The hepatocellular carcinoma suppressor 1 （HCCS1） gene was identified by both positional cloning from a predominant region of loss of heterozygosity （17p 13.3） in liver cancer and by functional screening for genes...The hepatocellular carcinoma suppressor 1 （HCCS1） gene was identified by both positional cloning from a predominant region of loss of heterozygosity （17p 13.3） in liver cancer and by functional screening for genes affecting cell proliferation in large-scale transfection assays. Its overexpression results in inhibition of cell proliferation in cell culture and tumor growth in nude mice. To understand its transcription regulation, the promoter architecture has been dissected in detail. The major start of transcription was mapped by primer extension to a C residue, 177 nucleotides upstream of the ATG codon. By assessing the promoter activity of a set of linker-scanning mutants of the minimal promoter （-60 to ＋148 region） in a transient transfection assay, we found that the ＋1 to ＋ 40 region is critical to HCCS1 gene transcription, containing binding sites for transcription factors NF-kB （-21 to ＋7 and ＋40 to ＋26）, p53 （＋29 to ＋9） and ETS （＋4 to ＋20 and ＋23 to ＋39）. Biochemical and molecular analyses revealed that the ETS transcription factors ETS-2 and Elf-1 bind to the two ETS sites in situ and contribute significantly to the transcriptionally active state of the HCCS1 gene, while NF-kB, p53 and two other members of the ETS family （ETS-1 and NERF2） appear to play little role. Our observations provide insight into the mechanistic aspects of HCCS1 transcription regulation.展开更多
Pancreatitis is the leading cause of hospitalization in gastroenterology,and no medications are available for treating this disease in current clinical practice.FxR plays an anti-inflammatory role in diverse inflammat...Pancreatitis is the leading cause of hospitalization in gastroenterology,and no medications are available for treating this disease in current clinical practice.FxR plays an anti-inflammatory role in diverse inflammatory diseases,while its function in pancreatitis remains unknown.In this study,we initially observed a marked increase of nuclear FXR in pancreatic tissues of human patients ithpancratis eleting theFXRinpancreati acinar cels FXRicnara/a)ledto moreseverepancreatitis in mousemodels of caerulein-induced acute and chronic pancreatitis,while the FXR agonist GW4064 significantly attenuated pancreatitis in caerulein or arginine-induced acute pancreatitis and caerulein-induced chronic pancreatitis.FXR deletion impaired the viability and stress responses of pancreatic exocrine organoids(PEOs)in vitro.Utilizing RNA-seq and ChIP-seq of PEOs,we identified Osginl as a direct target of FxR in the exocrine pancreas,which was also increasingly expressed in human pancreatitis tissues compared to normal pancreatic tissues.Pancreatic knockdown of Osgin1 by AAV-pan abolished the therapeutic effects of FXR activation on pancreatitis,whereas pancreatic overexpression of Osginl effectively alleviated caerulein-induced pancreatitis.Mechanistically,we found that the FXR-OSGINl axis stimulated autophagic flux in the pancreatic tissues and cell lines,which was considered as the intrinsic mechanisms through which FXR-OSGINI protecting against pancreatitis.Our results highlight the protective role of the FXR-OSGIN1 axis in pancreatitis and provided a new target for the treatment of this disease.展开更多
A biocathode with microbial catalyst in place of a noble metal was successfully developed for hydrogen evolution in a microbial electrolysis cell （MEC）. The strategy for fast biocathode cultivation was demonstrated....A biocathode with microbial catalyst in place of a noble metal was successfully developed for hydrogen evolution in a microbial electrolysis cell （MEC）. The strategy for fast biocathode cultivation was demonstrated. An exoelectrogenic reaction was initially extended with an H2-full atmosphere to enrich Ha-utilizing bacteria in a MEC bioanode. This bioanode was then inversely polarized with an applied voltage in a half-cell to enrich the hydrogen-evolving biocathode. The electrocatalytic hydrogen evolution reaction （HER） kinetics of the biocathode MEC could be enhanced by increasing the bicarbonate buffer concentration from 0.05 mol·L-1 to 0.5 mol· L-1 and/or by decreasing the cathode potential from -0.9 V to - 1.3 V vs. a saturated calomel electrode （SCE）. Within the tested potential region in this study, the HER rate of the biocathode MEC was primarily influenced by the microbial catalytic capability. In addition, increasing bicarbonate concentration enhances the electric migration rate of proton carriers. As a consequence, more mass H＋ can be released to accelerate the biocathode-catalyzed HER rate. A hydrogen production rate of 8.44 m3. m 3. d1 with a current density of 951.6 A. m-3 was obtained using the biocathode MEC under a cathode potential of - 1.3 V vs. SCE and 0.4 mol· L-1 bicarbonate. This study provided information on the optimization of hydrogen production in biocathode MEC and expanded the practical applications thereof.展开更多
Dear Editor,DNA methylation at the 5-position of cytosine(5mC)is a crucial epigenetic mark in regulating biological processes including gene silencing,gene imprinting,and X chromo-some inactivation(Jaenisch and Bird,2...Dear Editor,DNA methylation at the 5-position of cytosine(5mC)is a crucial epigenetic mark in regulating biological processes including gene silencing,gene imprinting,and X chromo-some inactivation(Jaenisch and Bird,2003;Smith and Meissner,2013).Human genome encodes three DNA methyltransferases,DNMT1,DNMT3A and DNMT3B to catalyze 5mC.Although not tightly restricted,DNMT1 is thought to maintain the established pattern of 5mC throughout DNA replication,while DNMT3A and DNMT3B are largely responsible for the de novo establishment of 5mC.It has long been questioned how de novo DNA 5mC patterns are established in different genomic regions and whether histone modifications crosstalk to the process.Until recently,it was reported that through recognition of histone H3K36me3 mark,DNMT3B plays a dominant role in medi-ating DNA 5mC in the genic region undergoing active tran-scription(Baubec et al.,2015;Neri et al,2017).However,5mC occurs at both intergenic and genic regions,while H3K36me3 is largely absent in the intergenic regions,indi-cating that the intergenic 5mC may be mediated through diferent mechanisms.展开更多
Dear Editor,The ongoing COVID-19 pandemic has resulted in over 25.0 million confirmed cases and over 840,000 deaths globally.As the third severe respiratory disease outbreak caused by the coronavirus,COVID-19 has led ...Dear Editor,The ongoing COVID-19 pandemic has resulted in over 25.0 million confirmed cases and over 840,000 deaths globally.As the third severe respiratory disease outbreak caused by the coronavirus,COVID-19 has led to much larger infected populations and coverage of geographic areas than SARS and MERS.Such high prevalence of infection has raised significant concerns about the emergence and spread of escape variants,which may evade human immunity and eventually render candidate vaccines and antibody-based therapeutics ineffective.Indeed,some naturally mutated SARS-CoV or MERS-CoV strains from the sequential outbreaks were reported to resist neutralization by the antibodies isolated during the first outbreak1,2.展开更多
A^(6)-methyladenosine(m^(6)A)is the most abundant internal chemical mark in eukaryotic messenger RNAs(mRNAs),regulating various processes in the life cycle of mRNA including splicing,nuclear export,degradation and tra...A^(6)-methyladenosine(m^(6)A)is the most abundant internal chemical mark in eukaryotic messenger RNAs(mRNAs),regulating various processes in the life cycle of mRNA including splicing,nuclear export,degradation and translation(reviewed in(Shi et al.,2019)).展开更多
Oxidation and reduction of some amino acids are one of the molecular mechanisms for regulating the function of proteins. The oxidation of methionine (Met) to methionine sulfoxide (Met(O)) results in decreasing or loss...Oxidation and reduction of some amino acids are one of the molecular mechanisms for regulating the function of proteins. The oxidation of methionine (Met) to methionine sulfoxide (Met(O)) results in decreasing or loss of the biological activity of related proteins. It was found that peptide methionine sulfoxide reductase (msrA) can reduce Met(O) to Met and therefore restored the biological function of the oxidized proteins. To reveal the methionine oxidation-reduction mechanism in human body, in this study, the cDNA sequence of bovine msrA was used as an information-probe to screen the human EST database. Based on a contig assembled from homologous ESTs, a 1 256-bp human MSRA cDNA was cloned from several human cDNA libraries. The cDNA contains an open reading frame (ORF) of 705 bp in length, which encodes 235 amino acid residues. Homology comparison revealed that human MSRA shares 88% and 61% identities with bovine and Escherichia coli msrA protein respectively. Expression pattern analysis revealed a展开更多
The author would like to add the below information in this correction.A similar study from Chao Lu group was published online on 5 September 2019 in Nature,entitled“The histone mark H3K36me2 recruits DNMT3A and shape...The author would like to add the below information in this correction.A similar study from Chao Lu group was published online on 5 September 2019 in Nature,entitled“The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape”(Weinberg et al.,2019).Although both studies reported the preferential recognition of H3K36me2 by DNMT3A PWWP,ours in addition uncovered a stimulation function by such interaction on the activity of DNMT3A.On the disease connections,we used a NSD2 gain-of-function model which led to the discovery of potential therapeutic implication of DNA inhibitors in the related cancers,while the other study only used NSD1 and DNMT3A loss-of-function models.展开更多
基金grants to Jing De Zhu from the Shanghai Science Foundation （04DZ14006 , 05DZ19318） the National Science Foundation （30450001, 30570850 , 10574134） the National Research Program for Basic Research of China （2004CB518804 , 2002CB713700）.
文摘The hepatocellular carcinoma suppressor 1 （HCCS1） gene was identified by both positional cloning from a predominant region of loss of heterozygosity （17p 13.3） in liver cancer and by functional screening for genes affecting cell proliferation in large-scale transfection assays. Its overexpression results in inhibition of cell proliferation in cell culture and tumor growth in nude mice. To understand its transcription regulation, the promoter architecture has been dissected in detail. The major start of transcription was mapped by primer extension to a C residue, 177 nucleotides upstream of the ATG codon. By assessing the promoter activity of a set of linker-scanning mutants of the minimal promoter （-60 to ＋148 region） in a transient transfection assay, we found that the ＋1 to ＋ 40 region is critical to HCCS1 gene transcription, containing binding sites for transcription factors NF-kB （-21 to ＋7 and ＋40 to ＋26）, p53 （＋29 to ＋9） and ETS （＋4 to ＋20 and ＋23 to ＋39）. Biochemical and molecular analyses revealed that the ETS transcription factors ETS-2 and Elf-1 bind to the two ETS sites in situ and contribute significantly to the transcriptionally active state of the HCCS1 gene, while NF-kB, p53 and two other members of the ETS family （ETS-1 and NERF2） appear to play little role. Our observations provide insight into the mechanistic aspects of HCCS1 transcription regulation.
基金supported by the National Key R&D Program of China(2018YFC2000500/3and2018YFC2000202)the National Natural Science Foundation of China(NSFC no.82070391(N.S.),no.321711175(X.L.),and no.81900791(Z.W.).
文摘Pancreatitis is the leading cause of hospitalization in gastroenterology,and no medications are available for treating this disease in current clinical practice.FxR plays an anti-inflammatory role in diverse inflammatory diseases,while its function in pancreatitis remains unknown.In this study,we initially observed a marked increase of nuclear FXR in pancreatic tissues of human patients ithpancratis eleting theFXRinpancreati acinar cels FXRicnara/a)ledto moreseverepancreatitis in mousemodels of caerulein-induced acute and chronic pancreatitis,while the FXR agonist GW4064 significantly attenuated pancreatitis in caerulein or arginine-induced acute pancreatitis and caerulein-induced chronic pancreatitis.FXR deletion impaired the viability and stress responses of pancreatic exocrine organoids(PEOs)in vitro.Utilizing RNA-seq and ChIP-seq of PEOs,we identified Osginl as a direct target of FxR in the exocrine pancreas,which was also increasingly expressed in human pancreatitis tissues compared to normal pancreatic tissues.Pancreatic knockdown of Osgin1 by AAV-pan abolished the therapeutic effects of FXR activation on pancreatitis,whereas pancreatic overexpression of Osginl effectively alleviated caerulein-induced pancreatitis.Mechanistically,we found that the FXR-OSGINl axis stimulated autophagic flux in the pancreatic tissues and cell lines,which was considered as the intrinsic mechanisms through which FXR-OSGINI protecting against pancreatitis.Our results highlight the protective role of the FXR-OSGIN1 axis in pancreatitis and provided a new target for the treatment of this disease.
基金This work was financial supported by grants from the National Natural Science Foundation of China （Grant Nos. 51108014, 21373022, 21073010, 21003007 and Ul137602）, National Major Research Program （No. 2011CB935700）, Beijing Nova Program （Z1311090004 13008）, Fundamental Research Funds for the Central Universities （YWF- 10-03-021）, Research Fund for the Doctoral Program of Higher Education of China （20111102120045） and Program for New Century Excellent Talents in University.
文摘A biocathode with microbial catalyst in place of a noble metal was successfully developed for hydrogen evolution in a microbial electrolysis cell （MEC）. The strategy for fast biocathode cultivation was demonstrated. An exoelectrogenic reaction was initially extended with an H2-full atmosphere to enrich Ha-utilizing bacteria in a MEC bioanode. This bioanode was then inversely polarized with an applied voltage in a half-cell to enrich the hydrogen-evolving biocathode. The electrocatalytic hydrogen evolution reaction （HER） kinetics of the biocathode MEC could be enhanced by increasing the bicarbonate buffer concentration from 0.05 mol·L-1 to 0.5 mol· L-1 and/or by decreasing the cathode potential from -0.9 V to - 1.3 V vs. a saturated calomel electrode （SCE）. Within the tested potential region in this study, the HER rate of the biocathode MEC was primarily influenced by the microbial catalytic capability. In addition, increasing bicarbonate concentration enhances the electric migration rate of proton carriers. As a consequence, more mass H＋ can be released to accelerate the biocathode-catalyzed HER rate. A hydrogen production rate of 8.44 m3. m 3. d1 with a current density of 951.6 A. m-3 was obtained using the biocathode MEC under a cathode potential of - 1.3 V vs. SCE and 0.4 mol· L-1 bicarbonate. This study provided information on the optimization of hydrogen production in biocathode MEC and expanded the practical applications thereof.
文摘Dear Editor,DNA methylation at the 5-position of cytosine(5mC)is a crucial epigenetic mark in regulating biological processes including gene silencing,gene imprinting,and X chromo-some inactivation(Jaenisch and Bird,2003;Smith and Meissner,2013).Human genome encodes three DNA methyltransferases,DNMT1,DNMT3A and DNMT3B to catalyze 5mC.Although not tightly restricted,DNMT1 is thought to maintain the established pattern of 5mC throughout DNA replication,while DNMT3A and DNMT3B are largely responsible for the de novo establishment of 5mC.It has long been questioned how de novo DNA 5mC patterns are established in different genomic regions and whether histone modifications crosstalk to the process.Until recently,it was reported that through recognition of histone H3K36me3 mark,DNMT3B plays a dominant role in medi-ating DNA 5mC in the genic region undergoing active tran-scription(Baubec et al.,2015;Neri et al,2017).However,5mC occurs at both intergenic and genic regions,while H3K36me3 is largely absent in the intergenic regions,indi-cating that the intergenic 5mC may be mediated through diferent mechanisms.
基金This work was supported by grants from the National Key R&D Program of China(2019YFA0904400)National Natural Science Foundation of China(81822027,81630090)+1 种基金National Megaprojects of China for Major Infectious Diseases(2018ZX10301403,2018ZX10101003)the staff from Core Facility of Microbiology and Parasitology,Shanghai Medical College,Fudan University.
文摘Dear Editor,The ongoing COVID-19 pandemic has resulted in over 25.0 million confirmed cases and over 840,000 deaths globally.As the third severe respiratory disease outbreak caused by the coronavirus,COVID-19 has led to much larger infected populations and coverage of geographic areas than SARS and MERS.Such high prevalence of infection has raised significant concerns about the emergence and spread of escape variants,which may evade human immunity and eventually render candidate vaccines and antibody-based therapeutics ineffective.Indeed,some naturally mutated SARS-CoV or MERS-CoV strains from the sequential outbreaks were reported to resist neutralization by the antibodies isolated during the first outbreak1,2.
基金FL was supported by the National Key Research and Development program of China(2016YFA0101800 and 2018YFA0108700)the national Natural Science Foundation of China(31925010)Shanghai Municipal Science and Technology Major Project(2017SHZDZX01).
文摘A^(6)-methyladenosine(m^(6)A)is the most abundant internal chemical mark in eukaryotic messenger RNAs(mRNAs),regulating various processes in the life cycle of mRNA including splicing,nuclear export,degradation and translation(reviewed in(Shi et al.,2019)).
文摘Oxidation and reduction of some amino acids are one of the molecular mechanisms for regulating the function of proteins. The oxidation of methionine (Met) to methionine sulfoxide (Met(O)) results in decreasing or loss of the biological activity of related proteins. It was found that peptide methionine sulfoxide reductase (msrA) can reduce Met(O) to Met and therefore restored the biological function of the oxidized proteins. To reveal the methionine oxidation-reduction mechanism in human body, in this study, the cDNA sequence of bovine msrA was used as an information-probe to screen the human EST database. Based on a contig assembled from homologous ESTs, a 1 256-bp human MSRA cDNA was cloned from several human cDNA libraries. The cDNA contains an open reading frame (ORF) of 705 bp in length, which encodes 235 amino acid residues. Homology comparison revealed that human MSRA shares 88% and 61% identities with bovine and Escherichia coli msrA protein respectively. Expression pattern analysis revealed a
文摘The author would like to add the below information in this correction.A similar study from Chao Lu group was published online on 5 September 2019 in Nature,entitled“The histone mark H3K36me2 recruits DNMT3A and shapes the intergenic DNA methylation landscape”(Weinberg et al.,2019).Although both studies reported the preferential recognition of H3K36me2 by DNMT3A PWWP,ours in addition uncovered a stimulation function by such interaction on the activity of DNMT3A.On the disease connections,we used a NSD2 gain-of-function model which led to the discovery of potential therapeutic implication of DNA inhibitors in the related cancers,while the other study only used NSD1 and DNMT3A loss-of-function models.
