The stimulator of interferon genes(STING)agonists have been widely applied to active cyclic guanosine monophophate(GMP)-adenosine monophosphate(AMP)synthase(cGAS)-STING signaling for tumor immunotherapy.However,the th...The stimulator of interferon genes(STING)agonists have been widely applied to active cyclic guanosine monophophate(GMP)-adenosine monophosphate(AMP)synthase(cGAS)-STING signaling for tumor immunotherapy.However,the therapeutic effect will be limited by factors such as the rapid degradation of STING protein and the immunosuppressive tumor microenvironment(TME).In this study,we constructed a manganese-based nano drug delivery system(NDDS)loaded with hydroxychloroquine(HCQ)for synergistic autophagy inhibition and STING activation-based immunotherapy.Hyaluronic acid(HA)/MnOOH@HCQ system can be uptake by 4T1 tumor cells via the CD44 receptor-mediated endocytosis.Subsequently,it responded to the acidic and reducing lysosomal microenvironment degradation to release Mn^(2+)and HCQ simultaneously.As a kind of STING agonist,Mn^(2+)can bind to cGAS in tumor cells,activating the cGAS-STING pathway and generating typeⅠ-interferons(IFN-Ⅰ),which helped alleviate the immunosuppressive TME.Meanwhile,HCQ downregulated the autophagy level caused by cGAS-STING pathway to block STING degradation,further sensitizing the cGAS-STING signal.Benefiting from this synergistic mechanism,HA/MnOOH@HCQ demonstrated the best anti-tumor effect with the smallest tumor weight and volume after treatment.Moreover,HA/MnOOH@HCQ also exhibited a good inhibitory effect on lung metastasis.This study provided a new strategy for enhancing cGAS-STING pathway-mediated anti-tumor immunotherapy.展开更多
The striatum, as the primary input nucleus in the basal ganglion,plays an important role in neural circuits crucial for the control of critical motivation, motor planning and procedural learning(Kreitzer and Malenka, ...The striatum, as the primary input nucleus in the basal ganglion,plays an important role in neural circuits crucial for the control of critical motivation, motor planning and procedural learning(Kreitzer and Malenka, 2008). Most cells in the striatum are GABAergic, including a large population (90%-95%) of medium spiny neurons (MSNs) and a small population of interneurons.展开更多
Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy,but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration.Herein,we designed a ca...Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy,but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration.Herein,we designed a cancer-associated fibroblasts(CAFs)triggered structure-transformable nano-assembly(HSD-P@V),which can directionally deliver valsartan(Val,CAFs regulator)and doxorubicin(DOX,senescence inducer)to the specific targets.In detail,DOX is conjugated with hyaluronic acid(HA)via diselenide bonds(Se-Se)to form HSD micelles,while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer,which is coated on Val nanocrystals(VNs)surface for improving the stability and achieving responsive release.Once arriving at tumor microenvironment and touching CAFs,HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment.VNs can degrade the extracellularmatrix,leading to the enhanced penetration of HSD.HSD targets tumor cells,releases DOX to induce senescence,and recruits effector immune cells.Furthermore,senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy.In vitro and in vivo results show that the nanoassembly remarkably inhibits tumor growth as well as lungmetastasis,and extends tumorbearing mice survival.This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.展开更多
The Phapon gold deposit, located in northern Laos, is a unique large-scale gold deposit in Luang Prabang-Loei metallogenic belt. It is hosted in the Lower Permian limestone and controlled by a NE-trending ductile-brit...The Phapon gold deposit, located in northern Laos, is a unique large-scale gold deposit in Luang Prabang-Loei metallogenic belt. It is hosted in the Lower Permian limestone and controlled by a NE-trending ductile-brittle fault system. There are three types of primary ore including auriferous calcite vein type, disseminated type, and breccia type, and the first two are important in the Phapon gold deposit. Based on fluid inclusion petrography and microthermometry, three types of primary fluid inclusions including type 1 liquid-rich aqueous, type 2 vapor-rich aqueous and type 3 daughter mineralbearing aqueous were identified in hydrothermal calcite grains. The ore-forming fluids are normally homogeneous, as indicated by the widespread type 1 inclusions with identical composition. The coexistence of type 1 and type 2 inclusions, showing similar final homogenization temperature but different compositions, indicate that fluid immiscibility did locally take place in both two types of ores. The results of microthermometry and H-O isotopes geochemistry indicate that there are little differences on ore-fluid geochemistry between the auriferous calcite vein-type and disseminated type ores. The oreforming fluids are characterized by medium-low temperatures(157–268 oC) and low salinity(1.6 wt.%–9.9 wt.% NaCl eq.). It is likely to have a metamorphic-dominant mixed source, which could be associated with dehydration and decarbonisation of Lower Permian limestone and Middle–Upper Triassic sandstones during the dynamic metamorphism. The fluid-wallrock interaction played a major role, and the locally occurred fluid-immiscible processes played a subordinate role in gold precipitation. Combined with the regional and ore deposit geology, and ore-fluid geochemistry, we suggest that the Phapon gold deposit is best considered to be a member of the epizonal orogenic deposit class.展开更多
The Truong Son metallogenic belt in central Laos and Vietnam is an important Fe-Cu-Sn-Au polymetallic ore district. The Pha Lek Fe deposit is closely related to Late Carboniferous– Early Permian I-type granitic magma...The Truong Son metallogenic belt in central Laos and Vietnam is an important Fe-Cu-Sn-Au polymetallic ore district. The Pha Lek Fe deposit is closely related to Late Carboniferous– Early Permian I-type granitic magmatism, and contains >50 Mt @ 45% to 50% of Fe ore. Ore minerals occur mainly as magnetite and hematite in the skarn alteration zone between a granitic pluton and metamorphosed Middle–Upper Devonian carbonates. The granitic pluton comprises granodiorite and granite, with zircon U-Pb dating indicating synchronous emplacement at 288.2±1.3 and 284.9±1.2 Ma, respectively. Zircons from these granitoids have ε_(Hf)(t) values of 2.9–11.2 and relatively young TDM2 ages(<1.0 Ga), indicating an origin by partial melting of depleted mafic crust or magma mixing. Previous studies have shown that these granitoids have high Y, Yb, and K_2O contents, and low Sr and Na_2O contents, which are interpreted as the melting of mafic continental crust. Pyrite of the main mineralization stage yields an ^(187)Re/^(188)Os-^(187)Os/^(188)Os isochron age of 287±17 Ma, indicating that mineralization is associated with Pha Lek granitic magmatism. A Late Carboniferous–Early Permian subduction-related skarn-type Fe mineralization model is proposed for the Pha Lek deposit. More evidence is needed to verify a hypothesis of volcanic overprinting during Late Triassic post-collisional extension.展开更多
Objective To investigate the H_ 2O_ 2-induced expression of human histone acetyltransferase-like protein (hALP), a telomerase regulation-associated gene, and its effects on the stress-triggered cellular senescence.Met...Objective To investigate the H_ 2O_ 2-induced expression of human histone acetyltransferase-like protein (hALP), a telomerase regulation-associated gene, and its effects on the stress-triggered cellular senescence.Methods The induced expression of hALP was measured by semi-quantitative RT-PCR and immunofluorescent histochemistry after treatment of HeLa cells by H_ 2O_ 2.The effects of hALP expression on cellular responses to H_ 2O_ 2 were analyzed by MTT, flowcytometry, and SA-β-gal staining, respectively.Results hALP mRNA could be dose-dependently induced by treatments of 0.2-1.6 mmol/L H_ 2O_ 2, and the induction could be observed after 6 hours and kept for 36 hours in the presence of 0.4 mmol/L H_ 2O_ 2.Meanwhile, the immunofluorescent staining showed marked stronger nuclear intensity of hALP protein in H_ 2O_ 2-treated HeLa cells.In the treatment of H_ 2O_ 2, the ectopic expression of hALP enhanced continuous growth and overcame G_ 2/M arrest as well as decreased senescence-associated β-gal staining.On the contrary, the transfected clones with antisense or blank vector and original HeLa cells presented growth suppression, G_ 2/M delay and higher percentage of SA-β-gal activities in the presence of H_ 2 O_ 2.Conclusions The expression of hALP could be up-regulated by treatment of H_ 2O_ 2, and elevated expression could enhance cellular resistance to H_ 2O_ 2-induced cellular senescence.The data might be of references to elucidation of basic biological function of hALP gene and its associated telomerase activity.展开更多
Colorectal cancer is often accompanied by multiple organ metastasis.Anaerobic Bifidobacterium Infantis(BI)bacterial can selectively grow in hypoxic colorectal tumor microenvironment(TME),to own the natural advantage o...Colorectal cancer is often accompanied by multiple organ metastasis.Anaerobic Bifidobacterium Infantis(BI)bacterial can selectively grow in hypoxic colorectal tumor microenvironment(TME),to own the natural advantage of preferentially colorectal tumor targeting.Herein,a self-guidance biological hybrid drug delivery system(BI-ES-Fe Alg/DOX)based on BI was constructed to inhibit the proliferation and metastasis of colon cancer.Results demonstrated that BI-ES-Fe Alg/DOX could overcome physical barriers to target and accumulate in colon tumor tissues.Then DOX was released to kill tumor cells along with the phase transition(solid to liquid)of Fe Alg hydrogel,due to Fe3+was reduced to Fe^(2+)by intracellular GSH.Meanwhile,BI-ES selectively colonized into tumors and expressed endostatin(ES)protein to down-regulate VEGF and b FGF expression,exerting anti-angiogenic effect.Moreover,Fe Alg catalyzed H_(2)O_(2)in the local tumor to generate cytotoxic·OH,further enhancing the antitumor effect.The pharmacodynamic result in AOM/DSS model proved that BI-ES-Fe Alg/DOX had the best therapeutic effect,with the final V/V0of 2.19±0.57,which was significantly lower than the other groups.Meanwhile,on CT-26tumor-bearing model,it also showed an outstanding anti-tumor effect with inhibition rate of 82.12%±3.08%.In addition,lung metastases decreased significantly in tumor metastasis model after BI-ES-Fe Alg/DOX treatment.展开更多
Obje, etive To analyze how the infection of human papillomavirus 16 （ HPV16 ） affects expression of DNA poly- merase β（DNA polB） with the aim of probing the mechanism of over-expression of DNA polB in human cance...Obje, etive To analyze how the infection of human papillomavirus 16 （ HPV16 ） affects expression of DNA poly- merase β（DNA polB） with the aim of probing the mechanism of over-expression of DNA polB in human cancers. Methods Four fragments of human DNA polB promoter were amplified and constructed into luciferase reporter vec- tor pGL-Basic, generating pGL-BP, pGL-BMH, pGL-BMS, and pGL-BAT constructs respectively, and co-transfected with HPV16 or HPV6 into Hep2 cells. Luciferase activity was assayed 48 hours after transfectiorL Semi-quantitative RT- PCR was used to measure mRNA expression of endogenous DNA polB. Immunohistochemistry and in situ hybridization were used to analyze DNA polB expression and HPV16 or HPV6 infection in 38 cases of cervical lesions respectively. Results With co-transfection of HPV16 and DNA polB promoter-driving reporters into Hep2 cells, pGL-BP re- porter in full-length DNA polB promoter presented markedly elevated luciferase activities （ P 〈 0.05 ）. However, the other three mutant reporters： pGL-BMH, pGL-BMS, and pGL-BAT, generated no reporting activities in the presence of HPV16 （P 〉0.05 ）. On the contrary, all of polB promoter reporters were little stimulated in co-transfection of HPV6 （P 〉0.05 ）. The transfection of HPV16 could enhance the endogenous polB mRNA expression compared with that of HPV6 （3.42 vs. 0.80, P 〈0.05）. The DNA polB expression was found in 8 of 10 HPV16-positive cervical intraepi- thelial neoplasia grade Ⅲ（ CIN Ⅲ） cases, while was only found in 3 of 11 HPV6-positive condyloma accuminatum cases, but was negative in all chronic cervicitis cases. The correlation of DNA polB expression with HPV16 infection in cervical lesions was significant （ P 〈0.05 ）. Conclusions HPV16 is able to specifically stimulate the expression of DNA polB in human epithelial cells through interaction with the core upstream regulatory sequences of DNA polB promoter. Over-expression of DNA polB might be an explanation for the molecular mechanism underlying HPV-related human cancers.展开更多
In the process of cultivating software engineering professionals,the practical teaching of professional courses is an indispensable link.In order to enable students to understand,consolidate and master theoretical kno...In the process of cultivating software engineering professionals,the practical teaching of professional courses is an indispensable link.In order to enable students to understand,consolidate and master theoretical knowledge,improve the ability to solve problems by combining theory with practice,and achieve the goal of combining theoretical knowledge with practice.Adopting the planning of through-type training,complete the teaching work of three practical courses of software system design,software system construction,and software product construction.Through the implementation of the plan,the digitization of teaching resources,the virtualization of real enterprises,the intelligentization of teaching guidance,the visualization of teaching process,and the panorama of learning process are realized.By adopting the teaching methods of taskdriven online practice teaching,artificial intelligence-based teaching training support and teaching process,and result big data evaluation,the students’comprehensive practical ability can be improved finally,and the whole practice teaching reform can provide experience for the follow-up reform.展开更多
The Haizi diabase-granite porphyry composite rock mass is located in the Wuding-Yanjing taphrogenic trough within the Paleoproterozoic Kangdian fault-uplift zone. According to field observations, the diabase is divide...The Haizi diabase-granite porphyry composite rock mass is located in the Wuding-Yanjing taphrogenic trough within the Paleoproterozoic Kangdian fault-uplift zone. According to field observations, the diabase is divided into two types: central facies and marginal facies;the granite porphyry directly contacts the central facies of diabase without transitional intermediate rock. In order to disclose its geological and petrological significances, this paper carried out the LA-ICP-MS zircon U-Pb dating and geochemical investigation on both masses of Haizi diabase and granite porphyry. The results showed that the207Pb/206Pb weighted average age of granite porphyry is 1764 ± 18 Ma and diabase 1765 ± 5.4 Ma. The geochemical investigations revealed that the Haizi diabase is a kind of high-potassium alkaline basalt and the granite porphyry a kind of low-potassium rhyolite, both enriched with high field intensity elements and depleted in large-ion lithophile elements;there is obvious component intermittence between the diabase and the granite porphyry, both being bimodal and showing characteristics of continental rift valley magmatite. The?in situ?Hf isotope of dating zircon showed that mantle materials participated in the formation and emplacement of Haizi granite porphyry and crust materials participated in the formation of diabase. This meant that crustal remelting and accretion of new crust occurred in this region in the 1.7 Ga period. It can be therefore inferred that the Haizi bimodal intrusive rock came into being due to the breakup of Kunyang rift valley and rapid ascent of mantle materials in the 1.7 Ga period, which echoed the global Columbia supercontinent breakup and was the first petrological record of that breakup found at the southwest margin of Yangtze platform.展开更多
With the rapid development of computer technology,network and information technology have been widely used in people’s daily lives,which has brought great convenience to labor and life.At the same time,people are inc...With the rapid development of computer technology,network and information technology have been widely used in people’s daily lives,which has brought great convenience to labor and life.At the same time,people are increasingly dependent on computer technology.In this case,the social demand for computer professionals is increasing.However,due to the rapid changes and continuous updates of computer technology,the training of talents in computer specialty in China is far from meeting the demand and quality requirements of the society for this kind of talents.Colleges and universities are the important departments that cultivate computer professionals and technicians for the society.When cultivating talents in computer specialty,colleges and universities must conform to the requirements of the development of the times,adjust teaching strategies in a timely manner according to the actual needs of the society,build a talent training system,build a practical training teaching system of computer specialty,innovate teaching modes and teaching contents,and improve students’professional skills through perfect practical teaching,so as to ensure that they can skillfully apply computer technology to solve practical problems in the learning process and further improve their employment competitiveness.Therefore,this paper analyzes the practical teaching system of computer specialty,puts forward corresponding solutions to the existing problems,constructs a multi-collaborative practical training system,and implements the system.The implementation results show that the system can better meet the needs of students at different levels,and the results are fairer.Students’recognition and sense of acquisition of courses have also been greatly improved.The accumulated experience and data also provide good support for our continuous improvement of the system in the future.展开更多
Software engineering is a highly practical major,and students need a lot of hands-on practice to transform the theoretical contents learned in class into the practical ability to solve practical problems,so practical ...Software engineering is a highly practical major,and students need a lot of hands-on practice to transform the theoretical contents learned in class into the practical ability to solve practical problems,so practical courses are an essential and important part in the process of training talents in software engineering.From the point of view of cultivating talents in software engineering,this paper expounds the important position of practical courses in software engineering in the process of cultivating talents,analyzes the problems in the existing practical courses,and puts forward the construction ideas and characteristics of practical courses in software engineering which strengthen the foundation,advance steadily,and face the output.Taking the practical course for software system development as an example,this paper introduces in detail the concrete implementation process,achievements,existing problems and countermeasures of the course.展开更多
The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits,and this process requires the proper recruitment of adaptor molecules...The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits,and this process requires the proper recruitment of adaptor molecules to selectively activate downstream pathways.Here,we identified that DOK6,a member of the Dok(downstream of tyrosine kinases)family,is required for the maintenance of peripheral axons,and that loss of Dok6 can cause typical peripheral neuropathy symptoms in mice,manifested as impaired sensory,abnormal posture,paw deformities,blocked nerve conduction,and dysmyelination.Furthermore,Dok6 is highly expressed in peripheral neurons but not in Schwann cells,and genetic deletion of Dok6 in peripheral neurons led to typical peripheral myelin outfolding,axon destruction,and hindered retrograde axonal transport.Specifically,DOK6 acts as an adaptor protein for selectivitymediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not for TrkA and TrkB.DOK6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation,including MAP1B,Tau and Dynein for axonal transport,and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and homeostasis.This finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies and other degenerative diseases.展开更多
The advancement of wearable devices continues to face the challenge of ensuring a sustainable power supply.Traditional human motion energy harvesters often suffer from low energy harvesting efficiency due to their rel...The advancement of wearable devices continues to face the challenge of ensuring a sustainable power supply.Traditional human motion energy harvesters often suffer from low energy harvesting efficiency due to their reliance on a single energy source.This study presents a novel pendulum inertial electromagnetic energy harvester(PI-EEH)to harvest multiplesource low-frequency human motion energy.The PI-EEH can simultaneously harvest both the leg swing energy and the foot impact energy during walking.A horizontal universal pendulum,combined with a frequency-up conversion mechanism,transforms irregular human motion into unidirectional high-frequency rotation.The output performance of the PI-EEH is evaluated through both theoretical analysis and experimental testing.A treadmill test is also conducted across various motion speeds to illustrate the benefits of PI-EEH.The peak power of PI-EEH can reach 54 mW at a speed of 3 km/h.Additionally,the PI-EEH can easily supply power for some wearable devices,like a GPS module and an acceleration sensor.The designed PIEEH offers a viable approach to harvesting energy from multiple-source human motion,which will have broad prospects in smart healthcare and IoT applications.展开更多
Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT....Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT.This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy.To achieve this goal,we first synthesized TRANSFERRIN(Tf)biomimetic mineralized nano-tellurium(Tf-Te)as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly.The autophagy inhibitor hydroxychloroquine(HCQ)and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ.After entering breast cancer cells through the“self-guidance system”,Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation,to efficiently induce PTT/PDT effect.Meanwhile,the disulfide bond broke down in response to GSH,and the nanoparticles disintegrated to release Fe2+and HCQ at fixed points.They simultaneously induce lysosomal alkalinization and increased osmotic pressure,effectively inhibit autophagy,and synergistically enhance the therapeutic effect of phototherapy.In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6%on 4T1 tumor-bearing mice.This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.展开更多
To develop an efficient thrombolytic therapy approach that addresses the limitations of current fibrinolytic drugs, such as short half-life, weak thrombus specificity and poor penetration ability, we constructed a NIR...To develop an efficient thrombolytic therapy approach that addresses the limitations of current fibrinolytic drugs, such as short half-life, weak thrombus specificity and poor penetration ability, we constructed a NIR-triggered detachable nanoplatform (PA/UK@IcpLipo) using thin-film hydration method. It was designed to integrate attack and defense mechanisms for thrombolytic therapy. This platform can actively identify thrombi by binding to GPIIb-IIIa receptors overexpressed on activated platelets. Upon NIR laser activation and interaction with thrombin in the thrombotic microenvironment, the thermosensitive liposomes rupture, releasing the PA/UK core for deep penetration into the thrombus. Our results showed that the PA/UK@IcpLipo nanoplatform efficiently promoted rapid thrombolysis under the action of UK (attack), followed by PA exerting an antiplatelet aggregation effect (defense). This dual-action approach significantly improved vascular reperfusion rates. The NIR-triggered detachable nanoplatform offered a promising solution for enhanced thrombolysis efficiency and reduced bleeding risk, addressing critical limitations of current fibrinolytic therapies.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82172719,82102918)Joint Funds of Henan Province Foundation for Science and Technology(No.232301420011).
文摘The stimulator of interferon genes(STING)agonists have been widely applied to active cyclic guanosine monophophate(GMP)-adenosine monophosphate(AMP)synthase(cGAS)-STING signaling for tumor immunotherapy.However,the therapeutic effect will be limited by factors such as the rapid degradation of STING protein and the immunosuppressive tumor microenvironment(TME).In this study,we constructed a manganese-based nano drug delivery system(NDDS)loaded with hydroxychloroquine(HCQ)for synergistic autophagy inhibition and STING activation-based immunotherapy.Hyaluronic acid(HA)/MnOOH@HCQ system can be uptake by 4T1 tumor cells via the CD44 receptor-mediated endocytosis.Subsequently,it responded to the acidic and reducing lysosomal microenvironment degradation to release Mn^(2+)and HCQ simultaneously.As a kind of STING agonist,Mn^(2+)can bind to cGAS in tumor cells,activating the cGAS-STING pathway and generating typeⅠ-interferons(IFN-Ⅰ),which helped alleviate the immunosuppressive TME.Meanwhile,HCQ downregulated the autophagy level caused by cGAS-STING pathway to block STING degradation,further sensitizing the cGAS-STING signal.Benefiting from this synergistic mechanism,HA/MnOOH@HCQ demonstrated the best anti-tumor effect with the smallest tumor weight and volume after treatment.Moreover,HA/MnOOH@HCQ also exhibited a good inhibitory effect on lung metastasis.This study provided a new strategy for enhancing cGAS-STING pathway-mediated anti-tumor immunotherapy.
基金supported by grants from the National Key Research and Development Program of China (2016YFA0100702 and 2016YFC0902502)the National Natural Science Foundation of China (31670789 and 31671316)the CAMS Innovation Fund for Medical Sciences (CIFMS, 2016I2M-2-001, 2016-I2M-1-001, 2016-I2M-1-004 and 2017-I2M-1004)
文摘The striatum, as the primary input nucleus in the basal ganglion,plays an important role in neural circuits crucial for the control of critical motivation, motor planning and procedural learning(Kreitzer and Malenka, 2008). Most cells in the striatum are GABAergic, including a large population (90%-95%) of medium spiny neurons (MSNs) and a small population of interneurons.
基金was supported by National Natural Science Foundation of China(81972893,82172719)Natural Science Foundation of Henan(212300410071)Training program for young key teachers in Henan Province(2020GGJS019).
文摘Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy,but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration.Herein,we designed a cancer-associated fibroblasts(CAFs)triggered structure-transformable nano-assembly(HSD-P@V),which can directionally deliver valsartan(Val,CAFs regulator)and doxorubicin(DOX,senescence inducer)to the specific targets.In detail,DOX is conjugated with hyaluronic acid(HA)via diselenide bonds(Se-Se)to form HSD micelles,while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer,which is coated on Val nanocrystals(VNs)surface for improving the stability and achieving responsive release.Once arriving at tumor microenvironment and touching CAFs,HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment.VNs can degrade the extracellularmatrix,leading to the enhanced penetration of HSD.HSD targets tumor cells,releases DOX to induce senescence,and recruits effector immune cells.Furthermore,senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy.In vitro and in vivo results show that the nanoassembly remarkably inhibits tumor growth as well as lungmetastasis,and extends tumorbearing mice survival.This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.
基金financially supported by the China Geological Survey Project (No. 121201010000150013)
文摘The Phapon gold deposit, located in northern Laos, is a unique large-scale gold deposit in Luang Prabang-Loei metallogenic belt. It is hosted in the Lower Permian limestone and controlled by a NE-trending ductile-brittle fault system. There are three types of primary ore including auriferous calcite vein type, disseminated type, and breccia type, and the first two are important in the Phapon gold deposit. Based on fluid inclusion petrography and microthermometry, three types of primary fluid inclusions including type 1 liquid-rich aqueous, type 2 vapor-rich aqueous and type 3 daughter mineralbearing aqueous were identified in hydrothermal calcite grains. The ore-forming fluids are normally homogeneous, as indicated by the widespread type 1 inclusions with identical composition. The coexistence of type 1 and type 2 inclusions, showing similar final homogenization temperature but different compositions, indicate that fluid immiscibility did locally take place in both two types of ores. The results of microthermometry and H-O isotopes geochemistry indicate that there are little differences on ore-fluid geochemistry between the auriferous calcite vein-type and disseminated type ores. The oreforming fluids are characterized by medium-low temperatures(157–268 oC) and low salinity(1.6 wt.%–9.9 wt.% NaCl eq.). It is likely to have a metamorphic-dominant mixed source, which could be associated with dehydration and decarbonisation of Lower Permian limestone and Middle–Upper Triassic sandstones during the dynamic metamorphism. The fluid-wallrock interaction played a major role, and the locally occurred fluid-immiscible processes played a subordinate role in gold precipitation. Combined with the regional and ore deposit geology, and ore-fluid geochemistry, we suggest that the Phapon gold deposit is best considered to be a member of the epizonal orogenic deposit class.
基金supported financially by the National Natural Science Foundation of China (Nos. 41402074 and 41502074)Applied Fundamental Research Funding of Sichuan Province, China (No. 2015JY0055)the National Geological Survey Foundation of China (No. 121201010000150013)
文摘The Truong Son metallogenic belt in central Laos and Vietnam is an important Fe-Cu-Sn-Au polymetallic ore district. The Pha Lek Fe deposit is closely related to Late Carboniferous– Early Permian I-type granitic magmatism, and contains >50 Mt @ 45% to 50% of Fe ore. Ore minerals occur mainly as magnetite and hematite in the skarn alteration zone between a granitic pluton and metamorphosed Middle–Upper Devonian carbonates. The granitic pluton comprises granodiorite and granite, with zircon U-Pb dating indicating synchronous emplacement at 288.2±1.3 and 284.9±1.2 Ma, respectively. Zircons from these granitoids have ε_(Hf)(t) values of 2.9–11.2 and relatively young TDM2 ages(<1.0 Ga), indicating an origin by partial melting of depleted mafic crust or magma mixing. Previous studies have shown that these granitoids have high Y, Yb, and K_2O contents, and low Sr and Na_2O contents, which are interpreted as the melting of mafic continental crust. Pyrite of the main mineralization stage yields an ^(187)Re/^(188)Os-^(187)Os/^(188)Os isochron age of 287±17 Ma, indicating that mineralization is associated with Pha Lek granitic magmatism. A Late Carboniferous–Early Permian subduction-related skarn-type Fe mineralization model is proposed for the Pha Lek deposit. More evidence is needed to verify a hypothesis of volcanic overprinting during Late Triassic post-collisional extension.
文摘Objective To investigate the H_ 2O_ 2-induced expression of human histone acetyltransferase-like protein (hALP), a telomerase regulation-associated gene, and its effects on the stress-triggered cellular senescence.Methods The induced expression of hALP was measured by semi-quantitative RT-PCR and immunofluorescent histochemistry after treatment of HeLa cells by H_ 2O_ 2.The effects of hALP expression on cellular responses to H_ 2O_ 2 were analyzed by MTT, flowcytometry, and SA-β-gal staining, respectively.Results hALP mRNA could be dose-dependently induced by treatments of 0.2-1.6 mmol/L H_ 2O_ 2, and the induction could be observed after 6 hours and kept for 36 hours in the presence of 0.4 mmol/L H_ 2O_ 2.Meanwhile, the immunofluorescent staining showed marked stronger nuclear intensity of hALP protein in H_ 2O_ 2-treated HeLa cells.In the treatment of H_ 2O_ 2, the ectopic expression of hALP enhanced continuous growth and overcame G_ 2/M arrest as well as decreased senescence-associated β-gal staining.On the contrary, the transfected clones with antisense or blank vector and original HeLa cells presented growth suppression, G_ 2/M delay and higher percentage of SA-β-gal activities in the presence of H_ 2 O_ 2.Conclusions The expression of hALP could be up-regulated by treatment of H_ 2O_ 2, and elevated expression could enhance cellular resistance to H_ 2O_ 2-induced cellular senescence.The data might be of references to elucidation of basic biological function of hALP gene and its associated telomerase activity.
基金supported by National Natural Science Foundation of China(82102918)Youth Talent Promotion Project in Henan Province(2020HYTP011)。
文摘Colorectal cancer is often accompanied by multiple organ metastasis.Anaerobic Bifidobacterium Infantis(BI)bacterial can selectively grow in hypoxic colorectal tumor microenvironment(TME),to own the natural advantage of preferentially colorectal tumor targeting.Herein,a self-guidance biological hybrid drug delivery system(BI-ES-Fe Alg/DOX)based on BI was constructed to inhibit the proliferation and metastasis of colon cancer.Results demonstrated that BI-ES-Fe Alg/DOX could overcome physical barriers to target and accumulate in colon tumor tissues.Then DOX was released to kill tumor cells along with the phase transition(solid to liquid)of Fe Alg hydrogel,due to Fe3+was reduced to Fe^(2+)by intracellular GSH.Meanwhile,BI-ES selectively colonized into tumors and expressed endostatin(ES)protein to down-regulate VEGF and b FGF expression,exerting anti-angiogenic effect.Moreover,Fe Alg catalyzed H_(2)O_(2)in the local tumor to generate cytotoxic·OH,further enhancing the antitumor effect.The pharmacodynamic result in AOM/DSS model proved that BI-ES-Fe Alg/DOX had the best therapeutic effect,with the final V/V0of 2.19±0.57,which was significantly lower than the other groups.Meanwhile,on CT-26tumor-bearing model,it also showed an outstanding anti-tumor effect with inhibition rate of 82.12%±3.08%.In addition,lung metastases decreased significantly in tumor metastasis model after BI-ES-Fe Alg/DOX treatment.
文摘Obje, etive To analyze how the infection of human papillomavirus 16 （ HPV16 ） affects expression of DNA poly- merase β（DNA polB） with the aim of probing the mechanism of over-expression of DNA polB in human cancers. Methods Four fragments of human DNA polB promoter were amplified and constructed into luciferase reporter vec- tor pGL-Basic, generating pGL-BP, pGL-BMH, pGL-BMS, and pGL-BAT constructs respectively, and co-transfected with HPV16 or HPV6 into Hep2 cells. Luciferase activity was assayed 48 hours after transfectiorL Semi-quantitative RT- PCR was used to measure mRNA expression of endogenous DNA polB. Immunohistochemistry and in situ hybridization were used to analyze DNA polB expression and HPV16 or HPV6 infection in 38 cases of cervical lesions respectively. Results With co-transfection of HPV16 and DNA polB promoter-driving reporters into Hep2 cells, pGL-BP re- porter in full-length DNA polB promoter presented markedly elevated luciferase activities （ P 〈 0.05 ）. However, the other three mutant reporters： pGL-BMH, pGL-BMS, and pGL-BAT, generated no reporting activities in the presence of HPV16 （P 〉0.05 ）. On the contrary, all of polB promoter reporters were little stimulated in co-transfection of HPV6 （P 〉0.05 ）. The transfection of HPV16 could enhance the endogenous polB mRNA expression compared with that of HPV6 （3.42 vs. 0.80, P 〈0.05）. The DNA polB expression was found in 8 of 10 HPV16-positive cervical intraepi- thelial neoplasia grade Ⅲ（ CIN Ⅲ） cases, while was only found in 3 of 11 HPV6-positive condyloma accuminatum cases, but was negative in all chronic cervicitis cases. The correlation of DNA polB expression with HPV16 infection in cervical lesions was significant （ P 〈0.05 ）. Conclusions HPV16 is able to specifically stimulate the expression of DNA polB in human epithelial cells through interaction with the core upstream regulatory sequences of DNA polB promoter. Over-expression of DNA polB might be an explanation for the molecular mechanism underlying HPV-related human cancers.
文摘In the process of cultivating software engineering professionals,the practical teaching of professional courses is an indispensable link.In order to enable students to understand,consolidate and master theoretical knowledge,improve the ability to solve problems by combining theory with practice,and achieve the goal of combining theoretical knowledge with practice.Adopting the planning of through-type training,complete the teaching work of three practical courses of software system design,software system construction,and software product construction.Through the implementation of the plan,the digitization of teaching resources,the virtualization of real enterprises,the intelligentization of teaching guidance,the visualization of teaching process,and the panorama of learning process are realized.By adopting the teaching methods of taskdriven online practice teaching,artificial intelligence-based teaching training support and teaching process,and result big data evaluation,the students’comprehensive practical ability can be improved finally,and the whole practice teaching reform can provide experience for the follow-up reform.
文摘The Haizi diabase-granite porphyry composite rock mass is located in the Wuding-Yanjing taphrogenic trough within the Paleoproterozoic Kangdian fault-uplift zone. According to field observations, the diabase is divided into two types: central facies and marginal facies;the granite porphyry directly contacts the central facies of diabase without transitional intermediate rock. In order to disclose its geological and petrological significances, this paper carried out the LA-ICP-MS zircon U-Pb dating and geochemical investigation on both masses of Haizi diabase and granite porphyry. The results showed that the207Pb/206Pb weighted average age of granite porphyry is 1764 ± 18 Ma and diabase 1765 ± 5.4 Ma. The geochemical investigations revealed that the Haizi diabase is a kind of high-potassium alkaline basalt and the granite porphyry a kind of low-potassium rhyolite, both enriched with high field intensity elements and depleted in large-ion lithophile elements;there is obvious component intermittence between the diabase and the granite porphyry, both being bimodal and showing characteristics of continental rift valley magmatite. The?in situ?Hf isotope of dating zircon showed that mantle materials participated in the formation and emplacement of Haizi granite porphyry and crust materials participated in the formation of diabase. This meant that crustal remelting and accretion of new crust occurred in this region in the 1.7 Ga period. It can be therefore inferred that the Haizi bimodal intrusive rock came into being due to the breakup of Kunyang rift valley and rapid ascent of mantle materials in the 1.7 Ga period, which echoed the global Columbia supercontinent breakup and was the first petrological record of that breakup found at the southwest margin of Yangtze platform.
文摘With the rapid development of computer technology,network and information technology have been widely used in people’s daily lives,which has brought great convenience to labor and life.At the same time,people are increasingly dependent on computer technology.In this case,the social demand for computer professionals is increasing.However,due to the rapid changes and continuous updates of computer technology,the training of talents in computer specialty in China is far from meeting the demand and quality requirements of the society for this kind of talents.Colleges and universities are the important departments that cultivate computer professionals and technicians for the society.When cultivating talents in computer specialty,colleges and universities must conform to the requirements of the development of the times,adjust teaching strategies in a timely manner according to the actual needs of the society,build a talent training system,build a practical training teaching system of computer specialty,innovate teaching modes and teaching contents,and improve students’professional skills through perfect practical teaching,so as to ensure that they can skillfully apply computer technology to solve practical problems in the learning process and further improve their employment competitiveness.Therefore,this paper analyzes the practical teaching system of computer specialty,puts forward corresponding solutions to the existing problems,constructs a multi-collaborative practical training system,and implements the system.The implementation results show that the system can better meet the needs of students at different levels,and the results are fairer.Students’recognition and sense of acquisition of courses have also been greatly improved.The accumulated experience and data also provide good support for our continuous improvement of the system in the future.
文摘Software engineering is a highly practical major,and students need a lot of hands-on practice to transform the theoretical contents learned in class into the practical ability to solve practical problems,so practical courses are an essential and important part in the process of training talents in software engineering.From the point of view of cultivating talents in software engineering,this paper expounds the important position of practical courses in software engineering in the process of cultivating talents,analyzes the problems in the existing practical courses,and puts forward the construction ideas and characteristics of practical courses in software engineering which strengthen the foundation,advance steadily,and face the output.Taking the practical course for software system development as an example,this paper introduces in detail the concrete implementation process,achievements,existing problems and countermeasures of the course.
基金supported by grants from the National Natural Science Foundation of China(32370883)National Science and Technology Innovation 2030 Grants(2021ZD0200902)+1 种基金the CAMS Innovation Fund for Medical Sciences(CIFMS2021-I2M-1-019 and 2021-I2M-1-024).
文摘The appropriate and specific response of nerve cells to various external cues is essential for the establishment and maintenance of neural circuits,and this process requires the proper recruitment of adaptor molecules to selectively activate downstream pathways.Here,we identified that DOK6,a member of the Dok(downstream of tyrosine kinases)family,is required for the maintenance of peripheral axons,and that loss of Dok6 can cause typical peripheral neuropathy symptoms in mice,manifested as impaired sensory,abnormal posture,paw deformities,blocked nerve conduction,and dysmyelination.Furthermore,Dok6 is highly expressed in peripheral neurons but not in Schwann cells,and genetic deletion of Dok6 in peripheral neurons led to typical peripheral myelin outfolding,axon destruction,and hindered retrograde axonal transport.Specifically,DOK6 acts as an adaptor protein for selectivitymediated neurotrophic signal transduction and retrograde transport for TrkC and Ret but not for TrkA and TrkB.DOK6 interacts with certain proteins in the trafficking machinery and controls their phosphorylation,including MAP1B,Tau and Dynein for axonal transport,and specifically activates the downstream ERK1/2 kinase pathway to maintain axonal survival and homeostasis.This finding provides new clues to potential insights into the pathogenesis and treatment of hereditary peripheral neuropathies and other degenerative diseases.
基金the support from the National Natural Science Foundation of China(Grant No.12232014)the Fundamental Research Funds for the Central Universities(Grant No.N2403027)the Ten Thousand Talents。
文摘The advancement of wearable devices continues to face the challenge of ensuring a sustainable power supply.Traditional human motion energy harvesters often suffer from low energy harvesting efficiency due to their reliance on a single energy source.This study presents a novel pendulum inertial electromagnetic energy harvester(PI-EEH)to harvest multiplesource low-frequency human motion energy.The PI-EEH can simultaneously harvest both the leg swing energy and the foot impact energy during walking.A horizontal universal pendulum,combined with a frequency-up conversion mechanism,transforms irregular human motion into unidirectional high-frequency rotation.The output performance of the PI-EEH is evaluated through both theoretical analysis and experimental testing.A treadmill test is also conducted across various motion speeds to illustrate the benefits of PI-EEH.The peak power of PI-EEH can reach 54 mW at a speed of 3 km/h.Additionally,the PI-EEH can easily supply power for some wearable devices,like a GPS module and an acceleration sensor.The designed PIEEH offers a viable approach to harvesting energy from multiple-source human motion,which will have broad prospects in smart healthcare and IoT applications.
基金This work was supported by the National Natural Science Foundation of China(Nos.82102918,81972893 and 82172719)the Key Program for Science and Technology Research in Henan Province(No.232102311093,China)the Training Plan for Young Backbone Teachers in Higher Education Institutions of Henan Province(No.2021ZDGGJS054,China).
文摘Autophagy is an important factor in reducing the efficacy of tumor phototherapy(including PTT and PDT).Accurate regulation of autophagy in tumor cells is a new strategy to improve the anti-tumor efficiency of PTT/PDT.This project intended to construct a tumor-activated autophagy regulator to efficiently block PTT/PDT-induced autophagy and realize synergistic sensitization to tumor phototherapy.To achieve this goal,we first synthesized TRANSFERRIN(Tf)biomimetic mineralized nano-tellurium(Tf-Te)as photosensitizer and then used disulfide bond reconstruction technology to induce Tf-Te self-assembly.The autophagy inhibitor hydroxychloroquine(HCQ)and iron ions carried by Tf were simultaneously loaded to prepare a tumor-responsive drug reservoir Tf-Te/HCQ.After entering breast cancer cells through the“self-guidance system”,Tf-Te/HCQ can generate hyperpyrexia and ROS under NIR laser irradiation,to efficiently induce PTT/PDT effect.Meanwhile,the disulfide bond broke down in response to GSH,and the nanoparticles disintegrated to release Fe2+and HCQ at fixed points.They simultaneously induce lysosomal alkalinization and increased osmotic pressure,effectively inhibit autophagy,and synergistically enhance the therapeutic effect of phototherapy.In vivo anti-tumor results have proved that the tumor inhibition rate of Tf-Te/HCQ can be as high as 88.6%on 4T1 tumor-bearing mice.This multifunctional drug delivery system might provide a new alternative for more precise and effective tumor phototherapy.
基金supported by National Natural Science Foundation of China(No.82102918)。
文摘To develop an efficient thrombolytic therapy approach that addresses the limitations of current fibrinolytic drugs, such as short half-life, weak thrombus specificity and poor penetration ability, we constructed a NIR-triggered detachable nanoplatform (PA/UK@IcpLipo) using thin-film hydration method. It was designed to integrate attack and defense mechanisms for thrombolytic therapy. This platform can actively identify thrombi by binding to GPIIb-IIIa receptors overexpressed on activated platelets. Upon NIR laser activation and interaction with thrombin in the thrombotic microenvironment, the thermosensitive liposomes rupture, releasing the PA/UK core for deep penetration into the thrombus. Our results showed that the PA/UK@IcpLipo nanoplatform efficiently promoted rapid thrombolysis under the action of UK (attack), followed by PA exerting an antiplatelet aggregation effect (defense). This dual-action approach significantly improved vascular reperfusion rates. The NIR-triggered detachable nanoplatform offered a promising solution for enhanced thrombolysis efficiency and reduced bleeding risk, addressing critical limitations of current fibrinolytic therapies.
