Small cell lung cancer(SCLC),a highly lethal lung cancer sub-type with distinct neuroendocrine-like features,accounts for 10%–15%of all lung cancers.The overall 5-year survival rate remains less than 10%.SCLC is char...Small cell lung cancer(SCLC),a highly lethal lung cancer sub-type with distinct neuroendocrine-like features,accounts for 10%–15%of all lung cancers.The overall 5-year survival rate remains less than 10%.SCLC is characterized by early metastasis,thus minimizing the potential patient benefits of surgery.In recent decades,the first-line treatment for SCLC has remained chemotherapy combining etoposide and cisplatin(E/P).Despite high rates of response to E/P treatment,SCLC eventually relapses and is almost universally resistant to treatment at recurrence,thus making SCLC a recalcitrant malignancy.Moreover,the limited knowledge regarding the molecular mechanisms underlying SCLC metastasis and resistance greatly hinders improvements in overall SCLC survival.To better understand the molecular mechanisms of SCLC and discover potential therapeutic targets,extensive efforts have continued for decades.展开更多
Cryo-Electron Microscopy(Cryo-EM)images are characterized by the low signal-to-noise ratio,low contrast,serious background noise,more impurities,less data,difficult data labeling,simpler image semantics,and relatively...Cryo-Electron Microscopy(Cryo-EM)images are characterized by the low signal-to-noise ratio,low contrast,serious background noise,more impurities,less data,difficult data labeling,simpler image semantics,and relatively fixed structure,while U-Net obtains low resolution when downsampling rate information to complete object category recognition,obtains highresolution information during upsampling to complete precise segmentation and positioning,fills in the underlying information through skip connection to improve the accuracy of image segmentation,and has advantages in biological image processing like Cryo-EM image.This article proposes A U-Net based residual intensive neural network(Urdnet),which combines point-level and pixel-level tags,used to accurately and automatically locate particles from cryo-electron microscopy images,and solve the bottleneck that cryo-EM Single-particle biologicalmacromolecule reconstruction requires tens of thousands of automatically picked particles.The 80S ribosome,HCN1 channel and TcdA1 toxin subunits,and other public protein datasets have been trained and tested on Urdnet.The experimental results show that Urdnet could reach the same excellent particle picking performances as the mainstream methods of RELION,DeepPicker,and acquire the 3Dstructure of picked particleswith higher resolution.展开更多
The genetic information coded in DNA leads to trait innovation via a gene regulatory network(GRN)in development.Here,we developed a conserved non-coding element interpretation method to integrate multi-omics data into...The genetic information coded in DNA leads to trait innovation via a gene regulatory network(GRN)in development.Here,we developed a conserved non-coding element interpretation method to integrate multi-omics data into gene regulatory network(CNEReg)to investigate the ruminant multi-chambered stomach innovation.We generated paired expression and chromatin accessibility data during rumen and esophagus development in sheep,and revealed 1601 active ruminantspecific conserved non-coding elements(active-RSCNEs).To interpret the function of these activeRSCNEs,we defined toolkit transcription factors(TTFs)and modeled their regulation on rumenspecific genes via batteries of active-RSCNEs during development.Our developmental GRN revealed 18 TTFs and 313 active-RSCNEs regulating 7 rumen functional modules.Notably,6 TTFs(OTX1,SOX21,HOXC8,SOX2,TP63,and PPARG),as well as 16 active-RSCNEs,functionally distinguished the rumen from the esophagus.Our study provides a systematic approach to understanding how gene regulation evolves and shapes complex traits by putting evo-devo concepts into practice with developmental multi-omics data.展开更多
The rumen is the hallmark organ of ruminants and hosts a diverse ecosystem of microorganisms that facilitates efficient digestion of plant fibers.We analyzed 897 transcriptomes from three Cetartiodactyla lineages:rumi...The rumen is the hallmark organ of ruminants and hosts a diverse ecosystem of microorganisms that facilitates efficient digestion of plant fibers.We analyzed 897 transcriptomes from three Cetartiodactyla lineages:ruminants,camels and cetaceans,as well as data from ruminant comparative genomics and functional assays to explore the genetic basis of rumen functional innovations.We identified genes with relatively high expression in the rumen,of which many appeared to be recruited from other tissues.These genes show functional enrichment in ketone body metabolism,regulation of microbial community,and epithelium absorption,which are the most prominent biological processes involved in rumen innovations.Several modes of genetic change underlying rumen functional innovations were uncovered,including coding mutations,genes newly evolved,and changes of regulatory elements.We validated that the key ketogenesis rate-limiting gene(HMGCS2)with five ruminant-specific mutations was under positive selection and exhibits higher synthesis activity than those of other mammals.Two newly evolved genes(LYZ1 and DEFB1)are resistant to Gram-positive bacteria and thereby may regulate microbial community equilibrium.Furthermore,we confirmed that the changes of regulatory elements accounted for the majority of rumen gene recruitment.These results greatly improve our understanding of rumen evolution and organ evo-devo in general.展开更多
Mesenchymal stem cell(MSC)-mediated immunomodulation has been harnessed for the treatment of human diseases,but its underlying mechanism has not been fully understood.Dead cells,including apoptotic cells have immunomo...Mesenchymal stem cell(MSC)-mediated immunomodulation has been harnessed for the treatment of human diseases,but its underlying mechanism has not been fully understood.Dead cells,including apoptotic cells have immunomodulatory properties.It has been repeatedly reported that the proportion of nonviable MSCs in a MSC therapeutic preparation varied from 5-50%in the ongoing clinical trials.It is conceivable that the nonviable cells in a MSC therapeutic preparation may play a role in the therapeutic effects of MSCs.We found that the MSC therapeutic preparation in the present study had about 5%dead MSCs(DMSCs),characterized by apoptotic cells.Namely,1×10^(6) MSCs in the preparation contained about 5×10^(4) DMSCs.We found that the treatment with even 5×10^(4) DMSCs alone had the equal therapeutic effects as with 1×10^(6) MSCs.This protective effect of the dead MSCs alone was confirmed in four mouse models,including concanavalin A(ConA)-and carbon tetrachloride(CCI4)-induced acute liver injury,LPS-induced lung injury and spinal cord injury.We also found that the infused MSCs died by apoptosis in vivo.Furthermore,the therapeutic effect was attributed to the elevated level of phosphatidylserine(PS)upon the injection of MSCs or DMSCs.The direct administration of PS liposomes(PSLs)mimic apoptotic cell fragments also exerted the protective effects as MSCs and DMSCs.The Mer tyrosine kinase(MerTK)deficiency or the knockout of chemokine receptor C-C motif chemokine receptor 2(CCR2)reversed these protective effects of MSCs or DMSCs.These results revealed that DMSCs alone in the therapeutic stem cell preparation or the apoptotic cells induced in vivo may exert the same immunomodulatory property as the'living MSCs preparation"through releasing PS,which was further recognized by MerTK and participated in modulating immune cells.展开更多
Precipitation-hardening in fcc-based high-entro py alloys(HEAs)have usually been realized by introducing complex intermetallic compounds.In this study,enhanced strength is ascribed to the existence of L1_(2) precipita...Precipitation-hardening in fcc-based high-entro py alloys(HEAs)have usually been realized by introducing complex intermetallic compounds.In this study,enhanced strength is ascribed to the existence of L1_(2) precipitates and B2/bcc conjoint phases in the fcc matrix.The nano-size particles in the Al_(0.5)CoCrFeNi HEA are produced by cold-rolling,followed by intermediate-temperature-annealing at 650℃.For L1_(2) ordering,the initial granular structure has transformed into lamella structure and then kept stable when the holding time prolonged to 200 h.The formation of this conjoint B2/bcc driven by the concentration profiles takes place when the diffusion process of elements is sufficient after long-time aging.Based on the microstructure analysis,changes in mechanical properties are associated with the shape,size scale and volume fraction of the precipitates.The peak ultimate tensile stress reaches 1221.5 MPa,1.97 times compared with the as-cast alloy,remaining plasticity of 21.3%.展开更多
UTX(also known as KDM6A),a histone 3 lysine 27 demethylase,is among the most frequently mutated epigenetic regulators in myelodysplastic syndrome(MDS)and acute myeloid leukemia(AML).Recent studies have suggested that ...UTX(also known as KDM6A),a histone 3 lysine 27 demethylase,is among the most frequently mutated epigenetic regulators in myelodysplastic syndrome(MDS)and acute myeloid leukemia(AML).Recent studies have suggested that UTX mutations promote MDS and AML by blocking the differentiation of hematopoietic stem and progenitor cells(HSPCs).Here,we performed an epigenetic drug library screening for small molecules able to release the differentiation block on HSPCs induced by UTX deficiency.We found that SP2509,a selective inhibitor of LSD1,specifically promoted the differentiation of Utx-null HSPCs while sparing wild-type HSPCs.Transcriptome profiling showed that Utx loss reduced the expression of differentiation-related and tumor suppressor genes,correlating with their potential roles in HSPC self-renewal and leukemogenesis.In contrast,SP2509 treatment reversed these changes in gene expression in Utx-null HSPCs.Accordingly,Utx loss decreased H3K4 methylation level probably through the COMPASS-like complex,while LSD1 inhibition by SP2509 partially reversed the reduction of H3K4 methylation in Utx-deficient HSPCs.Further,SP2509 promoted the differentiation of Utx-null AML cells in vitro and in vivo and,therefore,extended the survival of these leukemic mice.Thus,our study identified a novel strategy to specifically target both premalignant and malignant cells with Utx deficiency for differentiation therapy and provided insights into the molecular mechanisms underlying the role of Utx in regulating HSPCs and related diseases.展开更多
The cell identity of malignant cells and how they acquire it are fundamental for our understanding of cancer.Here,we report that esophageal squamous cell carcinoma(ESCC)cells display molecular features equally similar...The cell identity of malignant cells and how they acquire it are fundamental for our understanding of cancer.Here,we report that esophageal squamous cell carcinoma(ESCC)cells display molecular features equally similar but distinct to all three types of normal esophageal epithelial cells,which we term as confused cell identity(CCI).CCI is an independent prognostic marker associated with poor prognosis in ESCC.Further,we identify tropomyosin 4(TPM4)as a critical CCI gene that promotes the aggressiveness of ESCC in vitro and in vivo.And TPM4 creates CCI through activating the Jak/STAT-SOX2 pathway.Thus,our study suggests an unrecognized feature of ESCC cells,which might be of value for clinic prognosis and potential interference.展开更多
The sheep(Ovis aries) was one of the first grazing animals to be domesticated approximately 11,000 years ago in the Fertile Crescent(Chessa et al., 2009). Since domestication, a wide variety of sheep breeds with diffe...The sheep(Ovis aries) was one of the first grazing animals to be domesticated approximately 11,000 years ago in the Fertile Crescent(Chessa et al., 2009). Since domestication, a wide variety of sheep breeds with different production traitsand morphological characteristics have been shaped under the influence of natural and artificial selection. According to the fat content in tail, sheep can be mainly classified into two groups: thin-and fat-tailed breeds.展开更多
After online publication of the article1,the authors noticed one inadvertent mistake in Fig.5a that needs to be corrected.In detail,the pathological picture of PBS group in Fig.5a is inadvertently duplicated as the im...After online publication of the article1,the authors noticed one inadvertent mistake in Fig.5a that needs to be corrected.In detail,the pathological picture of PBS group in Fig.5a is inadvertently duplicated as the image of PBS group in Fig.7b in the main text.This duplication is a result of errors in figure assembly,and the correct Fig.5 is provided as follows.The key findings of the article are not affected by these corrections.展开更多
基金supported by grant from the National Natural Science Foundation of China(Grant No.82102779).
文摘Small cell lung cancer(SCLC),a highly lethal lung cancer sub-type with distinct neuroendocrine-like features,accounts for 10%–15%of all lung cancers.The overall 5-year survival rate remains less than 10%.SCLC is characterized by early metastasis,thus minimizing the potential patient benefits of surgery.In recent decades,the first-line treatment for SCLC has remained chemotherapy combining etoposide and cisplatin(E/P).Despite high rates of response to E/P treatment,SCLC eventually relapses and is almost universally resistant to treatment at recurrence,thus making SCLC a recalcitrant malignancy.Moreover,the limited knowledge regarding the molecular mechanisms underlying SCLC metastasis and resistance greatly hinders improvements in overall SCLC survival.To better understand the molecular mechanisms of SCLC and discover potential therapeutic targets,extensive efforts have continued for decades.
基金supported by Key Projects of the Ministry of Science and Technology of the People’s Republic of China(2018AAA0102301)the Open Research Fund of Hunan Provincial Key Laboratory of Network Investigational Technology,Grant No.2018WLZC001.
文摘Cryo-Electron Microscopy(Cryo-EM)images are characterized by the low signal-to-noise ratio,low contrast,serious background noise,more impurities,less data,difficult data labeling,simpler image semantics,and relatively fixed structure,while U-Net obtains low resolution when downsampling rate information to complete object category recognition,obtains highresolution information during upsampling to complete precise segmentation and positioning,fills in the underlying information through skip connection to improve the accuracy of image segmentation,and has advantages in biological image processing like Cryo-EM image.This article proposes A U-Net based residual intensive neural network(Urdnet),which combines point-level and pixel-level tags,used to accurately and automatically locate particles from cryo-electron microscopy images,and solve the bottleneck that cryo-EM Single-particle biologicalmacromolecule reconstruction requires tens of thousands of automatically picked particles.The 80S ribosome,HCN1 channel and TcdA1 toxin subunits,and other public protein datasets have been trained and tested on Urdnet.The experimental results show that Urdnet could reach the same excellent particle picking performances as the mainstream methods of RELION,DeepPicker,and acquire the 3Dstructure of picked particleswith higher resolution.
基金supported by the National Key R&D Program of China(Grant No.2020YFA0712402)the Strategic Priority Research Program of the Chinese Academy of Sciences(Grant No.XDPB17)+3 种基金the CAS Project for Young Scientists in Basic Research(Grant No.YSBR-077)the National Natural Science Foundation of China(Grant Nos.12025107,11871463,11688101,and 61621003)the National Thousand Youth Talents Plan,and the CAS“Light of West China”Program(Grant No.xbzg-zdsys-201913)China.We thank High Performance Computing(HPC)of Northwest A&F University(NWAFU)for providing computing resources。
文摘The genetic information coded in DNA leads to trait innovation via a gene regulatory network(GRN)in development.Here,we developed a conserved non-coding element interpretation method to integrate multi-omics data into gene regulatory network(CNEReg)to investigate the ruminant multi-chambered stomach innovation.We generated paired expression and chromatin accessibility data during rumen and esophagus development in sheep,and revealed 1601 active ruminantspecific conserved non-coding elements(active-RSCNEs).To interpret the function of these activeRSCNEs,we defined toolkit transcription factors(TTFs)and modeled their regulation on rumenspecific genes via batteries of active-RSCNEs during development.Our developmental GRN revealed 18 TTFs and 313 active-RSCNEs regulating 7 rumen functional modules.Notably,6 TTFs(OTX1,SOX21,HOXC8,SOX2,TP63,and PPARG),as well as 16 active-RSCNEs,functionally distinguished the rumen from the esophagus.Our study provides a systematic approach to understanding how gene regulation evolves and shapes complex traits by putting evo-devo concepts into practice with developmental multi-omics data.
基金supported by the National Natural Science Foundation of China(31822052,31572381)the National Thousand Youth Talents Plan to Y.J.+3 种基金National Natural Science Foundation of China(31660644)to S.H.National Natural Science Foundation of China(41422604)to S.L.The Villum Foundation(VKR 023447)the Independent Research Fund Denmark(8049-00098B)。
文摘The rumen is the hallmark organ of ruminants and hosts a diverse ecosystem of microorganisms that facilitates efficient digestion of plant fibers.We analyzed 897 transcriptomes from three Cetartiodactyla lineages:ruminants,camels and cetaceans,as well as data from ruminant comparative genomics and functional assays to explore the genetic basis of rumen functional innovations.We identified genes with relatively high expression in the rumen,of which many appeared to be recruited from other tissues.These genes show functional enrichment in ketone body metabolism,regulation of microbial community,and epithelium absorption,which are the most prominent biological processes involved in rumen innovations.Several modes of genetic change underlying rumen functional innovations were uncovered,including coding mutations,genes newly evolved,and changes of regulatory elements.We validated that the key ketogenesis rate-limiting gene(HMGCS2)with five ruminant-specific mutations was under positive selection and exhibits higher synthesis activity than those of other mammals.Two newly evolved genes(LYZ1 and DEFB1)are resistant to Gram-positive bacteria and thereby may regulate microbial community equilibrium.Furthermore,we confirmed that the changes of regulatory elements accounted for the majority of rumen gene recruitment.These results greatly improve our understanding of rumen evolution and organ evo-devo in general.
基金This work was supported by the National Natural Science Foundation Regional Innovation and Development(number U19A2003)National Major Scientific and Technological Special Project for"Significant New Drugs Development”(number 2018ZX09733001)+3 种基金Excellent Youth Foundation of the Sichuan Scientific Committee Grant in China(number 2019JDJQ008)Development Program of China(number 2016YFA0201402)the National Natural Science Foundation of China(number 81800421)the National Natural Science Foundation of China(number 81821002).
文摘Mesenchymal stem cell(MSC)-mediated immunomodulation has been harnessed for the treatment of human diseases,but its underlying mechanism has not been fully understood.Dead cells,including apoptotic cells have immunomodulatory properties.It has been repeatedly reported that the proportion of nonviable MSCs in a MSC therapeutic preparation varied from 5-50%in the ongoing clinical trials.It is conceivable that the nonviable cells in a MSC therapeutic preparation may play a role in the therapeutic effects of MSCs.We found that the MSC therapeutic preparation in the present study had about 5%dead MSCs(DMSCs),characterized by apoptotic cells.Namely,1×10^(6) MSCs in the preparation contained about 5×10^(4) DMSCs.We found that the treatment with even 5×10^(4) DMSCs alone had the equal therapeutic effects as with 1×10^(6) MSCs.This protective effect of the dead MSCs alone was confirmed in four mouse models,including concanavalin A(ConA)-and carbon tetrachloride(CCI4)-induced acute liver injury,LPS-induced lung injury and spinal cord injury.We also found that the infused MSCs died by apoptosis in vivo.Furthermore,the therapeutic effect was attributed to the elevated level of phosphatidylserine(PS)upon the injection of MSCs or DMSCs.The direct administration of PS liposomes(PSLs)mimic apoptotic cell fragments also exerted the protective effects as MSCs and DMSCs.The Mer tyrosine kinase(MerTK)deficiency or the knockout of chemokine receptor C-C motif chemokine receptor 2(CCR2)reversed these protective effects of MSCs or DMSCs.These results revealed that DMSCs alone in the therapeutic stem cell preparation or the apoptotic cells induced in vivo may exert the same immunomodulatory property as the'living MSCs preparation"through releasing PS,which was further recognized by MerTK and participated in modulating immune cells.
基金supported financially by the National Natural Science Foundation of China(Nos.51774240 and 51571161)the fund of the State Key Laboratory of Solidification Processing in NWPU(No.2019-TS-04)the National Training Program of Innovation and Entrepreneurship for Undergraduates(No.201910699109)。
文摘Precipitation-hardening in fcc-based high-entro py alloys(HEAs)have usually been realized by introducing complex intermetallic compounds.In this study,enhanced strength is ascribed to the existence of L1_(2) precipitates and B2/bcc conjoint phases in the fcc matrix.The nano-size particles in the Al_(0.5)CoCrFeNi HEA are produced by cold-rolling,followed by intermediate-temperature-annealing at 650℃.For L1_(2) ordering,the initial granular structure has transformed into lamella structure and then kept stable when the holding time prolonged to 200 h.The formation of this conjoint B2/bcc driven by the concentration profiles takes place when the diffusion process of elements is sufficient after long-time aging.Based on the microstructure analysis,changes in mechanical properties are associated with the shape,size scale and volume fraction of the precipitates.The peak ultimate tensile stress reaches 1221.5 MPa,1.97 times compared with the as-cast alloy,remaining plasticity of 21.3%.
基金This work was supported by the National Key R&D Program of China(2017YFA0505600)the National Natural Science Foundation of China(81570150 and 81670182).
文摘UTX(also known as KDM6A),a histone 3 lysine 27 demethylase,is among the most frequently mutated epigenetic regulators in myelodysplastic syndrome(MDS)and acute myeloid leukemia(AML).Recent studies have suggested that UTX mutations promote MDS and AML by blocking the differentiation of hematopoietic stem and progenitor cells(HSPCs).Here,we performed an epigenetic drug library screening for small molecules able to release the differentiation block on HSPCs induced by UTX deficiency.We found that SP2509,a selective inhibitor of LSD1,specifically promoted the differentiation of Utx-null HSPCs while sparing wild-type HSPCs.Transcriptome profiling showed that Utx loss reduced the expression of differentiation-related and tumor suppressor genes,correlating with their potential roles in HSPC self-renewal and leukemogenesis.In contrast,SP2509 treatment reversed these changes in gene expression in Utx-null HSPCs.Accordingly,Utx loss decreased H3K4 methylation level probably through the COMPASS-like complex,while LSD1 inhibition by SP2509 partially reversed the reduction of H3K4 methylation in Utx-deficient HSPCs.Further,SP2509 promoted the differentiation of Utx-null AML cells in vitro and in vivo and,therefore,extended the survival of these leukemic mice.Thus,our study identified a novel strategy to specifically target both premalignant and malignant cells with Utx deficiency for differentiation therapy and provided insights into the molecular mechanisms underlying the role of Utx in regulating HSPCs and related diseases.
基金supported by the National Natural Science Foundation of China(32030016)the Natural Science Foundation of Shaanxi Province(2020JQ-149)+2 种基金the State Key Laboratory of Genetics Resources and Evolution(GREKF19-11)the Innovation Foundation for Doctor Dissertation of Northwestern Polytechnical University to Zeshan Linthe Shaanxi Program for Support of Topnotch Young Professionals to Lei Chen。
基金We thank the members of the CC-LY laboratory for their technical support and suggestions,and the Core Facilities of West China Hospital.This work was supported by the National Key R&D Program of China(2017YFA0505600)the National Natural Science Foundation of China(81522003,82170171,81770157,and 82003156)+1 种基金the Sichuan Science and Technology Program(2020YFQ0059,2018JZ0077,2017TJPT0005,2022YFS0171 and 2022YFS0205)1.3.5.Project for Disciplines of Excellence,West China Hospital,Sichuan University,and the innovation initiative of Sichuan University,Grant no.2018SCUH0060.We thank the Chengdu OrganoidMed Medical Laboratory for their technical support.We also thank BioRender(biorender.com)for providing items for drawing scheme graphs.
文摘The cell identity of malignant cells and how they acquire it are fundamental for our understanding of cancer.Here,we report that esophageal squamous cell carcinoma(ESCC)cells display molecular features equally similar but distinct to all three types of normal esophageal epithelial cells,which we term as confused cell identity(CCI).CCI is an independent prognostic marker associated with poor prognosis in ESCC.Further,we identify tropomyosin 4(TPM4)as a critical CCI gene that promotes the aggressiveness of ESCC in vitro and in vivo.And TPM4 creates CCI through activating the Jak/STAT-SOX2 pathway.Thus,our study suggests an unrecognized feature of ESCC cells,which might be of value for clinic prognosis and potential interference.
基金supported by the research grants from the National Natural Science Foundation of China (31822052)the National Thousand Youth Talents Plan, the Key Laboratory Research Grant of Xinjiang Province (2017D04028)+1 种基金Tianshan Innovation Team program (2018D14004)the startup fund from Northwest A&F University (Z1090220306)。
文摘The sheep(Ovis aries) was one of the first grazing animals to be domesticated approximately 11,000 years ago in the Fertile Crescent(Chessa et al., 2009). Since domestication, a wide variety of sheep breeds with different production traitsand morphological characteristics have been shaped under the influence of natural and artificial selection. According to the fat content in tail, sheep can be mainly classified into two groups: thin-and fat-tailed breeds.
文摘After online publication of the article1,the authors noticed one inadvertent mistake in Fig.5a that needs to be corrected.In detail,the pathological picture of PBS group in Fig.5a is inadvertently duplicated as the image of PBS group in Fig.7b in the main text.This duplication is a result of errors in figure assembly,and the correct Fig.5 is provided as follows.The key findings of the article are not affected by these corrections.