Background: Cervical insufficiency is one of the major causes of preterm birth among pregnant women that leads to severe mortality and morbidity issues among newborns. Prophylactic cervical cerclage is a surgical proc...Background: Cervical insufficiency is one of the major causes of preterm birth among pregnant women that leads to severe mortality and morbidity issues among newborns. Prophylactic cervical cerclage is a surgical procedure performed between 11 and 14 weeks of gestation upon diagnosis of cervix insufficiency among pregnant women. Aims & Objectives: In this study, we aimed to evaluate the effectiveness of prophylactic cervical cerclage in comparison to other interventions to treat cervical insufficiency among pregnant women using a meta-analysis approach. Methods: We searched the three databases (Coachrane Library, PubMed, and MEDLINE) that were used for articles related to research aims by using MeSH keywords. The timeline of research was set from January 2015 to January 2024. The methodological quality assessment of included studies was performed by the Risk of Bias in Non-randomized Studies—of Interventions (ROBINS-I). A recent meta-analysis was conducted by using Review Manager 5.4.0 software. Results: About 441 research articles were extracted from three electronic databases and only 125 articles were assessed for eligibility criteria. Finally, 8 studies were included in the analysis for a recent meta-analysis. Six out of eight included retrospective or pilot studies were graded as having a moderate risk of bias, and two studies had low risk on the basis of owning bias. About 1008 pregnant women with cervical insufficiency were analyzed in a recent meta-analysis. By pooled analysis, it was evaluated that significant difference found in prolongation of delivery weeks (Mean difference = 1.05;Cl: 0.81 to 1.29: p > 0.00001), number of deliveries > 37 weeks (OR = 0.59;Cl: 0.19 to 1.84: p > 0.006), and preterm birth (OR = 0.73;Cl: 0.42 to 1.28: p > 0.50) among pregnant women receiving prophylactic cervical cerclage as compared to other treatment strategies. Conclusion: Recent meta-analysis suggested the prophylactic cervical cerclage reduces the rates of preterm birth, abortion rates, number of deliveries > 37 weeks, and other complications as compared to the other cervical cerclage types and conservative treatments.展开更多
This paper considers Stokes and Newton iterations to solve stationary Navier- Stokes equations based on the finite element discretization. We obtain new sufficient conditions of stability and convergence for the two i...This paper considers Stokes and Newton iterations to solve stationary Navier- Stokes equations based on the finite element discretization. We obtain new sufficient conditions of stability and convergence for the two iterations. Specifically, when 0 〈 σ =N｜｜f｜｜-1/v2≤1/√2＋1 , the Stokes iteration is stable and convergent, where N is defined in the paper. When 0 〈 σ ≤5/11, the Newton iteration is stable and convergent. This work gives a more accurate admissible range of data for stability and convergence of the two schemes, which improves the previous results. A numerical test is given to verify the theory.展开更多
By combination of iteration methods with the partition of unity method(PUM),some finite element parallel algorithms for the stationary incompressible magnetohydrodynamics(MHD)with different physical parameters are pre...By combination of iteration methods with the partition of unity method(PUM),some finite element parallel algorithms for the stationary incompressible magnetohydrodynamics(MHD)with different physical parameters are presented and analyzed.These algorithms are highly efficient.At first,a global solution is obtained on a coarse grid for all approaches by one of the iteration methods.By parallelized residual schemes,local corrected solutions are calculated on finer meshes with overlapping sub-domains.The subdomains can be achieved flexibly by a class of PUM.The proposed algorithm is proved to be uniformly stable and convergent.Finally,one numerical example is presented to confirm the theoretical findings.展开更多
The emerging of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused COVID-19 pandemic.The first case of COVID-19 was reported at early December in 2019 in Wuhan City,China.To examine specific antibodies ...The emerging of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused COVID-19 pandemic.The first case of COVID-19 was reported at early December in 2019 in Wuhan City,China.To examine specific antibodies against SARS-CoV-2 in biological samples before December 2019 would give clues when the epidemic of SARS-CoV-2 might start to circulate in populations.We obtained all 88,517 plasmas from 76,844 blood donors in Wuhan between 1 September and 31 December 2019.We first evaluated the pan-immunoglobin(pan-Ig)against SARS-CoV-2 in 43,850 samples from 32,484 blood donors with suitable sample quality and enough volume.Two hundred and sixty-four samples from 213 donors were pan-Ig reactive,then further tested IgG and IgM,and validated by neutralizing antibodies against SARS-CoV-2.Two hundred and thirteen samples(from 175 donors)were only pan-Ig reactive,8(from 4 donors)were pan-Ig and IgG reactive,and 43(from 34 donors)were pan-Ig and IgM reactive.Microneutralization assay showed all negative results.In addition,213 screened reactive donors were analyzed and did not show obviously temporal or regional tendency,but the distribution of age showed a difference compared with all tested donors.Then we reviewed SARS-CoV-2 antibody results from these donors who donated several times from September 2019 to June 2020,partly tested in a previous published study,no one was found a significant increase in S/CO of antibodies against SARS-CoV-2.Our findings showed no SARS-CoV-2-specific antibodies existing among blood donors in Wuhan,China before 2020,indicating no evidence of transmission of COVID-19 before December 2019 in Wuhan,China.展开更多
The coronavirus disease 2019(COVID-19)pandemic has devastated global health.Identifying key host factors essential for SARS-CoV-2 RNA replication is expected to unravel cellular targets for the development of broad-sp...The coronavirus disease 2019(COVID-19)pandemic has devastated global health.Identifying key host factors essential for SARS-CoV-2 RNA replication is expected to unravel cellular targets for the development of broad-spectrum antiviral drugs which have been quested for the preparedness of future viral outbreaks.Here,we have identified host proteins that associate with nonstructural protein 12(nsp12),the RNA-dependent RNA polymerase(RdRp)of SARS-CoV-2 using a mass spectrometry(MS)-based proteomic approach.Among the candidate factors,CDK2(Cyclin-dependent kinase 2),a member of cyclin-dependent kinases,interacts with nsp12 and causes its phosphorylation at T20,thus facilitating the assembly of the RdRp complex consisting of nsp12,nsp7 and nsp8 and promoting efficient synthesis of viral RNA.The crucial role of CDK2 in viral RdRp function is further supported by our observation that CDK2 inhibitors potently impair viral RNA synthesis and SARS-CoV-2 infection.Taken together,we have discovered CDK2 as a key host factor of SARS-CoV-2 RdRp complex,thus serving a promising target for the development of SARS-CoV-2 RdRp inhibitors.展开更多
Growth inhibition and cold-acclimation strategies help plants withstand cold stress,which adversely affects growth and survival.PHYTOCHROME B(phyB)regulates plant growth through perceiving both light and ambient tempe...Growth inhibition and cold-acclimation strategies help plants withstand cold stress,which adversely affects growth and survival.PHYTOCHROME B(phyB)regulates plant growth through perceiving both light and ambient temperature signals.However,the mechanism by which phyB mediates the plant response to cold stress remains elusive.Here,we show that the key transcription factors mediating cold acclimation,C-REPEAT BINDING FACTORs(CBFs),interact with PHYTOCHROME-INTERACTING FACTOR 3(PIF3)under cold stress,thus attenuating the mutually assured destruction of PIF3–phyB.Cold-stabilized phyB acts downstream of CBFs to positively regulate freezing tolerance by modulating the expression of stress-responsive and growth-related genes.Consistent with this,phyB mutants exhibited a freezing-sensitive phenotype,whereas phyB-overexpression transgenic plants displayed enhanced freezing tolerance.Further analysis showed that the PIF1,PIF4,and PIF5 proteins,all of which negatively regulate plant freezing tolerance,were destabilized by cold stress in a phytochrome-dependent manner.Collectively,our study reveals that CBFs–PIF3–phyB serves as an important regulatory module for modulating plant response to cold stress.展开更多
Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2) has become one major threat to human population health.The RNA-dependent RNA polymerase(RdRp) presents an ideal target of antivirals,whereas nucleoside analo...Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2) has become one major threat to human population health.The RNA-dependent RNA polymerase(RdRp) presents an ideal target of antivirals,whereas nucleoside analogs inhibitor is hindered by the proofreading activity of coronavirus.Herein,we report that corilagin(RAI-S-37) as a non-nucleoside inhibitor of SARS-CoV-2 RdRp,binds directly to RdRp,effectively inhibits the polymerase activity in both cell-free and cell-based assays,fully resists the proofreading activity and potently inhibits SARS-CoV-2 infection with a low 50% effective concentration(EC50) value of 0.13 μmol/L.Computation modeling predicts that RAI-S-37 lands at the palm domain of RdRp and prevents conformational changes required for nucleotide incorporation by RdRp.In addition,combination of RAI-S-37 with remdesivir exhibits additive activity against antiSARS-CoV-2 RdRp.Together with the current data available on the safety and pharmacokinetics of corilagin as a medicinal herbal agent,these results demonstrate the potential of being developed into one of the much-needed SARS-CoV-2 therapeutics.展开更多
SARS-CoV-2 is the pathogenic agent of COVID-19,which has evolved into a global pandemic.Compared with some other respiratory RNA viruses,SARS-CoV-2 is a poor inducer of type Ⅰ interferon(IFN).Here,we report that SARS...SARS-CoV-2 is the pathogenic agent of COVID-19,which has evolved into a global pandemic.Compared with some other respiratory RNA viruses,SARS-CoV-2 is a poor inducer of type Ⅰ interferon(IFN).Here,we report that SARS-CoV-2 nsp12,the viral RNA-dependent RNA polymerase(RdRp),suppresses host antiviral responses.SARS-CoV-2 nsp12 attenuated Sendai virus(SeV)-or poly(I:C)-induced IFN-β promoter activation in a dose-dependent manner.It also inhibited IFN promoter activation triggered by RIG-I,MDA5,MAVS,and IRF3 overexpression.Nsp12 did not impair IRF3 phosphorylation but suppressed the nuclear translocation of IRF3.Mutational analyses suggested that this suppression was not dependent on the polymerase activity of nsp12.Given these findings,our study reveals that SARS-CoV-2 RdRp can antagonize host antiviral innate immunity and thus provides insights into viral pathogenesis.展开更多
PHYTOCHROME-INTERACTING FACTORS(PIFs)are a group of basic helix-loop-helix transcription factors that can physically interact with photoreceptors,including phytochromes and cryptochromes.It was previously demonstrated...PHYTOCHROME-INTERACTING FACTORS(PIFs)are a group of basic helix-loop-helix transcription factors that can physically interact with photoreceptors,including phytochromes and cryptochromes.It was previously demonstrated that PIFs accumulated in darkness and repressed seedling photomorphogenesis,and that PIFs linked different photosensory and hormonal pathways to control plant growth and development.In this study,we show that PIFs positively regulate the ABA signaling pathway during the seedling stage specifically in darkness.We found that PIFs positively regulate ABI5 transcript and protein levels in darkness in response to exogenous ABA treatment by binding directly to the G-box motifs in the ABI5 promoter.Consistently,PIFs and the G-box motifs in the ABI5 promoter determine ABI5 expression in darkness,and overexpression of ABI5 could rescue the ABA-insensitive phenotypes of pifq mutants in the dark.Moreover,we discovered that PIFs can physically interact with the ABA receptors PYL8 and PYL9,and that this interaction is not regulated by ABA.Further analyses showed that PYL8 and PYL9 promote PIF4 protein accumulation in the dark and enhance PIF4 binding to the ABI5 promoter,but negatively regulate PIF4-mediated ABI5 activation.Taken together,our data demonstrate that PIFs interact with ABA receptors to orchestrate ABA signaling in darkness by controlling ABI5 expression,providing new insights into the pivotal roles of PIFs as signal integrators in regulating plant growth and development.展开更多
The soluble microbial products （SMP） in the biological treatment effluent are generally of great amount and are poorly biodegradable. Focusing on the biodegradation of anaerobic SMP, the biological activated carbon ...The soluble microbial products （SMP） in the biological treatment effluent are generally of great amount and are poorly biodegradable. Focusing on the biodegradation of anaerobic SMP, the biological activated carbon （BAC） was introduced into the anaerobic system. The experiments were conducted in two identical lab-scale up-flow anaerobic sludge blanket （UASB） reactors. The high strength organics were degraded in the first UASB reactor （UASB1） and the second UASB （UASB2, i.e., BAC） functioned as a polishing step to remove SMP produced in UASB1. The results showed that 90% of the SMP could be removed before granular activated carbon was saturated. After the saturation, the SMP removal decreased to 60% on the average. Analysis of granular activated carbon adsorption revealed that the main role of SMP removal in BAC reactor was biodegradation. A strain of SMP-degrading bacteria, which was found highly similar to Klebsiella sp., was isolated, enriched and inoculated back to the BAC reactor. When the influent chemical oxygen demand （COD） was 10,000 mg/L and the organic loading rate achieved 10 kg COD/（m 3 ·day）, the effluent from the BAC reactor could meet the discharge standard without further treatment. Anaerobic BAC reactor inoculated with the isolated Klebsiella was proved to be an effective, cheap and easy technical treatment approach for the removal of SMP in the treatment of easily-degradable wastewater with COD lower than 10,000 mg/L.展开更多
Eutrophication caused by high concentrations of nutrients is a huge problem for many natural lakes and reservoirs. Removing the nitrogen contamination from the low C/N water body has become an urgent need. Autotrophic...Eutrophication caused by high concentrations of nutrients is a huge problem for many natural lakes and reservoirs. Removing the nitrogen contamination from the low C/N water body has become an urgent need. Autotrophic denitrification with the sulfur compound as electron donor was investigated in the biofilter reactors. Through the lab-scale experiment,it was found that different sulfur compounds and different carriers caused very different treatment performances. Thiosulfate was selected to be the best electron donor and ceramsite was chosen as the suitable carrier due to the good denitrification efficiency, low cost and the good resistibility against the high hydraulic loads. Later the optimum running parameters of the process were determined. Then the pilot-scale experiment was carried out with the real micro-polluted water from the West Lake, China. The results indicated that the autotrophic denitrification with thiosulfate as electron donor was feasible and applicable for the micro-polluted lake water.展开更多
The global coronavirus disease 2019(COVID-19)pandemic is caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2),a positive-sense RNA virus.How the host immune system senses and responds to SARS-CoV-2 inf...The global coronavirus disease 2019(COVID-19)pandemic is caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2),a positive-sense RNA virus.How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved.Here,we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway.SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation.cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection.We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion.Furthermore,cytoplasmic chromatin-cGAS-STING pathway,but not MAVS-mediated viral RNA sensing pathway,contributes to interferon and pro-inflammatory gene expression upon cell fusion.Finally,we show that cGAS is required for host antiviral responses against SARS-CoV-2,and a STING-activating compound potently inhibits viral replication.Together,our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection,mediated by cytoplasmic chromatin from the infected cells.Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19.In addition,these findings extend our knowledge in host defense against viral infection by showing that host cells’self-nucleic acids can be employed as a“danger signal”to alarm the immune system.展开更多
The outbreak of coronavirus disease 2019(COVID-19) caused by SARS-CoV-2 has created a global health crisis. SARS-CoV-2 infects varieties of tissues where the known receptor ACE2 is low or almost absent, suggesting the...The outbreak of coronavirus disease 2019(COVID-19) caused by SARS-CoV-2 has created a global health crisis. SARS-CoV-2 infects varieties of tissues where the known receptor ACE2 is low or almost absent, suggesting the existence of alternative viral entry pathways. Here, we performed a genome-wide barcoded-CRISPRa screen to identify novel host factors that enable SARS-CoV-2 infection. Beyond known host proteins, i.e., ACE2, TMPRSS2, and NRP1, we identified multiple host components,among which LDLRAD3, TMEM30A, and CLEC4G were confirmed as functional receptors for SARS-CoV-2. All these membrane proteins bind directly to spike’s N-terminal domain(NTD). Their essential and physiological roles have been confirmed in either neuron or liver cells. In particular, LDLRAD3 and CLEC4G mediate SARS-CoV-2 entry and infection in an ACE2-independent fashion. The identification of the novel receptors and entry mechanisms could advance our understanding of the multiorgan tropism of SARS-CoV-2, and may shed light on the development of COVID-19 countermeasures.展开更多
In this paper,we consider a class of quasilinear Schrodinger-Poisson problems of the form∫-(a+b∫_(R)^(N)|■μ|^(2)dx)■μ+V(x)u+Фu-1/2u■(u^(2))-λ|u|^(p-2)u=0 in R^(N),-ΔФ=u^(2),u(x)→0,|x|→∞in R^(N),∫_(R)^(N...In this paper,we consider a class of quasilinear Schrodinger-Poisson problems of the form∫-(a+b∫_(R)^(N)|■μ|^(2)dx)■μ+V(x)u+Фu-1/2u■(u^(2))-λ|u|^(p-2)u=0 in R^(N),-ΔФ=u^(2),u(x)→0,|x|→∞in R^(N),∫_(R)^(N)|u|^(p)dx=1,where a>0,b≥0,N≥3,λappears as a Lagrangian multiplier,and 4<p<2·2^(*)=4N/N-2.We deal with two different cases simultaneously,namely lim|x|→∞V(x)=1 and limjxj!1 V(x)=V1.By using the method of invariant sets of the descending flow combined with the genus theory,we prove the existence of infinitely many sign-changing solutions.Our results extend and improve some recent work.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)continues to evolve,generating new variants that pose a threat to global health;therefore,it is imperative to obtain safe and broad‐spectrum antivirals aga...Severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)continues to evolve,generating new variants that pose a threat to global health;therefore,it is imperative to obtain safe and broad‐spectrum antivirals against SARS‐CoV‐2 and its variants.To this end,we screened compounds for their ability to inhibit viral entry,which is a critical step in virus infection.Twenty compounds that have been previously reported to inhibit SARS‐CoV‐2 replication were tested by using pseudoviruses containing the spike protein from the original strain(SARS‐CoV‐2‐WH01).The cytotoxicity of these compounds was determined.Furthermore,we identified six compounds with strong antagonistic activity against the WH01 pseudovirus,and low cytotoxicity was identified.These compounds were then evaluated for their efficacy against pseudoviruses expressing the spike protein from B.1.617.2(Delta)and B.1.1.529(Omicron),the two most prevalent circulating strains.These assays demonstrated that two phenothiazine compounds,trifluoperazine 2HCl and thioridazine HCl,inhibit the infection of Delta and Omicron pseudoviruses.Finally,we discovered that these two compounds were highly effective against authentic SARS‐CoV‐2 viruses,including the WH01,Delta,and Omicron strains.Our study identified potential broad‐spectrum SARS‐CoV‐2 inhibitors and provided insights into the development of novel therapeutics.展开更多
文摘Background: Cervical insufficiency is one of the major causes of preterm birth among pregnant women that leads to severe mortality and morbidity issues among newborns. Prophylactic cervical cerclage is a surgical procedure performed between 11 and 14 weeks of gestation upon diagnosis of cervix insufficiency among pregnant women. Aims & Objectives: In this study, we aimed to evaluate the effectiveness of prophylactic cervical cerclage in comparison to other interventions to treat cervical insufficiency among pregnant women using a meta-analysis approach. Methods: We searched the three databases (Coachrane Library, PubMed, and MEDLINE) that were used for articles related to research aims by using MeSH keywords. The timeline of research was set from January 2015 to January 2024. The methodological quality assessment of included studies was performed by the Risk of Bias in Non-randomized Studies—of Interventions (ROBINS-I). A recent meta-analysis was conducted by using Review Manager 5.4.0 software. Results: About 441 research articles were extracted from three electronic databases and only 125 articles were assessed for eligibility criteria. Finally, 8 studies were included in the analysis for a recent meta-analysis. Six out of eight included retrospective or pilot studies were graded as having a moderate risk of bias, and two studies had low risk on the basis of owning bias. About 1008 pregnant women with cervical insufficiency were analyzed in a recent meta-analysis. By pooled analysis, it was evaluated that significant difference found in prolongation of delivery weeks (Mean difference = 1.05;Cl: 0.81 to 1.29: p > 0.00001), number of deliveries > 37 weeks (OR = 0.59;Cl: 0.19 to 1.84: p > 0.006), and preterm birth (OR = 0.73;Cl: 0.42 to 1.28: p > 0.50) among pregnant women receiving prophylactic cervical cerclage as compared to other treatment strategies. Conclusion: Recent meta-analysis suggested the prophylactic cervical cerclage reduces the rates of preterm birth, abortion rates, number of deliveries > 37 weeks, and other complications as compared to the other cervical cerclage types and conservative treatments.
基金supported by the National Natural Science Foundation of China(No.11271298)
文摘This paper considers Stokes and Newton iterations to solve stationary Navier- Stokes equations based on the finite element discretization. We obtain new sufficient conditions of stability and convergence for the two iterations. Specifically, when 0 〈 σ =N｜｜f｜｜-1/v2≤1/√2＋1 , the Stokes iteration is stable and convergent, where N is defined in the paper. When 0 〈 σ ≤5/11, the Newton iteration is stable and convergent. This work gives a more accurate admissible range of data for stability and convergence of the two schemes, which improves the previous results. A numerical test is given to verify the theory.
基金supported by the National Natural Science Foundation of China(Grant Nos.12071404,12271465,12026254)by the Young Elite Scientist Sponsorship Program by CAST(Grant No.2020QNRC001)+3 种基金by the China Postdoctoral Science Foundation(Grant No.2018T110073)by the Natural Science Foundation of Hunan Province(Grant No.2019JJ40279)by the Excellent Youth Program of Scientific Research Project of Hunan Provincial Department of Education(Grant No.20B564)by the International Scientific and Technological Innovation Cooperation Base of Hunan Province for Computational Science(Grant No.2018WK4006).
文摘By combination of iteration methods with the partition of unity method(PUM),some finite element parallel algorithms for the stationary incompressible magnetohydrodynamics(MHD)with different physical parameters are presented and analyzed.These algorithms are highly efficient.At first,a global solution is obtained on a coarse grid for all approaches by one of the iteration methods.By parallelized residual schemes,local corrected solutions are calculated on finer meshes with overlapping sub-domains.The subdomains can be achieved flexibly by a class of PUM.The proposed algorithm is proved to be uniformly stable and convergent.Finally,one numerical example is presented to confirm the theoretical findings.
基金supported by the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-038).
文摘The emerging of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)caused COVID-19 pandemic.The first case of COVID-19 was reported at early December in 2019 in Wuhan City,China.To examine specific antibodies against SARS-CoV-2 in biological samples before December 2019 would give clues when the epidemic of SARS-CoV-2 might start to circulate in populations.We obtained all 88,517 plasmas from 76,844 blood donors in Wuhan between 1 September and 31 December 2019.We first evaluated the pan-immunoglobin(pan-Ig)against SARS-CoV-2 in 43,850 samples from 32,484 blood donors with suitable sample quality and enough volume.Two hundred and sixty-four samples from 213 donors were pan-Ig reactive,then further tested IgG and IgM,and validated by neutralizing antibodies against SARS-CoV-2.Two hundred and thirteen samples(from 175 donors)were only pan-Ig reactive,8(from 4 donors)were pan-Ig and IgG reactive,and 43(from 34 donors)were pan-Ig and IgM reactive.Microneutralization assay showed all negative results.In addition,213 screened reactive donors were analyzed and did not show obviously temporal or regional tendency,but the distribution of age showed a difference compared with all tested donors.Then we reviewed SARS-CoV-2 antibody results from these donors who donated several times from September 2019 to June 2020,partly tested in a previous published study,no one was found a significant increase in S/CO of antibodies against SARS-CoV-2.Our findings showed no SARS-CoV-2-specific antibodies existing among blood donors in Wuhan,China before 2020,indicating no evidence of transmission of COVID-19 before December 2019 in Wuhan,China.
基金supported by CAMS Innovation Fund for Medical Sciences 2021-I2M-1-038 and 2022-I2M-JB-014(to S.C.)Fundamental Research Funds for the Central Universities 3332021045(to S.G.)+2 种基金National Natural Science Foundation of China 81971950(to J.W.)and 82104250(to J.Z.)We thank the National Microbial Resource Center(No.NMRC-2020-3)the CAMS Collection Center of Pathogenic Microorganisms(CAMS-CCPM-A)for providing valuable reagents.
文摘The coronavirus disease 2019(COVID-19)pandemic has devastated global health.Identifying key host factors essential for SARS-CoV-2 RNA replication is expected to unravel cellular targets for the development of broad-spectrum antiviral drugs which have been quested for the preparedness of future viral outbreaks.Here,we have identified host proteins that associate with nonstructural protein 12(nsp12),the RNA-dependent RNA polymerase(RdRp)of SARS-CoV-2 using a mass spectrometry(MS)-based proteomic approach.Among the candidate factors,CDK2(Cyclin-dependent kinase 2),a member of cyclin-dependent kinases,interacts with nsp12 and causes its phosphorylation at T20,thus facilitating the assembly of the RdRp complex consisting of nsp12,nsp7 and nsp8 and promoting efficient synthesis of viral RNA.The crucial role of CDK2 in viral RdRp function is further supported by our observation that CDK2 inhibitors potently impair viral RNA synthesis and SARS-CoV-2 infection.Taken together,we have discovered CDK2 as a key host factor of SARS-CoV-2 RdRp complex,thus serving a promising target for the development of SARS-CoV-2 RdRp inhibitors.
基金This work was supported by grants from the Ministry of Agriculture of China,China(2016ZX08009003-002)the National Natural Science Foundation of China,China(31872658,31921001)Discipline Program of Beijing Outstanding University,China.
文摘Growth inhibition and cold-acclimation strategies help plants withstand cold stress,which adversely affects growth and survival.PHYTOCHROME B(phyB)regulates plant growth through perceiving both light and ambient temperature signals.However,the mechanism by which phyB mediates the plant response to cold stress remains elusive.Here,we show that the key transcription factors mediating cold acclimation,C-REPEAT BINDING FACTORs(CBFs),interact with PHYTOCHROME-INTERACTING FACTOR 3(PIF3)under cold stress,thus attenuating the mutually assured destruction of PIF3–phyB.Cold-stabilized phyB acts downstream of CBFs to positively regulate freezing tolerance by modulating the expression of stress-responsive and growth-related genes.Consistent with this,phyB mutants exhibited a freezing-sensitive phenotype,whereas phyB-overexpression transgenic plants displayed enhanced freezing tolerance.Further analysis showed that the PIF1,PIF4,and PIF5 proteins,all of which negatively regulate plant freezing tolerance,were destabilized by cold stress in a phytochrome-dependent manner.Collectively,our study reveals that CBFs–PIF3–phyB serves as an important regulatory module for modulating plant response to cold stress.
基金supported by the National MegaProject for Infectious Disease (2018ZX10301408, China)the National Mega-Project for Significant New Drug Discovery (2018ZX09711003-002-002, China)+3 种基金the National Natural Science Foundation of China (81802019 and 81902075)the Beijing Natural Science Foundation (7184228, China)CAMS Innovation Fund for Medical Sciences (2018-I2M-3-004 and 2020-I2M-2010, China)the Peking Union Medical College Youth Fund (3332016063 and 3332018096, China)。
文摘Severe acute respiratory syndrome coronavirus-2(SARS-CoV-2) has become one major threat to human population health.The RNA-dependent RNA polymerase(RdRp) presents an ideal target of antivirals,whereas nucleoside analogs inhibitor is hindered by the proofreading activity of coronavirus.Herein,we report that corilagin(RAI-S-37) as a non-nucleoside inhibitor of SARS-CoV-2 RdRp,binds directly to RdRp,effectively inhibits the polymerase activity in both cell-free and cell-based assays,fully resists the proofreading activity and potently inhibits SARS-CoV-2 infection with a low 50% effective concentration(EC50) value of 0.13 μmol/L.Computation modeling predicts that RAI-S-37 lands at the palm domain of RdRp and prevents conformational changes required for nucleotide incorporation by RdRp.In addition,combination of RAI-S-37 with remdesivir exhibits additive activity against antiSARS-CoV-2 RdRp.Together with the current data available on the safety and pharmacokinetics of corilagin as a medicinal herbal agent,these results demonstrate the potential of being developed into one of the much-needed SARS-CoV-2 therapeutics.
基金supported by grants from the National Major Sciences&Technology Project for Control and Prevention of Major Infectious Diseases in China(2018ZX10733403 and 2018ZX10101001 to Z.X.,2018ZX10301401 to X.L. and Z.Z.)the National Natural Science Foundation of China(81930063,81971948,81772201,and 31670169 to J.W.,X.L.,Z.X.,and Z.Z.)+1 种基金the National Key R&D Program of China(2020YFA0707600)the Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2016-I2M-1-014 to J.W.).
文摘SARS-CoV-2 is the pathogenic agent of COVID-19,which has evolved into a global pandemic.Compared with some other respiratory RNA viruses,SARS-CoV-2 is a poor inducer of type Ⅰ interferon(IFN).Here,we report that SARS-CoV-2 nsp12,the viral RNA-dependent RNA polymerase(RdRp),suppresses host antiviral responses.SARS-CoV-2 nsp12 attenuated Sendai virus(SeV)-or poly(I:C)-induced IFN-β promoter activation in a dose-dependent manner.It also inhibited IFN promoter activation triggered by RIG-I,MDA5,MAVS,and IRF3 overexpression.Nsp12 did not impair IRF3 phosphorylation but suppressed the nuclear translocation of IRF3.Mutational analyses suggested that this suppression was not dependent on the polymerase activity of nsp12.Given these findings,our study reveals that SARS-CoV-2 RdRp can antagonize host antiviral innate immunity and thus provides insights into viral pathogenesis.
基金supported by grants from the National Natural Science Foundation of China(31970262 and 31770321)the Ministry of Agriculture of China for Transgenic Research(2019ZX08010003-002-005)Beijing Outstanding University Discipline Program,and the Recruitm ent Program of Global Youth Experts of China.
文摘PHYTOCHROME-INTERACTING FACTORS(PIFs)are a group of basic helix-loop-helix transcription factors that can physically interact with photoreceptors,including phytochromes and cryptochromes.It was previously demonstrated that PIFs accumulated in darkness and repressed seedling photomorphogenesis,and that PIFs linked different photosensory and hormonal pathways to control plant growth and development.In this study,we show that PIFs positively regulate the ABA signaling pathway during the seedling stage specifically in darkness.We found that PIFs positively regulate ABI5 transcript and protein levels in darkness in response to exogenous ABA treatment by binding directly to the G-box motifs in the ABI5 promoter.Consistently,PIFs and the G-box motifs in the ABI5 promoter determine ABI5 expression in darkness,and overexpression of ABI5 could rescue the ABA-insensitive phenotypes of pifq mutants in the dark.Moreover,we discovered that PIFs can physically interact with the ABA receptors PYL8 and PYL9,and that this interaction is not regulated by ABA.Further analyses showed that PYL8 and PYL9 promote PIF4 protein accumulation in the dark and enhance PIF4 binding to the ABI5 promoter,but negatively regulate PIF4-mediated ABI5 activation.Taken together,our data demonstrate that PIFs interact with ABA receptors to orchestrate ABA signaling in darkness by controlling ABI5 expression,providing new insights into the pivotal roles of PIFs as signal integrators in regulating plant growth and development.
基金supported by the National Natural Science Foundation of China (No. 50808121)the Program for New Century Excellent Talents in University (No. NCET-11-0320)
文摘The soluble microbial products （SMP） in the biological treatment effluent are generally of great amount and are poorly biodegradable. Focusing on the biodegradation of anaerobic SMP, the biological activated carbon （BAC） was introduced into the anaerobic system. The experiments were conducted in two identical lab-scale up-flow anaerobic sludge blanket （UASB） reactors. The high strength organics were degraded in the first UASB reactor （UASB1） and the second UASB （UASB2, i.e., BAC） functioned as a polishing step to remove SMP produced in UASB1. The results showed that 90% of the SMP could be removed before granular activated carbon was saturated. After the saturation, the SMP removal decreased to 60% on the average. Analysis of granular activated carbon adsorption revealed that the main role of SMP removal in BAC reactor was biodegradation. A strain of SMP-degrading bacteria, which was found highly similar to Klebsiella sp., was isolated, enriched and inoculated back to the BAC reactor. When the influent chemical oxygen demand （COD） was 10,000 mg/L and the organic loading rate achieved 10 kg COD/（m 3 ·day）, the effluent from the BAC reactor could meet the discharge standard without further treatment. Anaerobic BAC reactor inoculated with the isolated Klebsiella was proved to be an effective, cheap and easy technical treatment approach for the removal of SMP in the treatment of easily-degradable wastewater with COD lower than 10,000 mg/L.
基金supported by the National Natural Science Foundation of China (No. 51478262)The Chinese National Key Projects of Water Pollution Control and Reclamation (No. 2012ZX07101-007-005)the Open Fund Project of Zhejiang Mariculture Research Institute (No. J2013005)
文摘Eutrophication caused by high concentrations of nutrients is a huge problem for many natural lakes and reservoirs. Removing the nitrogen contamination from the low C/N water body has become an urgent need. Autotrophic denitrification with the sulfur compound as electron donor was investigated in the biofilter reactors. Through the lab-scale experiment,it was found that different sulfur compounds and different carriers caused very different treatment performances. Thiosulfate was selected to be the best electron donor and ceramsite was chosen as the suitable carrier due to the good denitrification efficiency, low cost and the good resistibility against the high hydraulic loads. Later the optimum running parameters of the process were determined. Then the pilot-scale experiment was carried out with the real micro-polluted water from the West Lake, China. The results indicated that the autotrophic denitrification with thiosulfate as electron donor was feasible and applicable for the micro-polluted lake water.
基金This work was supported by grants from National Key R&D Program of China(2020YFA0707600 to Z.Z.,2020YFA0707800 to W.Wei.)the National Natural Science Foundation of China(81930063,31870893,and 81971948 to J.W.,Z.Z.,and X.L.)+3 种基金the National Major Sciences&Technology Project for Control and Prevention of Major Infectious Diseases in China(2018ZX10301401 to Z.Z.and X.L.)the Beijing Municipal Science&Technology Commission(Z181100001318009)Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(2016-I2M-1-014,2016-I2M-1-005 to J.W.and X.L.)the Beijing Advanced Innovation Center for Genomics(ICG)at Peking University,and the Peking-Tsinghua Center for Life Sciences.
文摘The global coronavirus disease 2019(COVID-19)pandemic is caused by severe acute respiratory syndrome coronavirus 2(SARSCoV-2),a positive-sense RNA virus.How the host immune system senses and responds to SARS-CoV-2 infection remain largely unresolved.Here,we report that SARS-CoV-2 infection activates the innate immune response through the cytosolic DNA sensing cGAS-STING pathway.SARS-CoV-2 infection induces the cellular level of 2′3′-cGAMP associated with STING activation.cGAS recognizes chromatin DNA shuttled from the nucleus as a result of cell-to-cell fusion upon SARS-CoV-2 infection.We further demonstrate that the expression of spike protein from SARS-CoV-2 and ACE2 from host cells is sufficient to trigger cytoplasmic chromatin upon cell fusion.Furthermore,cytoplasmic chromatin-cGAS-STING pathway,but not MAVS-mediated viral RNA sensing pathway,contributes to interferon and pro-inflammatory gene expression upon cell fusion.Finally,we show that cGAS is required for host antiviral responses against SARS-CoV-2,and a STING-activating compound potently inhibits viral replication.Together,our study reported a previously unappreciated mechanism by which the host innate immune system responds to SARS-CoV-2 infection,mediated by cytoplasmic chromatin from the infected cells.Targeting the cytoplasmic chromatin-cGAS-STING pathway may offer novel therapeutic opportunities in treating COVID-19.In addition,these findings extend our knowledge in host defense against viral infection by showing that host cells’self-nucleic acids can be employed as a“danger signal”to alarm the immune system.
基金supported by funds from the National Key R&D Program of China (2020YFA0707800 to W.W., 2020YFA0707600 to Z.Z.)Beijing Municipal Science & Technology Commission (Z181100001318009)+4 种基金the National Natural Science Foundation of China (31930016)Beijing Advanced Innovation Center for Genomics at Peking University and the Peking-Tsinghua Center for Life Sciences (to W.W.)the National Natural Science Foundation of China (31870893)the National Major Science & Technology Project for Control and Prevention of Major Infectious Diseases in China (2018ZX10301401 to Z.Z.)China Postdoctoral Science Foundation (2020M670031 to Y.L.)
文摘The outbreak of coronavirus disease 2019(COVID-19) caused by SARS-CoV-2 has created a global health crisis. SARS-CoV-2 infects varieties of tissues where the known receptor ACE2 is low or almost absent, suggesting the existence of alternative viral entry pathways. Here, we performed a genome-wide barcoded-CRISPRa screen to identify novel host factors that enable SARS-CoV-2 infection. Beyond known host proteins, i.e., ACE2, TMPRSS2, and NRP1, we identified multiple host components,among which LDLRAD3, TMEM30A, and CLEC4G were confirmed as functional receptors for SARS-CoV-2. All these membrane proteins bind directly to spike’s N-terminal domain(NTD). Their essential and physiological roles have been confirmed in either neuron or liver cells. In particular, LDLRAD3 and CLEC4G mediate SARS-CoV-2 entry and infection in an ACE2-independent fashion. The identification of the novel receptors and entry mechanisms could advance our understanding of the multiorgan tropism of SARS-CoV-2, and may shed light on the development of COVID-19 countermeasures.
基金supported by Shandong Natural Science Foundation of China(Grant No.ZR2020MA005).
文摘In this paper,we consider a class of quasilinear Schrodinger-Poisson problems of the form∫-(a+b∫_(R)^(N)|■μ|^(2)dx)■μ+V(x)u+Фu-1/2u■(u^(2))-λ|u|^(p-2)u=0 in R^(N),-ΔФ=u^(2),u(x)→0,|x|→∞in R^(N),∫_(R)^(N)|u|^(p)dx=1,where a>0,b≥0,N≥3,λappears as a Lagrangian multiplier,and 4<p<2·2^(*)=4N/N-2.We deal with two different cases simultaneously,namely lim|x|→∞V(x)=1 and limjxj!1 V(x)=V1.By using the method of invariant sets of the descending flow combined with the genus theory,we prove the existence of infinitely many sign-changing solutions.Our results extend and improve some recent work.
基金supported by grants from National Key R&D Program of China(2020YFA0707600 to Z.Z.and X.L.)the National Natural Science Foundation of China(81930063 and 81971948 to J.W.and X.L.)hinese Academy of Medical Science(CAMS)Innovation Fund for Medical Sciences(2021-I2M-1-038 to J.W.)。
文摘Severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)continues to evolve,generating new variants that pose a threat to global health;therefore,it is imperative to obtain safe and broad‐spectrum antivirals against SARS‐CoV‐2 and its variants.To this end,we screened compounds for their ability to inhibit viral entry,which is a critical step in virus infection.Twenty compounds that have been previously reported to inhibit SARS‐CoV‐2 replication were tested by using pseudoviruses containing the spike protein from the original strain(SARS‐CoV‐2‐WH01).The cytotoxicity of these compounds was determined.Furthermore,we identified six compounds with strong antagonistic activity against the WH01 pseudovirus,and low cytotoxicity was identified.These compounds were then evaluated for their efficacy against pseudoviruses expressing the spike protein from B.1.617.2(Delta)and B.1.1.529(Omicron),the two most prevalent circulating strains.These assays demonstrated that two phenothiazine compounds,trifluoperazine 2HCl and thioridazine HCl,inhibit the infection of Delta and Omicron pseudoviruses.Finally,we discovered that these two compounds were highly effective against authentic SARS‐CoV‐2 viruses,including the WH01,Delta,and Omicron strains.Our study identified potential broad‐spectrum SARS‐CoV‐2 inhibitors and provided insights into the development of novel therapeutics.
