Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limite...Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limited to a minority of patients with SCLC.In the present study,novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC.The functional role of the key gene identified in SCLC was determined both in vitro and in vivo.Results:A significant correlation was observed between patient survival and CD56dim natural killer(NK)cell proportion.Furthermore,we noted that the hub gene ubiquitin-specific protease 1(USP1)is closely correlated with both CD56dim NK cells and overall survival in SCLC.Bioinformatics analysis revealed that USP1 is upregulated in SCLC.In addition,gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses.By co-cultivating NK-92 cells with SCLC cells,we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition.Furthermore,using a nude-mice xenograft tumor model,we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC.USP1 overexpression can inhibit NK cell-mediated immunity;therefore,USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.展开更多
Urbanization has significantly altered the habitat structure and behavioral patterns of animals.In urban environments with frequent human disturbances,animals may undergo adaptive adjustments in their escape behaviors...Urbanization has significantly altered the habitat structure and behavioral patterns of animals.In urban environments with frequent human disturbances,animals may undergo adaptive adjustments in their escape behaviors.This study focuses on Eurasian Tree Sparrows(Passer montanus)from five cities across different latitudes in China,comparing their flight initiation distance(FID)in urban and rural areas to assess the impact of urbanization on their escape behavior and the trend of ecological homogenization.The results confirm the established pattern at the geographic level:a reduction of FID in urban habitats and a decrease in FID with increasing latitude.That is,northern populations of the Eurasian Tree Sparrow in China are bolder than the southern populations.In addition,FID is positively correlated with flock size,with rural flocks exhibiting more pronounced group behavior(observed flocking frequency for urban and rural is 28.74%vs.40.7%,flock size variance is 26.90 vs.55.63).Despite the differences between northern and southern latitudes,the variability of FID in urban individuals consistently remains lower than that in rural areas,supporting the trend of reduced variability in escape behavior among birds in urban environments.Driven by urbanization,the escape behavior of Eurasian Tree Sparrows tends toward ecological homogenization,meaning that behavioral differences between urban areas in different cities are diminishing.This trend may obscure the behavioral variability brought about by latitude gradients,indicating that urbanization not only shapes the behavioral adaptations of birds but also potentially weakens their behavioral diversity.展开更多
Atmospheric escape plays a critical role in shaping the long-term climate evolution of Mars.Among the various escape mechanisms,energetic neutral atoms(ENAs)generated through charge exchange between solar wind ions an...Atmospheric escape plays a critical role in shaping the long-term climate evolution of Mars.Among the various escape mechanisms,energetic neutral atoms(ENAs)generated through charge exchange between solar wind ions and exospheric neutrals serve as an important diagnostic for ion-neutral interactions and upper atmospheric loss.This study presents direct observations of hydrogen ENAs(H-ENAs)on the dayside of Mars by using the Mars Ion and Neutral Particle Analyzer(MINPA)onboard China’s Tianwen-1 orbiter.By analyzing H-ENA data during a coronal mass ejection and a stream interaction region from December 29,2021,to January 1,2022,and comparing these data with MAVEN/SWIA(Mars Atmosphere and Volatile EvolutioN/Solar Wind Ion Analyzer)solar wind measurements,we examine the temporal evolution of H-ENA flux and the associated sputtered escape of atmospheric constituents.The observed H-ENA velocity is consistent with upstream solar wind ions,and the H-ENA-to-ion intensity ratio is used to infer variations in exospheric density,revealing a delayed response to enhanced solar wind activity.Penetrating H-ENA intensities reach up to 5.3×10^(6)s^(−1) cm^(−2),with energy fluxes on the order of(0.5-8.1)×10^(−3) mW/m^(2).The estimated oxygen sputtered escape rate driven by penetrating H-ENAs ranges from 5.5×10^(23)s^(−1) to 5.2×10^(24)s^(−1),comparable to or exceeding previous estimates based on penetrating ions.The findings highlight the need for low-altitude H-ENA observations to better quantify their atmospheric interactions and refine our understanding of nonthermal escape processes at Mars.展开更多
Zebrafish larvae are useful for identifying chemicals against lateral line(LL)hair cell(HC)damage and this type of chemical screen mainly focuses on searching for protectors against cell death.To expand the candidate ...Zebrafish larvae are useful for identifying chemicals against lateral line(LL)hair cell(HC)damage and this type of chemical screen mainly focuses on searching for protectors against cell death.To expand the candidate pool of HC protectors,a self-built acoustic escape response(AER)-detecting system was developed to apply both low-frequency near-field sound transmission and AER image acquisition/processing modules.The device quickly confirmed the changed LL HC functions caused by most known ototoxins,protectors,and neural transmission modifiers,or knockdown of LL HC-expressing genes.With ten devices wired in tandem,five‘hit’chemicals were identified from 124 cyclin-dependent kinase inhibitors to partially restore cisplatin-damaged AER in less than a day.AS2863619,ribociclib,and SU9516 among the hits,protected the HCs in the mouse cochlea.Therefore,using free-swimming larval zebrafish,the self-made AER-detecting device can efficiently identify compounds that are protective against HC damage,including cell death and loss-of-function.展开更多
Background:Motif interacting with ubiquitin-containing novelDUB family-1(MINDY1)could enhance the stability of programmed death-ligand 1(PD-L1).The study aimed to investigate whether MINDY1 regulates the immune escape...Background:Motif interacting with ubiquitin-containing novelDUB family-1(MINDY1)could enhance the stability of programmed death-ligand 1(PD-L1).The study aimed to investigate whether MINDY1 regulates the immune escape of hepatocellular carcinoma(HCC)mediated by PD-L1.Methods:MINDY1 and PD-L1 levels were detected throughWestern blot.The link between MINDY1 and PD-L1 was validated using the co-immunoprecipitation assay.The malignant biology of HCC cells was assessed through Cell Counting Kit-8,Carboxyfluorescein Succinimidyl Ester staining,transwell,and wound healing assay.CD8^(+)T cells were isolated and then co-cultured with HCC cells.Enzyme-linked immunosorbent Assay kits detected CD8^(+)T cytokine content.CD8^(+)T cell activation markers,PD-L1 ubiquitination levels,andWnt/β-catenin pathway-associated protein levels were detected throughWestern blot.AHCC nude mouse model was developed,Ki-67 positivity and CD8^(+)T-cell infiltration were assessed through pathological staining and flow cytometry.Results:MINDY1 and PD-L1 levels were elevated in HCC.Overexpression of MINDY1 increased migrating and invading cells,elevated cell viability,and decreased apoptosis in HCC cells,leading to PD-L1 deubiquitination.Knockdown of MINDY1 reversed all of these indicators.Co-culturing withHCC cells overexpressing MINDY1 resulted in decreased proliferative capacity and cytotoxicity of CD8^(+)T cells,increased apoptosis,and decreased levels of cytokines and activation markers in CD8^(+)T cells.MINDY1 triggeredWnt/β-catenin pathway,Wnt activators further promoted PD-L1 deubiquitination and suppressed CD8^(+)T cell activation.MINDY1 overexpression increased PD-L1 and Ki67 positivity level in HCC tumors,suppressed CD8^(+)T-cell infiltration.Conclusion:MINDY1 promotes PD-L1 deubiquitination and inhibits CD8^(+)T cell activation by stimulating the Wnt/β-catenin pathway,consequently promoting HCC tumor immune escape.展开更多
Emerging therapies rely on the efficient and specific delivery of targeted agents into the cytosol,such as DNA,siRNA and proteins.Nanoparticles showed great potentials in safe delivery and transportation of the target...Emerging therapies rely on the efficient and specific delivery of targeted agents into the cytosol,such as DNA,siRNA and proteins.Nanoparticles showed great potentials in safe delivery and transportation of the targeted cargoes;however,the entrapment in endosomes and degradation by specific enzymes in the lysosome hindered the bioavailability,cytosolic delivery and subsequent therapeutic efficacy.In this case,the development of methods for efficient and specific delivery of targeted therapeutic agents focuses on overcoming the major challenge of endo/lysosomal escape,which relies on the development of safe and efficient nanodelivery systems.A deeper mechanistic understanding in the endo/lysosomal escape will guide the development of more efficient nano-delivery systems.In this review,we summarize various mechanisms by which nanoparticles escape from the endo/lysosome,and showcase the recent progress in dissecting the endo/lysosomal approaches based on nano-delivery systems.Emphasis will lie on the properties of nanoparticles that govern the endo/lysosomal escape pathway as well as the latest promising applications in vaccine delivery and genetic engineering field.展开更多
Escape theory has been exceptionally successful in conceptualizing and accurately predicting effects of numerous factors that affect predation risk and explaining variation in flight initiation distance(FID;predator–...Escape theory has been exceptionally successful in conceptualizing and accurately predicting effects of numerous factors that affect predation risk and explaining variation in flight initiation distance(FID;predator–prey distance when escape begins).Less explored is the relative orientation of an approaching predator,prey,and its eventual refuge.The relationship between an approaching threat and its refuge can be expressed as an angle we call the“interpath angle”or“Φ,”which describes the angle between the paths of predator and prey to the prey’s refuge and thus expresses the degree to which prey must run toward an approaching predator.In general,we might expect that prey would escape at greater distances if they must flee toward a predator to reach its burrow.The“race for life”model makes formal predictions about howΦshould affect FID.We evaluated the model by studying escape decisions in yellow-bellied marmots Marmota flaviventer,a species which flees to burrows.We found support for some of the model’s predictions,yet the relationship betweenΦand FID was less clear.Marmots may not assessΦin a continuous fashion;but we found that binning angle into 445°bins explained a similar amount of variation as models that analyzed angle continuously.Future studies ofΦ,especially those that focus on how different species perceive relative orientation,will likely enhance our understanding of its importance in flight decisions.展开更多
In order to visualize singularity of SGCMGs in gimbal angle space,a novel continuous bounded singularity parameter--Singularity Radius,whose sign can distinctly determine singularity type,is proposed.Then a rapid sing...In order to visualize singularity of SGCMGs in gimbal angle space,a novel continuous bounded singularity parameter--Singularity Radius,whose sign can distinctly determine singularity type,is proposed.Then a rapid singularity-escape steering law is proposed basing on gradient of Singularity Radius and residual base vector to drive the SGCMG system to neighboring singular boundary,and quickly escape elliptic singularities.Finally,simulation results on Pyramid-type and skew-type configuration demonstrate the effectiveness and rapidness of the proposed steering law.展开更多
Objective： To investigate the expression of Fas, Fas ligand （FasL） and CD80 on the cell surface of mouse acute myelomonocytic leukemia cell line WEHI-3 and the function of FasL. Methods： The expression of Fas, Fas...Objective： To investigate the expression of Fas, Fas ligand （FasL） and CD80 on the cell surface of mouse acute myelomonocytic leukemia cell line WEHI-3 and the function of FasL. Methods： The expression of Fas, FasL and CD80 was detected on WEHI-3 cell surface by flow cytometry. Simultaneously the function of FasL was determined by Thymidine （^3H-TdR） Incorporation. Results： The expression of CD80 and Fas on WEHI-3 cell surface was 5.06%±0.41% and 6.75%±2.31% （n=5） respectively, and the expression of FasL was up to 63.73%±5.23% （n=5）. The apoptotic rate of YAC-1 cells was 26%±4.5%, 35%±3.2% and 43%±2.7% （n=5） respectively when WEHI-3 （effector cell, E） and Fas^＋ YAC-1 cells （target cell, T） were cultured in the ratio of 3：1, 10：1 and 30：1. Conclusion： WEHI-3 cells express high FasL, low Fas and CD80, and can induce apoptosis of Fas^＋ YAC-1 cells.展开更多
Escape time algorithm is an effective theoretical algorithm of constructing fractal graphics. The key of this algorithm lies in the construction of escape time function. A new escape time function is presented based o...Escape time algorithm is an effective theoretical algorithm of constructing fractal graphics. The key of this algorithm lies in the construction of escape time function. A new escape time function is presented based on the research of escape time algorithm. An accelerated escape time algorithm is carried out in this paper. The experiments have demonstrated that the new algorithm is not only as precise as the old, but also faster when it is used to construct Julia set.展开更多
Gynecological cancers present significant treatment challenges due to drug resistance and adverse side effects.This review explores advancements in lysosomal escape mechanisms,essential for enhancing nano-therapeutic ...Gynecological cancers present significant treatment challenges due to drug resistance and adverse side effects.This review explores advancements in lysosomal escape mechanisms,essential for enhancing nano-therapeutic efficacy.Strategies such as pH-sensitive linkers and membrane fusion are examined,showcasing their potential to improve therapeutic outcomes in ovarian,cervical,and uterine cancers.We delve into novel materials and strategies developed to bypass the lysosomal barrier,including pH-sensitive linkers,fusogenic lipids,and nanoparticles(NPs)engineered for endosomal disruption.Mechanisms such as the proton sponge effect,where NPs induce osmotic swelling and rupture of the lysosomal membrane,and membrane fusion,which facilitates the release of therapeutic agents directly into the cytoplasm,are explored in detail.These innovations not only promise to improve therapeutic outcomes but also minimize side effects,marking a significant step forward in the treatment of ovarian,cervical,and uterine cancers.By providing a comprehensive analysis of current advancements and their implications for clinical applications,this review sheds light on the potential of lysosomal escape strategies to revolutionize gynecological cancer treatment,setting the stage for future research and development in this vital area.展开更多
A 62-year-old man had chronic hepatitis B virus （HBV） infection and was diagnosed with liver cirrhosis. At the time of diagnosis the patient＇s virologic markers were positive for hepatitis B surface antigen （HBsAg...A 62-year-old man had chronic hepatitis B virus （HBV） infection and was diagnosed with liver cirrhosis. At the time of diagnosis the patient＇s virologic markers were positive for hepatitis B surface antigen （HBsAg）, antibody to hepatitis B e antigen （anti-HBe） and antibody to hepatitis B core antigen （anti-HBc）, while antibody to hepatitis B surface antigen （anti-HBs） and HBV DNA were negative. Later the patient received chemotherapy for malignancy. However, this was interrupted due to elevated liver enzymes. At the same time HBV DNA became positive. Lamivudine （LMV） therapy was administered immediately. However, the levels of serum aminotransferase and total bilirubin （TB） were still rising. Finally the patient died of fulminant hepatic failure. A sequence revealed HBV genotype C （HBsAg subtype adw） with immune escape mutations, F8L, $34L, F41S, G44V, F93C, V96G, Lll0I, C149Y and F161Y. The high morbidity and mortality of this complication is one of the major obstacles to completing the standard treatment for malignancy in HBV carriers. Therefore, the relative risk of antiviral prophylactic failure should be further assessed and the optimal strategy for antiviral prophylaxis in HBsAg-positive patients with oncologic and hematologic malignancies undergoing chemotherapy should be revised.展开更多
Objective:Mantle cell lymphoma(MCL)is a rare subtype of non-Hodgkin lymphoma(NHL)with high heterogeneity and a high recurrence rate.How heterogenous cell populations contribute to relapse remains to be elucidated.Meth...Objective:Mantle cell lymphoma(MCL)is a rare subtype of non-Hodgkin lymphoma(NHL)with high heterogeneity and a high recurrence rate.How heterogenous cell populations contribute to relapse remains to be elucidated.Methods:We performed single cell RNA sequencing(scRNA-seq)on approximately 4,000 bone marrow cells sampled from one patient with multidrug resistant MCL.We identified 10 subpopulations comprising 4 malignant B cell subtypes,3 T cell subtypes,2 dendritic cell subtypes and 1 natural killer(NK)cell subtype.Subsequently,we identified cell markers,including a series of genes associated with immune escape and drug resistance.In addition,we explored the roles of these genes in the mechanism of immune escape and drug resistance,and we verified the expression imbalance and clinical prognostic potential by using GEO datasets including 211 MCL samples.Results:The major immune escape mechanisms of MCL included anti-perforin activity,decreased immunogenicity and direct inhibition of apoptosis and cell killing,as mediated by type I and II B cells.The drug resistance mechanisms of different cell clusters included drug metabolism,DNA damage repair,apoptosis and survival promotion.Type III B cells closely communicate with other cells.The key genes involved in the resistance mechanisms showed dysregulated expression and may have significant clinical prognostic value.Conclusion:This study investigated potential immune escape and drug resistance mechanisms in MCL.The results may guide individualized treatment and promote the development of therapeutic drugs.展开更多
Alice Munro is one of the famous Canadian writers and is renowned above all for the astonishing subtlety of her short stories.Her theme has often been the dilemmas of the female coming to terms with family, friends in...Alice Munro is one of the famous Canadian writers and is renowned above all for the astonishing subtlety of her short stories.Her theme has often been the dilemmas of the female coming to terms with family, friends in a small town. This paper attempts to make a brief introduction about the stories of Alice Munro's Runaway and explores the protagonist's choices in the dilemma situation, and then exposes the cruelty of reality is that they cannot get rid of the ineluctable reality of life. Escape is only a temporary action which cannot save them from endless triviality of life. What they should do is not to escape from life, but to adapt to the reality of life.展开更多
基金supported by grants from the Dongguan Science and Technology of Social Development Program(No.20231800940192)the Talent Development Foundation of the First Dongguan Affiliated Hospital of Guangdong Medical University(No.PU2023002).
文摘Objective:Small cell lung cancer(SCLC)is commonly recognized as the most fatal lung cancer type.Despite substantial advances in immune checkpoint blockade therapies for treating solid cancers,their benefits are limited to a minority of patients with SCLC.In the present study,novel indicators for predicting the outcomes and molecular targets for SCLC treatment were elucidated.Methods:We conducted bioinformatics analysis to identify the key genes associated with tumor-infiltrating lymphocytes in SCLC.The functional role of the key gene identified in SCLC was determined both in vitro and in vivo.Results:A significant correlation was observed between patient survival and CD56dim natural killer(NK)cell proportion.Furthermore,we noted that the hub gene ubiquitin-specific protease 1(USP1)is closely correlated with both CD56dim NK cells and overall survival in SCLC.Bioinformatics analysis revealed that USP1 is upregulated in SCLC.In addition,gene set enrichment analysis revealed that USP1 overexpression hinders NK cell-mediated immune responses.By co-cultivating NK-92 cells with SCLC cells,we demonstrated that NK cell cytotoxicity against SCLC could be improved either via USP1 knock-down or pharmacological inhibition.Furthermore,using a nude-mice xenograft tumor model,we noted that USP1 inhibition effectively suppressed tumor proliferation and increased the expression of NK cell-associated markers.Conclusions:Our study findings highlight the importance of NK cells in regulating SCLC.USP1 overexpression can inhibit NK cell-mediated immunity;therefore,USP1 may serve not only as a prognostic biomarker but also as a potential molecular target of SCLC therapy.
基金supported by the National Key R&D Program of China(2023YFF1304600)。
文摘Urbanization has significantly altered the habitat structure and behavioral patterns of animals.In urban environments with frequent human disturbances,animals may undergo adaptive adjustments in their escape behaviors.This study focuses on Eurasian Tree Sparrows(Passer montanus)from five cities across different latitudes in China,comparing their flight initiation distance(FID)in urban and rural areas to assess the impact of urbanization on their escape behavior and the trend of ecological homogenization.The results confirm the established pattern at the geographic level:a reduction of FID in urban habitats and a decrease in FID with increasing latitude.That is,northern populations of the Eurasian Tree Sparrow in China are bolder than the southern populations.In addition,FID is positively correlated with flock size,with rural flocks exhibiting more pronounced group behavior(observed flocking frequency for urban and rural is 28.74%vs.40.7%,flock size variance is 26.90 vs.55.63).Despite the differences between northern and southern latitudes,the variability of FID in urban individuals consistently remains lower than that in rural areas,supporting the trend of reduced variability in escape behavior among birds in urban environments.Driven by urbanization,the escape behavior of Eurasian Tree Sparrows tends toward ecological homogenization,meaning that behavioral differences between urban areas in different cities are diminishing.This trend may obscure the behavioral variability brought about by latitude gradients,indicating that urbanization not only shapes the behavioral adaptations of birds but also potentially weakens their behavioral diversity.
基金supported by the National Natural Science Foundation of China (Grant Nos. 42188101, 42274211, 41974170, 42374184, 42122032, and 41974196)the Chinese Academy of Sciences (Grant Nos. QYZDJSSW-JSC028, XDA15052500, XDA17010301, and XDB41000000)+3 种基金the CNSA (Grant No. D050103)the Specialized Research Fund for State Key Laboratories of Chinathe Specialized Research Fund for Laboratory of Geospace Environment of the University of Science and Technology of Chinasupported by the International Space Science Institute (ISSI) in Bern and Beijing through the ISSI/ISSI-BJ International Team Project titled “Understanding the Mars Space Environment Through Multi-Spacecraft Measurements” (ISSI Team Project No. 23-582 and ISSI-BJ Team Project No. 58)
文摘Atmospheric escape plays a critical role in shaping the long-term climate evolution of Mars.Among the various escape mechanisms,energetic neutral atoms(ENAs)generated through charge exchange between solar wind ions and exospheric neutrals serve as an important diagnostic for ion-neutral interactions and upper atmospheric loss.This study presents direct observations of hydrogen ENAs(H-ENAs)on the dayside of Mars by using the Mars Ion and Neutral Particle Analyzer(MINPA)onboard China’s Tianwen-1 orbiter.By analyzing H-ENA data during a coronal mass ejection and a stream interaction region from December 29,2021,to January 1,2022,and comparing these data with MAVEN/SWIA(Mars Atmosphere and Volatile EvolutioN/Solar Wind Ion Analyzer)solar wind measurements,we examine the temporal evolution of H-ENA flux and the associated sputtered escape of atmospheric constituents.The observed H-ENA velocity is consistent with upstream solar wind ions,and the H-ENA-to-ion intensity ratio is used to infer variations in exospheric density,revealing a delayed response to enhanced solar wind activity.Penetrating H-ENA intensities reach up to 5.3×10^(6)s^(−1) cm^(−2),with energy fluxes on the order of(0.5-8.1)×10^(−3) mW/m^(2).The estimated oxygen sputtered escape rate driven by penetrating H-ENAs ranges from 5.5×10^(23)s^(−1) to 5.2×10^(24)s^(−1),comparable to or exceeding previous estimates based on penetrating ions.The findings highlight the need for low-altitude H-ENA observations to better quantify their atmospheric interactions and refine our understanding of nonthermal escape processes at Mars.
基金supported by grants from Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions(2023SHIBS0002)the National Key Research and Development Program of China(2023YFF1203505)+5 种基金the National Key R&D Program of China(2024YFC2417900)Shenzhen Municipal Science and Technology Innovation Council(202110293000007)Shenzhen Science and Technology Program(KJZD20230923114909019)the National Key R&D Program of China(2018YFA0801006)the National Natural Science Foundation of China(31771618)Guangdong Natural Science Foundation(2022A1515011878).
文摘Zebrafish larvae are useful for identifying chemicals against lateral line(LL)hair cell(HC)damage and this type of chemical screen mainly focuses on searching for protectors against cell death.To expand the candidate pool of HC protectors,a self-built acoustic escape response(AER)-detecting system was developed to apply both low-frequency near-field sound transmission and AER image acquisition/processing modules.The device quickly confirmed the changed LL HC functions caused by most known ototoxins,protectors,and neural transmission modifiers,or knockdown of LL HC-expressing genes.With ten devices wired in tandem,five‘hit’chemicals were identified from 124 cyclin-dependent kinase inhibitors to partially restore cisplatin-damaged AER in less than a day.AS2863619,ribociclib,and SU9516 among the hits,protected the HCs in the mouse cochlea.Therefore,using free-swimming larval zebrafish,the self-made AER-detecting device can efficiently identify compounds that are protective against HC damage,including cell death and loss-of-function.
基金Xuzhou City’s Project for introducing Clinical Medical Expert Teams(No.2018TD001)Innovation Team Project of Xuzhou Medical University Affiliated Hospital Development Fund,Project Number:XYFC202202.
文摘Background:Motif interacting with ubiquitin-containing novelDUB family-1(MINDY1)could enhance the stability of programmed death-ligand 1(PD-L1).The study aimed to investigate whether MINDY1 regulates the immune escape of hepatocellular carcinoma(HCC)mediated by PD-L1.Methods:MINDY1 and PD-L1 levels were detected throughWestern blot.The link between MINDY1 and PD-L1 was validated using the co-immunoprecipitation assay.The malignant biology of HCC cells was assessed through Cell Counting Kit-8,Carboxyfluorescein Succinimidyl Ester staining,transwell,and wound healing assay.CD8^(+)T cells were isolated and then co-cultured with HCC cells.Enzyme-linked immunosorbent Assay kits detected CD8^(+)T cytokine content.CD8^(+)T cell activation markers,PD-L1 ubiquitination levels,andWnt/β-catenin pathway-associated protein levels were detected throughWestern blot.AHCC nude mouse model was developed,Ki-67 positivity and CD8^(+)T-cell infiltration were assessed through pathological staining and flow cytometry.Results:MINDY1 and PD-L1 levels were elevated in HCC.Overexpression of MINDY1 increased migrating and invading cells,elevated cell viability,and decreased apoptosis in HCC cells,leading to PD-L1 deubiquitination.Knockdown of MINDY1 reversed all of these indicators.Co-culturing withHCC cells overexpressing MINDY1 resulted in decreased proliferative capacity and cytotoxicity of CD8^(+)T cells,increased apoptosis,and decreased levels of cytokines and activation markers in CD8^(+)T cells.MINDY1 triggeredWnt/β-catenin pathway,Wnt activators further promoted PD-L1 deubiquitination and suppressed CD8^(+)T cell activation.MINDY1 overexpression increased PD-L1 and Ki67 positivity level in HCC tumors,suppressed CD8^(+)T-cell infiltration.Conclusion:MINDY1 promotes PD-L1 deubiquitination and inhibits CD8^(+)T cell activation by stimulating the Wnt/β-catenin pathway,consequently promoting HCC tumor immune escape.
基金support from the Postdoctoral Fellowship Scheme of The Chinese University of Hong Kong,the Postdoctoral Fellowship Program of CPSF(GZC20241828)The China Postdoctoral Science Foundation(2024M763416).
文摘Emerging therapies rely on the efficient and specific delivery of targeted agents into the cytosol,such as DNA,siRNA and proteins.Nanoparticles showed great potentials in safe delivery and transportation of the targeted cargoes;however,the entrapment in endosomes and degradation by specific enzymes in the lysosome hindered the bioavailability,cytosolic delivery and subsequent therapeutic efficacy.In this case,the development of methods for efficient and specific delivery of targeted therapeutic agents focuses on overcoming the major challenge of endo/lysosomal escape,which relies on the development of safe and efficient nanodelivery systems.A deeper mechanistic understanding in the endo/lysosomal escape will guide the development of more efficient nano-delivery systems.In this review,we summarize various mechanisms by which nanoparticles escape from the endo/lysosome,and showcase the recent progress in dissecting the endo/lysosomal approaches based on nano-delivery systems.Emphasis will lie on the properties of nanoparticles that govern the endo/lysosomal escape pathway as well as the latest promising applications in vaccine delivery and genetic engineering field.
基金K.W.was supported by the National Science Foundation’s Research Experience for Undergraduates grant program(DBI 126713 to the Rocky Mountain Biological Laboratory)as well as the University of Connecticut Department of Ecology and Evolutionary Biology Katie Bu Undergraduate Research Award.J.G.was supported by the Rocky Mountain Biological LaboratoryD.T.B.was supported by the National Science Foundation(DEB-1119660 and 1557130 to D.T.B.as well as DBI-126713 to the Rocky Mountain Biological Laboratory).
文摘Escape theory has been exceptionally successful in conceptualizing and accurately predicting effects of numerous factors that affect predation risk and explaining variation in flight initiation distance(FID;predator–prey distance when escape begins).Less explored is the relative orientation of an approaching predator,prey,and its eventual refuge.The relationship between an approaching threat and its refuge can be expressed as an angle we call the“interpath angle”or“Φ,”which describes the angle between the paths of predator and prey to the prey’s refuge and thus expresses the degree to which prey must run toward an approaching predator.In general,we might expect that prey would escape at greater distances if they must flee toward a predator to reach its burrow.The“race for life”model makes formal predictions about howΦshould affect FID.We evaluated the model by studying escape decisions in yellow-bellied marmots Marmota flaviventer,a species which flees to burrows.We found support for some of the model’s predictions,yet the relationship betweenΦand FID was less clear.Marmots may not assessΦin a continuous fashion;but we found that binning angle into 445°bins explained a similar amount of variation as models that analyzed angle continuously.Future studies ofΦ,especially those that focus on how different species perceive relative orientation,will likely enhance our understanding of its importance in flight decisions.
基金funded under the National Natural Science Foundation of China(No.61873312)。
文摘In order to visualize singularity of SGCMGs in gimbal angle space,a novel continuous bounded singularity parameter--Singularity Radius,whose sign can distinctly determine singularity type,is proposed.Then a rapid singularity-escape steering law is proposed basing on gradient of Singularity Radius and residual base vector to drive the SGCMG system to neighboring singular boundary,and quickly escape elliptic singularities.Finally,simulation results on Pyramid-type and skew-type configuration demonstrate the effectiveness and rapidness of the proposed steering law.
基金Supported by a grant from National Natural Sciences Foundation of China (30240022).
文摘Objective： To investigate the expression of Fas, Fas ligand （FasL） and CD80 on the cell surface of mouse acute myelomonocytic leukemia cell line WEHI-3 and the function of FasL. Methods： The expression of Fas, FasL and CD80 was detected on WEHI-3 cell surface by flow cytometry. Simultaneously the function of FasL was determined by Thymidine （^3H-TdR） Incorporation. Results： The expression of CD80 and Fas on WEHI-3 cell surface was 5.06%±0.41% and 6.75%±2.31% （n=5） respectively, and the expression of FasL was up to 63.73%±5.23% （n=5）. The apoptotic rate of YAC-1 cells was 26%±4.5%, 35%±3.2% and 43%±2.7% （n=5） respectively when WEHI-3 （effector cell, E） and Fas^＋ YAC-1 cells （target cell, T） were cultured in the ratio of 3：1, 10：1 and 30：1. Conclusion： WEHI-3 cells express high FasL, low Fas and CD80, and can induce apoptosis of Fas^＋ YAC-1 cells.
文摘Escape time algorithm is an effective theoretical algorithm of constructing fractal graphics. The key of this algorithm lies in the construction of escape time function. A new escape time function is presented based on the research of escape time algorithm. An accelerated escape time algorithm is carried out in this paper. The experiments have demonstrated that the new algorithm is not only as precise as the old, but also faster when it is used to construct Julia set.
文摘Gynecological cancers present significant treatment challenges due to drug resistance and adverse side effects.This review explores advancements in lysosomal escape mechanisms,essential for enhancing nano-therapeutic efficacy.Strategies such as pH-sensitive linkers and membrane fusion are examined,showcasing their potential to improve therapeutic outcomes in ovarian,cervical,and uterine cancers.We delve into novel materials and strategies developed to bypass the lysosomal barrier,including pH-sensitive linkers,fusogenic lipids,and nanoparticles(NPs)engineered for endosomal disruption.Mechanisms such as the proton sponge effect,where NPs induce osmotic swelling and rupture of the lysosomal membrane,and membrane fusion,which facilitates the release of therapeutic agents directly into the cytoplasm,are explored in detail.These innovations not only promise to improve therapeutic outcomes but also minimize side effects,marking a significant step forward in the treatment of ovarian,cervical,and uterine cancers.By providing a comprehensive analysis of current advancements and their implications for clinical applications,this review sheds light on the potential of lysosomal escape strategies to revolutionize gynecological cancer treatment,setting the stage for future research and development in this vital area.
基金National Basic Research Priorities Program of China(2011CB106303)The National Natural Science Foundation of China(31200699)The Fundamental Research Funds for the Central Universities(HUST:2012QN140)
文摘A 62-year-old man had chronic hepatitis B virus （HBV） infection and was diagnosed with liver cirrhosis. At the time of diagnosis the patient＇s virologic markers were positive for hepatitis B surface antigen （HBsAg）, antibody to hepatitis B e antigen （anti-HBe） and antibody to hepatitis B core antigen （anti-HBc）, while antibody to hepatitis B surface antigen （anti-HBs） and HBV DNA were negative. Later the patient received chemotherapy for malignancy. However, this was interrupted due to elevated liver enzymes. At the same time HBV DNA became positive. Lamivudine （LMV） therapy was administered immediately. However, the levels of serum aminotransferase and total bilirubin （TB） were still rising. Finally the patient died of fulminant hepatic failure. A sequence revealed HBV genotype C （HBsAg subtype adw） with immune escape mutations, F8L, $34L, F41S, G44V, F93C, V96G, Lll0I, C149Y and F161Y. The high morbidity and mortality of this complication is one of the major obstacles to completing the standard treatment for malignancy in HBV carriers. Therefore, the relative risk of antiviral prophylactic failure should be further assessed and the optimal strategy for antiviral prophylaxis in HBsAg-positive patients with oncologic and hematologic malignancies undergoing chemotherapy should be revised.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant No.81873450)the Open Research Fund from Beijing Advanced Innovation Center for Big Data-Based Precision Medicine,Beijing Tongren Hospital,Beihang University&Capital Medical University(Grant No.BHTR-KFJJ-202009)The authors thank Life-Ontology Biological Technology Co.,Ltd for assistance with bioinfbrmatics analysis.
文摘Objective:Mantle cell lymphoma(MCL)is a rare subtype of non-Hodgkin lymphoma(NHL)with high heterogeneity and a high recurrence rate.How heterogenous cell populations contribute to relapse remains to be elucidated.Methods:We performed single cell RNA sequencing(scRNA-seq)on approximately 4,000 bone marrow cells sampled from one patient with multidrug resistant MCL.We identified 10 subpopulations comprising 4 malignant B cell subtypes,3 T cell subtypes,2 dendritic cell subtypes and 1 natural killer(NK)cell subtype.Subsequently,we identified cell markers,including a series of genes associated with immune escape and drug resistance.In addition,we explored the roles of these genes in the mechanism of immune escape and drug resistance,and we verified the expression imbalance and clinical prognostic potential by using GEO datasets including 211 MCL samples.Results:The major immune escape mechanisms of MCL included anti-perforin activity,decreased immunogenicity and direct inhibition of apoptosis and cell killing,as mediated by type I and II B cells.The drug resistance mechanisms of different cell clusters included drug metabolism,DNA damage repair,apoptosis and survival promotion.Type III B cells closely communicate with other cells.The key genes involved in the resistance mechanisms showed dysregulated expression and may have significant clinical prognostic value.Conclusion:This study investigated potential immune escape and drug resistance mechanisms in MCL.The results may guide individualized treatment and promote the development of therapeutic drugs.
文摘Alice Munro is one of the famous Canadian writers and is renowned above all for the astonishing subtlety of her short stories.Her theme has often been the dilemmas of the female coming to terms with family, friends in a small town. This paper attempts to make a brief introduction about the stories of Alice Munro's Runaway and explores the protagonist's choices in the dilemma situation, and then exposes the cruelty of reality is that they cannot get rid of the ineluctable reality of life. Escape is only a temporary action which cannot save them from endless triviality of life. What they should do is not to escape from life, but to adapt to the reality of life.
