Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders(NDDs)that exhibit delayed speech development,intellectual disability,and congenital abnormalities.The etiology of NDDs i...Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders(NDDs)that exhibit delayed speech development,intellectual disability,and congenital abnormalities.The etiology of NDDs is unclear.Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells(RGCs),respectively,in the mouse neocortex during early gestation.Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone(VZ).Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ.The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs.The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions,the loss of which leads to periventricular heterotopias.We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.展开更多
Gold nanoparticles(GNPs)have been extensively used in nanomedicine and neuroscience owing to their biological inertness,peculiar opto-electronic and physico-chemical features.However,the effect of GNPs shape on the ne...Gold nanoparticles(GNPs)have been extensively used in nanomedicine and neuroscience owing to their biological inertness,peculiar opto-electronic and physico-chemical features.However,the effect of GNPs shape on the neurophysiological properties of single neuron is still unclear.To tackle this issue,different shape GNPs(nanosphere,nanotriakisoctahedron and nanoflower)were synthesized to investigate the effect of GNPs on the voltage-dependent sodium channel and the action potential(AP)of hippocampal CA1 neurons in mice.The results indicated that GNPs inhibited the amplitudes of voltage-gated sodium current(I_(Na))and led to a hyperpolarizing shift in the voltage-dependence curve of both activation and inactivation of I_(Na).GNPs also increased neuronal excitability and altered some properties of AP.Moreover,most alterations in AP properties were observed in nanoflower GNPs treated CA1 neurons,suggesting that the neurotoxicity of gold nanoparticles is surface roughness-dependent.These results may provide a valuable direction in the clinical application of GNPs.展开更多
The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies(GWASs) were mostly based on European d...The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies(GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent(SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou(631 <-6.00 D and 574 > 0.00 D) and Wenzhou(593 <-6.00 D and54 >-1.75 D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci, which show genome-wide significant associations with SE, including 1 q25.2 FAM163 A, 10 p11.22 NRP1/PRAD3, and 10 p11.21 ANKRD30 A/MTRNR2 L7, together explaining 3.34% of SE variance. 10 p11.21 is successfully replicated.The allele frequencies of all three loci show significant differences between major continental groups(P < 0.001). The SE reducing(more myopic) allele of rs10913877(1 q25.2 FAM163 A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans(EAS = 0.60,EUR = 0.20, and AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5, and ARPP19. These results provide new insights into myopia pathogenesis and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.展开更多
AIM:To establish an animal model of form deprivation amblyopia based on a simulated cataract intraocular lens(IOLs).METHODS:Poly(dimethyl siloxane)-SiO_(2)thin films(PSF)with different degrees of opacity as IOL materi...AIM:To establish an animal model of form deprivation amblyopia based on a simulated cataract intraocular lens(IOLs).METHODS:Poly(dimethyl siloxane)-SiO_(2)thin films(PSF)with different degrees of opacity as IOL materials were prepared.The light transmission of the PSF-IOL was measured,and its in vitro biosafety was determined by cell counting kit(CCK)-8 assay using the HLEC-B3 cell line and ARPE-19 cell line.Subsequently,the in vivo safety was determined by implanting the PSF-IOL with 10%wt SiO_(2)into the right eyes of New Zealand white rabbits(PSF-IOL group),and compared with two control groups:contralateral comparison group and normal control(NC)group(Contralateral comparison group:the fellow eye;NC group:a group of binocular normal rabbits without intervention).The flash visual-evoked potentials(F-VEPs)were measured to verify amblyopia.RESULTS:PSFs containing 0,2%,and 10%wt SiO_(2)were successfully constructed.The 0 SiO_(2)PSF was transparent,while the 10%wt SiO_(2)PSF was completely opaque.It was found that PSF did not induce unwanted cytotoxicity in HLECs and ARPE19 cells in vitro.In vitro,PSF-IOL with 10%wt SiO_(2)was also non-toxic,and no significant inflammation or structural changes occurred after four weeks of PSF-IOL implantation.Finally,our IOL-simulated congenital cataract rabbit detected by F-VEPs suggested tentative amblyopia.CONCLUSION:A PSF-IOL that mimics cataracts is created.A novel form deprivation model is created by the IOL-simulated congenital cataract rabbit.It can be developed fast and stable and holds great potential for future study.展开更多
Background The exudative form of age-related macular degeneration(AMD)is characterized by abnormal blood vessel growth,which is stimulated by vascular endothelial growth factor(VEGF)released from retinal pigment epith...Background The exudative form of age-related macular degeneration(AMD)is characterized by abnormal blood vessel growth,which is stimulated by vascular endothelial growth factor(VEGF)released from retinal pigment epithelium(RPE).The angiogenic behaviors of vascular endothelial cells in vitro depend on forkhead box protein P1(Foxp1),a transcription repressor widely expressed in human and murine tissues during development.In this study,we aimed to determine whether loss of Foxp1 affects laser-induced choroidal neovascularization(CNV)in mouse.Methods Eye-selective deletion of Foxp1 was obtained by crossing Foxp1flox/flox with Six3-Cre mice.Laser photocoagulation was delivered to six-to eight-week-old mice to induce CNV.The expression of Foxp1 and Cre was determined by immunofluorescence in cryostat sections of the eyes.Fundus fluorescein angiography(FFA),optical coherence tomography(OCT),and B4 isolectin staining were applied to analyze the leakage,bulge height,and area of CNV lesions,respectively.RPE-choroid tissues were isolated for the determination of VEGF and pigment epithelium derived factor(PEDF)by Western blotting.Results Foxp1 was expressed in retinal ganglion cells,RPE,and the choroidal endothelial cells.Laser photocoagulation increased the number of Foxp1+-endothelial cells and induced CNV.Six3-Cre reduced Foxp1 expression in RPE but not the endothelium,leading to a lower level of VEGF in the RPE-choroid.Foxp1 knockout inhibited pathological angiogenesis and vascular leakage of the laser-induced CNV lesions.Conclusions Foxp1 regulates the expression of VEGF in the RPE,and inhibition of Foxp1 could potentially be a novel strategy for the prevention and therapy of neovascularization related to AMD.展开更多
Myopia is the leading cause of visual impairment worldwide.The lack of a“rapid predictive index”for myopia development and progression hinders the clinic management and prevention of myopia.This article reviews the ...Myopia is the leading cause of visual impairment worldwide.The lack of a“rapid predictive index”for myopia development and progression hinders the clinic management and prevention of myopia.This article reviews the studies describing changes that occur in the choroid during myopia development and proposes that it is possible to detect myopia development at an earlier stage than is currently possible in a clinical setting using choroidal blood perfusion as a“rapid predictive index”of myopia.展开更多
Myopia is the leading cause of visual impairment worldwide.The lack of a"rapid predictive index"for myopia development and progression hinders the clinic management and prevention of myopia.This article revi...Myopia is the leading cause of visual impairment worldwide.The lack of a"rapid predictive index"for myopia development and progression hinders the clinic management and prevention of myopia.This article reviews the studies describing changes that occur in the choroid during myopia development and proposes that it is possible to detect myopia development at an earlier stage than is currently possible in a clinical setting using choroidal blood perfusion as a"rapid predictive index"of myopia.展开更多
Postzygotic mutations are acquired in normal tissues throughout an individual’s lifetime and hold clues for identifying mutagenic factors.Here,we investigated postzygotic mutation spectra of healthy individuals using...Postzygotic mutations are acquired in normal tissues throughout an individual’s lifetime and hold clues for identifying mutagenic factors.Here,we investigated postzygotic mutation spectra of healthy individuals using optimized ultra-deep exome sequencing of the time-series samples from the same volunteer as well as the samples from different individuals.In blood,sperm,and muscle cells,we resolved three common types of mutational signatures.Signatures A and B represent clocklike mutational processes,and the polymorphisms of epigenetic regulation genes influence the proportion of signature B in mutation profiles.Notably,signature C,characterized by C>T transitions at GpCpN sites,tends to be a feature of diverse normal tissues.Mutations of this type are likely to occur early during embryonic development,supported by their relatively high allelic frequencies,presence in multiple tissues,and decrease in occurrence with age.Almost none of the public datasets for tumors feature this signature,except for 19.6%of samples of clear cell renal cell carcinoma with increased activation of the hypoxia-inducible factor 1(HIF-1)signaling pathway.Moreover,the accumulation of signature C in the mutation profile was accelerated in a human embryonic stem cell line with drug-induced activation of HIF-1α.Thus,embryonic hypoxia may explain this novel signature across multiple normal tissues.Our study suggests that hypoxic condition in an early stage of embryonic development is a crucial factor inducing C>T transitions at GpCpN sites;and individuals’genetic background may also influence their postzygotic mutation profiles.展开更多
基金supported by the Wenzhou Municipal Science and Technology Bureau(Y20210901)the Natural Science Foundation of Zhejiang Province(LQ20H090001)the Scientific Research Fund of Wenling Science and Technology Bureau(2018C320001).
文摘Heterozygous loss-of-function variants of FOXP4 are associated with neurodevelopmental disorders(NDDs)that exhibit delayed speech development,intellectual disability,and congenital abnormalities.The etiology of NDDs is unclear.Here we found that FOXP4 and N-cadherin are expressed in the nuclei and apical end-feet of radial glial cells(RGCs),respectively,in the mouse neocortex during early gestation.Knockdown or dominant-negative inhibition of Foxp4 abolishes the apical condensation of N-cadherin in RGCs and the integrity of neuroepithelium in the ventricular zone(VZ).Inhibition of Foxp4 leads to impeded radial migration of cortical neurons and ectopic neurogenesis from the proliferating VZ.The ectopic differentiation and deficient migration disappear when N-cadherin is over-expressed in RGCs.The data indicate that Foxp4 is essential for N-cadherin-based adherens junctions,the loss of which leads to periventricular heterotopias.We hypothesize that FOXP4 variant-associated NDDs may be caused by disruption of the adherens junctions and malformation of the cerebral cortex.
基金Project(LY19C090004)supported by the Natural Science Foundation of Zhejiang Province,ChinaProjects(BK20200710,BK2018077)supported by the Natural Science Foundation of Jiangsu Province,China+1 种基金Project(NHKY-2019-19)supported by the Nanjing Polytechnic Institute Start Fund,ChinaProject(202012920026Y)supported by the Innovation and Entrepreneurship Training Program of Jiangsu Province College Students,China。
文摘Gold nanoparticles(GNPs)have been extensively used in nanomedicine and neuroscience owing to their biological inertness,peculiar opto-electronic and physico-chemical features.However,the effect of GNPs shape on the neurophysiological properties of single neuron is still unclear.To tackle this issue,different shape GNPs(nanosphere,nanotriakisoctahedron and nanoflower)were synthesized to investigate the effect of GNPs on the voltage-dependent sodium channel and the action potential(AP)of hippocampal CA1 neurons in mice.The results indicated that GNPs inhibited the amplitudes of voltage-gated sodium current(I_(Na))and led to a hyperpolarizing shift in the voltage-dependence curve of both activation and inactivation of I_(Na).GNPs also increased neuronal excitability and altered some properties of AP.Moreover,most alterations in AP properties were observed in nanoflower GNPs treated CA1 neurons,suggesting that the neurotoxicity of gold nanoparticles is surface roughness-dependent.These results may provide a valuable direction in the clinical application of GNPs.
基金supported by the Strategic Priority Research Program of Chinese Academy of Sciences (XDB38010400)National Key R&D Program of China (2018YFC0116500)+4 种基金Science and Technology Service Network Initiative of Chinese Academy of Sciences (KFJSTS-ZDTP-079)Science and Technology Planning Project of Guangdong Province (2013B20400003)the Fundamental Research Funds of the State Key Laboratory of Ophthalmologythe Open Project of Key Laboratory of Genomic and Precision Medicine of the CASsupported by the China Scholarship Council (CSC) and China Postdoctoral Science Foundation (2019TQ0365)。
文摘The global "myopia boom" has raised significant international concerns. Despite a higher myopia prevalence in Asia, previous large-scale genome-wide association studies(GWASs) were mostly based on European descendants. Here, we report a GWAS of spherical equivalent(SE) in 1852 Chinese Han individuals with extreme SE from Guangzhou(631 <-6.00 D and 574 > 0.00 D) and Wenzhou(593 <-6.00 D and54 >-1.75 D), followed by a replication study in two independent cohorts with totaling 3538 East Asian individuals. The discovery GWAS and meta-analysis identify three novel loci, which show genome-wide significant associations with SE, including 1 q25.2 FAM163 A, 10 p11.22 NRP1/PRAD3, and 10 p11.21 ANKRD30 A/MTRNR2 L7, together explaining 3.34% of SE variance. 10 p11.21 is successfully replicated.The allele frequencies of all three loci show significant differences between major continental groups(P < 0.001). The SE reducing(more myopic) allele of rs10913877(1 q25.2 FAM163 A) demonstrates the highest frequency in East Asians and much lower frequencies in Europeans and Africans(EAS = 0.60,EUR = 0.20, and AFR = 0.18). The gene-based analysis additionally identifies three novel genes associated with SE, including EI24, LHX5, and ARPP19. These results provide new insights into myopia pathogenesis and indicate the role of genetic heterogeneity in myopia epidemiology among different ethnicities.
基金Supported by National Natural Science Foundation of China(No.81870680).
文摘AIM:To establish an animal model of form deprivation amblyopia based on a simulated cataract intraocular lens(IOLs).METHODS:Poly(dimethyl siloxane)-SiO_(2)thin films(PSF)with different degrees of opacity as IOL materials were prepared.The light transmission of the PSF-IOL was measured,and its in vitro biosafety was determined by cell counting kit(CCK)-8 assay using the HLEC-B3 cell line and ARPE-19 cell line.Subsequently,the in vivo safety was determined by implanting the PSF-IOL with 10%wt SiO_(2)into the right eyes of New Zealand white rabbits(PSF-IOL group),and compared with two control groups:contralateral comparison group and normal control(NC)group(Contralateral comparison group:the fellow eye;NC group:a group of binocular normal rabbits without intervention).The flash visual-evoked potentials(F-VEPs)were measured to verify amblyopia.RESULTS:PSFs containing 0,2%,and 10%wt SiO_(2)were successfully constructed.The 0 SiO_(2)PSF was transparent,while the 10%wt SiO_(2)PSF was completely opaque.It was found that PSF did not induce unwanted cytotoxicity in HLECs and ARPE19 cells in vitro.In vitro,PSF-IOL with 10%wt SiO_(2)was also non-toxic,and no significant inflammation or structural changes occurred after four weeks of PSF-IOL implantation.Finally,our IOL-simulated congenital cataract rabbit detected by F-VEPs suggested tentative amblyopia.CONCLUSION:A PSF-IOL that mimics cataracts is created.A novel form deprivation model is created by the IOL-simulated congenital cataract rabbit.It can be developed fast and stable and holds great potential for future study.
文摘Background The exudative form of age-related macular degeneration(AMD)is characterized by abnormal blood vessel growth,which is stimulated by vascular endothelial growth factor(VEGF)released from retinal pigment epithelium(RPE).The angiogenic behaviors of vascular endothelial cells in vitro depend on forkhead box protein P1(Foxp1),a transcription repressor widely expressed in human and murine tissues during development.In this study,we aimed to determine whether loss of Foxp1 affects laser-induced choroidal neovascularization(CNV)in mouse.Methods Eye-selective deletion of Foxp1 was obtained by crossing Foxp1flox/flox with Six3-Cre mice.Laser photocoagulation was delivered to six-to eight-week-old mice to induce CNV.The expression of Foxp1 and Cre was determined by immunofluorescence in cryostat sections of the eyes.Fundus fluorescein angiography(FFA),optical coherence tomography(OCT),and B4 isolectin staining were applied to analyze the leakage,bulge height,and area of CNV lesions,respectively.RPE-choroid tissues were isolated for the determination of VEGF and pigment epithelium derived factor(PEDF)by Western blotting.Results Foxp1 was expressed in retinal ganglion cells,RPE,and the choroidal endothelial cells.Laser photocoagulation increased the number of Foxp1+-endothelial cells and induced CNV.Six3-Cre reduced Foxp1 expression in RPE but not the endothelium,leading to a lower level of VEGF in the RPE-choroid.Foxp1 knockout inhibited pathological angiogenesis and vascular leakage of the laser-induced CNV lesions.Conclusions Foxp1 regulates the expression of VEGF in the RPE,and inhibition of Foxp1 could potentially be a novel strategy for the prevention and therapy of neovascularization related to AMD.
文摘Myopia is the leading cause of visual impairment worldwide.The lack of a“rapid predictive index”for myopia development and progression hinders the clinic management and prevention of myopia.This article reviews the studies describing changes that occur in the choroid during myopia development and proposes that it is possible to detect myopia development at an earlier stage than is currently possible in a clinical setting using choroidal blood perfusion as a“rapid predictive index”of myopia.
文摘Myopia is the leading cause of visual impairment worldwide.The lack of a"rapid predictive index"for myopia development and progression hinders the clinic management and prevention of myopia.This article reviews the studies describing changes that occur in the choroid during myopia development and proposes that it is possible to detect myopia development at an earlier stage than is currently possible in a clinical setting using choroidal blood perfusion as a"rapid predictive index"of myopia.
基金supported by the grants from the Strategic Priority Research Program of Chinese Academy of Sciences(Grant No.XDB13020500)the National Natural Science Foundation of China(NSFC)(Grant Nos.91131905,31471199,and 91631304)+3 种基金the Key Research Program of Chinese Academy of Sciences(Grant No.KJZD-EW-L14 to CZ)the NSFC(Grant Nos.31440057 and 31701081 to WC)the 111 Project(Grant No.B13003 to WC and DZ)the Innovation Promotion Association of Chinese Academy of Sciences(Grant Nos.2016098 to DZ and 2019103 to AC)。
文摘Postzygotic mutations are acquired in normal tissues throughout an individual’s lifetime and hold clues for identifying mutagenic factors.Here,we investigated postzygotic mutation spectra of healthy individuals using optimized ultra-deep exome sequencing of the time-series samples from the same volunteer as well as the samples from different individuals.In blood,sperm,and muscle cells,we resolved three common types of mutational signatures.Signatures A and B represent clocklike mutational processes,and the polymorphisms of epigenetic regulation genes influence the proportion of signature B in mutation profiles.Notably,signature C,characterized by C>T transitions at GpCpN sites,tends to be a feature of diverse normal tissues.Mutations of this type are likely to occur early during embryonic development,supported by their relatively high allelic frequencies,presence in multiple tissues,and decrease in occurrence with age.Almost none of the public datasets for tumors feature this signature,except for 19.6%of samples of clear cell renal cell carcinoma with increased activation of the hypoxia-inducible factor 1(HIF-1)signaling pathway.Moreover,the accumulation of signature C in the mutation profile was accelerated in a human embryonic stem cell line with drug-induced activation of HIF-1α.Thus,embryonic hypoxia may explain this novel signature across multiple normal tissues.Our study suggests that hypoxic condition in an early stage of embryonic development is a crucial factor inducing C>T transitions at GpCpN sites;and individuals’genetic background may also influence their postzygotic mutation profiles.
