Objective: To observe the expression of TLR4 in kidney tissue of rats with diabetic nephropathy and discuss the role of TLR4 in the occurrence and development of the diabetic nephropathy. Methods: A total of 60 clean ...Objective: To observe the expression of TLR4 in kidney tissue of rats with diabetic nephropathy and discuss the role of TLR4 in the occurrence and development of the diabetic nephropathy. Methods: A total of 60 clean male SD rats were selected and randomly divided into the modeling group and control group after 1 week of breeding, including 30 rats in each group. Biochemical indices as well as the protein expression of TLR4 were observed and compared between two groups at 2 w, 4 w, 6 w, 8 w and 12 w after the modeling, and the correlation between TLR4 and each biochemical indexes was analyzed. Results: Rats in the modeling group had higher levels of blood glucose, 24-hour urine protein and blood urea nitrogen after the modeling, and showed the increase in the serum creatinine, kidney/body weight ratio, CRP and serum TNF-毩 at 4w after the modeling, with the significant difference compared to results of the control group ( P <0.05). The cross-section area and mean volume of glomerulus in the modeling group at 4 w, 6 w, 8 w and 12 w were significantly higher than those in the control group, with the statistically significant difference ( P <0.05). The expression of TLR4 at each time point in the control group was relatively low. Rats in the modeling group had the high expression of TLR4 in kidney's glomerular basement membrane, proximal convoluted tubule and renal interstitial area since 2 w, with the significant difference compared to the control group ( P <0.05). The expression in rats of the modeling group was higher than the one of the control group since the 2nd week. As the time flied, its expression increased, with the statistically significant difference between two groups ( P <0.05). There was certain correlation between the protein expression of TLR4 and the increased serum titer of 24hour urine protein excretion, serum creatinine, CRP and TNF-毩. Conclusions: TLR4 may activate the immuno-inflammatory reactions to play a role in the occurrence and development of the diabetic nephropathy.展开更多
Interaction between the HIV-1 Vif protein and the cellular host APOBEC3G protein is a promising target for inhibition of HIV-1 replication. Considering that human cells are a very complicated environment for the study...Interaction between the HIV-1 Vif protein and the cellular host APOBEC3G protein is a promising target for inhibition of HIV-1 replication. Considering that human cells are a very complicated environment for the study of protein interactions, the goal of this study was to check whether fission yeast could be used as a model cell for studying the Vif-APOBEC3G interaction. Vif and APOBEC3G were expressed in fusion with GFP protein in the S. pombe SP223 strain. Subcellular localizations of Vif and APOBEC3G were observed with fluorescent microscopy. Codon optimization was used to over express the Vif protein in S. pombe cells. The degradation of APOBEC3G mediated by Vif was tested through expressing Vif and GFP-APOBEC3G proteins in the same cell. Western Blot analysis was used to measure the corresponding protein levels under different experimental conditions. The results showed that the Vif protein was predominantly localized in the nucleus of S. pombe cells, APOBEC3G was localized in the cytoplasm and concentrated at punctate bodies that were often in close proximity to the nucleus but were not necessarily restricted from other regions in the cytoplasm. Vif protein expression levels were increased significantly by using codon optimization and APOBEC3G was degraded when Vif was over-expressed in the same S. pombe cells. These results indicate that fission yeast is a good model for studying the interaction between the Vif and APOBEC3G proteins.展开更多
Neutralizing antibodies are considered to be an important protective parameter used in HIV-1 vaccine evaluation. However, the exact role that neutralizing antibodies plays in controlling the disease progression of HIV...Neutralizing antibodies are considered to be an important protective parameter used in HIV-1 vaccine evaluation. However, the exact role that neutralizing antibodies plays in controlling the disease progression of HIV-1 infected peoples is still undetermined. In this paper, we compared the protective function of the neutralizing antibody response in the plasma from LTNP and TP against clade B and clade C pseudoviruses. No difference in the neutralizing activities between the plasma from LTNP and TP was found, which was consistent with the most recent reports. In addition, no correlations between the titer or breadth and CD4+ or viral load in HIV-1 infected individuals were found. The protective roles played by neutralizing antibodies in controlling disease progression of HIV-1 infected people need to be considered in a new viewpoint.展开更多
This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive(N)and nivolumab–chemotherapy(N/C)combinations based on PD-L1 expression.Eligible patients exhibited resec...This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive(N)and nivolumab–chemotherapy(N/C)combinations based on PD-L1 expression.Eligible patients exhibited resectable clinical stage IIA–IIIB(AJCC 8th edition)NSCLC without EGFR/ALK alterations.Patients received either mono-nivolumab(N)or nivolumab+nabpaclitaxel+carboplatin(N/C)for three cycles based on PD-L1 expression.The primary endpoint was the major pathological response(MPR).Key secondary endpoints included the pathologic complete response(pCR),objective response rate(ORR),and event-free survival(EFS).Baseline PD-L1 expression and perioperative circulating tumor DNA(ctDNA)status were correlated with pCR and EFS.Fifty-two patients were enrolled,with 46 undergoing surgeries.The MPR was 50.0%(26/52),with 25.0%(13/52)achieving pCR,and 16.7%and 66.7%for patients with PD-L1≥50%in N and N/C groups,respectively.Thirteen(25.0%)patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment.Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR(39.1%)compared with those remained positive(6.7%,odds ratio=6.14,95%CI 0.84-Inf,p=0.077).With a median follow-up of 25.1 months,the 18-month EFS rate was 64.8%(95%CI 51.9–81.0%).For patients with ctDNA–vs.ctDNA+,the 18m-EFS rate was 93.8%vs 47.3%(HR,0.15;95%CI 0.04,0.94;p=0.005).Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression≥50%.ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits,which requires further confirmation in a prospective clinical trial(NCT04015778).展开更多
EMERGING-CTONG 1103 showed improved progression-free survival(PFS)with neoadjuvant erlotinib vs.chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer(...EMERGING-CTONG 1103 showed improved progression-free survival(PFS)with neoadjuvant erlotinib vs.chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer(NSCLC)(NCT01407822).Herein,we report the final results.Recruited patients were randomly allocated 1:1 to the erlotinib group(150 mg/day orally;neoadjuvant phase for 42 days and adjuvant phase to 12 months)or to the GC group(gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 intravenously;2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase).Objective response rate(ORR),complete pathologic response(pCR),PFS,and overall survival(OS)were assessed along with safety.Post hoc analysis was performed for subsequent treatments after disease recurrence.Among investigated 72 patients(erlotinib,n=37;GC,n=35),the median follow-up was 62.5 months.The median OS was 42.2 months(erlotinib)and 36.9 months(GC)(hazard ratio[HR],0.83;95%confidence interval[CI],0.47-1.47;p=0.513).The 3-and_(5-y)ear OS rates were 58.6%and 40.8%with erlotinib and 55.9%and 27.6%with GC(p_(3-y)=0.819,p_(5-y)=0.252).Subsequent treatment was administered in 71.9%and 81.8%of patients receiving erlotinib and GC,respectively;targeted therapy contributed mostly to OS(HR,0.35;95%CI,0.18-0.70).After disease progression,the ORR was 53.3%,and the median PFS was 10.9 months during the EGFR-TKI rechallenge.During postoperative therapy,grade 3 or 4 adverse events(AEs)were 13.5%in the erlotinib group and 29.4%in the GC group.No serious adverse events were observed.Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting.展开更多
5-Formylcytosine(5fC), as an important epigenetic modification, plays a vital role in diverse biological processes and multiple diseases by regulating gene expression. Owing to the extremely low abundance of 5fC in al...5-Formylcytosine(5fC), as an important epigenetic modification, plays a vital role in diverse biological processes and multiple diseases by regulating gene expression. Owing to the extremely low abundance of 5fC in all mammalian tissues and high structural similarity with other cytosine derivatives, the precise and sensitive detection of 5fC is challenging. Herein, a photo-elutable and template-free isothermal amplification strategy has been proposed for the sensitive detection of 5fC in genomic DNA based on5fC-specific biotinylation, enrichment, photocleavage, and terminal deoxynucleotidyl transferase(Td T)-assisted fluorescence signal amplification, which is termed 5fC-PTIAS. By introducing the highly specific chemolabeling and the one-step photoelution processes, this strategy possesses a minimal nonspecific background as well as a much higher amplification efficiency. With the high signal-to-noise ratio, this strategy can achieve the accurate quantification of 5fC in various biological samples including mouse brain, kidney, and liver, with a limit of detection(LOD) of 0.025‰ in DNA(S/N=3). These results not only confirm the widespread distribution of 5fC but also indicate its significant variation in different tissues and ages. The bisulfite-and mass spectrometry-free strategy is highly sensitive, selective, and easily mastered, holding great promise in detecting other epigenetic modifications with much lower levels.展开更多
Immunotherapy with checkpoint inhibitors (CPIs)is a new approach to cancer therapy that harnesses and enhances the innate abilities of the immune system to recognize and fight cancers.It has become a breakthrough in t...Immunotherapy with checkpoint inhibitors (CPIs)is a new approach to cancer therapy that harnesses and enhances the innate abilities of the immune system to recognize and fight cancers.It has become a breakthrough in the history of cancer treatment and is of epoch-making significance [1 ]. In the past century,Nobel Prize has been awarded to the advances in immunology for 15 times.This year,it won for the 16th time.James P.Allison from the University of Texas MD Anderson Cancer Center and Japanese immunologist Tasuku Honjo were awarded the 2018 Nobel Prize in Physiology or Medicine,for their great contributions to the discovery of the CTLA-4 and PD-1 and the development of promising cancer therapy by inhibition of negative immune regulation.Their research shows how different strategies to inhibit the brakes on the immune system can be used in the treatment of cancer,which became a landmark in the history of cancer therapy.展开更多
A reliable and sensitive strategy which can assess nucleic acid levels in living cells would be essential for fundamental research of biomedical applications. Some nanomaterial-based fluorescence biosensors recently d...A reliable and sensitive strategy which can assess nucleic acid levels in living cells would be essential for fundamental research of biomedical applications. Some nanomaterial-based fluorescence biosensors recently developed for detecting nucleic acids, however, are often with expensive, complicated and timeconsuming preparation process. Here, by using a facile bottom-up synthesis method, a two-dimensional(2 D) coordination polymer(CP) nanosheet, [Cu(tz)](Htz = 1,2,4-triazole), was successfully prepared after optimizing reaction conditions. These ultrathin CP nanosheets with thickness of 4.7 ± 1.1 nm could readily form nanosensors by assembly with DNA probes, which exhibited a low limit of detection(LOD)for p53 DNA fragment as 144 pmol/L. Furthermore, by integrating [Cu(tz)] nanosheets with hybridization chain reaction(HCR) probes, mi R-21, one kind of micro RNA upregulated in many cancer cells, can be sensitively detected with a LOD of 100 pmol/L and monitored in living cells, giving consistent results with those obtained by quantitative reverse-transcription polymerase chain reaction(q RT-PCR) analysis.Thus [Cu(tz)] nanosheets, which not only possess much better nucleic acids sensing performance than bulk cystals, but also exhibit nucleic acid delivery functions, could be used as a novel nanoplatform in biomedical imaging and sensing applications.展开更多
5-Hydroxymethylcytosine(5 hmC),an intermediate product of DNA demethylation,is important for the regulation of gene expression during development and even tumorigenesis.The challenges associated with determination of ...5-Hydroxymethylcytosine(5 hmC),an intermediate product of DNA demethylation,is important for the regulation of gene expression during development and even tumorigenesis.The challenges associated with determination of 5 hm C level include its extremely low abundance and high structural similarity with other cytosine derivatives,which resulted in sophisticated treatment with large amount of sample input.Herein,we developed a primer-initiated strand displacement amplification(PISDA)strategy to quantify the global 5 hm C in genomic DNA from mammalian tissues with high sensitivity/selectivity,low input and simple operation.This sensitive fluorescence method is based on 5 hmC-specific glucosylation,primer ligation and DNA amplification.After the primer was labeled on 5 hm C site,DNA polymerase and nicking enzyme will repeatedly act on each primer,causing a significant increase of fluorescence signal to magnify the minor difference of 5 hm C content from other cytosine derivatives.This method enables highly sensitive analysis of 5 hm C with a detection limit of 0.003%in DNA(13.6 fmol,S/N=3)from sample input of only 150 ng,which takes less than 15 min for determination.Further determination of 5 hmC in different tissues not only confirms the widespread presence of 5 hmC but also indicates its significant variation in different tissues and ages.Importantly,this PISDA strategy exhibits distinct advantages of bisulfite-free treatment,mild conditions and simple operation without the involvement of either expensive equipment or large amount of DNA sample.This method can be easily performed in almost all research and medical laboratories,and would provide a promising prospect to detect global 5 hmC in mammalian tissues.展开更多
The influence of MgO content in slag on wetting and corrosion behavior between slag and MgO–C refractory was investigated.It can be known from the high-temperature wetting experiment that as the MgO content in the sl...The influence of MgO content in slag on wetting and corrosion behavior between slag and MgO–C refractory was investigated.It can be known from the high-temperature wetting experiment that as the MgO content in the slag increases,the final contact angle between the slag and the MgO–C refractory gradually increases and the penetration depth of the slag into the refractory gradually decreases from 60.54μm(when the MgO content is 8%)to 28.11μm(when the MgO content is 12%).The CaO and SiO_(2)in the slag penetrate into the MgO–C refractory along the pores or surface cracks formed by carbon oxidation and react with MgO to generate a large amount of low-melting compound CaO–MgO–SiO_(2),which accelerates the corrosion of the refractory.As the MgO content in slag increases,the viscosity of the slag increases and the fluidity becomes worse,so that the mass transfer and diffusion of molecules or ions in the slag are weakened.In addition,the increase in MgO reduces the activity of FeO in the slag,which inhibits the interfacial chemical reaction,thereby weakening the wetting effect caused by the reaction.展开更多
文摘Objective: To observe the expression of TLR4 in kidney tissue of rats with diabetic nephropathy and discuss the role of TLR4 in the occurrence and development of the diabetic nephropathy. Methods: A total of 60 clean male SD rats were selected and randomly divided into the modeling group and control group after 1 week of breeding, including 30 rats in each group. Biochemical indices as well as the protein expression of TLR4 were observed and compared between two groups at 2 w, 4 w, 6 w, 8 w and 12 w after the modeling, and the correlation between TLR4 and each biochemical indexes was analyzed. Results: Rats in the modeling group had higher levels of blood glucose, 24-hour urine protein and blood urea nitrogen after the modeling, and showed the increase in the serum creatinine, kidney/body weight ratio, CRP and serum TNF-毩 at 4w after the modeling, with the significant difference compared to results of the control group ( P <0.05). The cross-section area and mean volume of glomerulus in the modeling group at 4 w, 6 w, 8 w and 12 w were significantly higher than those in the control group, with the statistically significant difference ( P <0.05). The expression of TLR4 at each time point in the control group was relatively low. Rats in the modeling group had the high expression of TLR4 in kidney's glomerular basement membrane, proximal convoluted tubule and renal interstitial area since 2 w, with the significant difference compared to the control group ( P <0.05). The expression in rats of the modeling group was higher than the one of the control group since the 2nd week. As the time flied, its expression increased, with the statistically significant difference between two groups ( P <0.05). There was certain correlation between the protein expression of TLR4 and the increased serum titer of 24hour urine protein excretion, serum creatinine, CRP and TNF-毩. Conclusions: TLR4 may activate the immuno-inflammatory reactions to play a role in the occurrence and development of the diabetic nephropathy.
基金National Grand Fundamental Research 973 Program of China (2006CB504206).
文摘Interaction between the HIV-1 Vif protein and the cellular host APOBEC3G protein is a promising target for inhibition of HIV-1 replication. Considering that human cells are a very complicated environment for the study of protein interactions, the goal of this study was to check whether fission yeast could be used as a model cell for studying the Vif-APOBEC3G interaction. Vif and APOBEC3G were expressed in fusion with GFP protein in the S. pombe SP223 strain. Subcellular localizations of Vif and APOBEC3G were observed with fluorescent microscopy. Codon optimization was used to over express the Vif protein in S. pombe cells. The degradation of APOBEC3G mediated by Vif was tested through expressing Vif and GFP-APOBEC3G proteins in the same cell. Western Blot analysis was used to measure the corresponding protein levels under different experimental conditions. The results showed that the Vif protein was predominantly localized in the nucleus of S. pombe cells, APOBEC3G was localized in the cytoplasm and concentrated at punctate bodies that were often in close proximity to the nucleus but were not necessarily restricted from other regions in the cytoplasm. Vif protein expression levels were increased significantly by using codon optimization and APOBEC3G was degraded when Vif was over-expressed in the same S. pombe cells. These results indicate that fission yeast is a good model for studying the interaction between the Vif and APOBEC3G proteins.
基金supported in part by the National Key S&T Special Projects on Major Infectious Diseases (Grant No. 2008ZX10001-002, 2008ZX10001-012)the National Natural Science Foundation of China (No. 30700706)
文摘Neutralizing antibodies are considered to be an important protective parameter used in HIV-1 vaccine evaluation. However, the exact role that neutralizing antibodies plays in controlling the disease progression of HIV-1 infected peoples is still undetermined. In this paper, we compared the protective function of the neutralizing antibody response in the plasma from LTNP and TP against clade B and clade C pseudoviruses. No difference in the neutralizing activities between the plasma from LTNP and TP was found, which was consistent with the most recent reports. In addition, no correlations between the titer or breadth and CD4+ or viral load in HIV-1 infected individuals were found. The protective roles played by neutralizing antibodies in controlling disease progression of HIV-1 infected people need to be considered in a new viewpoint.
基金supported by the Bristol Myers Squibb(grant number BMSCA209-8D8)the Chinese Thoracic Oncology Group(CTONG1804)ctDNA analysis was performed by Fujian Key Laboratory of Advanced Technology for Cancer Screening and Early Diagnosis and the Berry Oncology Corporation without compensation.
文摘This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive(N)and nivolumab–chemotherapy(N/C)combinations based on PD-L1 expression.Eligible patients exhibited resectable clinical stage IIA–IIIB(AJCC 8th edition)NSCLC without EGFR/ALK alterations.Patients received either mono-nivolumab(N)or nivolumab+nabpaclitaxel+carboplatin(N/C)for three cycles based on PD-L1 expression.The primary endpoint was the major pathological response(MPR).Key secondary endpoints included the pathologic complete response(pCR),objective response rate(ORR),and event-free survival(EFS).Baseline PD-L1 expression and perioperative circulating tumor DNA(ctDNA)status were correlated with pCR and EFS.Fifty-two patients were enrolled,with 46 undergoing surgeries.The MPR was 50.0%(26/52),with 25.0%(13/52)achieving pCR,and 16.7%and 66.7%for patients with PD-L1≥50%in N and N/C groups,respectively.Thirteen(25.0%)patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment.Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR(39.1%)compared with those remained positive(6.7%,odds ratio=6.14,95%CI 0.84-Inf,p=0.077).With a median follow-up of 25.1 months,the 18-month EFS rate was 64.8%(95%CI 51.9–81.0%).For patients with ctDNA–vs.ctDNA+,the 18m-EFS rate was 93.8%vs 47.3%(HR,0.15;95%CI 0.04,0.94;p=0.005).Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression≥50%.ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits,which requires further confirmation in a prospective clinical trial(NCT04015778).
基金The authors thank all patients and their families.The authors would like to acknowledge the editorial support provided by Keyra Martinez Dunn,MD,of Edanz(www.edanz.com),which was funded by Shanghai Roche Pharmaceutical Ltd.This study was funded by the Chinese Thoracic Oncology Group(CTONG),Shanghai Roche Pharmaceutical Ltd.
文摘EMERGING-CTONG 1103 showed improved progression-free survival(PFS)with neoadjuvant erlotinib vs.chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer(NSCLC)(NCT01407822).Herein,we report the final results.Recruited patients were randomly allocated 1:1 to the erlotinib group(150 mg/day orally;neoadjuvant phase for 42 days and adjuvant phase to 12 months)or to the GC group(gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 intravenously;2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase).Objective response rate(ORR),complete pathologic response(pCR),PFS,and overall survival(OS)were assessed along with safety.Post hoc analysis was performed for subsequent treatments after disease recurrence.Among investigated 72 patients(erlotinib,n=37;GC,n=35),the median follow-up was 62.5 months.The median OS was 42.2 months(erlotinib)and 36.9 months(GC)(hazard ratio[HR],0.83;95%confidence interval[CI],0.47-1.47;p=0.513).The 3-and_(5-y)ear OS rates were 58.6%and 40.8%with erlotinib and 55.9%and 27.6%with GC(p_(3-y)=0.819,p_(5-y)=0.252).Subsequent treatment was administered in 71.9%and 81.8%of patients receiving erlotinib and GC,respectively;targeted therapy contributed mostly to OS(HR,0.35;95%CI,0.18-0.70).After disease progression,the ORR was 53.3%,and the median PFS was 10.9 months during the EGFR-TKI rechallenge.During postoperative therapy,grade 3 or 4 adverse events(AEs)were 13.5%in the erlotinib group and 29.4%in the GC group.No serious adverse events were observed.Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting.
基金supported by the Scientific Technology Project of Shenzhen City(Nos.JCYJ20200109142410170 and JCYJ20210324124003008)the National Natural Science Foundation of China(No.21974153)+2 种基金the Scientific Technology Project of Guangzhou City(No.202103000003)the Guangdong Natural Science Foundation(No.2019A1515010587)the Guangdong Science and Technology Plan Project(No.2020B1212060077)。
文摘5-Formylcytosine(5fC), as an important epigenetic modification, plays a vital role in diverse biological processes and multiple diseases by regulating gene expression. Owing to the extremely low abundance of 5fC in all mammalian tissues and high structural similarity with other cytosine derivatives, the precise and sensitive detection of 5fC is challenging. Herein, a photo-elutable and template-free isothermal amplification strategy has been proposed for the sensitive detection of 5fC in genomic DNA based on5fC-specific biotinylation, enrichment, photocleavage, and terminal deoxynucleotidyl transferase(Td T)-assisted fluorescence signal amplification, which is termed 5fC-PTIAS. By introducing the highly specific chemolabeling and the one-step photoelution processes, this strategy possesses a minimal nonspecific background as well as a much higher amplification efficiency. With the high signal-to-noise ratio, this strategy can achieve the accurate quantification of 5fC in various biological samples including mouse brain, kidney, and liver, with a limit of detection(LOD) of 0.025‰ in DNA(S/N=3). These results not only confirm the widespread distribution of 5fC but also indicate its significant variation in different tissues and ages. The bisulfite-and mass spectrometry-free strategy is highly sensitive, selective, and easily mastered, holding great promise in detecting other epigenetic modifications with much lower levels.
文摘Immunotherapy with checkpoint inhibitors (CPIs)is a new approach to cancer therapy that harnesses and enhances the innate abilities of the immune system to recognize and fight cancers.It has become a breakthrough in the history of cancer treatment and is of epoch-making significance [1 ]. In the past century,Nobel Prize has been awarded to the advances in immunology for 15 times.This year,it won for the 16th time.James P.Allison from the University of Texas MD Anderson Cancer Center and Japanese immunologist Tasuku Honjo were awarded the 2018 Nobel Prize in Physiology or Medicine,for their great contributions to the discovery of the CTLA-4 and PD-1 and the development of promising cancer therapy by inhibition of negative immune regulation.Their research shows how different strategies to inhibit the brakes on the immune system can be used in the treatment of cancer,which became a landmark in the history of cancer therapy.
基金supported by the National Key Research and Development Program of China (No.2018YFA0902801)the National Natural Science Foundations of China (Nos.21775169,21801259 and 21974153)+4 种基金the Scientific Technology Project of Shenzhen City (No.JCYJ20200109142410170)the Scientific Technology Project of Guangzhou City (No.202103000003)the Guangdong Natural Science Foundation (Nos.2018A030313290,2019A1515010587)the Guangdong Science and Technology Plan Project (No.2020B1212060077)the Fundamental Research Funds for the Central Universities,SYSU (No.19lgpy142)。
文摘A reliable and sensitive strategy which can assess nucleic acid levels in living cells would be essential for fundamental research of biomedical applications. Some nanomaterial-based fluorescence biosensors recently developed for detecting nucleic acids, however, are often with expensive, complicated and timeconsuming preparation process. Here, by using a facile bottom-up synthesis method, a two-dimensional(2 D) coordination polymer(CP) nanosheet, [Cu(tz)](Htz = 1,2,4-triazole), was successfully prepared after optimizing reaction conditions. These ultrathin CP nanosheets with thickness of 4.7 ± 1.1 nm could readily form nanosensors by assembly with DNA probes, which exhibited a low limit of detection(LOD)for p53 DNA fragment as 144 pmol/L. Furthermore, by integrating [Cu(tz)] nanosheets with hybridization chain reaction(HCR) probes, mi R-21, one kind of micro RNA upregulated in many cancer cells, can be sensitively detected with a LOD of 100 pmol/L and monitored in living cells, giving consistent results with those obtained by quantitative reverse-transcription polymerase chain reaction(q RT-PCR) analysis.Thus [Cu(tz)] nanosheets, which not only possess much better nucleic acids sensing performance than bulk cystals, but also exhibit nucleic acid delivery functions, could be used as a novel nanoplatform in biomedical imaging and sensing applications.
基金supported by the Scientific Technology Project of Shenzhen City(Nos.JCYJ20200109142410170,JCYJ20210324120601004 and JCYJ20210324124003008)the National Natural Science Foundations of China(Nos.21775169,21801259 and 21974153)+2 种基金the Scientific Technology Project of Guangzhou City(No.202103000003)the Guangdong Natural Science Foundation(No.2019A1515010587)the Guangdong Science and Technology Plan Project(No.2020B1212060077)。
文摘5-Hydroxymethylcytosine(5 hmC),an intermediate product of DNA demethylation,is important for the regulation of gene expression during development and even tumorigenesis.The challenges associated with determination of 5 hm C level include its extremely low abundance and high structural similarity with other cytosine derivatives,which resulted in sophisticated treatment with large amount of sample input.Herein,we developed a primer-initiated strand displacement amplification(PISDA)strategy to quantify the global 5 hm C in genomic DNA from mammalian tissues with high sensitivity/selectivity,low input and simple operation.This sensitive fluorescence method is based on 5 hmC-specific glucosylation,primer ligation and DNA amplification.After the primer was labeled on 5 hm C site,DNA polymerase and nicking enzyme will repeatedly act on each primer,causing a significant increase of fluorescence signal to magnify the minor difference of 5 hm C content from other cytosine derivatives.This method enables highly sensitive analysis of 5 hm C with a detection limit of 0.003%in DNA(13.6 fmol,S/N=3)from sample input of only 150 ng,which takes less than 15 min for determination.Further determination of 5 hmC in different tissues not only confirms the widespread presence of 5 hmC but also indicates its significant variation in different tissues and ages.Importantly,this PISDA strategy exhibits distinct advantages of bisulfite-free treatment,mild conditions and simple operation without the involvement of either expensive equipment or large amount of DNA sample.This method can be easily performed in almost all research and medical laboratories,and would provide a promising prospect to detect global 5 hmC in mammalian tissues.
基金This work was financially supported by the National Natural Science Foundation of China(Grant Nos.51874171 and 51974154)supported by University of Science and Technology Liaoning talents program(601009840-09).
文摘The influence of MgO content in slag on wetting and corrosion behavior between slag and MgO–C refractory was investigated.It can be known from the high-temperature wetting experiment that as the MgO content in the slag increases,the final contact angle between the slag and the MgO–C refractory gradually increases and the penetration depth of the slag into the refractory gradually decreases from 60.54μm(when the MgO content is 8%)to 28.11μm(when the MgO content is 12%).The CaO and SiO_(2)in the slag penetrate into the MgO–C refractory along the pores or surface cracks formed by carbon oxidation and react with MgO to generate a large amount of low-melting compound CaO–MgO–SiO_(2),which accelerates the corrosion of the refractory.As the MgO content in slag increases,the viscosity of the slag increases and the fluidity becomes worse,so that the mass transfer and diffusion of molecules or ions in the slag are weakened.In addition,the increase in MgO reduces the activity of FeO in the slag,which inhibits the interfacial chemical reaction,thereby weakening the wetting effect caused by the reaction.