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
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
AIM: To study the role of Fas and Fas ligand (FasL) in biological behaviors of gallbladder carcinoma, and their correlated action and mechanism in tumor escape.METHODS: Streptavidin-biotin-peroxidase immunohistochemis...AIM: To study the role of Fas and Fas ligand (FasL) in biological behaviors of gallbladder carcinoma, and their correlated action and mechanism in tumor escape.METHODS: Streptavidin-biotin-peroxidase immunohistochemistry technique was used to study the expression of Fas and FasL protein in 26 gallbladder carcinoma tissues,18 gallbladder adenoma tissues, 3 gallbladder dysplasia tissues and 20 chronic cholecystitis tissues. Apoptosis of the infiltrating lymphocytes in these tissues was studied by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Expression of both proteins and apoptosis of the tumor infiltrating lymphocytes in cancer tissues of primary foci was compared with clinicopathological features of gallbladder carcinoma.RESULTS: The positive rates of Fas were not significantly different among carcinoma, adenoma, dysplasia and chronic cholecystitis. The positive rate of FasL in carcinoma was significantly higher than that in chronic cholecystitis (x2 = 4.89, P＜0.05). The apoptotic index (AI) in carcinoma was significantly higher than that in adenoma (t'= 4.19, P＜0.01) and chronic cholecystitis (t'= 8.06, P＜0.01). The AI was significantly lower in well-differentiated carcinoma and Nevin Ⅰ-Ⅲ carcinoma than that in poorly-differentiated carcinoma (t'= 2.63, P＜0.05) and Nevin Ⅳ-Ⅴ carcinoma(t'= 3.33, P＜0.01). The confidence interval (CI) ofinfiltrating lymphocytes in adenoma, chronic cholecystitis, well-differentiated carcinoma and Nevin Ⅰ-Ⅲ carcinoma wasvery significantly lower than that in carcinoma (t' = 6.99,P＜0.01), adenoma (t' = 3.66, P＜0.01), poorly-differentiated carcinoma (t' = 5.31, P＜0.01) and Nevin Ⅳ-Ⅴ carcinoma(t' = 3.76, P＜0.01), respectively. The CI of apoptosis of infiltrating lymphocytes in well-differentiated carcinoma was significantly lower than that in poorly-differentiated carcinoma (t = 2.52, P＜0.05), and was not significantly lower in Nevin Ⅰ-Ⅲ carcinoma than in Nevin Ⅳ-Ⅴ carcinoma (t = 1.42, P＞0.05). Apoptosis of infiltrating lymphocytes was not discovered in adenoma and chronic cholecystitis. CONCLUSION: FasL expressed in gallbladder carcinoma cells permits tumor cells to escape from immune surveillance of organism by inducing apoptosis in infiltrating lymphocytes of carcinoma tissues. Up-regulation of FasL expression plays an important role in invasive depth, histological classification and metastasis of gallbladder carcinoma.展开更多
BACKGROUND Hepatocellular carcinoma(HCC)is characterized by dysregulation of the immune microenvironment and the development of chemoresistance.Specifically,expression of the programmed cell death protein 1(PD-1)/prog...BACKGROUND Hepatocellular carcinoma(HCC)is characterized by dysregulation of the immune microenvironment and the development of chemoresistance.Specifically,expression of the programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1)axis,an immune checkpoint,may lead to tumour immune escape,resulting in disease progression.The latest research shows that tumour immune escape may be caused by the upregulation of PD-L1 mediated by hypoxia-inducible factor-1 alpha(HIF-1α),and simultaneous inhibition of HIF-1αand PD-L1 has the potential to enhance the host’s antitumour immunity.Moreover,inhibition of the PD-1/PD-L1 axis may mitigate tumour chemoresistance.Shuyu pills(SYPs)contain immunity-enhancing and antitumour components,making them a potential HCC treatment.AIM To investigate the efficacy of SYPs for HCC treatment via simultaneous HIF-1α and PD-L1 inhibition and the mechanism involved.METHODS A subcutaneous xenograft tumour model was first established in BALB/c nude mice by the subcutaneous injection of 1×107 SMMC-7721 cells.Male mice(male,5 weeks old;n=24)were then randomly divided into the following four groups(n=6):Control(0.9%normal saline),SYP(200 mg/kg),SYP+cisplatin(DDP)(200 mg/kg+5 mg/kg DDP weekly via intraperitoneal injection),and DDP(5 mg/kg cisplatin weekly via intraperitoneal injection).The dose of saline or SYPs for the indicated mouse groups was 0.2 mL/d via intragastric administration.The tumour volumes and body weights of the mice were measured every 2 d.The mice were euthanized by cervical dislocation after 14 d of continuous treatment,and the xenograft tissues were excised and weighed.Western blot assays were used to measure the protein expression of HIF-1α,PD1,PD-L1,CD4+T cells,and CD8+T cells in HCC tumours from mice.Quantitative reverse transcription polymerase chain reaction was used for real-time quantitative detection of PD-1,PD-L1,and HIF-1α mRNA expression.An immunofluorescence assay was conducted to examine the expression of CD4+T cells and CD8+T cells.RESULTS Compared to mice in the control group,those in the SYP and SYP+DDP groups exhibited reduced tumour volumes and tumour weights.Moreover,the protein and mRNA expression levels of the oncogene HIF1α and that of the negative immunomodulatory factors PD-1 and PD-L1 were decreased in both the SYP and SYP+DDP groups,with the decrease effects being more prominent in the SYP+DDP group than in the SYP group(HIF-1α protein:Control vs SYP,P=0.0129;control vs SYP+DDP,P=0.0004;control vs DDP,P=0.0152,SYP+DDP vs DDP,P=0.0448;HIF-1αmRNA:control vs SYP,P=0.0009;control vs SYP+DDP,P<0.0001;control vs DDP,P=0.0003,SYP vs SYP+DDP,P=0.0192.PD-1 protein:Control vs SYP,P=0.0099;control vs SYP+DDP,P<0.0001,SPY vs SYP+DDP,P=0.0009;SYP+DDP vs DDP,P<0.0001;PD-1 mRNA:control vs SYP,P=0.0002;control vs SYP+DDP,P<0.0001;control vs DDP,P=0.0003,SPY vs SYP+DDP,P=0.0003;SYP+DDP vs DDP,P=0.0002.PD-L1 protein:control vs SYP,P<0.0001;control vs SYP+DDP,P<0.0001;control vs DDP,P<0.0001,SPY vs SYP+DDP,P=0.0040;SYP+DDP vs DDP,P=0.0010;PD-L1 mRNA:Control vs SYP,P<0.0001;control vs SYP+DDP,P<0.0001;control vs DDP,P<0.0001,SPY vs SYP+DDP,P<0.0001;SYP+DDP vs DDP,P=0.0014).Additionally,the quantitative and protein expression levels of CD4+T cells and CD8+T cells were simultaneously upregulated in the SYP+DDP group,whereas only the expression of CD4+T cells was upregulated in the SYP group.(CD4+T cell quantitative:Control vs SYP+DDP,P<0.0001,SYP vs SYP+DDP,P=0.0005;SYP+DDP vs DDP,P=0.0002.CD4+T cell protein:Control vs SYP,P=0.0033;Control vs SYP+DDP,P<0.0001;Control vs DDP,P=0.0021,SYP vs SYP+DDP,P=0.0004;SYP+DDP vs DDP,P=0.0006.Quantitative CD8+T cells:Control vs SYP+DDP,P=0.0013;SYP vs SYP+DDP,P=0.0347;SYP+DDP vs DDP,P=0.0043.CD8+T cell protein:Control vs SYP+DDP,P<0.0001;SYP vs SYP+DDP,P<0.0001;SYP+DDP vs DDP,P<0.0001).Finally,expression of HIF-1αwas positively correlated with that of PD-1/PD-L1 and negatively correlated with the expression of CD4+T cells and CD8+T cells.CONCLUSION SYPs inhibit immune escape and enhance chemosensitization in HCC via simultaneous inhibition of HIF-1α and PD-L1,thus inhibiting the growth of subcutaneous xenograft HCC tumours.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.
基金Supported by the National High Technology Research and Development Program of China (863 Program), No. 2002AA214061
文摘AIM: To study the role of Fas and Fas ligand (FasL) in biological behaviors of gallbladder carcinoma, and their correlated action and mechanism in tumor escape.METHODS: Streptavidin-biotin-peroxidase immunohistochemistry technique was used to study the expression of Fas and FasL protein in 26 gallbladder carcinoma tissues,18 gallbladder adenoma tissues, 3 gallbladder dysplasia tissues and 20 chronic cholecystitis tissues. Apoptosis of the infiltrating lymphocytes in these tissues was studied by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) method. Expression of both proteins and apoptosis of the tumor infiltrating lymphocytes in cancer tissues of primary foci was compared with clinicopathological features of gallbladder carcinoma.RESULTS: The positive rates of Fas were not significantly different among carcinoma, adenoma, dysplasia and chronic cholecystitis. The positive rate of FasL in carcinoma was significantly higher than that in chronic cholecystitis (x2 = 4.89, P＜0.05). The apoptotic index (AI) in carcinoma was significantly higher than that in adenoma (t'= 4.19, P＜0.01) and chronic cholecystitis (t'= 8.06, P＜0.01). The AI was significantly lower in well-differentiated carcinoma and Nevin Ⅰ-Ⅲ carcinoma than that in poorly-differentiated carcinoma (t'= 2.63, P＜0.05) and Nevin Ⅳ-Ⅴ carcinoma(t'= 3.33, P＜0.01). The confidence interval (CI) ofinfiltrating lymphocytes in adenoma, chronic cholecystitis, well-differentiated carcinoma and Nevin Ⅰ-Ⅲ carcinoma wasvery significantly lower than that in carcinoma (t' = 6.99,P＜0.01), adenoma (t' = 3.66, P＜0.01), poorly-differentiated carcinoma (t' = 5.31, P＜0.01) and Nevin Ⅳ-Ⅴ carcinoma(t' = 3.76, P＜0.01), respectively. The CI of apoptosis of infiltrating lymphocytes in well-differentiated carcinoma was significantly lower than that in poorly-differentiated carcinoma (t = 2.52, P＜0.05), and was not significantly lower in Nevin Ⅰ-Ⅲ carcinoma than in Nevin Ⅳ-Ⅴ carcinoma (t = 1.42, P＞0.05). Apoptosis of infiltrating lymphocytes was not discovered in adenoma and chronic cholecystitis. CONCLUSION: FasL expressed in gallbladder carcinoma cells permits tumor cells to escape from immune surveillance of organism by inducing apoptosis in infiltrating lymphocytes of carcinoma tissues. Up-regulation of FasL expression plays an important role in invasive depth, histological classification and metastasis of gallbladder carcinoma.
基金Supported by National Natural Science Foundation of China,No.U20A20408,and No.82074450Special Natural Science Fund for the Construction of an Innovative Province in Hunan Province,No.S2020JJMSXM1250+1 种基金the Natural Science Foundation of Hunan Province,No.2020JJ4066Hunan Province"domestic first-class cultivation discipline"Integrated Traditional Chinese and Western medicine open fund project,No.2018ZXYJH28 and No.2020ZXYJH35.
文摘BACKGROUND Hepatocellular carcinoma(HCC)is characterized by dysregulation of the immune microenvironment and the development of chemoresistance.Specifically,expression of the programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1)axis,an immune checkpoint,may lead to tumour immune escape,resulting in disease progression.The latest research shows that tumour immune escape may be caused by the upregulation of PD-L1 mediated by hypoxia-inducible factor-1 alpha(HIF-1α),and simultaneous inhibition of HIF-1αand PD-L1 has the potential to enhance the host’s antitumour immunity.Moreover,inhibition of the PD-1/PD-L1 axis may mitigate tumour chemoresistance.Shuyu pills(SYPs)contain immunity-enhancing and antitumour components,making them a potential HCC treatment.AIM To investigate the efficacy of SYPs for HCC treatment via simultaneous HIF-1α and PD-L1 inhibition and the mechanism involved.METHODS A subcutaneous xenograft tumour model was first established in BALB/c nude mice by the subcutaneous injection of 1×107 SMMC-7721 cells.Male mice(male,5 weeks old;n=24)were then randomly divided into the following four groups(n=6):Control(0.9%normal saline),SYP(200 mg/kg),SYP+cisplatin(DDP)(200 mg/kg+5 mg/kg DDP weekly via intraperitoneal injection),and DDP(5 mg/kg cisplatin weekly via intraperitoneal injection).The dose of saline or SYPs for the indicated mouse groups was 0.2 mL/d via intragastric administration.The tumour volumes and body weights of the mice were measured every 2 d.The mice were euthanized by cervical dislocation after 14 d of continuous treatment,and the xenograft tissues were excised and weighed.Western blot assays were used to measure the protein expression of HIF-1α,PD1,PD-L1,CD4+T cells,and CD8+T cells in HCC tumours from mice.Quantitative reverse transcription polymerase chain reaction was used for real-time quantitative detection of PD-1,PD-L1,and HIF-1α mRNA expression.An immunofluorescence assay was conducted to examine the expression of CD4+T cells and CD8+T cells.RESULTS Compared to mice in the control group,those in the SYP and SYP+DDP groups exhibited reduced tumour volumes and tumour weights.Moreover,the protein and mRNA expression levels of the oncogene HIF1α and that of the negative immunomodulatory factors PD-1 and PD-L1 were decreased in both the SYP and SYP+DDP groups,with the decrease effects being more prominent in the SYP+DDP group than in the SYP group(HIF-1α protein:Control vs SYP,P=0.0129;control vs SYP+DDP,P=0.0004;control vs DDP,P=0.0152,SYP+DDP vs DDP,P=0.0448;HIF-1αmRNA:control vs SYP,P=0.0009;control vs SYP+DDP,P<0.0001;control vs DDP,P=0.0003,SYP vs SYP+DDP,P=0.0192.PD-1 protein:Control vs SYP,P=0.0099;control vs SYP+DDP,P<0.0001,SPY vs SYP+DDP,P=0.0009;SYP+DDP vs DDP,P<0.0001;PD-1 mRNA:control vs SYP,P=0.0002;control vs SYP+DDP,P<0.0001;control vs DDP,P=0.0003,SPY vs SYP+DDP,P=0.0003;SYP+DDP vs DDP,P=0.0002.PD-L1 protein:control vs SYP,P<0.0001;control vs SYP+DDP,P<0.0001;control vs DDP,P<0.0001,SPY vs SYP+DDP,P=0.0040;SYP+DDP vs DDP,P=0.0010;PD-L1 mRNA:Control vs SYP,P<0.0001;control vs SYP+DDP,P<0.0001;control vs DDP,P<0.0001,SPY vs SYP+DDP,P<0.0001;SYP+DDP vs DDP,P=0.0014).Additionally,the quantitative and protein expression levels of CD4+T cells and CD8+T cells were simultaneously upregulated in the SYP+DDP group,whereas only the expression of CD4+T cells was upregulated in the SYP group.(CD4+T cell quantitative:Control vs SYP+DDP,P<0.0001,SYP vs SYP+DDP,P=0.0005;SYP+DDP vs DDP,P=0.0002.CD4+T cell protein:Control vs SYP,P=0.0033;Control vs SYP+DDP,P<0.0001;Control vs DDP,P=0.0021,SYP vs SYP+DDP,P=0.0004;SYP+DDP vs DDP,P=0.0006.Quantitative CD8+T cells:Control vs SYP+DDP,P=0.0013;SYP vs SYP+DDP,P=0.0347;SYP+DDP vs DDP,P=0.0043.CD8+T cell protein:Control vs SYP+DDP,P<0.0001;SYP vs SYP+DDP,P<0.0001;SYP+DDP vs DDP,P<0.0001).Finally,expression of HIF-1αwas positively correlated with that of PD-1/PD-L1 and negatively correlated with the expression of CD4+T cells and CD8+T cells.CONCLUSION SYPs inhibit immune escape and enhance chemosensitization in HCC via simultaneous inhibition of HIF-1α and PD-L1,thus inhibiting the growth of subcutaneous xenograft HCC tumours.
