Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(...Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(NK) cells targeting hematologic malignancies(HMs).Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine(PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients.Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors.Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.展开更多
The propagation characteristics of oblique incidence terahertz(THz) waves through non-uniform plasma are investigated by the shift-operator finite-difference time-domain(SO-FDTD) method combined with the phase matchin...The propagation characteristics of oblique incidence terahertz(THz) waves through non-uniform plasma are investigated by the shift-operator finite-difference time-domain(SO-FDTD) method combined with the phase matching condition.The electron density distribution of the non-uniform plasma is assumed to be in a Gaussian profile. Validation of the present method is performed by comparing the results with those obtained by an analytical method for a homogeneous plasma slab.Then the effects of parameters of THz wave and plasma layer on the propagation properties are analyzed. It is found that the transmission coefficients greatly depend on the incident angle as well as on the thickness of the plasma, while the polarization of the incident wave has little influence on the propagation process in the range of frequency considered in this paper. The results confirm that the THz wave can pass through the plasma sheath effectively under certain conditions,which makes it a potential candidate to overcome the ionization blackout problem.展开更多
Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using world...Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.展开更多
Objective:NK cells play crucial roles in the immune defense mechanisms against viral infections and transformed cells.However,the developmental progression,transcriptomic landscape,and functional subtypes of liver NK ...Objective:NK cells play crucial roles in the immune defense mechanisms against viral infections and transformed cells.However,the developmental progression,transcriptomic landscape,and functional subtypes of liver NK cells are not well defined.Hepatocellular carcinoma(HCC)accounts for approximately 80%of primary liver cancer worldwide,yet the biological characteristics of NK cells in the HCC environment are unclear.Therefore,we aimed to determine these cells’roles in tumorigenesis and prognosis.Methods:We compared the single-cell RNA sequencing profiles of NK cells purified from blood(n=1),healthy liver tissues(n=3),HCC tumor tissues(n=4),and peritumor liver tissues(n=1)to identify NK cell subsets.Furthermore,we performed bioinformatics analysis by using The Cancer Genome Atlas(TCGA)data to identify prognostic biomarkers simultaneously overexpressed in the blood and tumor tissues of patients with HCC.Results:Transcriptomic analysis revealed 5 NK cell subsets(L1-NK-CD56bright,L2-NK-CD56dim,L3-NK-HLA,L4-LrNK-FCGR3A,and L5-LrNK-XCL1)in the healthy liver tissues.However,the transitional L3 subset and the CXCR6+CD16+L4 subset with strong anti-tumor activity were absent in the HCC and peritumor liver tissues.Furthermore,4 common prognosis-associated genes(RHOB,TALDO1,HLA-DPA1,and TKT)were significantly overexpressed in the paired tumor tissue and blood.Conclusions:Our study revealed 5 specific subsets of NK cells in healthy human liver tissues.However,only 3 of the 5 NK cell subsets were present in HCC and peritumor tissues.The cytotoxic NK cell subsets were absent in HCC tissues.Furthermore,we identified 4 potential non-invasive prognostic biomarkers in patients with HCC.展开更多
The possibility to enhance the stability and robustness of electrohydraulic brake(EHB)systems is considered a subject of great importance in the automotive field.In such a context,the present study focuses on an actua...The possibility to enhance the stability and robustness of electrohydraulic brake(EHB)systems is considered a subject of great importance in the automotive field.In such a context,the present study focuses on an actuator with a four-way sliding valve and a hydraulic cylinder.A 4-order nonlinear mathematical model is introduced accordingly.Through the linearization of the feedback law of the high order EHB model,a sliding mode control method is proposed for the hydraulic pressure.The hydraulic pressure tracking controls are simulated and analyzed by MATLAB/Simulink soft considering separately different conditions,i.e.,a sine wave,a square wave and a square wave with superimposed sine disturbance.The results show that the proposed strategy can track the target within 0.25 s,and the mean observed error is less than 1.2 bar.Moreover,with such a strategy,faster response and less overshoot are possible,which should be regarded as significant advantages.展开更多
Antibiotic resistance genes(ARGs)can be easily promoted by antibiotics,however,the structural effects of antibiotics on the proliferation of ARGs dynamic and the associated mechanisms remain obscure in,especially,acti...Antibiotic resistance genes(ARGs)can be easily promoted by antibiotics,however,the structural effects of antibiotics on the proliferation of ARGs dynamic and the associated mechanisms remain obscure in,especially,activated sludge sequencing batch reactors.In the present study,the effects of 9 sulfonamides(SAs)with different structures on the proliferation dynamic of sulfonamide resistance genes(Suls)in the activated sludge sequencing batch reactors and the corresponding mechanisms were determined(30 days),and the results showed that the largest proliferation value(ΔA^(R))of Suls dynamic for SAs(sulfachloropyridazine)was approximately 2.9 times than that of the smallest one(sulfadiazine).The proliferation of Suls was significantly related to the structural features(minHBint6,SssNH,SHBd and SpMax2_Bhm)that represent the biological activity of SAs.To interpret the phenomenon,a mechanistic model was developed and the results indicated that the biodegradation of SAs(T_(1/2))rather than conjugative transfer frequency or mutation frequency tends to be the key process for affecting Suls proliferation.T_(1/2)was proved to be dependent on the interactions between SAs and receptors(E_(binding)),the cleavage mode(bond dissociation energy),and the site of nucleophilic assault.Besides,the metagenomic analysis showed that SAs posed significant effect on antibiotic resistome and Tnp31 played a vital role in the proliferation of Suls.Overall,our findings provide important insight into a theoretical basis for understanding the structural effects of SAs on the proliferation of ARGs in SBR systems.展开更多
Three-dimensional(3D)hydrogel models play a crucial role in tissue engineering for promoting tissue regeneration.A biomimetic microchannel network system in the 3D hydrogel model is necessary for optimal cellular func...Three-dimensional(3D)hydrogel models play a crucial role in tissue engineering for promoting tissue regeneration.A biomimetic microchannel network system in the 3D hydrogel model is necessary for optimal cellular function.This report describes the preparation of a biomimetic hydrogel scaffold with an internal microchannel network,using electrospinning techniques and the sacrificial template method for 3D cell culture.Microchannels and cavities were created within the gelatin methacryloyl(GelMA)hydrogel by sacrificing polyvinyl alcohol(PVA)electrospun fibers(>10µm),resulting in the creation of microvessel-like channels.Mechanical characterizations,swelling properties,and biodegradation analysis were conducted to investigate the feasibility of a biomimetic microchannel network hydrogel scaffold for 3D cell culture applications.Compared to pure GelMA hydrogel,the hydrogel with microchannels promoted cell proliferation,adhesion,and endothelial tube formation.Moreover,the results confirmed that the biomimetic microchannel network scaffold had a major impact on the distribution and arrangement of human umbilical vein endothelial cells(HUVECs)and can enable the formation of artificial microvasculature by the culture of HUVECs and cell media perfusion.展开更多
Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation betwe...Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono- and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC.展开更多
Efficient immune responses against invading pathogens often involve coordination between cells from both the innate and adaptive immune systems.For multiple decades,it has been believed that CD8+memory T cells and nat...Efficient immune responses against invading pathogens often involve coordination between cells from both the innate and adaptive immune systems.For multiple decades,it has been believed that CD8+memory T cells and natural killer(NK)cells constantly and uniformly recirculate.Only recently was the existence of noncirculating memory T and NK cells that remain resident in the peripheral tissues,termed tissue-resident memory T(TRM)cells and tissue-resident NK(trNK)cells,observed in various organs owing to improved techniques.TRM cells populate a wide range of peripheral organs,including the skin,sensory ganglia,gut,lungs,brain,salivary glands,female reproductive tract,and others.Recent findings have demonstrated the existence of TRM in the secondary lymphoid organs(SLOs)as well,leading to revision of the classic theory that they exist only in peripheral organs.trNK cells have been identified in the uterus,skin,kidney,adipose tissue,and salivary glands.These tissue-resident lymphocytes do not recirculate in the blood or lymphatic system and often adopt a unique phenotype that is distinct from those of circulating immune cells.In this review,we will discuss the recent findings on the tissue residency of both innate and adaptive lymphocytes,with a particular focus on CD8+memory T cells,and describe some advances regarding unconventional T cells(invariant NKT cells,mucosal-associated invariant T cells(MAIT),andγδT cells)and the emerging family of trNK cells.Specifically,we will focus on the phenotypes and functions of these subsets and discuss their implications in anti-viral and anti-tumor immunity.展开更多
The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute ...The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute inflammation, chronic infection, autoimmune disease, and tumors. The liver contains a large proportion of natural killer (NK) cells, which exhibit heterogeneity in phenotypic and functional characteristics. NK cell activation, well known for its role in the immune surveillance against tumor and pathogen-infected cells, depends on the balance between numerous activating and inhibitory signals. In addition to the innate direct "killer" functions, NK cell activity contributes to regulate innate and adaptive immunity (helper or regulator). Under the setting of liver diseases, NK cells are of great importance for stimulating or inhibiting immune responses, leading to either immune activation or immune tolerance. Here, we focus on the relationship between NK cell biology, such as their phenotypic features and functional diversity, and liver diseases.展开更多
Background:The interaction between activating receptor NKp30 and its major tumor ligand B7-H6 is important for NK cell-mediated tumor rejection.However,the regulation of B7-H6 by tumor therapeutics remains largely unk...Background:The interaction between activating receptor NKp30 and its major tumor ligand B7-H6 is important for NK cell-mediated tumor rejection.However,the regulation of B7-H6 by tumor therapeutics remains largely unknown.In this study,we investigated the regulation of B7-H6 by all-trans retinoic acid(atRA),a terminal differentiation inducer of tumor cells that is extensively used for clinical leukemia therapy.Methods:We investigated the role of NKp30:B7-H6 axis in NK cell-mediated tumor lysis against leukemia cells and the influence of atRA treatment on the cytotoxicity of NK cells using NK cell lines(NK92 and NKG)and leukemia cell lines(U-937 and THP-1).We evaluated the effect of atRA treatment on the expression of B7-H6 using real-time PCR,flow cytometry and western blotting.We used CRISPR/Cas9 to knockdown B7-H6 expression and siRNA to knockdown c-Myc in U-937 cells to evaluate the role of B7-H6 and c-Myc in atRA-induced tumor resistance against NK cells.Results:NK cell-mediated U-937 cell lysis was mainly dependent on NKp30/B7-H6 interaction.Blockade of B7-H6 by monoclonal antibody significantly impaired NK cytotoxicity.atRA treatment induced U-937 resistance to NK cell cytotoxicity by reducing B7-H6 expression,and showed no effect on NK cytotoxicity against B7-H6 knockdown U-937 cells.Epigenetic modifications,such as DNA methylation and histone deacetylase(HDAC),were not responsible for atRA-mediated B7-H6 down-regulation as inhibitors of these pathways could not restore B7-H6 mRNA expression.On the other hand,atRA treatment reduced c-Myc expression,which in turn inhibited the transcription of B7-H6 on leukemia cells.Conclusion:atRA treatment promotes tumor cell resistance against NK cellmediated lysis by down-regulating B7-H6 expression via the c-Myc signaling pathway,suggesting that more attention needs to be paid to the immunological adverse effects in the clinical use of atRA treatment.展开更多
γδ T cells are heterogeneous lymphocytes located in various tissues.However,a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associat...γδ T cells are heterogeneous lymphocytes located in various tissues.However,a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved.In this study,we performed single-cell RNA sequencing(scRNA-seq)to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples.We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors(pre-γδ T cells).The developmental potential of hepatic γδ T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments.The adoptive transfer of hematopoietic progenitor Lin^(-)Sca-1^(+)Mac-1^(+)(LSM)cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-γδ T cells and interferon-gamma^(+)(IFN-γ^(+))but not interleukin-17a^(+)(IL-17a^(+))γδ T cells in the liver.Importantly,thymectomized mouse models showed that IFN-γ-producing γδ T cells could originate from liver LSM cells in a thymus-independent manner.These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-γδ T cells and functionally mature γδ T cells,which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.展开更多
We present a facile synthetic strategy to create mesoporous Cu_(2)O nanocrystals with tunable pore structures and surface functional groups of amine derivatives for efficient and preferable electrochemical conversion ...We present a facile synthetic strategy to create mesoporous Cu_(2)O nanocrystals with tunable pore structures and surface functional groups of amine derivatives for efficient and preferable electrochemical conversion of CO_(2) into ethylene.The structural characteristics of theseCu_(2)O nanocrystals can be manipulated using a set of amine derivatives,such as pyridine,4,4'-bipyridine,and hexamethylenetetramine,during the oxidative etching process of Cu nanocrystals by bubbling gaseous oxygen in N,N-dimethylformamide solution.These amine derivatives not only serve as surface functional groups but also significantly affect the resulting pore structures.The synergistic effect of pore structure confinement and surface amine functionalization leads to the superb Faradaic efficiency(FE)of 51.9% for C_(2)H_(4),respectively,together with the C_(2)H_(4) partial current density of -209.4 mA·cm^(-2) at -0.8 V vs.reversible hydrogen electrode(RHE).The relatively high selectivity towards C_(2)H_(4) was investigated using DFT simulations,where 4,4'-bipyridine functionalized Cu_(2)O seemed to favor the C_(2)H_(4) formation with the low free energy of the intermediates.This study provides a feasible strategy to manipulate the pore structure and surface functionalization of mesoporous Cu_(2)O nanocrystals by regulating the oxidative etching process,which sheds light on the rational preparation of high-performance CO_(2)RR electrocatalysts.展开更多
基金supported by the National Key R&D Program of China (2019YFA0508502/3 and 2021YFC2300604)the Natural Science Foundation of China (Reference numbers 82388201, 82241216, and 32270963)+1 种基金the Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM (QYZD20220008)the Anhui Key Research and Development Plan (Reference number 2023z04020011)。
文摘Objective: The human cluster of differentiation(CD)300A, a type-I transmembrane protein with immunoreceptor tyrosine-based inhibitory motifs, was investigated as a potential immune checkpoint for human natural killer(NK) cells targeting hematologic malignancies(HMs).Methods: We implemented a stimulation system involving the CD300A ligand, phosphatidylserine(PS), exposed to the outer surface of malignant cells. Additionally, we utilized CD300A overexpression, a CD300A blocking system, and a xenotransplantation model to evaluate the impact of CD300A on NK cell efficacy against HMs in in vitro and in vivo settings. Furthermore, we explored the association between CD300A and HM progression in patients.Results: Our findings indicated that PS hampers the function of NK cells. Increased CD300A expression inhibited HM lysis by NK cells. CD300A overexpression shortened the survival of HM-xenografted mice by impairing transplanted NK cells. Blocking PS–CD300A signals with antibodies significantly amplified the expression of lysis function-related proteins and effector cytokines in NK cells, thereby augmenting the ability to lyse HMs. Clinically, heightened CD300A expression correlated with shorter survival and an “exhausted” phenotype of intratumoral NK cells in patients with HMs or solid tumors.Conclusions: These results propose CD300A as a potential target for invigorating NK cell-based treatments against HMs.
基金Project supported by the National Basic Research Program of China(Grant No.2014CB340203)the National Natural Science Foundation of China(Grant Nos.61431010 and 61501350)the Natural Science Foundation of Shaanxi Province,China(Grant Nos.2018JM6016 and 2016JM1001)
文摘The propagation characteristics of oblique incidence terahertz(THz) waves through non-uniform plasma are investigated by the shift-operator finite-difference time-domain(SO-FDTD) method combined with the phase matching condition.The electron density distribution of the non-uniform plasma is assumed to be in a Gaussian profile. Validation of the present method is performed by comparing the results with those obtained by an analytical method for a homogeneous plasma slab.Then the effects of parameters of THz wave and plasma layer on the propagation properties are analyzed. It is found that the transmission coefficients greatly depend on the incident angle as well as on the thickness of the plasma, while the polarization of the incident wave has little influence on the propagation process in the range of frequency considered in this paper. The results confirm that the THz wave can pass through the plasma sheath effectively under certain conditions,which makes it a potential candidate to overcome the ionization blackout problem.
基金supported by grants from the National Key R&D Program of China(Grant No.2019YFA0508502)the CAMS Innovation Fund for Medical Sciences(Grant No.2019-I2M-5-073)the National Natural Science Foundation of China(Grant Nos.81788101,81972679,and 81821001)。
文摘Objective:Natural killer(NK)cells have gained considerable attention due to their potential in treating"cold tumors,"and are therefore considered as one of the new strategies for curing cancer,by using worldwide development of their new possibilities and interventions with NK cell-related therapeutic products.Methods:We constructed a trispecific killer engager(TriKE)consisting of anti-CD16,IL-15,and anti-CD19.This TriKE was designed to attract CD19^(+)tumor cells to CD16^(+)NK cells,whereas IL-15 sustained the proliferation,development,and survival of NK cells.Results:Treatment with 161519 TriKE in the presence of CD19^(+)targets upregulated expression of CD69,CD107 a,TRAIL,IFN-γ,and TNF-α in NK cells,and significantly improved the proliferation and cytotoxicity of NK cells.NK cells"armed"with 161519 TriKE showed stronger cytolysis against CD19+targets compared with that of"unarmed"NK cells.A preclinical model of B-cell lymphoma in human peripheral blood mononuclear cell-reconstituted xenograft mice showed significant inhibition of tumor growth and prolonged overall survival after treatment with 161519 TriKE,when compared with that in control mice or mice treated with 1619 BiKE.Combined use of IL-2 was a more effective treatment with 1619 BiKE,when compared with that using 161519 TriKE.Conclusions:The newly generated 161519 TriKE enhanced the proliferation,activation,cytokine secretion,and cytotoxicity of NK cells in the presence of CD19+tumor cells.The 161519 TriKE aided inhibition of tumor growth and prolonged the overall survival of murine xenografts,and could be used to treat CD19-positive cancers.
基金supported by the National Key R&D Program of China(Grant Nos.2021YFC2300601 and 2019YFA0508502/3)National Natural Science Foundation of China(Grant Nos.81972679 and 8202290021)+1 种基金Anhui Provincial Natural Science Foundation(Grant Nos.2008085J35 and 2008085MH252)USTC Research Funds of the Double First-Class Initiative(Grant No.YD3520002002).
文摘Objective:NK cells play crucial roles in the immune defense mechanisms against viral infections and transformed cells.However,the developmental progression,transcriptomic landscape,and functional subtypes of liver NK cells are not well defined.Hepatocellular carcinoma(HCC)accounts for approximately 80%of primary liver cancer worldwide,yet the biological characteristics of NK cells in the HCC environment are unclear.Therefore,we aimed to determine these cells’roles in tumorigenesis and prognosis.Methods:We compared the single-cell RNA sequencing profiles of NK cells purified from blood(n=1),healthy liver tissues(n=3),HCC tumor tissues(n=4),and peritumor liver tissues(n=1)to identify NK cell subsets.Furthermore,we performed bioinformatics analysis by using The Cancer Genome Atlas(TCGA)data to identify prognostic biomarkers simultaneously overexpressed in the blood and tumor tissues of patients with HCC.Results:Transcriptomic analysis revealed 5 NK cell subsets(L1-NK-CD56bright,L2-NK-CD56dim,L3-NK-HLA,L4-LrNK-FCGR3A,and L5-LrNK-XCL1)in the healthy liver tissues.However,the transitional L3 subset and the CXCR6+CD16+L4 subset with strong anti-tumor activity were absent in the HCC and peritumor liver tissues.Furthermore,4 common prognosis-associated genes(RHOB,TALDO1,HLA-DPA1,and TKT)were significantly overexpressed in the paired tumor tissue and blood.Conclusions:Our study revealed 5 specific subsets of NK cells in healthy human liver tissues.However,only 3 of the 5 NK cell subsets were present in HCC and peritumor tissues.The cytotoxic NK cell subsets were absent in HCC tissues.Furthermore,we identified 4 potential non-invasive prognostic biomarkers in patients with HCC.
基金supported by the National Natural Science Foundation of China[grant number 51565011]the Foundation of Educational Department of Jiangxi Province[grant number GJJ180302].
文摘The possibility to enhance the stability and robustness of electrohydraulic brake(EHB)systems is considered a subject of great importance in the automotive field.In such a context,the present study focuses on an actuator with a four-way sliding valve and a hydraulic cylinder.A 4-order nonlinear mathematical model is introduced accordingly.Through the linearization of the feedback law of the high order EHB model,a sliding mode control method is proposed for the hydraulic pressure.The hydraulic pressure tracking controls are simulated and analyzed by MATLAB/Simulink soft considering separately different conditions,i.e.,a sine wave,a square wave and a square wave with superimposed sine disturbance.The results show that the proposed strategy can track the target within 0.25 s,and the mean observed error is less than 1.2 bar.Moreover,with such a strategy,faster response and less overshoot are possible,which should be regarded as significant advantages.
基金supported by the National Natural Science Foundation of China (Nos.32160303 and 31760165)the Education Department of Jiangxi Province (No.GJJ211001)+1 种基金the Scientific and Technological Project of Ji’an City (No.20211–025333)the Key Project of Natural Science Foundation of Jiangxi Province (2022)。
文摘Antibiotic resistance genes(ARGs)can be easily promoted by antibiotics,however,the structural effects of antibiotics on the proliferation of ARGs dynamic and the associated mechanisms remain obscure in,especially,activated sludge sequencing batch reactors.In the present study,the effects of 9 sulfonamides(SAs)with different structures on the proliferation dynamic of sulfonamide resistance genes(Suls)in the activated sludge sequencing batch reactors and the corresponding mechanisms were determined(30 days),and the results showed that the largest proliferation value(ΔA^(R))of Suls dynamic for SAs(sulfachloropyridazine)was approximately 2.9 times than that of the smallest one(sulfadiazine).The proliferation of Suls was significantly related to the structural features(minHBint6,SssNH,SHBd and SpMax2_Bhm)that represent the biological activity of SAs.To interpret the phenomenon,a mechanistic model was developed and the results indicated that the biodegradation of SAs(T_(1/2))rather than conjugative transfer frequency or mutation frequency tends to be the key process for affecting Suls proliferation.T_(1/2)was proved to be dependent on the interactions between SAs and receptors(E_(binding)),the cleavage mode(bond dissociation energy),and the site of nucleophilic assault.Besides,the metagenomic analysis showed that SAs posed significant effect on antibiotic resistome and Tnp31 played a vital role in the proliferation of Suls.Overall,our findings provide important insight into a theoretical basis for understanding the structural effects of SAs on the proliferation of ARGs in SBR systems.
基金supported by the National Natural Science Foundation of China(No.31870934)the Natural Science Foundation for Young Scientists of Shanxi Province(No.202103021223100),China.
文摘Three-dimensional(3D)hydrogel models play a crucial role in tissue engineering for promoting tissue regeneration.A biomimetic microchannel network system in the 3D hydrogel model is necessary for optimal cellular function.This report describes the preparation of a biomimetic hydrogel scaffold with an internal microchannel network,using electrospinning techniques and the sacrificial template method for 3D cell culture.Microchannels and cavities were created within the gelatin methacryloyl(GelMA)hydrogel by sacrificing polyvinyl alcohol(PVA)electrospun fibers(>10µm),resulting in the creation of microvessel-like channels.Mechanical characterizations,swelling properties,and biodegradation analysis were conducted to investigate the feasibility of a biomimetic microchannel network hydrogel scaffold for 3D cell culture applications.Compared to pure GelMA hydrogel,the hydrogel with microchannels promoted cell proliferation,adhesion,and endothelial tube formation.Moreover,the results confirmed that the biomimetic microchannel network scaffold had a major impact on the distribution and arrangement of human umbilical vein endothelial cells(HUVECs)and can enable the formation of artificial microvasculature by the culture of HUVECs and cell media perfusion.
基金This work was supported by grants from the Chinese Government Department of Science & Technology of China (2012ZX10002006 2012ZX 10002014+4 种基金 2013 ZX 10002002 2012AA020901 2010CB911901 2013CB944901) and the Natural Science Foundation of China (81273220 81472646).
文摘Hepatocellular carcinoma (HCC) is currently the third leading cause of cancer mortality and a common poor-prognosis malignancy due to postoperative recurrence and metastasis. There is a significant correlation between chronic hepatitis B virus (HBV) infection and hepatocarcinogenesis. As the first line of host defense against viral infections and tumors, natural killer (NK) cells express a large number of immune recognition receptors (NK receptors (NKRs)) to recognize ligands on hepatocytes, liver sinusoidal endothelial cells, stellate cells and Kupffer cells, which maintain the balance between immune response and immune tolerance of NK cells. Unfortunately, the percentage and absolute number of liver NK cells decrease significantly during the development and progression of HCC. The abnormal expression of NK cell receptors and dysfunction of liver NK cells contribute to the progression of chronic HBV infection and HCC and are significantly associated with poor prognosis for liver cancer. In this review, we focus on the role of NK cell receptors in anti-tumor immune responses in HCC, particularly HBV-related HCC. We discuss specifically how tumor cells evade attack from NK cells and how emerging understanding of NKRs may aid the development of novel treatments for HCC. Novel mono- and combination therapeutic strategies that target the NK cell receptor-ligand system may potentially lead to successful and effective immunotherapy in HCC.
基金by the National Key R&D Program of China(2018YFA0507403)the National Natural Science Foundation of China(81788101,81701631,31390433,and 31670908)the Chinese Academy of Sciences(XDB29030000).
文摘Efficient immune responses against invading pathogens often involve coordination between cells from both the innate and adaptive immune systems.For multiple decades,it has been believed that CD8+memory T cells and natural killer(NK)cells constantly and uniformly recirculate.Only recently was the existence of noncirculating memory T and NK cells that remain resident in the peripheral tissues,termed tissue-resident memory T(TRM)cells and tissue-resident NK(trNK)cells,observed in various organs owing to improved techniques.TRM cells populate a wide range of peripheral organs,including the skin,sensory ganglia,gut,lungs,brain,salivary glands,female reproductive tract,and others.Recent findings have demonstrated the existence of TRM in the secondary lymphoid organs(SLOs)as well,leading to revision of the classic theory that they exist only in peripheral organs.trNK cells have been identified in the uterus,skin,kidney,adipose tissue,and salivary glands.These tissue-resident lymphocytes do not recirculate in the blood or lymphatic system and often adopt a unique phenotype that is distinct from those of circulating immune cells.In this review,we will discuss the recent findings on the tissue residency of both innate and adaptive lymphocytes,with a particular focus on CD8+memory T cells,and describe some advances regarding unconventional T cells(invariant NKT cells,mucosal-associated invariant T cells(MAIT),andγδT cells)and the emerging family of trNK cells.Specifically,we will focus on the phenotypes and functions of these subsets and discuss their implications in anti-viral and anti-tumor immunity.
基金This work was supported by grants from the National Natural Science Foundation of China (Nos. 81771685, 91429303, 31390433, 81761128013, and 91542000) and Ministry of Science and Technology of China (973 Basic Science Project, No. 2013CB944902).
文摘The liver has been characterized as a frontline lymphoid organ with complex immunological features such as liver immunity and liver tolerance. Liver tolerance plays an important role in liver diseases including acute inflammation, chronic infection, autoimmune disease, and tumors. The liver contains a large proportion of natural killer (NK) cells, which exhibit heterogeneity in phenotypic and functional characteristics. NK cell activation, well known for its role in the immune surveillance against tumor and pathogen-infected cells, depends on the balance between numerous activating and inhibitory signals. In addition to the innate direct "killer" functions, NK cell activity contributes to regulate innate and adaptive immunity (helper or regulator). Under the setting of liver diseases, NK cells are of great importance for stimulating or inhibiting immune responses, leading to either immune activation or immune tolerance. Here, we focus on the relationship between NK cell biology, such as their phenotypic features and functional diversity, and liver diseases.
基金This work was supported by the National Key R&D Program of China(2019YFA0508502)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-073)the National Natural Science Foundation of China(31700754,81788101,and 81821001).
文摘Background:The interaction between activating receptor NKp30 and its major tumor ligand B7-H6 is important for NK cell-mediated tumor rejection.However,the regulation of B7-H6 by tumor therapeutics remains largely unknown.In this study,we investigated the regulation of B7-H6 by all-trans retinoic acid(atRA),a terminal differentiation inducer of tumor cells that is extensively used for clinical leukemia therapy.Methods:We investigated the role of NKp30:B7-H6 axis in NK cell-mediated tumor lysis against leukemia cells and the influence of atRA treatment on the cytotoxicity of NK cells using NK cell lines(NK92 and NKG)and leukemia cell lines(U-937 and THP-1).We evaluated the effect of atRA treatment on the expression of B7-H6 using real-time PCR,flow cytometry and western blotting.We used CRISPR/Cas9 to knockdown B7-H6 expression and siRNA to knockdown c-Myc in U-937 cells to evaluate the role of B7-H6 and c-Myc in atRA-induced tumor resistance against NK cells.Results:NK cell-mediated U-937 cell lysis was mainly dependent on NKp30/B7-H6 interaction.Blockade of B7-H6 by monoclonal antibody significantly impaired NK cytotoxicity.atRA treatment induced U-937 resistance to NK cell cytotoxicity by reducing B7-H6 expression,and showed no effect on NK cytotoxicity against B7-H6 knockdown U-937 cells.Epigenetic modifications,such as DNA methylation and histone deacetylase(HDAC),were not responsible for atRA-mediated B7-H6 down-regulation as inhibitors of these pathways could not restore B7-H6 mRNA expression.On the other hand,atRA treatment reduced c-Myc expression,which in turn inhibited the transcription of B7-H6 on leukemia cells.Conclusion:atRA treatment promotes tumor cell resistance against NK cellmediated lysis by down-regulating B7-H6 expression via the c-Myc signaling pathway,suggesting that more attention needs to be paid to the immunological adverse effects in the clinical use of atRA treatment.
基金supported by grants from the National Natural Science Foundation of China(91842305,81771686)the National Key R&D Program of China(2019YFA0508503)+1 种基金the National Major Science&Technology Project for Control and Prevention of Major Infectious Diseases in China(2018ZX10301401)the Shandong Provincial Key Research and Development Program(Major Scientific and Technological Innovation Project)(2019JZZY021013).
文摘γδ T cells are heterogeneous lymphocytes located in various tissues.However,a systematic and comprehensive understanding of the origins of γδ T cell heterogeneity and the extrathymic developmental pathway associated with liver γδ T cells remain largely unsolved.In this study,we performed single-cell RNA sequencing(scRNA-seq)to comprehensively catalog the heterogeneity of γδ T cells derived from murine liver and thymus samples.We revealed the developmental trajectory of γδ T cells and found that the liver contains γδ T cell precursors(pre-γδ T cells).The developmental potential of hepatic γδ T precursor cells was confirmed through in vitro coculture experiments and in vivo adoptive transfer experiments.The adoptive transfer of hematopoietic progenitor Lin^(-)Sca-1^(+)Mac-1^(+)(LSM)cells from fetal or adult liver samples to sublethally irradiated recipients resulted in the differentiation of liver LSM cells into pre-γδ T cells and interferon-gamma^(+)(IFN-γ^(+))but not interleukin-17a^(+)(IL-17a^(+))γδ T cells in the liver.Importantly,thymectomized mouse models showed that IFN-γ-producing γδ T cells could originate from liver LSM cells in a thymus-independent manner.These results suggested that liver hematopoietic progenitor LSM cells were able to differentiate into pre-γδ T cells and functionally mature γδ T cells,which implied that these cells are involved in a distinct developmental pathway independent of thymus-derived γδ T cells.
基金financially supported by Shandong Provincial Natural Science Foundation(No.ZR2022MB120&ZR2020MB048)the University Feature Laboratory for Energy Conversion and Nanocatalysis of Shandong ProvinceHundred Outstanding Talent Program of Jining University(No.2020ZYRC05).
文摘We present a facile synthetic strategy to create mesoporous Cu_(2)O nanocrystals with tunable pore structures and surface functional groups of amine derivatives for efficient and preferable electrochemical conversion of CO_(2) into ethylene.The structural characteristics of theseCu_(2)O nanocrystals can be manipulated using a set of amine derivatives,such as pyridine,4,4'-bipyridine,and hexamethylenetetramine,during the oxidative etching process of Cu nanocrystals by bubbling gaseous oxygen in N,N-dimethylformamide solution.These amine derivatives not only serve as surface functional groups but also significantly affect the resulting pore structures.The synergistic effect of pore structure confinement and surface amine functionalization leads to the superb Faradaic efficiency(FE)of 51.9% for C_(2)H_(4),respectively,together with the C_(2)H_(4) partial current density of -209.4 mA·cm^(-2) at -0.8 V vs.reversible hydrogen electrode(RHE).The relatively high selectivity towards C_(2)H_(4) was investigated using DFT simulations,where 4,4'-bipyridine functionalized Cu_(2)O seemed to favor the C_(2)H_(4) formation with the low free energy of the intermediates.This study provides a feasible strategy to manipulate the pore structure and surface functionalization of mesoporous Cu_(2)O nanocrystals by regulating the oxidative etching process,which sheds light on the rational preparation of high-performance CO_(2)RR electrocatalysts.