Wuhan Tianhe International Airport (WUH) was suspended to contain the spread of COVID-19,while Shanghai Hongqiao International Airport (SHA) saw a tremendousflight reduction.Closure of a major international airport is...Wuhan Tianhe International Airport (WUH) was suspended to contain the spread of COVID-19,while Shanghai Hongqiao International Airport (SHA) saw a tremendousflight reduction.Closure of a major international airport is extremely rare and thus represents a unique opportunity to straightforwardly observe the impact of airport emissions on local air quality.In this study,a series of statistical tools were applied to analyze the variations in air pollutant levels in the vicinity of WUH and SHA.The results of bivariate polar plots show that airport SHA and WUH are a major source of nitrogen oxides.NOx,NO_(2)and NO diminished by 55.8%,44.1%,76.9%,and 40.4%,33.3% and 59.4% during the COVID-19 lockdown compared to those in the same period of 2018 and 2019,under a reduction in aircraft activities by 58.6%and61.4%.The concentration of NO_(2),SO_(2)and PM_(2.5)decreased by 77.3%,8.2%,29.5%,right after the closure of airport WUH on 23 January 2020.The average concentrations of NO,NO_(2)and NOxscatter plots at downwind of SHA after the lockdown were 78.0%,47.9%,57.4%and 62.3%,34.8%,41.8%lower than those during the same period in 2018 and 2019.However,a significant increase in O_(3)levels by 50.0% and 25.9%at WUH and SHA was observed,respectively.These results evidently show decreased nitrogen oxides concentrations in the airport vicinity due to reduced aircraft activities,while amplified O_(3)pollution due to a lower titration by NO under strong reduction in NOxemissions.展开更多
In the spacer acquisition stage of CRISPR-Cas immunity,spacer orientation and protospacer adjacent motif(PAM)removal are two prerequisites for functional spacer integration.Cas4 has been implicated in both processing ...In the spacer acquisition stage of CRISPR-Cas immunity,spacer orientation and protospacer adjacent motif(PAM)removal are two prerequisites for functional spacer integration.Cas4 has been implicated in both processing the prespacer and determining the spacer orientation.In Cas4-lacking systems,host 3′–5′DnaQ family exonucleases were recently reported to play a Cas4-like role.However,the molecular details of DnaQ functions remain elusive.Here,we characterized the spacer acquisition of the adaptation module of the Streptococcus thermophilus type I-E system,in which a DnaQ domain naturally fuses with Cas2.We presented X-ray crystal structures and cryo-electron microscopy structures of this adaptation module.Our biochemical data showed that DnaQ trimmed PAM-containing and PAM-deficient overhangs with different efficiencies.Based on these results,we proposed a time-dependent model for DnaQ-mediated spacer acquisition to elucidate PAM removal and spacer orientation determination in Cas4-lacking CRISPR-Cas systems.展开更多
Large scale genomic aberrations including duplication,deletion,translocation,and other structural changes are the cause of a subtype of hereditary genetic disorders and contribute to onset or progress of cancer.The cu...Large scale genomic aberrations including duplication,deletion,translocation,and other structural changes are the cause of a subtype of hereditary genetic disorders and contribute to onset or progress of cancer.The current prime editor,PE2,consisting of Cas9-nickase and reverse transcriptase enables efficient editing of genomic deletion and insertion,however,at small scale.Here,we designed a novel prime editor by fusing reverse transcriptase(RT)to nuclease wild-type Cas9(WT-PE)to edit large genomic fragment.展开更多
Doublecortin-like kinase 1(DCLK1)is upregulated in many tumors and is a marker for tumor stem cells.Accumulating evidence suggests DCLK1 constitutes a promising drug target for cancer therapy.However,the regulation of...Doublecortin-like kinase 1(DCLK1)is upregulated in many tumors and is a marker for tumor stem cells.Accumulating evidence suggests DCLK1 constitutes a promising drug target for cancer therapy.However,the regulation of DCLK1 kinase activity is poorly understood,particularly the function of its autoinhibitory domain(AID),and,moreover,no physiological activators of DCLK1 have presently been reported.Here we determined the first DCLK1 kinase structure in the autoinhibited state and identified the neuronal calcium sensor HPCAL1 as an activator of DCLK1.The C-terminal AID functions to block the ATP-binding site and is competitive with ATP.HPCAL1 binds directly to the AID in a Ca^(2+)-dependent manner,which releases the autoinhibition.We also analyzed cancer-associated mutations occurring in the AID and elucidate how these mutations disrupt DCLK1 autoinhibition to elicit kinase activity upregulation.Our results present a molecular mechanism for autoinhibition and activation of DCLK1 kinase activity and provide insights into DCLK1-associated tumorigenesis.展开更多
基金supported by the Shanghai Municipal Bureau of Ecology and Environment (Environmental Research Project [2017]17 and [2018]10)the Institute of Urban Governance, Shanghai Jiao Tong University (Key Special Project of China) No. SJTU-2019UGBD-01)。
文摘Wuhan Tianhe International Airport (WUH) was suspended to contain the spread of COVID-19,while Shanghai Hongqiao International Airport (SHA) saw a tremendousflight reduction.Closure of a major international airport is extremely rare and thus represents a unique opportunity to straightforwardly observe the impact of airport emissions on local air quality.In this study,a series of statistical tools were applied to analyze the variations in air pollutant levels in the vicinity of WUH and SHA.The results of bivariate polar plots show that airport SHA and WUH are a major source of nitrogen oxides.NOx,NO_(2)and NO diminished by 55.8%,44.1%,76.9%,and 40.4%,33.3% and 59.4% during the COVID-19 lockdown compared to those in the same period of 2018 and 2019,under a reduction in aircraft activities by 58.6%and61.4%.The concentration of NO_(2),SO_(2)and PM_(2.5)decreased by 77.3%,8.2%,29.5%,right after the closure of airport WUH on 23 January 2020.The average concentrations of NO,NO_(2)and NOxscatter plots at downwind of SHA after the lockdown were 78.0%,47.9%,57.4%and 62.3%,34.8%,41.8%lower than those during the same period in 2018 and 2019.However,a significant increase in O_(3)levels by 50.0% and 25.9%at WUH and SHA was observed,respectively.These results evidently show decreased nitrogen oxides concentrations in the airport vicinity due to reduced aircraft activities,while amplified O_(3)pollution due to a lower titration by NO under strong reduction in NOxemissions.
基金National Natural Science Foundation of China(32270761,31741027,81672722,32222040 and 32070049)Ministry of Science and Technology(MoST)of China(2022YFC2303700 and 2021YFA301900)China Postdoctoral Science Foundation(2022M712272).
文摘In the spacer acquisition stage of CRISPR-Cas immunity,spacer orientation and protospacer adjacent motif(PAM)removal are two prerequisites for functional spacer integration.Cas4 has been implicated in both processing the prespacer and determining the spacer orientation.In Cas4-lacking systems,host 3′–5′DnaQ family exonucleases were recently reported to play a Cas4-like role.However,the molecular details of DnaQ functions remain elusive.Here,we characterized the spacer acquisition of the adaptation module of the Streptococcus thermophilus type I-E system,in which a DnaQ domain naturally fuses with Cas2.We presented X-ray crystal structures and cryo-electron microscopy structures of this adaptation module.Our biochemical data showed that DnaQ trimmed PAM-containing and PAM-deficient overhangs with different efficiencies.Based on these results,we proposed a time-dependent model for DnaQ-mediated spacer acquisition to elucidate PAM removal and spacer orientation determination in Cas4-lacking CRISPR-Cas systems.
基金We thank Yang Yang for providing python script for HTS data analysis.This work was supported by National Natural Science Foundation of China.No.U19A2002,No.81771220 and No.81974238.
文摘Large scale genomic aberrations including duplication,deletion,translocation,and other structural changes are the cause of a subtype of hereditary genetic disorders and contribute to onset or progress of cancer.The current prime editor,PE2,consisting of Cas9-nickase and reverse transcriptase enables efficient editing of genomic deletion and insertion,however,at small scale.Here,we designed a novel prime editor by fusing reverse transcriptase(RT)to nuclease wild-type Cas9(WT-PE)to edit large genomic fragment.
基金Financial support for this work was provided by the National Natural Science Foundation of China(31741027,82103226,81672722,and 81501368)Natural Science Foundation of Henan Province(212300410243).
文摘Doublecortin-like kinase 1(DCLK1)is upregulated in many tumors and is a marker for tumor stem cells.Accumulating evidence suggests DCLK1 constitutes a promising drug target for cancer therapy.However,the regulation of DCLK1 kinase activity is poorly understood,particularly the function of its autoinhibitory domain(AID),and,moreover,no physiological activators of DCLK1 have presently been reported.Here we determined the first DCLK1 kinase structure in the autoinhibited state and identified the neuronal calcium sensor HPCAL1 as an activator of DCLK1.The C-terminal AID functions to block the ATP-binding site and is competitive with ATP.HPCAL1 binds directly to the AID in a Ca^(2+)-dependent manner,which releases the autoinhibition.We also analyzed cancer-associated mutations occurring in the AID and elucidate how these mutations disrupt DCLK1 autoinhibition to elicit kinase activity upregulation.Our results present a molecular mechanism for autoinhibition and activation of DCLK1 kinase activity and provide insights into DCLK1-associated tumorigenesis.