injury.展开更多
CRISPR/Cas9 system has become a promising gene editing tool for cancer treatment.However,development of a simple and effective nanocarrier to incorporate CRISPR/Cas9 system and chemotherapeutic drugs to concurrently t...CRISPR/Cas9 system has become a promising gene editing tool for cancer treatment.However,development of a simple and effective nanocarrier to incorporate CRISPR/Cas9 system and chemotherapeutic drugs to concurrently tackle the biological safety and packaging capacity of viral vectors and combine gene editing-chemo for cancer therapy still remains challenges.Herein,a chain-shattering Pt(IV)-backboned polymeric nanoplatform is developed for the delivery of EZH2-targeted CRISPR/Cas9 system(NPCSPt/pEZH2)and synergistic treatment of prostate cancer.The pEZH2/Pt(II)could be effectively triggered to unpack/release from NPCSPt/pEZH2 in a chain-shattering manner in cancer cells.The EZH2 gene disruption efficiency could be achieved up to 32.2%of PC-3 cells in vitro and 21.3%of tumor tissues in vivo,leading to effective suppression of EZH2 protein expression.Moreover,significant H3K27me3 downregulation could occur after EZH2 suppression,resulting in a more permissive chromatin structure that increases the accessibility of released Pt(II)to nuclear DNA for enhanced apoptosis.Taken together,substantial proliferation inhibition of prostate cancer cells and further 85.4%growth repression against subcutaneous xenograft tumor could be achieved.This chain-shattering Pt(IV)-backboned polymeric nanoplatform system not only provides a prospective nanocarrier for CRISPR/Cas9 system delivery,but also broadens the potential of combining gene editing-chemo synergistic cancer therapy.展开更多
Chemotherapeutic and radiation therapy have emerged as two most important treatment strategies to treat cancer in clinical practice;however,to improve anticancer efficacy,combination chemotherapy still remains challen...Chemotherapeutic and radiation therapy have emerged as two most important treatment strategies to treat cancer in clinical practice;however,to improve anticancer efficacy,combination chemotherapy still remains challenge.Dichloroacetate(DCA)could produce significant cytotoxic effects in certain tumor cells through its distinct mechanism.Radiation therapy with fast neutrons(FNT)has high relative biolgical effectiveness compared to other radiotherapeutics.Herein,we reported the combination chemotherapy with FNT for effective tumor growth inhibition with the assistance of a multilayered nanofiber loading DCA and DCA derivatives.We first synthesized a biodegradable polylysine to condense DCA with negative charge,or to conjugate DCA by condensing synthesis,to obtain Ion-DCA and Co-DCA,respectively.DCA,Ion-DCA or Co-DCA was then loaded into fibers to form multilayer drug-loaded mats.Upon adhesion on the surface of subcutaneous and orthotopic liver tumors,the multilayer drug-loaded mats realized a controllable release of DCA,which reversed the Warburg effect and inhibited cancer cell proliferation.Meantime,irradiation of fast neutrons could seriously damage DNA structure.Combination of the controllable release of DCA and FNT resulted in synergistic cell apoptosis in vitro,and the tumor inhibition in vivo.This study thus provides a new approach to integrate chemotherapy and FNT with the assistance of biocompatible nanofiber for synergistic tumor therapy.展开更多
The combination of tumor ablation and immunotherapy is a promising strategy against tumor relapse and metastasis.Photothermal therapy(PTT)triggers the release of tumor-specific antigens and damage associated molecular...The combination of tumor ablation and immunotherapy is a promising strategy against tumor relapse and metastasis.Photothermal therapy(PTT)triggers the release of tumor-specific antigens and damage associated molecular patterns(DAMPs)in-situ.However,the immunosuppressive tumor microenvironment restrains the activity of the effector immune cells.Therefore,systematic immunomodulation is critical to stimulate the tumor microenvironment and augment the anti-tumor therapeutic effect.To this end,polyethylene glycol(PEG)-stabilized platinum(Pt)nanoparticles(Pt NPs)conjugated with a PD-L1 inhibitor(BMS-1)through a thermo-sensitive linkage were constructed.Upon near-infrared(NIR)exposure,BMS-1 was released and maleimide(Mal)was exposed on the surface of Pt NPs,which captured the antigens released from the ablated tumor cells,resulting in the enhanced antigen internalization and presentation.In addition,the Pt NPs acted as immune adjuvants by stimulating dendritic cells(DCs)maturation.Furthermore,BMS-1 relieved T cell exhaustion and induced the infiltration of effector T cells into the tumor tissues.Thus,Pt NPs can ablate tumors through PTT,and augment the anti-tumor immune response through enhanced antigen presentation and T cells infiltration,thereby preventing tumor relapse and metastasis.展开更多
文摘Incorporation of synthetic heme(FeP) into recombinant human serum albumin(rHSA) provides an artificial hemoprotein(rHSA-FeP) which can bind and release oxygen reversibly under physiological conditions(in aqueous media, pH 7.3, 37 ℃) like hemoglobin(Hb) and myoglobin. An rHSA host absorbs maximally eight FeP molecules, and the solution properties are almost identical to those of rHSA itself. The second-order structure and surface charge distribution of rHSA were always constant independent of the binding numbers of FeP. Its O 2-binding ability satisfies the initial clinical requirements for red cell substitute. Although the NO-binding affinity is 8-fold high compared to the Hbs, administration of this fluid into rats showed negligible change in the blood pressure. Physiological responses to exchange transfusion with this rHSA-FeP into anaesthetized rats have also been evaluated.
基金This research was supported by the fund of The National Key Research and Development Program of China(2017YFF0204800)。
文摘Any linear stage of machine tool has inherent six-degree-of-freedom(6-DOF)geometric errors.Its motion control system,however,has only the position feedback.Moreover,the feedback point is not the commanded cutting point.This is the main reason why the positioning error along each axis and the volumetric error in the working space are inevitable.This paper presents a compact 5-DOF sensor system that can be embedded in each axis of motion as additional feedback sensors of the machine tool for the detection of three angular errors and two straightness errors.Using the derived volumetric error model,the feedback point can be transferred to the cutting point.The design principle of the developed 5-DOF sensor system is described.An in-depth study of systematic error compensation due to crosstalk of straightness error and angular error is analyzed.A prototype has been built into a three-axis NC milling machine.The results of a series of the comparison experiments demonstrate the feasibility of the developed sensor system.
基金the National Natural Science Foundation of China(81570840 and 81200926)the Academician-Led Science and Technological Innovation of Chongqing(cstc2017jcyj-yszxX0006)the Research Foundation of the Department of Ophthalmology in Daping Hospital,AMU(9-2543).
文摘In the visual pathway, optic nerve(ON) injury may cause secondary degeneration of neurons in distal regions, such as the visual cortex. However, the role of the neuroinflammatory response in regulating secondary impairment in the visual cortex after ON injury remains unclear. The NOD-like receptor family pyrin domain containing 3(NLRP3) is an important regulator of neuroinflammation. In this study, we established a mouse model of unilateral ON crush(ONC) and showed that the expression of NLRP3 was significantly increased in the primary visual cortex(V1) as a response to ONC and that the NLRP3 inflammasome was activated in the contralateral V1 1 days–14 days after ONC. Ablation of the NLRP3 gene significantly decreased the trans-neuronal degeneration within 14 days. Visual electrophysiological function was improved in NLRP3-/- mice. Taken together, these findings suggest that NLRP3 is a potential therapeutic target for protecting visual cortical neurons against degeneration after ON injury.
基金The authors acknowledge the financial support from National Natural Science Foundation of China(Grant Nos.51773198,51673188,and 21975246)The animal study protocol was approved by the Institutional Animal Care and Use Committee at Chinese Academy of Sciences.
文摘CRISPR/Cas9 system has become a promising gene editing tool for cancer treatment.However,development of a simple and effective nanocarrier to incorporate CRISPR/Cas9 system and chemotherapeutic drugs to concurrently tackle the biological safety and packaging capacity of viral vectors and combine gene editing-chemo for cancer therapy still remains challenges.Herein,a chain-shattering Pt(IV)-backboned polymeric nanoplatform is developed for the delivery of EZH2-targeted CRISPR/Cas9 system(NPCSPt/pEZH2)and synergistic treatment of prostate cancer.The pEZH2/Pt(II)could be effectively triggered to unpack/release from NPCSPt/pEZH2 in a chain-shattering manner in cancer cells.The EZH2 gene disruption efficiency could be achieved up to 32.2%of PC-3 cells in vitro and 21.3%of tumor tissues in vivo,leading to effective suppression of EZH2 protein expression.Moreover,significant H3K27me3 downregulation could occur after EZH2 suppression,resulting in a more permissive chromatin structure that increases the accessibility of released Pt(II)to nuclear DNA for enhanced apoptosis.Taken together,substantial proliferation inhibition of prostate cancer cells and further 85.4%growth repression against subcutaneous xenograft tumor could be achieved.This chain-shattering Pt(IV)-backboned polymeric nanoplatform system not only provides a prospective nanocarrier for CRISPR/Cas9 system delivery,but also broadens the potential of combining gene editing-chemo synergistic cancer therapy.
基金This work was supported by the National Natural Science Foundation of China(Nos.51273194,21975246 and 51903233).
文摘Chemotherapeutic and radiation therapy have emerged as two most important treatment strategies to treat cancer in clinical practice;however,to improve anticancer efficacy,combination chemotherapy still remains challenge.Dichloroacetate(DCA)could produce significant cytotoxic effects in certain tumor cells through its distinct mechanism.Radiation therapy with fast neutrons(FNT)has high relative biolgical effectiveness compared to other radiotherapeutics.Herein,we reported the combination chemotherapy with FNT for effective tumor growth inhibition with the assistance of a multilayered nanofiber loading DCA and DCA derivatives.We first synthesized a biodegradable polylysine to condense DCA with negative charge,or to conjugate DCA by condensing synthesis,to obtain Ion-DCA and Co-DCA,respectively.DCA,Ion-DCA or Co-DCA was then loaded into fibers to form multilayer drug-loaded mats.Upon adhesion on the surface of subcutaneous and orthotopic liver tumors,the multilayer drug-loaded mats realized a controllable release of DCA,which reversed the Warburg effect and inhibited cancer cell proliferation.Meantime,irradiation of fast neutrons could seriously damage DNA structure.Combination of the controllable release of DCA and FNT resulted in synergistic cell apoptosis in vitro,and the tumor inhibition in vivo.This study thus provides a new approach to integrate chemotherapy and FNT with the assistance of biocompatible nanofiber for synergistic tumor therapy.
基金The authors acknowledge the financial support from National Natural Science Foundation of China(Grant Nos.21975246 and 51903233)The project was supported by Open Research Fund of State Key Laboratory of Polymer Physics and Chemistry,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences.
文摘The combination of tumor ablation and immunotherapy is a promising strategy against tumor relapse and metastasis.Photothermal therapy(PTT)triggers the release of tumor-specific antigens and damage associated molecular patterns(DAMPs)in-situ.However,the immunosuppressive tumor microenvironment restrains the activity of the effector immune cells.Therefore,systematic immunomodulation is critical to stimulate the tumor microenvironment and augment the anti-tumor therapeutic effect.To this end,polyethylene glycol(PEG)-stabilized platinum(Pt)nanoparticles(Pt NPs)conjugated with a PD-L1 inhibitor(BMS-1)through a thermo-sensitive linkage were constructed.Upon near-infrared(NIR)exposure,BMS-1 was released and maleimide(Mal)was exposed on the surface of Pt NPs,which captured the antigens released from the ablated tumor cells,resulting in the enhanced antigen internalization and presentation.In addition,the Pt NPs acted as immune adjuvants by stimulating dendritic cells(DCs)maturation.Furthermore,BMS-1 relieved T cell exhaustion and induced the infiltration of effector T cells into the tumor tissues.Thus,Pt NPs can ablate tumors through PTT,and augment the anti-tumor immune response through enhanced antigen presentation and T cells infiltration,thereby preventing tumor relapse and metastasis.