A series of fluorescent chemosensors 1-3 were synthesized to detect transition metal ions. At the room temperature, fluorescence intensities of these chemosensors in acetonitrile without transition metal ions were fou...A series of fluorescent chemosensors 1-3 were synthesized to detect transition metal ions. At the room temperature, fluorescence intensities of these chemosensors in acetonitrile without transition metal ions were found to be very weak, due to the process of the efficient intramolecular photoinduced electron transfer （PET）. However, after addition of the transition metal ions, the chemoscnsor 1-3 exhibits obvious fluorescence enhancement. Moreover, the intensity of the fluorescence emission of chemosensors increases significantly in the presence of Zn^2＋ and Cd^2＋. The fluorescent chemosensors with different polyamine as receptors show diverse affinity abilities to the transition metal ions and signal the receptor-metal ion interaction by the intensity change of fluorescence emission.展开更多
Flag leaf angle is one of the key target traits in high yield wheat breeding.A smaller flag leaf angle reduces shading and enables plants to grow at a higher density,which increases yield.Here we identified a mutant,j...Flag leaf angle is one of the key target traits in high yield wheat breeding.A smaller flag leaf angle reduces shading and enables plants to grow at a higher density,which increases yield.Here we identified a mutant,je0407,with an 84.34%-89.35%smaller flag leaf angle compared with the wild type.The mutant also had an abnormal lamina joint and no ligule or auricle.Genetic analysis indicated that the ligule was controlled by two recessive genes,which were mapped to chromosomes 2AS and 2DL.The mutant allele on chromosome 2AS was named Tafla1b,and it was fine mapped to a 1 Mb physical interval.The mutant allele on chr.2DL was identified as Taspl8b,a novel allele of TaSPL8 with a missense mutation in the second exon,which was used to develop a cleaved amplified polymorphic sequence marker.F3 and F4 lines derived from crosses between Jing411 and je0407 were genotyped to investigate interactions between the Tafla1b and Taspl8b alleles.Plants with the Tafla1b/Taspl8a genotype had 58.41%-82.76%smaller flag leaf angles,6.4%-24.9%shorter spikes,and a greater spikelet density(0.382 more spikelets per cm)compared with the wild type.Plants with the Tafla1a/Taspl8b genotype had 52.62%-82.24%smaller flag leaf angles and no differences in plant height or spikelet density compared with the wild type.Tafla1b/Taspl8b plants produced erect leaves with an abnormal lamina joint.The two alleles had dosage effects on ligule formation and flag leaf angle,but no significant effect on thousand-grain weight.The mutant alleles provide novel resources for improvement of wheat plant architecture.展开更多
Objective:CD8+T cells are the key effector cells in the anti-tumor immune response.The mechanism underlying the infiltration of CD8+T cells in esophageal squamous cell carcinoma(ESCC)has not been clearly elucidated.Me...Objective:CD8+T cells are the key effector cells in the anti-tumor immune response.The mechanism underlying the infiltration of CD8+T cells in esophageal squamous cell carcinoma(ESCC)has not been clearly elucidated.Methods:Fresh ESCC tissues were collected and grouped according to the infiltration density of CD8+T cells.After the transcriptome sequencing on these samples and the combined analyses with The Cancer Genome Atlas(TCGA)ESCC data,a secreted protein DEFB1 was selected to explore its potential role in the infiltration of CD8+T cells.Bioinformatics analyses,histological verification and in vitro experiments were then performed.Results:DEFB1 was highly expressed in ESCC,and the high expression of DEFB1 was an independent risk factor for overall survival.Since the up-regulation or down-regulation of DEFB1 did not affect the proliferation,migration and apoptosis of ESCC cells,we speculated that the oncogenic effect of DEFB1 was achieved by regulating microenvironmental characteristics.Bioinformatics analyses suggested that DEFB1 might play a major role in the inflammatory response and anti-tumor immune response,and correlate to the infiltration of immature dendritic cell(imDC)in ESCC.Histological analyses further confirmed that there were less CD8+T cells infiltrated,less CD83+mature DC(mDC)infiltrated and more CD1a+imDC infiltrated in those ESCC samples with high expression of DEFB1.After the treatment with recombinant DEFB1 protein,the maturation of DC was hindered significantly,followed by the impairment of the killing effects of T cells in both 2D and 3D culture in vitro.Conclusions:Tumor-derived DEFB1 can inhibit the maturation of DC and weaken the function of CD8+T cells,accounting for the immune tolerance in ESCC.The role of DEFB1 in ESCC deserves further exploration.展开更多
The molecular geometries, frontier molecular orbital properties, and absorption and emission properties of three 4-phenoxy-1,8-naphthalimide derivatives, namely 4-phenoxy-N-（2-hydroxyethyl）-1,8-naphthalimide（1）,4-...The molecular geometries, frontier molecular orbital properties, and absorption and emission properties of three 4-phenoxy-1,8-naphthalimide derivatives, namely 4-phenoxy-N-（2-hydroxyethyl）-1,8-naphthalimide（1）,4-（2-tert-butylphenoxy）-N-（2-hydroxyethyl）-1,8-naphthalimide（2）, and 4-[2,4-di（tert-butyl）]phenoxy-N-（2-hydroxyethyl）-1,8-naphthalimide（3）, are investigated by density functional theory（DFT） and time-dependent density functional theory（TD-DFT） calculations in conjunction with polarizable continuum models（PCMs）. Four functionals and ten basis sets are employed for 1 to calculate the electron transition energies, which were compared with the experimental observations. Our results reveal that the B3LYP/6-311＋G（d,p） method is the best choice to reproduce the experimental spectra. Moreover, the effects of substituents on the molecular geometries, electronic structures, absorption and emission spectra are also studied at the B3LYP/6-311＋G（d,p） level. We find that the gap between the highest occupied molecular orbital（HOMO） and the lowest unoccupied molecular orbital（LUMO） decreases with increasing the number of tert-butyl substituents onto the phenoxy groups, suggesting red-shift of the absorption and emission bands. This is related to the increase of conjugation from 1 to 2 and 3. Our calculations are in good agreement with the experimental results.展开更多
Two 1,8-naphthalimide derivatives of 7H-benzimidazo[2,1,-a]benz[de] isoquino- lin-7-one（1） and 4-bromo-7H-benzimidazo[2,1,-a]benz[de]isoquinolin-7-one（2） have been synthesized and characterized by elemental analys...Two 1,8-naphthalimide derivatives of 7H-benzimidazo[2,1,-a]benz[de] isoquino- lin-7-one（1） and 4-bromo-7H-benzimidazo[2,1,-a]benz[de]isoquinolin-7-one（2） have been synthesized and characterized by elemental analysis, IR, 1H NMR, UV-Vis and fluorescence spectra. For the two compounds, density functional theory（DFT） calculations of the structures and natural population atomic charge analysis have been performed at the B3LYP/6-311G＊＊ level of theory. Based on Onsager reaction filed model and by using TD-DFT method at the B3LYP/6-311G＊＊ level, electron spectra of 1 and 2 with solvent effect in CHCl3 solvent have been predicted, which are in agreement with the experimental ones. Comparative studies on 1 and 2 indicate that introducing an electron-withdrawing group of Br into the 4-position of naphthalene ring in 2 does not significantly make the molecular geometry of 2 different from that of 1, but evidently changes the atomic charge redistribution, moves the positive-negative charges center and then changes the dipole moment in 2. Additionally, for compound 2, the existence of Br atom has also influenced the peak intensity and peak locations in both electron and fluorescence spectra.展开更多
Intestinal flora affects the maturation of the host immune system,serves as a biomarker and efficacy predictor in the immunotherapy of several cancers,and has an important role in the development of colorectal cancer(...Intestinal flora affects the maturation of the host immune system,serves as a biomarker and efficacy predictor in the immunotherapy of several cancers,and has an important role in the development of colorectal cancer(CRC).Anti-PD-1/PD-L1 antibodies have shown satisfactory results in MSI-H/d MMR CRC but performed poorly in patients with MSS/p MMR CRC.In recent years an increasing number of studies have shown that intestinal flora has an important impact on anti-PD-1/PD-L1 antibody efficacy in CRC patients.Preclinical and clinical evidence have suggested that anti-PD-1/PD-L1 antibody efficacy can be improved by altering the composition of the intestinal flora in CRC.Herein,we summarize the studies related to the influence of intestinal flora on anti-PD-1/PD-L1 antibody efficacy in CRC and discuss the potential underlying mechanism(s).We have focused on the impact of the intestinal flora on the efficacy and safety of anti-PD-1/PD-L1 antibodies in CRC and how to better utilize the intestinal flora as an adjuvant to improve the efficacy of anti-PD-1/PD-L1 antibodies.In addition,we have provided a basis for the potential of the intestinal flora as a new treatment modality and indicator for determining patient prognosis.展开更多
Fusarium graminearum is an important plant pathogenic fungus that causes disease and yield reduction in many cereal crops, such as wheat and barley. Gyp8 stimulates GTP hydrolysis on Ypt1 in yeast. However, the functi...Fusarium graminearum is an important plant pathogenic fungus that causes disease and yield reduction in many cereal crops, such as wheat and barley. Gyp8 stimulates GTP hydrolysis on Ypt1 in yeast. However, the functions of Gyp8 in plant pathogenic fungi are still unknown. In this study, we investigated the roles of Fg Gyp8 in F. graminearum by genetic and pathological analyses. Through gene knockout and phenotypic analyses, we found that Fg Gyp8 is required for vegetative growth in F. graminearum. The conidiation, conidial size and number of septa per conidium of ΔFggyp8 mutant are significantly reduced when compared to the wild type PH-1. Furthermore, Fg Gyp8 is crucial for pathogenicity on wheat coleoptiles and wheat heads. Fg Gyp8 contains a conserved TBC domain. Domain deletion analysis showed that the TBC domain, C-and N-terminal regions of Fg Gyp8 are all important for its biological functions in F. graminearum. Moreover, we showed that Fg Gyp8 catalyzes the hydrolysis of the GTP on Fg Rab1 to GDP in vitro, indicating that Fg Gyp8 is a GTPase-activating protein(GAP) for Fg Rab1. In addition, we demonstrated that Fg Gyp8 is required for Fg Snc1-mediated fusion of secretory vesicles with the plasma membrane in F. graminearum. Finally, we showed that Fg Gyp8 has functional redundancy with another Fg Rab1 GAP, Fg Gyp1, in F. graminearum. Taken together, we conclude that Fg Gyp8 is required for vegetative growth, conidiogenesis, pathogenicity and acts as a GAP for Fg Rab1 in F. graminearum.展开更多
BACKGROUND Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and T cell immunoglobulin and mucin domain-containing protein 3(TIM-3)are beneficial to the resumption of anti-tumor immunity...BACKGROUND Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and T cell immunoglobulin and mucin domain-containing protein 3(TIM-3)are beneficial to the resumption of anti-tumor immunity response and hold extreme potential as efficient therapies for certain malignancies.However,ICIs with a single target exhibit poor overall response rate in hepatocellular carcinoma(HCC)patients due to the complex pathological mechanisms of HCC.AIM To investigate the effects of combined TIM-3 and PD-1 blockade on tumor development in an HCC mouse model,aiming to identify more effective immunotherapies and provide more treatment options for HCC patients.METHODS The levels of PD-1 and TIM-3 on CD4+and CD8+T cells from tumor tissues,ascites,and matched adjacent tissues from HCC patients were determined with flow cytometry.An HCC xenograft mouse model was established and treated with anti-TIM-3 monoclonal antibody(mAb)and/or anti-PD-1 mAb.Tumor growth in each group was measured.Hematoxylin and eosin staining and immunohistochemical staining were used to evaluate T cell infiltration in tumors.The percentage of CD4+and CD8+T cells in tissue samples from mice was tested with flow cytometry.The percentages of PD-1+CD8+,TIM-3+CD8+,and PD-1+TIM-3+CD8+T cells was accessed by flow cytometry.The levels of the cytokines including tumor necrosis factor alpha(TNF-α),interferon-γ(IFN-γ),interleukin(IL)-6,and IL-10 in tumor tissues were gauged with enzyme-linked immunosorbent assay kits.RESULTS We confirmed that PD-1 and TIM-3 expression was substantially upregulated in CD4+and CD8+T cells isolated from tumor tissues and ascites of HCC patients.TIM-3 mAb and PD-1 mAb treatment both reduced tumor volume and weight,while combined blockade had more substantial anti-tumor effects than individual treatment.Then we showed that combined therapy increased T cell infiltration into tumor tissues,and downregulated PD-1 and TIM-3 expression on CD8+T cells in tumor tissues.Moreover,combined treatment facilitated the production of T cell effector cytokines TNF-α and IFN-γ,and reduced the production of immunosuppressive cytokines IL-10 and IL-6 in tumor tissues.Thus,we implicated that combined blockade could ameliorate T cell exhaustion in HCC mouse model.CONCLUSION Combined TIM-3 and PD-1 blockade restrains HCC development by facilitating CD4+ and CD8+T cell-mediated antitumor immune responses.展开更多
BACKGROUND Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters.Herein,we firstly pro...BACKGROUND Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters.Herein,we firstly provide the evidence that a nonsense variant of ATP8B1 gene(c.1558A>T)in heterozygous form is involved in BRIC pathogenesis.CASE SUMMARY A 29-year-old male showed severe jaundice and laboratory tests consistent with intrahepatic cholestasis despite normal gamma-glutamyltranspeptidase.Acute and chronic liver diseases with viral,metabolic and autoimmune etiology were excluded.Normal intra/extra-hepatic bile ducts were demonstrated by magnetic resonance.Liver biopsy showed:Cholestasis in the centrilobular and intermediate zones with bile plugs and intra-hepatocyte pigment,Kupffer’s cell activation/hyperplasia and preserved biliary ducts.Being satisfied benign recurrent intrahepatic cholestasis diagnostic criteria,ATP8B1 and ABCB11 gene analysis was performed.Surprisingly,we found a novel nonsense variant of ATP8B1 gene(c.1558A>T)in heterozygosis.The variant was confirmed by Sanger sequencing following a standard protocol and tested for familial segregation,showing a maternal inheritance.Immunohistochemistry confirmed a significant reduction of mutated gene related protein(familial intrahepatic cholestasis 1).The patient was treated with ursodeoxycholic acid 15 mg/kg per day and colestyramine 8 g daily with total bilirubin decrease and normalization at the 6th and 12th mo.CONCLUSION A genetic abnormality,different from those already known,could be involved in familial intrahepatic cholestatic disorders and/or pro-cholestatic genetic predisposition,thus encouraging further mutation detection in this field.展开更多
[Objective]The study aimed to screen the starch-degrading bacterium in bagasse and carry on the identification of strains s2g5-1 and s3g4-8.[Method]By using a variety of selective media,varieties of starch degrading b...[Objective]The study aimed to screen the starch-degrading bacterium in bagasse and carry on the identification of strains s2g5-1 and s3g4-8.[Method]By using a variety of selective media,varieties of starch degrading bacterium were isolated from the sugar cane bagasse form different stages of natural fermentation,then,primary screening and secondary screening were performed.[Result] Starch-degrading strains s2g5-1 and s3g4-8 were screened,and they were identified as Bacillus amyloliquefaciens according to their morphological,physiological,biochemical and molecular characteristics.[Conclusion]The research provided theoretical basis for factory application of bagasse.展开更多
AIM： To study the relationship between MCP-1-2518A/ G, IL-8-251A/T polymorphism and acute pancreatitis （AP） in the Han population of Suzhou, China. METHODS： A case-control study was conducted to compare the distri...AIM： To study the relationship between MCP-1-2518A/ G, IL-8-251A/T polymorphism and acute pancreatitis （AP） in the Han population of Suzhou, China. METHODS： A case-control study was conducted to compare the distribution of genotype and genetic frequency of MCP-1-2518A/G, IL-8-251A/T gene polymorphism among AP （n = 101）, including mild AP （n = 78） and severe AP （n = 23） and control healthy individuals （n = 120） with polymerase chain reaction- restriction fragment length polymorphism （PCR-RFLP） and DNA sequencing, and analyze the relationship between the MCP-1-2518A/G, IL-8-251A/T gene polymorphism and the susceptibility to AP. RESULTS： Significant differences were found in the distribution of genotype of MCP-1-2518A/G between the healthy control group and mild AP group （χ^2 = 32.015, P 〈 0.001）, the same was evident between the healthy control group and severe AP group （χ^2 = 12.932, P 〈 0.05） in Suzhou. However, no difference of genotypic distribution was noted between MAP and SAP （Z2 = 0.006, P = 0.997）. The genetic frequencies of G allele in mild AP were 72.4% （113/156） and 76.1% （35/46） in severe AP, both were higher than the controls, 47.1% （113/240） （χ^2 = 24.804; P 〈 0.001, and 4,2 = 13：005; P 〈 0.001）, but no difference was found between severe AP and mild AP （χ^2 = 0.242, P = 0.623）. No difference was found in the distribution of genotype of IL-8-251A/T between the healthy control group and AP group neither in the frequency of A and T allele. CONCLUSION： The MCP-1-2518 AA genotype of the population in Suzhou may be a protective genotype of AP, while one with higher frequency of G allele is more likely to suffer from pancreatitis. But the genotype of AA and the frequency of G allele could not predict the risk of severe AP. No correlation is found between the IL-8-251 polymorphism and the liability of AP.展开更多
A novel coronavirus, severe acute respiratory syndrome (SA RS)-associated coronavirus (SARS-CoV), has been identified as the causal agent of SARS. Spike (S) protein is a major structural glycoprotein of the SARS virus...A novel coronavirus, severe acute respiratory syndrome (SA RS)-associated coronavirus (SARS-CoV), has been identified as the causal agent of SARS. Spike (S) protein is a major structural glycoprotein of the SARS virus and a potential target for SARS-specific cell-mediated immune responses. A pa nel of S protein-derived peptides was tested for their binding affinity to HLA -A *0201 molecules. Peptides with high affinity for HLA-A *0201 were then as se ssed for their capacity to elicit specific immune responses mediated by cytotoxi c T lymphocytes (CTLs) both in vivo, in HLA-A2.1/K b transgenic mice, a nd in vitro, from peripheral blood lymphocytes (PBLs) harvested from healthy HLA-A 2.1 + donors. SARS-CoV protein-derived peptide-1 (SSp-1 RLNEVAKNL), induced pepti de-specific CTLs both in vivo (transgenic mice) and in vitro (human PBL s), which specifically released interferon-gamma (IFN-gamma) upon stimulation with SSp-1-pulsed autologous dendritic cells (DCs) or T2 cells. SSp-1-specif ic CTLs also lysed major histocompatibility complex (MHC)-matched tumor cell lines engineered to express S proteins. HLA-A *0201-SSp-1 tetramer staining re vealed the presence of significant populations of SSp-1-specific CTLs in SSp- 1-induced CD8 + T cells. We propose that the newly identified epitope SSp-1 w ill help in the characterization of virus control mechanisms and immunopathology in SARS-CoV infection, and may be relevant to the development of immunotherape utic approaches for SARS.展开更多
The plant hormone abscisic acid （ABA） regulates many important physiological and developmental processes in plants. The objective of this study was to clone the ABA 8′-hydroxylase gene in common wheat. In the prese...The plant hormone abscisic acid （ABA） regulates many important physiological and developmental processes in plants. The objective of this study was to clone the ABA 8′-hydroxylase gene in common wheat. In the present study, we used the eDNA sequence of barley HvCYP707A1 gene （GenBank accession no. AB239299） as a probe for BLAST search against the common wheat （Triticum aestivum L.） EST database in GenBank. All wheat ESTs sharing high similarity with the reference gene were subjected to contig assembly. Primers were designed based on the constructed contigs to clone the wheat CYP707A1 gene, designated as TaCYP707A1. The genomic DNA sequence of TaCYPTO7A1 gene comprised five exons and four introns, with a size of 2225 bp. The corresponding cDNA sequence of TaCYP707A1 was 1737 bp, containing an open reading frame （ORF） of 1431 bp, a 42-bp 5′-untranslated region （UTR） and a 264-bp 3′UTR, with 94.9% of identical sequences to HvCYP707A1 gene （AB239299）. The neighbor joining tree indicated that the deduced amino acid sequences of TaCYP707A1 gene was highly similar to those of barley and rice. The TaCYP707A1 gene was located on chromosome 6BL using a set of Chinese Spring nullisomic-tetrasomic lines and ditelosomic line 6BS. These results will be of high importance in understanding of molecular mechanism of ABA catabolism.展开更多
基金supported by the National Natural Science Foundation of China(No.20332020,No.20472079).
文摘A series of fluorescent chemosensors 1-3 were synthesized to detect transition metal ions. At the room temperature, fluorescence intensities of these chemosensors in acetonitrile without transition metal ions were found to be very weak, due to the process of the efficient intramolecular photoinduced electron transfer （PET）. However, after addition of the transition metal ions, the chemoscnsor 1-3 exhibits obvious fluorescence enhancement. Moreover, the intensity of the fluorescence emission of chemosensors increases significantly in the presence of Zn^2＋ and Cd^2＋. The fluorescent chemosensors with different polyamine as receptors show diverse affinity abilities to the transition metal ions and signal the receptor-metal ion interaction by the intensity change of fluorescence emission.
基金supported by the National Key Research and Development Project of China(2022YFD1200700)the Crop Varietal Improvement and Insect Pests Control by Nuclear Radiation,Innovation Program of Chinese Academy of Agricultural Sciences,and the China Agriculture Research System(CARS-03).
文摘Flag leaf angle is one of the key target traits in high yield wheat breeding.A smaller flag leaf angle reduces shading and enables plants to grow at a higher density,which increases yield.Here we identified a mutant,je0407,with an 84.34%-89.35%smaller flag leaf angle compared with the wild type.The mutant also had an abnormal lamina joint and no ligule or auricle.Genetic analysis indicated that the ligule was controlled by two recessive genes,which were mapped to chromosomes 2AS and 2DL.The mutant allele on chromosome 2AS was named Tafla1b,and it was fine mapped to a 1 Mb physical interval.The mutant allele on chr.2DL was identified as Taspl8b,a novel allele of TaSPL8 with a missense mutation in the second exon,which was used to develop a cleaved amplified polymorphic sequence marker.F3 and F4 lines derived from crosses between Jing411 and je0407 were genotyped to investigate interactions between the Tafla1b and Taspl8b alleles.Plants with the Tafla1b/Taspl8a genotype had 58.41%-82.76%smaller flag leaf angles,6.4%-24.9%shorter spikes,and a greater spikelet density(0.382 more spikelets per cm)compared with the wild type.Plants with the Tafla1a/Taspl8b genotype had 52.62%-82.24%smaller flag leaf angles and no differences in plant height or spikelet density compared with the wild type.Tafla1b/Taspl8b plants produced erect leaves with an abnormal lamina joint.The two alleles had dosage effects on ligule formation and flag leaf angle,but no significant effect on thousand-grain weight.The mutant alleles provide novel resources for improvement of wheat plant architecture.
基金supported by the National Natural Science Foundation of China(No.81972681,82103677)Tianjin Education Commission Research Plan Project(No.2021KJ201)+1 种基金Shenzhen High-level Hospital Construction Fund(No.G2022139)Tianjin Key Medical Discipline(Specialty)Construction Project(No.TJYXZDXK-009A).
文摘Objective:CD8+T cells are the key effector cells in the anti-tumor immune response.The mechanism underlying the infiltration of CD8+T cells in esophageal squamous cell carcinoma(ESCC)has not been clearly elucidated.Methods:Fresh ESCC tissues were collected and grouped according to the infiltration density of CD8+T cells.After the transcriptome sequencing on these samples and the combined analyses with The Cancer Genome Atlas(TCGA)ESCC data,a secreted protein DEFB1 was selected to explore its potential role in the infiltration of CD8+T cells.Bioinformatics analyses,histological verification and in vitro experiments were then performed.Results:DEFB1 was highly expressed in ESCC,and the high expression of DEFB1 was an independent risk factor for overall survival.Since the up-regulation or down-regulation of DEFB1 did not affect the proliferation,migration and apoptosis of ESCC cells,we speculated that the oncogenic effect of DEFB1 was achieved by regulating microenvironmental characteristics.Bioinformatics analyses suggested that DEFB1 might play a major role in the inflammatory response and anti-tumor immune response,and correlate to the infiltration of immature dendritic cell(imDC)in ESCC.Histological analyses further confirmed that there were less CD8+T cells infiltrated,less CD83+mature DC(mDC)infiltrated and more CD1a+imDC infiltrated in those ESCC samples with high expression of DEFB1.After the treatment with recombinant DEFB1 protein,the maturation of DC was hindered significantly,followed by the impairment of the killing effects of T cells in both 2D and 3D culture in vitro.Conclusions:Tumor-derived DEFB1 can inhibit the maturation of DC and weaken the function of CD8+T cells,accounting for the immune tolerance in ESCC.The role of DEFB1 in ESCC deserves further exploration.
基金supported by the Scientific Research Fund of Hubei Provincial Education Department(No.Q20122909)the Open Fund of Key Laboratory of Biologic Resources Protection and Utilization of Hubei Province(No.PKLHB1314)the First-class Discipline of Forestry in Hubei Minzu University
文摘The molecular geometries, frontier molecular orbital properties, and absorption and emission properties of three 4-phenoxy-1,8-naphthalimide derivatives, namely 4-phenoxy-N-（2-hydroxyethyl）-1,8-naphthalimide（1）,4-（2-tert-butylphenoxy）-N-（2-hydroxyethyl）-1,8-naphthalimide（2）, and 4-[2,4-di（tert-butyl）]phenoxy-N-（2-hydroxyethyl）-1,8-naphthalimide（3）, are investigated by density functional theory（DFT） and time-dependent density functional theory（TD-DFT） calculations in conjunction with polarizable continuum models（PCMs）. Four functionals and ten basis sets are employed for 1 to calculate the electron transition energies, which were compared with the experimental observations. Our results reveal that the B3LYP/6-311＋G（d,p） method is the best choice to reproduce the experimental spectra. Moreover, the effects of substituents on the molecular geometries, electronic structures, absorption and emission spectra are also studied at the B3LYP/6-311＋G（d,p） level. We find that the gap between the highest occupied molecular orbital（HOMO） and the lowest unoccupied molecular orbital（LUMO） decreases with increasing the number of tert-butyl substituents onto the phenoxy groups, suggesting red-shift of the absorption and emission bands. This is related to the increase of conjugation from 1 to 2 and 3. Our calculations are in good agreement with the experimental results.
基金Supported by Doctor Foundation of Shandong Province(No.BS2010CL021)Natural Science Foundation of Shandong Province(ZR2009AL020)Jiangsu Key Laboratory for Chemistry of Low-dimensional Materials P.R.China(JSKC12106 and JSKC12107)
文摘Two 1,8-naphthalimide derivatives of 7H-benzimidazo[2,1,-a]benz[de] isoquino- lin-7-one（1） and 4-bromo-7H-benzimidazo[2,1,-a]benz[de]isoquinolin-7-one（2） have been synthesized and characterized by elemental analysis, IR, 1H NMR, UV-Vis and fluorescence spectra. For the two compounds, density functional theory（DFT） calculations of the structures and natural population atomic charge analysis have been performed at the B3LYP/6-311G＊＊ level of theory. Based on Onsager reaction filed model and by using TD-DFT method at the B3LYP/6-311G＊＊ level, electron spectra of 1 and 2 with solvent effect in CHCl3 solvent have been predicted, which are in agreement with the experimental ones. Comparative studies on 1 and 2 indicate that introducing an electron-withdrawing group of Br into the 4-position of naphthalene ring in 2 does not significantly make the molecular geometry of 2 different from that of 1, but evidently changes the atomic charge redistribution, moves the positive-negative charges center and then changes the dipole moment in 2. Additionally, for compound 2, the existence of Br atom has also influenced the peak intensity and peak locations in both electron and fluorescence spectra.
基金supported by grants from National Cancer Center Climbing Fund(Grant No.NCC201916B03)Provincial-ministerial Co-construction Project of Henan Province Science and Technology Key Point Tackling Plan(Grant No.SBGJ202102064)Henan Provincial Scientific and Technological Project(Grant Nos.222102310363 and 222102310677)。
文摘Intestinal flora affects the maturation of the host immune system,serves as a biomarker and efficacy predictor in the immunotherapy of several cancers,and has an important role in the development of colorectal cancer(CRC).Anti-PD-1/PD-L1 antibodies have shown satisfactory results in MSI-H/d MMR CRC but performed poorly in patients with MSS/p MMR CRC.In recent years an increasing number of studies have shown that intestinal flora has an important impact on anti-PD-1/PD-L1 antibody efficacy in CRC patients.Preclinical and clinical evidence have suggested that anti-PD-1/PD-L1 antibody efficacy can be improved by altering the composition of the intestinal flora in CRC.Herein,we summarize the studies related to the influence of intestinal flora on anti-PD-1/PD-L1 antibody efficacy in CRC and discuss the potential underlying mechanism(s).We have focused on the impact of the intestinal flora on the efficacy and safety of anti-PD-1/PD-L1 antibodies in CRC and how to better utilize the intestinal flora as an adjuvant to improve the efficacy of anti-PD-1/PD-L1 antibodies.In addition,we have provided a basis for the potential of the intestinal flora as a new treatment modality and indicator for determining patient prognosis.
基金National Natural Science Foundation of China (31970141)the Natural Science Foundation of Fujian Province, China (2020J06047)+1 种基金the Foundation of Minjiang University, China (MJY19019)the Foundation of Fujian Agriculture and Forestry University, China (KFb22050XA)。
文摘Fusarium graminearum is an important plant pathogenic fungus that causes disease and yield reduction in many cereal crops, such as wheat and barley. Gyp8 stimulates GTP hydrolysis on Ypt1 in yeast. However, the functions of Gyp8 in plant pathogenic fungi are still unknown. In this study, we investigated the roles of Fg Gyp8 in F. graminearum by genetic and pathological analyses. Through gene knockout and phenotypic analyses, we found that Fg Gyp8 is required for vegetative growth in F. graminearum. The conidiation, conidial size and number of septa per conidium of ΔFggyp8 mutant are significantly reduced when compared to the wild type PH-1. Furthermore, Fg Gyp8 is crucial for pathogenicity on wheat coleoptiles and wheat heads. Fg Gyp8 contains a conserved TBC domain. Domain deletion analysis showed that the TBC domain, C-and N-terminal regions of Fg Gyp8 are all important for its biological functions in F. graminearum. Moreover, we showed that Fg Gyp8 catalyzes the hydrolysis of the GTP on Fg Rab1 to GDP in vitro, indicating that Fg Gyp8 is a GTPase-activating protein(GAP) for Fg Rab1. In addition, we demonstrated that Fg Gyp8 is required for Fg Snc1-mediated fusion of secretory vesicles with the plasma membrane in F. graminearum. Finally, we showed that Fg Gyp8 has functional redundancy with another Fg Rab1 GAP, Fg Gyp1, in F. graminearum. Taken together, we conclude that Fg Gyp8 is required for vegetative growth, conidiogenesis, pathogenicity and acts as a GAP for Fg Rab1 in F. graminearum.
基金Supported by the First-Class Discipline Construction Founded Project of Ningxia Medical University and the School of Clinical Medicine,No.2020008.
文摘BACKGROUND Immune checkpoint inhibitors(ICIs)targeting programmed cell death protein 1(PD-1)and T cell immunoglobulin and mucin domain-containing protein 3(TIM-3)are beneficial to the resumption of anti-tumor immunity response and hold extreme potential as efficient therapies for certain malignancies.However,ICIs with a single target exhibit poor overall response rate in hepatocellular carcinoma(HCC)patients due to the complex pathological mechanisms of HCC.AIM To investigate the effects of combined TIM-3 and PD-1 blockade on tumor development in an HCC mouse model,aiming to identify more effective immunotherapies and provide more treatment options for HCC patients.METHODS The levels of PD-1 and TIM-3 on CD4+and CD8+T cells from tumor tissues,ascites,and matched adjacent tissues from HCC patients were determined with flow cytometry.An HCC xenograft mouse model was established and treated with anti-TIM-3 monoclonal antibody(mAb)and/or anti-PD-1 mAb.Tumor growth in each group was measured.Hematoxylin and eosin staining and immunohistochemical staining were used to evaluate T cell infiltration in tumors.The percentage of CD4+and CD8+T cells in tissue samples from mice was tested with flow cytometry.The percentages of PD-1+CD8+,TIM-3+CD8+,and PD-1+TIM-3+CD8+T cells was accessed by flow cytometry.The levels of the cytokines including tumor necrosis factor alpha(TNF-α),interferon-γ(IFN-γ),interleukin(IL)-6,and IL-10 in tumor tissues were gauged with enzyme-linked immunosorbent assay kits.RESULTS We confirmed that PD-1 and TIM-3 expression was substantially upregulated in CD4+and CD8+T cells isolated from tumor tissues and ascites of HCC patients.TIM-3 mAb and PD-1 mAb treatment both reduced tumor volume and weight,while combined blockade had more substantial anti-tumor effects than individual treatment.Then we showed that combined therapy increased T cell infiltration into tumor tissues,and downregulated PD-1 and TIM-3 expression on CD8+T cells in tumor tissues.Moreover,combined treatment facilitated the production of T cell effector cytokines TNF-α and IFN-γ,and reduced the production of immunosuppressive cytokines IL-10 and IL-6 in tumor tissues.Thus,we implicated that combined blockade could ameliorate T cell exhaustion in HCC mouse model.CONCLUSION Combined TIM-3 and PD-1 blockade restrains HCC development by facilitating CD4+ and CD8+T cell-mediated antitumor immune responses.
文摘BACKGROUND Benign recurrent intrahepatic cholestasis is a genetic disorder with recurrent cholestatic jaundice due to ATP8B1 and ABCB11 gene mutations encoding for hepato-canalicular transporters.Herein,we firstly provide the evidence that a nonsense variant of ATP8B1 gene(c.1558A>T)in heterozygous form is involved in BRIC pathogenesis.CASE SUMMARY A 29-year-old male showed severe jaundice and laboratory tests consistent with intrahepatic cholestasis despite normal gamma-glutamyltranspeptidase.Acute and chronic liver diseases with viral,metabolic and autoimmune etiology were excluded.Normal intra/extra-hepatic bile ducts were demonstrated by magnetic resonance.Liver biopsy showed:Cholestasis in the centrilobular and intermediate zones with bile plugs and intra-hepatocyte pigment,Kupffer’s cell activation/hyperplasia and preserved biliary ducts.Being satisfied benign recurrent intrahepatic cholestasis diagnostic criteria,ATP8B1 and ABCB11 gene analysis was performed.Surprisingly,we found a novel nonsense variant of ATP8B1 gene(c.1558A>T)in heterozygosis.The variant was confirmed by Sanger sequencing following a standard protocol and tested for familial segregation,showing a maternal inheritance.Immunohistochemistry confirmed a significant reduction of mutated gene related protein(familial intrahepatic cholestasis 1).The patient was treated with ursodeoxycholic acid 15 mg/kg per day and colestyramine 8 g daily with total bilirubin decrease and normalization at the 6th and 12th mo.CONCLUSION A genetic abnormality,different from those already known,could be involved in familial intrahepatic cholestatic disorders and/or pro-cholestatic genetic predisposition,thus encouraging further mutation detection in this field.
基金Supported by the Central Public-interest Scientific Institution Basal Research Fund(2008hzs1J021,2009hzs1J033)~~
文摘[Objective]The study aimed to screen the starch-degrading bacterium in bagasse and carry on the identification of strains s2g5-1 and s3g4-8.[Method]By using a variety of selective media,varieties of starch degrading bacterium were isolated from the sugar cane bagasse form different stages of natural fermentation,then,primary screening and secondary screening were performed.[Result] Starch-degrading strains s2g5-1 and s3g4-8 were screened,and they were identified as Bacillus amyloliquefaciens according to their morphological,physiological,biochemical and molecular characteristics.[Conclusion]The research provided theoretical basis for factory application of bagasse.
文摘AIM： To study the relationship between MCP-1-2518A/ G, IL-8-251A/T polymorphism and acute pancreatitis （AP） in the Han population of Suzhou, China. METHODS： A case-control study was conducted to compare the distribution of genotype and genetic frequency of MCP-1-2518A/G, IL-8-251A/T gene polymorphism among AP （n = 101）, including mild AP （n = 78） and severe AP （n = 23） and control healthy individuals （n = 120） with polymerase chain reaction- restriction fragment length polymorphism （PCR-RFLP） and DNA sequencing, and analyze the relationship between the MCP-1-2518A/G, IL-8-251A/T gene polymorphism and the susceptibility to AP. RESULTS： Significant differences were found in the distribution of genotype of MCP-1-2518A/G between the healthy control group and mild AP group （χ^2 = 32.015, P 〈 0.001）, the same was evident between the healthy control group and severe AP group （χ^2 = 12.932, P 〈 0.05） in Suzhou. However, no difference of genotypic distribution was noted between MAP and SAP （Z2 = 0.006, P = 0.997）. The genetic frequencies of G allele in mild AP were 72.4% （113/156） and 76.1% （35/46） in severe AP, both were higher than the controls, 47.1% （113/240） （χ^2 = 24.804; P 〈 0.001, and 4,2 = 13：005; P 〈 0.001）, but no difference was found between severe AP and mild AP （χ^2 = 0.242, P = 0.623）. No difference was found in the distribution of genotype of IL-8-251A/T between the healthy control group and AP group neither in the frequency of A and T allele. CONCLUSION： The MCP-1-2518 AA genotype of the population in Suzhou may be a protective genotype of AP, while one with higher frequency of G allele is more likely to suffer from pancreatitis. But the genotype of AA and the frequency of G allele could not predict the risk of severe AP. No correlation is found between the IL-8-251 polymorphism and the liability of AP.
文摘A novel coronavirus, severe acute respiratory syndrome (SA RS)-associated coronavirus (SARS-CoV), has been identified as the causal agent of SARS. Spike (S) protein is a major structural glycoprotein of the SARS virus and a potential target for SARS-specific cell-mediated immune responses. A pa nel of S protein-derived peptides was tested for their binding affinity to HLA -A *0201 molecules. Peptides with high affinity for HLA-A *0201 were then as se ssed for their capacity to elicit specific immune responses mediated by cytotoxi c T lymphocytes (CTLs) both in vivo, in HLA-A2.1/K b transgenic mice, a nd in vitro, from peripheral blood lymphocytes (PBLs) harvested from healthy HLA-A 2.1 + donors. SARS-CoV protein-derived peptide-1 (SSp-1 RLNEVAKNL), induced pepti de-specific CTLs both in vivo (transgenic mice) and in vitro (human PBL s), which specifically released interferon-gamma (IFN-gamma) upon stimulation with SSp-1-pulsed autologous dendritic cells (DCs) or T2 cells. SSp-1-specif ic CTLs also lysed major histocompatibility complex (MHC)-matched tumor cell lines engineered to express S proteins. HLA-A *0201-SSp-1 tetramer staining re vealed the presence of significant populations of SSp-1-specific CTLs in SSp- 1-induced CD8 + T cells. We propose that the newly identified epitope SSp-1 w ill help in the characterization of virus control mechanisms and immunopathology in SARS-CoV infection, and may be relevant to the development of immunotherape utic approaches for SARS.
基金supported by the National Basic Research Program of China(2009CB118300)the National 863 Program of China(2006AA10Z1A7and2006AA100102)the International Collaboration Project from the Ministry of Agriculture of China(2006-G2)
文摘The plant hormone abscisic acid （ABA） regulates many important physiological and developmental processes in plants. The objective of this study was to clone the ABA 8′-hydroxylase gene in common wheat. In the present study, we used the eDNA sequence of barley HvCYP707A1 gene （GenBank accession no. AB239299） as a probe for BLAST search against the common wheat （Triticum aestivum L.） EST database in GenBank. All wheat ESTs sharing high similarity with the reference gene were subjected to contig assembly. Primers were designed based on the constructed contigs to clone the wheat CYP707A1 gene, designated as TaCYP707A1. The genomic DNA sequence of TaCYPTO7A1 gene comprised five exons and four introns, with a size of 2225 bp. The corresponding cDNA sequence of TaCYP707A1 was 1737 bp, containing an open reading frame （ORF） of 1431 bp, a 42-bp 5′-untranslated region （UTR） and a 264-bp 3′UTR, with 94.9% of identical sequences to HvCYP707A1 gene （AB239299）. The neighbor joining tree indicated that the deduced amino acid sequences of TaCYP707A1 gene was highly similar to those of barley and rice. The TaCYP707A1 gene was located on chromosome 6BL using a set of Chinese Spring nullisomic-tetrasomic lines and ditelosomic line 6BS. These results will be of high importance in understanding of molecular mechanism of ABA catabolism.
