The extremely poor prognosis of patients is largely due to hepatocyte growth factor(HGF)/MET signaling,which promotes migration and invasion of glioblastoma(IDH wildtype;GBM;WHO grade 4).1,2 Clinical trials targeting ...The extremely poor prognosis of patients is largely due to hepatocyte growth factor(HGF)/MET signaling,which promotes migration and invasion of glioblastoma(IDH wildtype;GBM;WHO grade 4).1,2 Clinical trials targeting MET,the only receptor of HGF,have yielded unimpressive results in GBM.3,4 Here we found that HGF induced strong chemotaxis on GBM cells,but MET expression was extremely low.We,therefore,used single-cell RNA sequencing(scRNA-seq)coupled with label-free proteome profiling to identify membrane proteins associated with HGF/MET signaling amplification in GBM and to provide a novel modulator,MPZL1,for HGF/MET-targeted therapy.展开更多
Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer metastasis, accompanied with vast epigenetic changes.AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in m...Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer metastasis, accompanied with vast epigenetic changes.AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in multiple biological processes. Although afew studies have shed light on AMPK regulating cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein weshow that AMPK activation by metformin relieves the repressive H3K9me2-mediated silencing of epithelial genes (e.g., CDH1)during EMT processes and inhibits lung cancer metastasis. PHF2, a H3K9me2 demethylase, was identified to interact with AMPKα2.Genetic deletion of PHF2 aggravates lung cancer metastasis and abolishes the H3K9me2 downregulation and anti-metastasis effectof metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering thetranscription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reducesH3K9me2 and suppresses lung cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the antimetastasiseffect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higherphosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis viaPHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as thepotential epigenetic target in cancer metastasis.展开更多
Letϕ:Pc(M1)→Pc(M2)be a surjective Lp-isometry between Grassmann spaces of projections with the trace value c in semifinite factors M1 and M2.Based on the characterization of surjective Lp-isometries of unitary groups...Letϕ:Pc(M1)→Pc(M2)be a surjective Lp-isometry between Grassmann spaces of projections with the trace value c in semifinite factors M1 and M2.Based on the characterization of surjective Lp-isometries of unitary groups in finite factors,we show thatϕor I−ϕcan be extended to a∗-isomorphism or a∗-antiisomorphism.In particular,ϕis given by a∗-(anti-)isomorphism unless M1 and M2 are finite and c=12.展开更多
Swine acute diarrhea syndrome coronavirus(SADS‐CoV)is a recently discovered coronavirus that causes severe and acute diarrhea and rapid weight loss in piglets.SADS‐CoV was reported to be capable of infecting cell li...Swine acute diarrhea syndrome coronavirus(SADS‐CoV)is a recently discovered coronavirus that causes severe and acute diarrhea and rapid weight loss in piglets.SADS‐CoV was reported to be capable of infecting cell lines derived from diverse species,including bats,mice,hamsters,rats,chickens,pigs,nonhuman primates,and humans,implying its high risk of cross‐species infection.However,its receptor is still unknown.In this study,the receptor‐binding domain of the SADS‐CoV spike(S)protein was purified and then subjected to affinity purification(AP)‐coupled mass spectrometry(MS)‐based proteomic analysis to identify the interactors of the SADS‐CoV S protein.Forty‐three host proteins were identified,and a Gene Ontology analysis indicated that these interactors can be grouped into categories such as“cell‐cell adhesion”,“translation”“viral transcription”,suggesting that these processes may participate in the SADS‐CoV life cycles.RNA interference‐based screening of these interactors indicated that PPIB and vimentin can affect SADS‐CoV replication.Our study provides an overarching view into the host interactome of the SADS‐CoV S protein and highlights potential targets for the development of therapeutics against SADS‐CoV.展开更多
The recent outbreak of novel coronavirus pneumonia(COVID-19)caused by a new coronavirus has posed a great threat to public health.Identifying safe and effective antivirals is of urgent demand to cure the huge number o...The recent outbreak of novel coronavirus pneumonia(COVID-19)caused by a new coronavirus has posed a great threat to public health.Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients.Virusencoded proteases are considered potential drug targets.The human immunodeficiency virus protease inhibitors(lopinavir/ritonavir)has been recommended in the global Solidarity Trial in March launched by World Health Organization.However,there is currently no experimental evidence to support or against its clinical use.We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro,and discussed the possible inhibitory mechanism in silico.The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical.Among the four tested compounds,lopinavir showed the best inhibitory effect against the novel coronavirus infection.However,further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen[marketed as Kaletraò,contained lopinavir/ritonavir(200 mg/50 mg)tablets,recommended dosage is 400 mg/10 mg(2 tablets)twice daily].This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration.Nevertheless,the structure–activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.展开更多
Let X be an infinite-dimensional real or complex Banach space,and B(X)the Banach algebra of all bounded linear operators on X.In this paper,given any non-negative integer n,we characterize the surjective additive maps...Let X be an infinite-dimensional real or complex Banach space,and B(X)the Banach algebra of all bounded linear operators on X.In this paper,given any non-negative integer n,we characterize the surjective additive maps on B(X)preserving Fredholm operators with fixed nullity or defect equal to n in both directions,and describe completely the structure of these maps.展开更多
基金the Natural Science Foundation of Guangdong Province,China(No.2022A1515012552)Shenzhen Science and Technology Innovation Committee of China(SZSTI+3 种基金No.JCYJ20220818102611025)Research Initiation Project of Shunde Hospital,Southern Medical University(No.CRSP2022002)Research Initiation Project of the First Affiliated Hospital of Gannan Medical University(No.QD202316)Beijing Sisco Clinical Oncology Research Foundation of China(No.Y-2022METAZMS-0118).
文摘The extremely poor prognosis of patients is largely due to hepatocyte growth factor(HGF)/MET signaling,which promotes migration and invasion of glioblastoma(IDH wildtype;GBM;WHO grade 4).1,2 Clinical trials targeting MET,the only receptor of HGF,have yielded unimpressive results in GBM.3,4 Here we found that HGF induced strong chemotaxis on GBM cells,but MET expression was extremely low.We,therefore,used single-cell RNA sequencing(scRNA-seq)coupled with label-free proteome profiling to identify membrane proteins associated with HGF/MET signaling amplification in GBM and to provide a novel modulator,MPZL1,for HGF/MET-targeted therapy.
基金China Postdoctoral Science Foundation(Grant 2021M703345)the National Natural Science Foundation of China(Grant 31871414,81821005)+3 种基金Shanghai Science and Technology Development Funds(Grant 22YF1457100,22ZR1415200)the Lingang Laboratory(Grant Nos.LG202103-03-04,LG202103-03-05)Shanghai Special Program for Research on Aging and Women and Children’s Health(No.2020YJZX0136)Talent Program of Shanghai Pulmonary Hospital(No.fkgg1809,fkzr2317).
文摘Epithelial to mesenchymal transition (EMT) plays a crucial role in cancer metastasis, accompanied with vast epigenetic changes.AMP-activated protein kinase (AMPK), a cellular energy sensor, plays regulatory roles in multiple biological processes. Although afew studies have shed light on AMPK regulating cancer metastasis, the inside epigenetic mechanisms remain unknown. Herein weshow that AMPK activation by metformin relieves the repressive H3K9me2-mediated silencing of epithelial genes (e.g., CDH1)during EMT processes and inhibits lung cancer metastasis. PHF2, a H3K9me2 demethylase, was identified to interact with AMPKα2.Genetic deletion of PHF2 aggravates lung cancer metastasis and abolishes the H3K9me2 downregulation and anti-metastasis effectof metformin. Mechanistically, AMPK phosphorylates PHF2 at S655 site, enhancing PHF2 demethylation activity and triggering thetranscription of CDH1. Furthermore, the PHF2-S655E mutant that mimics AMPK-mediated phosphorylation status further reducesH3K9me2 and suppresses lung cancer metastasis, while PHF2-S655A mutant presents opposite phenotype and reverses the antimetastasiseffect of metformin. PHF2-S655 phosphorylation strikingly reduces in lung cancer patients and the higherphosphorylation level predicts better survival. Altogether, we reveal the mechanism of AMPK inhibiting lung cancer metastasis viaPHF2 mediated H3K9me2 demethylation, thereby promoting the clinical application of metformin and highlighting PHF2 as thepotential epigenetic target in cancer metastasis.
基金supported by the Science and Technology Research Program of Chongqing Municipal Education Commission(Grant No.KJQN2021000529)the Natural Science Foundation of Chongqing Science and Technology Commission(Grant No.cstc2020jcyj-msxm X0723)+2 种基金supported by Young Talent Fund of University Association for Science and Technology in Shaanxi(Grant No.20210507)supported by National Natural Science Foundation of China(Grant Nos.11871127and 11971463)supported by National Natural Science Foundation of China(Grant Nos.11971463,11871303 and 11871127)。
文摘Letϕ:Pc(M1)→Pc(M2)be a surjective Lp-isometry between Grassmann spaces of projections with the trace value c in semifinite factors M1 and M2.Based on the characterization of surjective Lp-isometries of unitary groups in finite factors,we show thatϕor I−ϕcan be extended to a∗-isomorphism or a∗-antiisomorphism.In particular,ϕis given by a∗-(anti-)isomorphism unless M1 and M2 are finite and c=12.
基金supported by National Natural Science Foundation of China(31830096)the Open Research Fund Program of Wuhan National Bio‐Safety Level 4 Lab of CAS(2020ACCP‐MS01)the Youth Innovation Promotion Association CAS(grants 2018367 to L.‐K.Z).
文摘Swine acute diarrhea syndrome coronavirus(SADS‐CoV)is a recently discovered coronavirus that causes severe and acute diarrhea and rapid weight loss in piglets.SADS‐CoV was reported to be capable of infecting cell lines derived from diverse species,including bats,mice,hamsters,rats,chickens,pigs,nonhuman primates,and humans,implying its high risk of cross‐species infection.However,its receptor is still unknown.In this study,the receptor‐binding domain of the SADS‐CoV spike(S)protein was purified and then subjected to affinity purification(AP)‐coupled mass spectrometry(MS)‐based proteomic analysis to identify the interactors of the SADS‐CoV S protein.Forty‐three host proteins were identified,and a Gene Ontology analysis indicated that these interactors can be grouped into categories such as“cell‐cell adhesion”,“translation”“viral transcription”,suggesting that these processes may participate in the SADS‐CoV life cycles.RNA interference‐based screening of these interactors indicated that PPIB and vimentin can affect SADS‐CoV replication.Our study provides an overarching view into the host interactome of the SADS‐CoV S protein and highlights potential targets for the development of therapeutics against SADS‐CoV.
基金supported in part by grants from the National Science and Technology Major Projects(Grant Number 2018ZX09711003)National Key Research and Development Project(2020YFC0841700)+1 种基金the National Natural Science Foundation of China(Grant Number 31621061)the Hubei Science and Technology Project(Grant Number 2020FCA003)。
文摘The recent outbreak of novel coronavirus pneumonia(COVID-19)caused by a new coronavirus has posed a great threat to public health.Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients.Virusencoded proteases are considered potential drug targets.The human immunodeficiency virus protease inhibitors(lopinavir/ritonavir)has been recommended in the global Solidarity Trial in March launched by World Health Organization.However,there is currently no experimental evidence to support or against its clinical use.We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro,and discussed the possible inhibitory mechanism in silico.The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical.Among the four tested compounds,lopinavir showed the best inhibitory effect against the novel coronavirus infection.However,further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen[marketed as Kaletraò,contained lopinavir/ritonavir(200 mg/50 mg)tablets,recommended dosage is 400 mg/10 mg(2 tablets)twice daily].This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration.Nevertheless,the structure–activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.
基金supported by National Natural Science Foundation of China(11771261,11701351)Natural Science Basic Research Plan in Shaanxi Province of China(2018JQ1082)the Fundamental Research Funds for the Central Universities(GK202103007,GK202107014).
文摘Let X be an infinite-dimensional real or complex Banach space,and B(X)the Banach algebra of all bounded linear operators on X.In this paper,given any non-negative integer n,we characterize the surjective additive maps on B(X)preserving Fredholm operators with fixed nullity or defect equal to n in both directions,and describe completely the structure of these maps.
