Waardenburg syndrome typeⅡ（WS2） is associated with syndromic deafness.A subset of WS2,WS2A,accounting for approximately 15%of patients,is attributed to mutations in the microphthalmia-associated transcription facto...Waardenburg syndrome typeⅡ（WS2） is associated with syndromic deafness.A subset of WS2,WS2A,accounting for approximately 15%of patients,is attributed to mutations in the microphthalmia-associated transcription factor（MITF） gene.We examined the genetic basis of WS2 in a large Chinese family.All 9 exons of the MITF gene,the single coding exon（exon 2） of the most common hereditary deafness gene GJB2 and the mitochondrial DNA（mtDNA） 12S rRNA were sequenced.A novel heterozygous mutation c.[742_743delAAinsT;746_747delCA]in exon 8 of the MITF gene co-segregates with WS2 in the family.The MITF mutation results in a premature termination codon and a truncated MITF protein with only 247 of the 419 wild type amino acids.The deaf proband had this MITF gene heterozygous mutation as well as a c.[109G〉A]＋ [235delC]compound heterozygous pathogenic mutation in the GJB2 gene.No pathogenic mutation was found in mtDNA 12S rRNA in this family.Thus,a novel compound heterozygous mutation,c.[742_743delAAinsT;746_747delCA]in MITF exon 8 was the key genetic reason for WS2 in this family,and a digenic effect of MITF and GJB2 genes may contribute to deafness of the proband.展开更多
In the organizational setting of marine engineering,a significant number of information security incidents have been arised from the employees’failure to comply with the information security policies(ISPs).This may b...In the organizational setting of marine engineering,a significant number of information security incidents have been arised from the employees’failure to comply with the information security policies(ISPs).This may be treated as a principal-agent problem with moral hazard between the employer and the employee for the practical compliance effort of an employee is not observable without high cost-.On the other hand,according to the deterrence theory,the employer and the employee are inherently self-interested beings.It is worth examining to what extent the employee is self-interested in the marine ISPs compliance context.Moreover,it is important to clarify the proper degree of severity of punishment in terms of the deterrent effect.In this study,a marine ISPs compliance game model has been proposed to evaluate the deterrence effect of punishment on the non-compliance behavior of employee individuals.It is found that in a non-punishment contract,the employee will decline to comply with the marine ISPs;but in a punishment contract,appropriate punishment will lead her to select the marine ISPs compliance effort level expected by the employer,and cause no potential backfire effect.展开更多
Objective:Angiogenesis plays a vital role in tumor growth and metastasis.Here,we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A(VEGFA)at the transcriptional level...Objective:Angiogenesis plays a vital role in tumor growth and metastasis.Here,we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A(VEGFA)at the transcriptional level to treat triple-negative breast cancer(TNBC).Methods:We used a cell-based seryl tRNA synthetase(SerRS)promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS,a potent transcriptional repressor of VEGFA.The levels of SerRS and VEGFA were examined by quantitative RT-PCR(qRT-PCR),western blotting,and/or ELISAs in TNBC cells after candidate molecule administration.Zebrafish,the Matrigel plug angiogenesis assay in mice,the TNBC allograft,and xenograft mouse models were used to evaluate thein vivoanti-angiogenic and anti-cancer activities.Furthermore,the potential direct targets of the candidates were identified by proteomics and biochemical studies.Results:We found the most active compound was 3-(4-methoxyphenyl)quinolin-4(1H)-one(MEQ),an isoflavone derivative.In TNBC cells,MEQ treatment resulted in increased SerRS mRNA(P<0.001)and protein levels and downregulated VEGFA production.Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ.MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice,resulting in inhibited tumor growth and prolonged overall survival(P<0.05).Finally,we found that MEQ regulated SerRS transcription by interacting with MTA2(Metastasis Associated 1 Family Member 2).Conclusions:Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target,and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.展开更多
基金supported by the grants from the National Basic Research Program of China(Nos.2011CB504500, 2011CB504506 and 2010CB945503)the National Basic Research Program of China(No.2011504502)+1 种基金the Shanghai Municipal Commission of Science and Technology Program (No.09DJ140061)the National Natural Science Foundation of China(No.81070793)
文摘Waardenburg syndrome typeⅡ（WS2） is associated with syndromic deafness.A subset of WS2,WS2A,accounting for approximately 15%of patients,is attributed to mutations in the microphthalmia-associated transcription factor（MITF） gene.We examined the genetic basis of WS2 in a large Chinese family.All 9 exons of the MITF gene,the single coding exon（exon 2） of the most common hereditary deafness gene GJB2 and the mitochondrial DNA（mtDNA） 12S rRNA were sequenced.A novel heterozygous mutation c.[742_743delAAinsT;746_747delCA]in exon 8 of the MITF gene co-segregates with WS2 in the family.The MITF mutation results in a premature termination codon and a truncated MITF protein with only 247 of the 419 wild type amino acids.The deaf proband had this MITF gene heterozygous mutation as well as a c.[109G〉A]＋ [235delC]compound heterozygous pathogenic mutation in the GJB2 gene.No pathogenic mutation was found in mtDNA 12S rRNA in this family.Thus,a novel compound heterozygous mutation,c.[742_743delAAinsT;746_747delCA]in MITF exon 8 was the key genetic reason for WS2 in this family,and a digenic effect of MITF and GJB2 genes may contribute to deafness of the proband.
基金funded in part by the National Natural Science Foundation of China (No.70972058,No.71272092 and No.71431002)。
文摘In the organizational setting of marine engineering,a significant number of information security incidents have been arised from the employees’failure to comply with the information security policies(ISPs).This may be treated as a principal-agent problem with moral hazard between the employer and the employee for the practical compliance effort of an employee is not observable without high cost-.On the other hand,according to the deterrence theory,the employer and the employee are inherently self-interested beings.It is worth examining to what extent the employee is self-interested in the marine ISPs compliance context.Moreover,it is important to clarify the proper degree of severity of punishment in terms of the deterrent effect.In this study,a marine ISPs compliance game model has been proposed to evaluate the deterrence effect of punishment on the non-compliance behavior of employee individuals.It is found that in a non-punishment contract,the employee will decline to comply with the marine ISPs;but in a punishment contract,appropriate punishment will lead her to select the marine ISPs compliance effort level expected by the employer,and cause no potential backfire effect.
基金This work was supported by grants from the National Natural Science Foundation of China(Grant Nos.81772974,81972882,and 81874297)the Bilateral Inter-Governmental S&T Cooperation Project from Ministry of Science and Technology of China(Grant No.2018YFE0114300)+2 种基金the 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University.We thank Dr.Scott McKercher(The Scripps Research Institute,La Jolla,CA,USA)Dr.Phillip Bryant(Childrens Hospital of Philadelphia,PA,USA)Dr.Cameron R.McKay(Nankai University School of Medicine,Tianjin,China)for revising the manuscript.
文摘Objective:Angiogenesis plays a vital role in tumor growth and metastasis.Here,we aimed to find novel efficient antiangiogenic molecules targeting vascular endothelial growth factor A(VEGFA)at the transcriptional level to treat triple-negative breast cancer(TNBC).Methods:We used a cell-based seryl tRNA synthetase(SerRS)promoter-driven dual-luciferase reporter system to screen an in-house library of 384 naturally occurring small molecules and their derivatives to find candidate molecules that could upregulate the expression of SerRS,a potent transcriptional repressor of VEGFA.The levels of SerRS and VEGFA were examined by quantitative RT-PCR(qRT-PCR),western blotting,and/or ELISAs in TNBC cells after candidate molecule administration.Zebrafish,the Matrigel plug angiogenesis assay in mice,the TNBC allograft,and xenograft mouse models were used to evaluate thein vivoanti-angiogenic and anti-cancer activities.Furthermore,the potential direct targets of the candidates were identified by proteomics and biochemical studies.Results:We found the most active compound was 3-(4-methoxyphenyl)quinolin-4(1H)-one(MEQ),an isoflavone derivative.In TNBC cells,MEQ treatment resulted in increased SerRS mRNA(P<0.001)and protein levels and downregulated VEGFA production.Both the vascular development of zebrafish and Matrigel plug angiogenesis in mice were inhibited by MEQ.MEQ also suppressed the angiogenesis in TNBC allografts and xenografts in mice,resulting in inhibited tumor growth and prolonged overall survival(P<0.05).Finally,we found that MEQ regulated SerRS transcription by interacting with MTA2(Metastasis Associated 1 Family Member 2).Conclusions:Our findings suggested that the MTA2/SerRS/VEGFA axis is a drug-treatable anti-angiogenic target,and MEQ is a promising anti-tumor molecule that merits further investigation for clinical applications.
