In renewing tissues,mutations conferring selective advantage may result in clonal expansions1-4.In contrast to somatic tissues,mutations driving clonal expansions in spermatogonia(CES)are also transmitted to the next ...In renewing tissues,mutations conferring selective advantage may result in clonal expansions1-4.In contrast to somatic tissues,mutations driving clonal expansions in spermatogonia(CES)are also transmitted to the next generation.This results in an effective increase of de novo mutation rate for CES drivers5-8.CES was originally discovered through extreme recurrence of de novo mutations causing Apert syndrome5.Here,we develop a systematic approach to discover CES drivers as hotspots of human de novo mutation.Our analysis of 54,715 trios ascertained for rare conditions9-13,6,065 control trios12,14-19 and population variation from 807,162 mostly healthy individuals20 identifies genes manifesting rates of de novo mutations inconsistent with plausible models of disease ascertainment.We propose 23 genes hypermutable at loss-of-function(LoF)sites as candidate CES drivers.An extra 17 genes feature hypermutable missense mutations at individual positions,suggesting CES acting through gain of function.CES increases the average mutation rate roughly 17-fold for LoF genes in both control trios and sperm and roughly 500-fold for pooled gain-of-function sites in sperm21.Positive selection in the male germline elevates the prevalence of genetic disorders and increases polymorphism levels,masking the effect of negative selection in human populations.展开更多
Evolocumab,an inhibitory monoclonal antibody of proprotein convertase subtilisin-kexin type 9(PCSK9),presents as an effective method to decrease low-density lipoprotein cholesterol(LDL-C)and reduce the risk of major a...Evolocumab,an inhibitory monoclonal antibody of proprotein convertase subtilisin-kexin type 9(PCSK9),presents as an effective method to decrease low-density lipoprotein cholesterol(LDL-C)and reduce the risk of major adverse cardiovascular events,which has attracted widespread attention.Compared to statins,it is reported to be more efficient and less restricted to liver function.However,up to now,there has been no relevant reports about the safety of evolocumab in patients with biliary dysfunctions(1).Here,we presented a rare case with an unprecedented complication of evolocumab in a jaundice patient with pancreatic carcinoma,who suffered from short-term recurrent jaundice and acute obstructive suppurative cholangitis(AOSC)due to biliary stent blockage after successful stent implantation.展开更多
background Monoclonal antibodies(mAbs)targeting immune checkpoint molecules such as programmed death ligand 1(PD-L1),which is expressed in both immune and tumour cells,are conventional immunotherapy approaches.Althoug...background Monoclonal antibodies(mAbs)targeting immune checkpoint molecules such as programmed death ligand 1(PD-L1),which is expressed in both immune and tumour cells,are conventional immunotherapy approaches.Although approved as monotherapy for the first-line treatment of several cancers,mAbs targeting PD-L1 have shown limited efficacy in colorectal cancer(CRC).Here,we investigated if nucleic acids translated into anti-PD L1 nanobodies(PDL1Nbs)effectively suppress CRC tumourigenesis in mouse models.Methods Mice were transplanted with MC-38 mouse sporadic CRC(sCRC)cells or challenged with azoxymethane and dextran sodium sulfate,a combination treatment that induces colitis-associated CRC(CAC).The tumour-bearing mice were treated with a PDL1Nb-encoding plasmid DNA(pDNA)delivered via polymers,or treated with PDL1Nb-encoding nucleoside-modified messenger RNA(PDL1Nb mRNA)delivered via lipid nanoparticles(LNP).Moreover,bone marrow haematopoietic stem cells(BMHSCs)were differentiated and maturated by treating growth factors in the presence of PDL1Nb mRNA-LNP or control luciferase mRNA-LNP with/without lipopolysaccharide.We examined sCRC tumour proliferation and growth,CAC tumour incidences and numbers,tumour infiltration of immune cells and bone marrow-derived macrophages(BMDMs).results Polymer delivery of PDL1Nb pDNA efficiently repressed sCRC progression in tumour-bearing mice.Intriguingly,LNP delivery of the quadruple PDL1Nb(qPDL1Nb)mRNA showed a greater efficacy than the delivery of the monomeric PDL1Nb(mPDL1Nb)mRNA in suppressing sCRC tumour progression.Moreover,qPDL1Nb mRNA-LNP treatment significantly reduced CAC incidence.Mechanistically,PD-L1 blockade by qPDL1Nb resulted in marked decreases in tumour-infiltrating myeloid-derived suppressor cells and tumour-associated macrophages,as well as expression of PD-L1,but increases in tumour-infiltrating CD3+CD8+cells during CAC tumourigenesis.Notably,in vitro LNP delivery of PDL1Nb mRNA into BMHSCs significantly inhibited their differentiation and maturation into BMDMs and strikingly reduced the expression of PD-L1,CD80,CD86 and CD206 in BMDMs.展开更多
The degradation caused by surface states restricts the performance of near-surface semiconductor quantum dots(QDs).Here,we demonstrate optimized passivation techniques to improve the resonance fluorescence(RF)with dot...The degradation caused by surface states restricts the performance of near-surface semiconductor quantum dots(QDs).Here,we demonstrate optimized passivation techniques to improve the resonance fluorescence(RF)with dotto-dot comparisons.These optimized techniques,for the first time,reduce the linewidth and noise level of existing pulsed-RF signals,as well as revive pulsed-RF signals which originally are vanishing.The improvements are confirmed to originate from reduced surface state density and electric field after passivation,through optical and surface science characterizations.Our study promotes applications of the passivation techniques in thin-film quantum devices,paving the way for the further development of optimal QD-based quantum light sources.展开更多
Targeting the DNA damage response(DDR)exhibits potent efficacy in inducing immune activation and enhancing patient prognosis.However,the benefits of DDR regulation are not universally observed across all patients,owin...Targeting the DNA damage response(DDR)exhibits potent efficacy in inducing immune activation and enhancing patient prognosis.However,the benefits of DDR regulation are not universally observed across all patients,owing to the intricate compensatory mechanisms operative in certain cancers.There still exists a gap in the function of activated DDR protein in esophageal squamous cell carcinoma(ESCC).Here,we demonstrate that increased expression of DDR genes contributes to the progression of esophageal squamous cell carcinoma and suppresses the tumor immune microenvironment.Notably,the abundant presence of the DDR protein KIN in ESCC tissues facilitates efficient DNA damage clearance and promotes escape from apoptosis.Depletion of KIN significantly inhibited proliferation and induced DNA damage accumulation in ESCC cells.Mechanistically,KIN functions to support the recruitment of the R-loop regulator DHX9 to R-loop sites,thereby addressing DNA damage associated R-loops.Intriguingly,the depletion of KIN activates the STING pathway via NFκB signaling,which is induced by the accumulation of R-loops,ultimately initiating an innate immune response.Depletion of KIN improved the immune microenvironment and the effect of immune therapy in mouse model.Collectively,our findings identify KIN as a novel R-loop binding protein that facilitates the recruitment of the R-loop resolution complex and suppresses tumor-intrinsic innate immunity.展开更多
Synthetic aperture radar(SAR)records important information about the interaction of electromagnetic waves with the Earth’s surface.However,long-term and high-resolution backscatter coefficient data are still lacking ...Synthetic aperture radar(SAR)records important information about the interaction of electromagnetic waves with the Earth’s surface.However,long-term and high-resolution backscatter coefficient data are still lacking in many urban studies(e.g.,building height estimation).Here,we proposed a framework to reconstruct the 1-km backscatter coefficient in 1990-2022 utilizing the Sentinel-1 Ground Range Detected data and Landsat time series data in the Jing-Jin-Ji(JJJ)region.First,we developed a regression model to convert the optical signals from Landsat into backscatter coefficients as the Sentinel-1 data,using observations from 2015 to 2022.Then,we reconstructed backscatter coefficients from 1990 to 2022 using the long-term Landsat data.Using the reconstructed backscatter coefficients,we analyzed the dynamic patterns of building height over the past decades.The proposed approach performs well on estimating the backscatter coefficient and its spatial pattern,with the annual mean absolute error,root mean square error,and R^(2) of 1.10 dB,1.50 dB,and 0.64,respectively.The temporal trends revealed from the reconstructed backscatter data are reliable compared with satellite observations at a relatively coarse resolution,with Pearson’s coefficients above 0.92 in 6 sample cities.The derived building height from the reconstructed SAR data indicates that the JJJ region experienced a noticeable upward expansion in 1990-2022,e.g.,Beijing has the fastest growth rate of 0.420 km^(3)/decade regarding the total building volumes.The proposed framework of reconstructing SAR data from optical satellite images provides a new insight to complement the long-term and high-resolution backscatter from local to global scales.展开更多
文摘In renewing tissues,mutations conferring selective advantage may result in clonal expansions1-4.In contrast to somatic tissues,mutations driving clonal expansions in spermatogonia(CES)are also transmitted to the next generation.This results in an effective increase of de novo mutation rate for CES drivers5-8.CES was originally discovered through extreme recurrence of de novo mutations causing Apert syndrome5.Here,we develop a systematic approach to discover CES drivers as hotspots of human de novo mutation.Our analysis of 54,715 trios ascertained for rare conditions9-13,6,065 control trios12,14-19 and population variation from 807,162 mostly healthy individuals20 identifies genes manifesting rates of de novo mutations inconsistent with plausible models of disease ascertainment.We propose 23 genes hypermutable at loss-of-function(LoF)sites as candidate CES drivers.An extra 17 genes feature hypermutable missense mutations at individual positions,suggesting CES acting through gain of function.CES increases the average mutation rate roughly 17-fold for LoF genes in both control trios and sperm and roughly 500-fold for pooled gain-of-function sites in sperm21.Positive selection in the male germline elevates the prevalence of genetic disorders and increases polymorphism levels,masking the effect of negative selection in human populations.
基金supported by the National High Level Hospital Clinical Research Funding(No.2022-PUMCH-A-186)the Non-profit 121 Central Research Institute Fund of Chinese Academy of 122 Medical Sciences(No.2023-JKCS-01).
文摘Evolocumab,an inhibitory monoclonal antibody of proprotein convertase subtilisin-kexin type 9(PCSK9),presents as an effective method to decrease low-density lipoprotein cholesterol(LDL-C)and reduce the risk of major adverse cardiovascular events,which has attracted widespread attention.Compared to statins,it is reported to be more efficient and less restricted to liver function.However,up to now,there has been no relevant reports about the safety of evolocumab in patients with biliary dysfunctions(1).Here,we presented a rare case with an unprecedented complication of evolocumab in a jaundice patient with pancreatic carcinoma,who suffered from short-term recurrent jaundice and acute obstructive suppurative cholangitis(AOSC)due to biliary stent blockage after successful stent implantation.
基金supported by the IBR Pilot Awards(SM and W-MC)associated with the COBRE grant P30GM131944(W Steven Ward,PI)the Yao Family Professorship(W-MC)and the B.H.and Alice C.Beams Foundation(SM)and was partially supported by U01CA188387-01(WJ and W-MC)+3 种基金the Kosasa Foundation and the Office of the Vice President for Research at the University of Hawai’i(SM)The Pardi Laboratory was supported by the National Institute of Allergy and Infectious Diseases(NIAID,R01AI153064)The Experimental NeuroAcoustics and Biophysics Laboratory(ENABL,PA)was supported by the American Cancer Society’s grant IRG-18-160-16seed funds from the Department of Neurosurgery,University of Maryland School of Medicine,Baltimore,Maryland.
文摘background Monoclonal antibodies(mAbs)targeting immune checkpoint molecules such as programmed death ligand 1(PD-L1),which is expressed in both immune and tumour cells,are conventional immunotherapy approaches.Although approved as monotherapy for the first-line treatment of several cancers,mAbs targeting PD-L1 have shown limited efficacy in colorectal cancer(CRC).Here,we investigated if nucleic acids translated into anti-PD L1 nanobodies(PDL1Nbs)effectively suppress CRC tumourigenesis in mouse models.Methods Mice were transplanted with MC-38 mouse sporadic CRC(sCRC)cells or challenged with azoxymethane and dextran sodium sulfate,a combination treatment that induces colitis-associated CRC(CAC).The tumour-bearing mice were treated with a PDL1Nb-encoding plasmid DNA(pDNA)delivered via polymers,or treated with PDL1Nb-encoding nucleoside-modified messenger RNA(PDL1Nb mRNA)delivered via lipid nanoparticles(LNP).Moreover,bone marrow haematopoietic stem cells(BMHSCs)were differentiated and maturated by treating growth factors in the presence of PDL1Nb mRNA-LNP or control luciferase mRNA-LNP with/without lipopolysaccharide.We examined sCRC tumour proliferation and growth,CAC tumour incidences and numbers,tumour infiltration of immune cells and bone marrow-derived macrophages(BMDMs).results Polymer delivery of PDL1Nb pDNA efficiently repressed sCRC progression in tumour-bearing mice.Intriguingly,LNP delivery of the quadruple PDL1Nb(qPDL1Nb)mRNA showed a greater efficacy than the delivery of the monomeric PDL1Nb(mPDL1Nb)mRNA in suppressing sCRC tumour progression.Moreover,qPDL1Nb mRNA-LNP treatment significantly reduced CAC incidence.Mechanistically,PD-L1 blockade by qPDL1Nb resulted in marked decreases in tumour-infiltrating myeloid-derived suppressor cells and tumour-associated macrophages,as well as expression of PD-L1,but increases in tumour-infiltrating CD3+CD8+cells during CAC tumourigenesis.Notably,in vitro LNP delivery of PDL1Nb mRNA into BMHSCs significantly inhibited their differentiation and maturation into BMDMs and strikingly reduced the expression of PD-L1,CD80,CD86 and CD206 in BMDMs.
基金supported by the National Natural Science Foundation of China(62474168 and 12012422)the Chinese Academy of Sciences Project for Young Scientists in Basic Research(YSBR-112)+2 种基金the National Key R&D Program of China(2019YFA0308700)the Chinese Academy of Sciences,the Anhui Initiative in Quantum Information Technologies,the Shanghai Municipal Science and Technology Major Project(2019SHZDZX01)the Innovation Program for Quantum Science and Technology(2021ZD0300204 and 2021ZD0301400).
文摘The degradation caused by surface states restricts the performance of near-surface semiconductor quantum dots(QDs).Here,we demonstrate optimized passivation techniques to improve the resonance fluorescence(RF)with dotto-dot comparisons.These optimized techniques,for the first time,reduce the linewidth and noise level of existing pulsed-RF signals,as well as revive pulsed-RF signals which originally are vanishing.The improvements are confirmed to originate from reduced surface state density and electric field after passivation,through optical and surface science characterizations.Our study promotes applications of the passivation techniques in thin-film quantum devices,paving the way for the further development of optimal QD-based quantum light sources.
基金funded by National Key R&D Program of China(2023YFC3503205、2023YFC3503200)National Natural Science Foundation of China(82472658)+2 种基金CAMS Initiative for Innovative Medicine(2021-I2M-1-018)Sanming Project of Medicine in Shenzhen(No.SZSM202311002)Shenzhen Medical Research Funds(C2303002).
文摘Targeting the DNA damage response(DDR)exhibits potent efficacy in inducing immune activation and enhancing patient prognosis.However,the benefits of DDR regulation are not universally observed across all patients,owing to the intricate compensatory mechanisms operative in certain cancers.There still exists a gap in the function of activated DDR protein in esophageal squamous cell carcinoma(ESCC).Here,we demonstrate that increased expression of DDR genes contributes to the progression of esophageal squamous cell carcinoma and suppresses the tumor immune microenvironment.Notably,the abundant presence of the DDR protein KIN in ESCC tissues facilitates efficient DNA damage clearance and promotes escape from apoptosis.Depletion of KIN significantly inhibited proliferation and induced DNA damage accumulation in ESCC cells.Mechanistically,KIN functions to support the recruitment of the R-loop regulator DHX9 to R-loop sites,thereby addressing DNA damage associated R-loops.Intriguingly,the depletion of KIN activates the STING pathway via NFκB signaling,which is induced by the accumulation of R-loops,ultimately initiating an innate immune response.Depletion of KIN improved the immune microenvironment and the effect of immune therapy in mouse model.Collectively,our findings identify KIN as a novel R-loop binding protein that facilitates the recruitment of the R-loop resolution complex and suppresses tumor-intrinsic innate immunity.
基金supported by the National Natural Science Foundation of China(42101418 and 42371413)the National Natural Science Foundation of China/RGC Joint Research Scheme(42361164614 and N_HKU722/23)+1 种基金the NSFC Excellent Young Scientists Fund(Overseas)the Chinese University Scientific Fund.
文摘Synthetic aperture radar(SAR)records important information about the interaction of electromagnetic waves with the Earth’s surface.However,long-term and high-resolution backscatter coefficient data are still lacking in many urban studies(e.g.,building height estimation).Here,we proposed a framework to reconstruct the 1-km backscatter coefficient in 1990-2022 utilizing the Sentinel-1 Ground Range Detected data and Landsat time series data in the Jing-Jin-Ji(JJJ)region.First,we developed a regression model to convert the optical signals from Landsat into backscatter coefficients as the Sentinel-1 data,using observations from 2015 to 2022.Then,we reconstructed backscatter coefficients from 1990 to 2022 using the long-term Landsat data.Using the reconstructed backscatter coefficients,we analyzed the dynamic patterns of building height over the past decades.The proposed approach performs well on estimating the backscatter coefficient and its spatial pattern,with the annual mean absolute error,root mean square error,and R^(2) of 1.10 dB,1.50 dB,and 0.64,respectively.The temporal trends revealed from the reconstructed backscatter data are reliable compared with satellite observations at a relatively coarse resolution,with Pearson’s coefficients above 0.92 in 6 sample cities.The derived building height from the reconstructed SAR data indicates that the JJJ region experienced a noticeable upward expansion in 1990-2022,e.g.,Beijing has the fastest growth rate of 0.420 km^(3)/decade regarding the total building volumes.The proposed framework of reconstructing SAR data from optical satellite images provides a new insight to complement the long-term and high-resolution backscatter from local to global scales.
