Background Chinese indigenous pigs are popular with consumers for their juiciness,flavour and meat quality,but they have lower meat production.Insulin-like growth factor 2(IGF2) is a maternally imprinted growth factor...Background Chinese indigenous pigs are popular with consumers for their juiciness,flavour and meat quality,but they have lower meat production.Insulin-like growth factor 2(IGF2) is a maternally imprinted growth factor that promotes skeletal muscle growth by regulating cell proliferation and differentiation.A single nucleotide polymorphism(SNP) within intron 3 of porcine IGF2 disrupts a binding site for the repressor,zinc finger BED-type containing 6(ZBED6),leading to up-regulation of IGF2 and causing major effects on muscle growth,heart size,and backfat thickness.This favorable mutation is common in Western commercial pig populations,but absent in most Chinese indigenous pig breeds.To improve meat production of Chinese indigenous pigs,we used cytosine base editor 3(CBE3)to introduce IGF2 intron3-C3071T mutation into porcine embryonic fibroblasts(PEFs) isolated from a male Liang Guang Small Spotted pig(LGSS),and single-cell clones harboring the desired mutation were selected for somatic cell nuclear transfer(SCNT) to generate the founder line of IGF2^(T/T) pigs.Results We found the heterozygous progeny IGF2^(C/T) pigs exhibited enhanced expression of IGF2,increased lean meat by 18%-36%,enlarged loin muscle area by 3%-17%,improved intramuscular fat(IMF) content by 18%-39%,marbling score by 0.75-1,meat color score by 0.53-1.25,and reduced backfat thickness by 5%-16%.The enhanced accumulation of intramuscular fat in IGF2^(C/T) pigs was identified to be regulated by the PI3K-AKT/AMPK pathway,which activated SREBP1 to promote adipogenesis.Conclusions We demonstrated the introduction of IGF2-intron3-C3071T in Chinese LGSS can improve both meat production and quality,and first identified the regulation of IMF deposition by IGF2 through SREBP1 via the PI3KAKT/AMPK signaling pathways.Our study provides a further understanding of the biological functions of IGF2and an example for improving porcine economic traits through precise base editing.展开更多
New Delhi metallo-β-lactamase 1(NDM-1) can hydrolyze most β-lactam antibiotics, which is the major factor for drug resistance of Gram-negative bacteria. The binding of most reversible inhibitors to NDM-1 is relative...New Delhi metallo-β-lactamase 1(NDM-1) can hydrolyze most β-lactam antibiotics, which is the major factor for drug resistance of Gram-negative bacteria. The binding of most reversible inhibitors to NDM-1 is relatively weak due to the shallow active pocket of NDM-1. Alternatively, irreversible covalent inhibitors can prevent their dissociation from the target, leading to permanent inactivation of the protein.Herein, we report a series of irreversible covalent inhibitors of NDM-1 targeting the conserved Lys211 in the active pocket. Several methods, including mass spectrometry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, fluorescent labeling, and coumarin probe were used to demonstrate that pentafluorophenyl ester formed a covalent bond with Lys211. Moreover, our target inhibitor, in combination with meropenem, achieved an antibacterial effect on drug-resistant bacteria, along with an excellent safety profile. Our new strategy in designing lysine-targeted irreversible covalent NDM-1 inhibitors provides a potential option for the clinical treatment of Gram-negative bacteria.展开更多
Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression w...Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression with patients'poor prognosis.Silencing the expression of ANXA3effectively inhibits the proliferation and metastasis of TNBC,suggesting that ANXA3 can be a promising therapeutic target to treat TNBC.Herein,we report a first-in-class ANXA3-targeted small molecule(R)-SL18,which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells.(R)-SL18 directly bound to ANXA3 and increased its ubiquitination,thereby inducing ANXA3 degradation with moderate family selectivity.Importantly,(R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model.Furthermore,(R)-SL18 could reduce theβ-catenin level,and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells.Collectively,our data suggested that targeting degradation of ANXA3 by(R)-SL18 possesses the potential to treat TNBC.展开更多
Although signifi cant research eff orts have been targeted toward conservation and management of endangered terrestrial fl ora and fauna,attempts have been limited to conserve threatened seaweeds.Silvetia siliquosa is...Although signifi cant research eff orts have been targeted toward conservation and management of endangered terrestrial fl ora and fauna,attempts have been limited to conserve threatened seaweeds.Silvetia siliquosa is an ecologically and commercially vital brown alga that is uniquely distributed in the Yellow-Bohai Sea and along the southwest coast of Korea.A massive decline in its distribution range and biomass from the mid-1990s onward indicates that this species has become endangered.In the present study,we used nuclear internal transcribed spacer and concatenated mitochondrial cytochrome oxidase I subunit+intergenic spacer to estimate the genetic diversity,population connectivity,and degree of genetic diff erentiation of S.siliquosa in China and Korea.The molecular results exhibited strikingly low levels of haplotype/ribotype and nucleotide diversity in S.siliquosa populations,with only three mitochondrial haplotypes and nuclear ribotypes detected in 136 and 143 specimens,respectively.The analysis of molecular variance revealed 85%-95%of genetic variance among populations.Population diff erentiation coeffi cient(F_(ST))and gene fl ow(N_(m))suggested that two populations(JIN and GWA)along the southern coast of Korea are highly divergent from the others,with weak genetic exchange.No signifi cant genetic diff erentiation was observed among populations either in China or along the geographically proximate west coast of Korea.Thus,four independent management units were designated for sustainable management:the LII and RUS populations in China,the YEO and CHA populations along the west coast of Korea,and each of the GWA and JIN populations along the south coast of Korea.We suggest that artifi cial cultivation and transplantation of S.siliquosa are the eff ective approaches for restoration and conservation.展开更多
The present paper calculates 35 industrial sectors similarity matrices for the period of 1997-2008 using China s input-output tables for 1997, 2002 and 2007, and uses these to measure inter-industry technology spillov...The present paper calculates 35 industrial sectors similarity matrices for the period of 1997-2008 using China s input-output tables for 1997, 2002 and 2007, and uses these to measure inter-industry technology spillover to analyze the spillover effects on industrial sectors lahor productivity. The empirical analysis shows that inter-industry technology spillover has a significant positive effect on the labor productivity of each industry. The elasticity of productivity effects of inter-industry technology spillover is not only larger than that of direct R＆D input, but also increases over time. We group the industries into four major categories and find that the inter-industry technology spillover effect within the categories is, on average, greater than that between the four categories, indicating that technology spillover occurs more easily between similar industries. This research shows that the interindustry technology spillover effect in China has begun to increase, and the government should take advantage of this effect.展开更多
基金supported by the National Natural Science Foundation of China (3207269732030102)+2 种基金CARS-PIG-35R&D Programmes of Guangdong Province (2018B020203003)Laboratory of Lingnan Modern Agriculture Project (NZ2021006)。
文摘Background Chinese indigenous pigs are popular with consumers for their juiciness,flavour and meat quality,but they have lower meat production.Insulin-like growth factor 2(IGF2) is a maternally imprinted growth factor that promotes skeletal muscle growth by regulating cell proliferation and differentiation.A single nucleotide polymorphism(SNP) within intron 3 of porcine IGF2 disrupts a binding site for the repressor,zinc finger BED-type containing 6(ZBED6),leading to up-regulation of IGF2 and causing major effects on muscle growth,heart size,and backfat thickness.This favorable mutation is common in Western commercial pig populations,but absent in most Chinese indigenous pig breeds.To improve meat production of Chinese indigenous pigs,we used cytosine base editor 3(CBE3)to introduce IGF2 intron3-C3071T mutation into porcine embryonic fibroblasts(PEFs) isolated from a male Liang Guang Small Spotted pig(LGSS),and single-cell clones harboring the desired mutation were selected for somatic cell nuclear transfer(SCNT) to generate the founder line of IGF2^(T/T) pigs.Results We found the heterozygous progeny IGF2^(C/T) pigs exhibited enhanced expression of IGF2,increased lean meat by 18%-36%,enlarged loin muscle area by 3%-17%,improved intramuscular fat(IMF) content by 18%-39%,marbling score by 0.75-1,meat color score by 0.53-1.25,and reduced backfat thickness by 5%-16%.The enhanced accumulation of intramuscular fat in IGF2^(C/T) pigs was identified to be regulated by the PI3K-AKT/AMPK pathway,which activated SREBP1 to promote adipogenesis.Conclusions We demonstrated the introduction of IGF2-intron3-C3071T in Chinese LGSS can improve both meat production and quality,and first identified the regulation of IMF deposition by IGF2 through SREBP1 via the PI3KAKT/AMPK signaling pathways.Our study provides a further understanding of the biological functions of IGF2and an example for improving porcine economic traits through precise base editing.
基金funded by the National Natural Science Foundation of China (No. 82073688 to X. Sun and No. 82103971 to Y. Liang)Science and Technology Commission of Shanghai Municipality (No. 21S11907300 to X. Sun)Shanghai Science and Technology Development Fund from Central Leading Local Government (No. YDZX20223100001004 to X. Sun)。
文摘New Delhi metallo-β-lactamase 1(NDM-1) can hydrolyze most β-lactam antibiotics, which is the major factor for drug resistance of Gram-negative bacteria. The binding of most reversible inhibitors to NDM-1 is relatively weak due to the shallow active pocket of NDM-1. Alternatively, irreversible covalent inhibitors can prevent their dissociation from the target, leading to permanent inactivation of the protein.Herein, we report a series of irreversible covalent inhibitors of NDM-1 targeting the conserved Lys211 in the active pocket. Several methods, including mass spectrometry, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, fluorescent labeling, and coumarin probe were used to demonstrate that pentafluorophenyl ester formed a covalent bond with Lys211. Moreover, our target inhibitor, in combination with meropenem, achieved an antibacterial effect on drug-resistant bacteria, along with an excellent safety profile. Our new strategy in designing lysine-targeted irreversible covalent NDM-1 inhibitors provides a potential option for the clinical treatment of Gram-negative bacteria.
基金supported by the National Natural Science Foundation of China(Nos.82073688,82103971 and 81930075)Shanghai Science and Technology Development Fund from Central Leading Local Government(No.YDZX20223100001004,China)+1 种基金Science and Technology Commission of Shanghai Municipality(No.21S11907300,China)Program of Shanghai Academic/Technology Research Leader(No.20XD1400700,China)。
文摘Triple-negative breast cancer(TNBC)is a nasty disease with extremely high malignancy and poor prognosis.Annexin A3(ANXA3)is a potential prognosis biomarker,displaying an excellent correlation of ANXA3 overexpression with patients'poor prognosis.Silencing the expression of ANXA3effectively inhibits the proliferation and metastasis of TNBC,suggesting that ANXA3 can be a promising therapeutic target to treat TNBC.Herein,we report a first-in-class ANXA3-targeted small molecule(R)-SL18,which demonstrated excellent anti-proliferative and anti-invasive activities to TNBC cells.(R)-SL18 directly bound to ANXA3 and increased its ubiquitination,thereby inducing ANXA3 degradation with moderate family selectivity.Importantly,(R)-SL18 showed a safe and effective therapeutic potency in a high ANXA3-expressing TNBC patient-derived xenograft model.Furthermore,(R)-SL18 could reduce theβ-catenin level,and accordingly inhibit the Wnt/β-catenin signaling pathway in TNBC cells.Collectively,our data suggested that targeting degradation of ANXA3 by(R)-SL18 possesses the potential to treat TNBC.
基金Supported by the National Natural Science Foundation of China(Nos.31971395,41761144057)。
文摘Although signifi cant research eff orts have been targeted toward conservation and management of endangered terrestrial fl ora and fauna,attempts have been limited to conserve threatened seaweeds.Silvetia siliquosa is an ecologically and commercially vital brown alga that is uniquely distributed in the Yellow-Bohai Sea and along the southwest coast of Korea.A massive decline in its distribution range and biomass from the mid-1990s onward indicates that this species has become endangered.In the present study,we used nuclear internal transcribed spacer and concatenated mitochondrial cytochrome oxidase I subunit+intergenic spacer to estimate the genetic diversity,population connectivity,and degree of genetic diff erentiation of S.siliquosa in China and Korea.The molecular results exhibited strikingly low levels of haplotype/ribotype and nucleotide diversity in S.siliquosa populations,with only three mitochondrial haplotypes and nuclear ribotypes detected in 136 and 143 specimens,respectively.The analysis of molecular variance revealed 85%-95%of genetic variance among populations.Population diff erentiation coeffi cient(F_(ST))and gene fl ow(N_(m))suggested that two populations(JIN and GWA)along the southern coast of Korea are highly divergent from the others,with weak genetic exchange.No signifi cant genetic diff erentiation was observed among populations either in China or along the geographically proximate west coast of Korea.Thus,four independent management units were designated for sustainable management:the LII and RUS populations in China,the YEO and CHA populations along the west coast of Korea,and each of the GWA and JIN populations along the south coast of Korea.We suggest that artifi cial cultivation and transplantation of S.siliquosa are the eff ective approaches for restoration and conservation.
基金supported by the National Natural Science Foundation of China (Grant No.70873071)the National Social Science Foundation of China(Grant No.08AJY001)
文摘The present paper calculates 35 industrial sectors similarity matrices for the period of 1997-2008 using China s input-output tables for 1997, 2002 and 2007, and uses these to measure inter-industry technology spillover to analyze the spillover effects on industrial sectors lahor productivity. The empirical analysis shows that inter-industry technology spillover has a significant positive effect on the labor productivity of each industry. The elasticity of productivity effects of inter-industry technology spillover is not only larger than that of direct R＆D input, but also increases over time. We group the industries into four major categories and find that the inter-industry technology spillover effect within the categories is, on average, greater than that between the four categories, indicating that technology spillover occurs more easily between similar industries. This research shows that the interindustry technology spillover effect in China has begun to increase, and the government should take advantage of this effect.
