Recent studies have found that erythropoietin promotes the recovery of neurological function after traumatic brain injury.However,the precise mechanism of action remains unclea r.In this study,we induced moderate trau...Recent studies have found that erythropoietin promotes the recovery of neurological function after traumatic brain injury.However,the precise mechanism of action remains unclea r.In this study,we induced moderate traumatic brain injury in mice by intrape ritoneal injection of erythro poietin for 3 consecutive days.RNA sequencing detected a total of 4065 differentially expressed RNAs,including 1059 mRNAs,92 microRNAs,799 long non-coding RNAs,and 2115circular RNAs.Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses revealed that the coding and non-coding RNAs that were differentially expressed after traumatic brain injury and treatment with erythropoietin play roles in the axon guidance pathway,Wnt pathway,and MAPK pathway.Constructing competing endogenous RNA networks showed that regulatory relationship between the differentially expressed non-coding RNAs and mRNAs.Because the axon guidance pathway was repeatedly enriched,the expression of Wnt5a and Ephb6,key factors in the axonal guidance pathway,was assessed.Ephb6 expression decreased and Wnt5a expression increased after traumatic brain injury,and these effects were reversed by treatment with erythro poietin.These findings suggest that erythro poietin can promote recove ry of nerve function after traumatic brain injury through the axon guidance pathway.展开更多
The organized alignment of cells in various tissues plays a significant role in the maintenance of specific functions.To induce such an alignment,ideal scaffolds should simulate the characteristics and morphologies of...The organized alignment of cells in various tissues plays a significant role in the maintenance of specific functions.To induce such an alignment,ideal scaffolds should simulate the characteristics and morphologies of natural tissues.Aligned structures that guide cell orientation are used to facilitate tissue regeneration and repair.We here review how various aligned structures are fabricated,including aligned electrospun nanofibers,aligned porous or channeled structures,micropatterns and combinations thereof,and their application in nerve,skeletal muscle,tendon,and tubular dentin regeneration.The future use of aligned structures in tissue engineering is also discussed.展开更多
Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel tar...Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases,but no systematic screening for DR has been performed.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.DR data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European controls.Genetic instrumental variables were identified using multiple filters.In the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with DR.Bidirectional MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses.By systemically searching druggable gene lists,the ChEMBL database,DrugBank,and Gene Ontology database,the druggability and relevant functional pathways of the identified proteins were systematically evaluated.Results:Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate<0.05 including 11 with positive associations and 13 with negative associations.For each standard deviation increase in plasm protein levels,the odds ratios(ORs)for DR varied from 0.51(95%CI:0.36-0.73;P=2.22×10-5)for tubulin polymerization-promoting protein family member 3(TPPP3)to 2.02(95%CI:1.44-2.83;P=5.01×10-5)for olfactomedin like 3(OLFML3).Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR analyses.Four proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)were negatively associated with DR risk,while neurogenic locus notch homolog protein 2(NOTCH2)showed a positive association.No confounding factors were detected between pQTLs and DR according to the phenotypic scan.Drugability assessments highlighted 6 proteins already in drug development endeavor and 18 novel drug targets,with metalloproteinase inhibitor 3(TIMP)currently in phase I clinical trials for DR.GO analysis identified 18 of 24 plasma proteins enriching 22 pathways related to cell differentiation and proliferation regulation.Conclusions:Twenty-four promising drug targets for DR were identified,including four plasma proteins with particular co-localization evidence.These findings offer new insights into DR's etiology and therapeutic targeting,exemplifying the value of genomic and proteomic data in drug target discovery.展开更多
Purpose:To identify plasma proteins that are causally related to primary open-angle glaucoma(POAG)for potential therapeutic targeting.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were deri...Purpose:To identify plasma proteins that are causally related to primary open-angle glaucoma(POAG)for potential therapeutic targeting.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.POAG data were sourced from the largest FinnGen study,comprising 8,530 DR cases and 391,275 European controls.A two-sample MR analysis,supplemented by bidirectional MR,Bayesian co-localization analysis,and phenotype scanning,was conducted to examine the causal relationships between plasma proteins and POAG.The analysis was validated by identifying associations between plasma proteins and POAG-related traits,including intraocular pressure(IOP),retinal nerve fibre layer(RNFL),and ganglion cell and inner plexiform layer(GCIPL).By searching druggable gene lists,the ChEMBL database,and the ClinicalTrials.gov database,the druggability and clinical development activity of the identified proteins were systematically evaluated.Results:Eighteen proteins were identified with significant associations with POAG risk after multiple comparison adjustments.The ORs per standard deviation increase in protein levels ranged from 0.39(95%CI:0.24–0.62;P=7.70×10-5)for phospholipase C gamma 1(PLCG1)to 1.29(95%CI:1.16–1.44;P=6.72×10-6)for nidogen-1(NID1).Bidirectional MR indicated that reverse causality did not interfere with the results of the main MR analyses.Five proteins exhibited strong co-localization evidence(PH4≥0.8):protein sel-1 homolog 1(SEL1L),tyrosine-protein kinase receptor UFO(AXL),nidogen-1(NID1)and FAD-linked sulfhydryl oxidase ALR(GFER)were negatively associated with POAG risk,while roundabout homolog 1(ROBO1)showed a positive association.The phenotype scanning did not reveal any confounding factors between pQTLs and POAG.Further,validation analyses identified nine proteins causally related to POAG traits,with five proteins including interleukin-18 receptor 1(IL18R1),interleukin-1 receptor type 1(IL1R1),phospholipase C gamma 1(PLCG1),ribonuclease pancreatic(RNASE1),serine protease inhibitor Kazal-type 6(SPINK6)revealing consistent directional associations.In addition,18 causal proteins were highlighted for their druggability,of which 5 proteins are either already approved drugs or in clinical trials and 13 proteins are novel drug targets.Conclusions:This study identifies 18 plasma proteins as potential therapeutic targets for POAG,particularly emphasizing the role of genomic and proteomic integration in drug discovery.Future experimental and clinical studies should be conducted to validate the efficacy of these proteins and to conduct more comprehensive proteomic explorations,thus taking a significant leap toward innovative POAG treatments.展开更多
Background The hippocampus and amygdala are densely interconnected structures that work together in multiple affective and cognitive processes that are important to the etiology of major depressive disorder(MDD).Each ...Background The hippocampus and amygdala are densely interconnected structures that work together in multiple affective and cognitive processes that are important to the etiology of major depressive disorder(MDD).Each of these structures consists of several heterogeneous subfields.We aim to explore the topologic properties of the volume-based intrinsic network within the hippocampus–amygdala complex in medication-nale patients with first-episode MDD.Methods High-resolution T1-weighted magnetic resonance imaging scans were acquired from 123 first-episode,medication-nale,and noncomorbid MDD patients and 81 age-,sex-,and education level-matched healthy control participants(HCs).The structural covariance network(SCN)was constructed for each group using the volumes of the hippocampal subfields and amygdala subregions;the weights of the edges were defined by the partial correlation coefficients between each pair of subfields/subregions,controlled for age,sex,education level,and intracranial volume.The global and nodal graphmetrics were calculated and compared between groups.Results Compared with HCs,the SCN within the hippocampus–amygdala complex in patients with MDD showed a shortened mean characteristic path length,reduced modularity,and reduced small-worldness index.At the nodal level,the left hippocampal tail showed increased measures of centrality,segregation,and integration,while nodes in the left amygdala showed decreased measures of centrality,segregation,and integration in patients with MDD compared with HCs.Conclusion Our results provide the first evidence of atypical topologic characteristics within the hippocampus–amygdala complex in patients with MDD using structure network analysis.It provides more delineate mechanism of those two structures that underlying neuropathologic process in MDD.展开更多
Background:Abnormalities of cortical thickness(CTh)in patients with their first episode psychosis(FEP)have been frequently reported,but findings are inconsistent.Objective:To define the most consistent CTh changes in ...Background:Abnormalities of cortical thickness(CTh)in patients with their first episode psychosis(FEP)have been frequently reported,but findings are inconsistent.Objective:To define the most consistent CTh changes in patients with FEP by meta-analysis of publishedwholebrain studies.Methods:The meta-analysis used seed-based dmapping(SDM)software to obtain the most prominent regional CTh changes in FEP,and meta-regression analyses to explore the effects of demographics and clinical characteristics.The meta-analysis results were verified in an independent sample of 142 FEP patients and 142 age-and sex-matched healthy controls(HCs),using both a vertex-wise and a region of interest analysis,with multiple comparisons correction.Results:The meta-analysis identified lower CTh in the rightmiddle temporal cortex(MTC)extending to superior temporal cortex(STC),insula,and anterior cingulate cortex(ACC)in FEP compared with HCs.No significant correlations were identified between CTh alterations and demographic or clinical variables.These results were replicated in the independent dataset analysis.Conclusion:This study identifies a robust pattern of cortical abnormalities in FEP and extends understanding of gray matter abnormalities and pathological mechanisms in FEP.展开更多
基金supported by the National Natural Science Foundation of China,No.81771355the Natural Science Foundation of Chongqing Science and Technology Bureau,Nos.CSTC2015jcyjA10096,cstc2021jcyj-msxmX0262(all to ZL)。
文摘Recent studies have found that erythropoietin promotes the recovery of neurological function after traumatic brain injury.However,the precise mechanism of action remains unclea r.In this study,we induced moderate traumatic brain injury in mice by intrape ritoneal injection of erythro poietin for 3 consecutive days.RNA sequencing detected a total of 4065 differentially expressed RNAs,including 1059 mRNAs,92 microRNAs,799 long non-coding RNAs,and 2115circular RNAs.Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses revealed that the coding and non-coding RNAs that were differentially expressed after traumatic brain injury and treatment with erythropoietin play roles in the axon guidance pathway,Wnt pathway,and MAPK pathway.Constructing competing endogenous RNA networks showed that regulatory relationship between the differentially expressed non-coding RNAs and mRNAs.Because the axon guidance pathway was repeatedly enriched,the expression of Wnt5a and Ephb6,key factors in the axonal guidance pathway,was assessed.Ephb6 expression decreased and Wnt5a expression increased after traumatic brain injury,and these effects were reversed by treatment with erythro poietin.These findings suggest that erythro poietin can promote recove ry of nerve function after traumatic brain injury through the axon guidance pathway.
基金This work was financially supported by the National Key Research and Development Program of China(2018YFA0703000)the NationalNatural Science Foundation of China(81670972,31872752)+1 种基金Key Research and Development Program of Zhejiang,China(2017C01054,2018C03062,2017C01063)Postdoctoral Science Foundation of China(2020TQ0257,2020M681896).
文摘The organized alignment of cells in various tissues plays a significant role in the maintenance of specific functions.To induce such an alignment,ideal scaffolds should simulate the characteristics and morphologies of natural tissues.Aligned structures that guide cell orientation are used to facilitate tissue regeneration and repair.We here review how various aligned structures are fabricated,including aligned electrospun nanofibers,aligned porous or channeled structures,micropatterns and combinations thereof,and their application in nerve,skeletal muscle,tendon,and tubular dentin regeneration.The future use of aligned structures in tissue engineering is also discussed.
基金funded by the Hainan Province Clinical Medical Center(82171084)the National Natural Science Foundation of China(82371086).
文摘Background:Diabetic retinopathy(DR)urgently needs novel and effective therapeutic targets.Integrated analyses of plasma proteomic and genetic markers can clarify the causal relevance of proteins and discover novel targets for diseases,but no systematic screening for DR has been performed.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.DR data were sourced from the largest FinnGen study,comprising 10,413 DR cases and 308,633 European controls.Genetic instrumental variables were identified using multiple filters.In the two-sample MR analysis,Wald ratio and inverse variance-weighted(IVW)MR were utilized to investigate the causality of plasma proteins with DR.Bidirectional MR,Bayesian Co-localization,and phenotype scanning were employed to test for potential reverse causality and confounding factors in the main MR analyses.By systemically searching druggable gene lists,the ChEMBL database,DrugBank,and Gene Ontology database,the druggability and relevant functional pathways of the identified proteins were systematically evaluated.Results:Genetically predicted levels of 24 proteins were significantly associated with DR risk at a false discovery rate<0.05 including 11 with positive associations and 13 with negative associations.For each standard deviation increase in plasm protein levels,the odds ratios(ORs)for DR varied from 0.51(95%CI:0.36-0.73;P=2.22×10-5)for tubulin polymerization-promoting protein family member 3(TPPP3)to 2.02(95%CI:1.44-2.83;P=5.01×10-5)for olfactomedin like 3(OLFML3).Bidirectional MR indicated there was no reverse causality that interfered with the results of the main MR analyses.Four proteins exhibited strong co-localization evidence(PH4≥0.8):cytoplasmic tRNA synthetase(WARS),acrosin binding protein(ACRBP),and intercellular adhesion molecule 1(ICAM1)were negatively associated with DR risk,while neurogenic locus notch homolog protein 2(NOTCH2)showed a positive association.No confounding factors were detected between pQTLs and DR according to the phenotypic scan.Drugability assessments highlighted 6 proteins already in drug development endeavor and 18 novel drug targets,with metalloproteinase inhibitor 3(TIMP)currently in phase I clinical trials for DR.GO analysis identified 18 of 24 plasma proteins enriching 22 pathways related to cell differentiation and proliferation regulation.Conclusions:Twenty-four promising drug targets for DR were identified,including four plasma proteins with particular co-localization evidence.These findings offer new insights into DR's etiology and therapeutic targeting,exemplifying the value of genomic and proteomic data in drug target discovery.
基金supported by the Hainan Province Clinical Medical Center,the National Natural Science Foundation of China(82171084,82371086).
文摘Purpose:To identify plasma proteins that are causally related to primary open-angle glaucoma(POAG)for potential therapeutic targeting.Methods:Summary statistics of plasma protein quantitative trait loci(pQTL)were derived from two extensive genome-wide analysis study(GWAS)datasets and one systematic review,with over 100 thousand participants covering thousands of plasma proteins.POAG data were sourced from the largest FinnGen study,comprising 8,530 DR cases and 391,275 European controls.A two-sample MR analysis,supplemented by bidirectional MR,Bayesian co-localization analysis,and phenotype scanning,was conducted to examine the causal relationships between plasma proteins and POAG.The analysis was validated by identifying associations between plasma proteins and POAG-related traits,including intraocular pressure(IOP),retinal nerve fibre layer(RNFL),and ganglion cell and inner plexiform layer(GCIPL).By searching druggable gene lists,the ChEMBL database,and the ClinicalTrials.gov database,the druggability and clinical development activity of the identified proteins were systematically evaluated.Results:Eighteen proteins were identified with significant associations with POAG risk after multiple comparison adjustments.The ORs per standard deviation increase in protein levels ranged from 0.39(95%CI:0.24–0.62;P=7.70×10-5)for phospholipase C gamma 1(PLCG1)to 1.29(95%CI:1.16–1.44;P=6.72×10-6)for nidogen-1(NID1).Bidirectional MR indicated that reverse causality did not interfere with the results of the main MR analyses.Five proteins exhibited strong co-localization evidence(PH4≥0.8):protein sel-1 homolog 1(SEL1L),tyrosine-protein kinase receptor UFO(AXL),nidogen-1(NID1)and FAD-linked sulfhydryl oxidase ALR(GFER)were negatively associated with POAG risk,while roundabout homolog 1(ROBO1)showed a positive association.The phenotype scanning did not reveal any confounding factors between pQTLs and POAG.Further,validation analyses identified nine proteins causally related to POAG traits,with five proteins including interleukin-18 receptor 1(IL18R1),interleukin-1 receptor type 1(IL1R1),phospholipase C gamma 1(PLCG1),ribonuclease pancreatic(RNASE1),serine protease inhibitor Kazal-type 6(SPINK6)revealing consistent directional associations.In addition,18 causal proteins were highlighted for their druggability,of which 5 proteins are either already approved drugs or in clinical trials and 13 proteins are novel drug targets.Conclusions:This study identifies 18 plasma proteins as potential therapeutic targets for POAG,particularly emphasizing the role of genomic and proteomic integration in drug discovery.Future experimental and clinical studies should be conducted to validate the efficacy of these proteins and to conduct more comprehensive proteomic explorations,thus taking a significant leap toward innovative POAG treatments.
基金This study is supported by grants from 1.3.5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(ZYJC21041)The Research Project of Shanghai Science and Technology Commission(20dz2260300)The Fundamental Research Funds for the Central Universities.
文摘Background The hippocampus and amygdala are densely interconnected structures that work together in multiple affective and cognitive processes that are important to the etiology of major depressive disorder(MDD).Each of these structures consists of several heterogeneous subfields.We aim to explore the topologic properties of the volume-based intrinsic network within the hippocampus–amygdala complex in medication-nale patients with first-episode MDD.Methods High-resolution T1-weighted magnetic resonance imaging scans were acquired from 123 first-episode,medication-nale,and noncomorbid MDD patients and 81 age-,sex-,and education level-matched healthy control participants(HCs).The structural covariance network(SCN)was constructed for each group using the volumes of the hippocampal subfields and amygdala subregions;the weights of the edges were defined by the partial correlation coefficients between each pair of subfields/subregions,controlled for age,sex,education level,and intracranial volume.The global and nodal graphmetrics were calculated and compared between groups.Results Compared with HCs,the SCN within the hippocampus–amygdala complex in patients with MDD showed a shortened mean characteristic path length,reduced modularity,and reduced small-worldness index.At the nodal level,the left hippocampal tail showed increased measures of centrality,segregation,and integration,while nodes in the left amygdala showed decreased measures of centrality,segregation,and integration in patients with MDD compared with HCs.Conclusion Our results provide the first evidence of atypical topologic characteristics within the hippocampus–amygdala complex in patients with MDD using structure network analysis.It provides more delineate mechanism of those two structures that underlying neuropathologic process in MDD.
基金supported by the National Natural Science Foundation of China(grant nos 81621003,81761128023,81820108018,82027808,and 82001795)NIH/NIMH R01MH112189-01,China Postdoctoral Science Foundation(2020M673245)+3 种基金Post-Doctor Research Project of West China Hospital of Sichuan University(2021HXBH025)US-China joint grant(grant nos NSFC81761128023)Instituto de Salud Carlos III/European Union(ERDF/ESF,‘Investing in your future’:CPII19/00009 and PI19/00394)the project SLT006/17/00357,from PERIS 2016-2020(Departament de Salut),CERCA Programme/Generalitat de Catalunya.
文摘Background:Abnormalities of cortical thickness(CTh)in patients with their first episode psychosis(FEP)have been frequently reported,but findings are inconsistent.Objective:To define the most consistent CTh changes in patients with FEP by meta-analysis of publishedwholebrain studies.Methods:The meta-analysis used seed-based dmapping(SDM)software to obtain the most prominent regional CTh changes in FEP,and meta-regression analyses to explore the effects of demographics and clinical characteristics.The meta-analysis results were verified in an independent sample of 142 FEP patients and 142 age-and sex-matched healthy controls(HCs),using both a vertex-wise and a region of interest analysis,with multiple comparisons correction.Results:The meta-analysis identified lower CTh in the rightmiddle temporal cortex(MTC)extending to superior temporal cortex(STC),insula,and anterior cingulate cortex(ACC)in FEP compared with HCs.No significant correlations were identified between CTh alterations and demographic or clinical variables.These results were replicated in the independent dataset analysis.Conclusion:This study identifies a robust pattern of cortical abnormalities in FEP and extends understanding of gray matter abnormalities and pathological mechanisms in FEP.
