Objective:Autosomal recessive bestrophinopathy(ARB),a retinal degenerative disease,is characterized by central visual loss,yellowish multifocal diffuse subretinal deposits,and a dramatic decrease in the light peak on ...Objective:Autosomal recessive bestrophinopathy(ARB),a retinal degenerative disease,is characterized by central visual loss,yellowish multifocal diffuse subretinal deposits,and a dramatic decrease in the light peak on electrooculogram.The potential pathogenic mechanism involves mutations in the BEST1 gene,which encodes Ca2+-activated Cl−channels in the retinal pigment epithelium(RPE),resulting in degeneration of RPE and photoreceptor.In this study,the complete clinical characteristics of two Chinese ARB families were summarized.Methods:Pacific Biosciences(PacBio)single-molecule real-time(SMRT)sequencing was performed on the probands to screen for disease-causing gene mutations,and Sanger sequencing was applied to validate variants in the patients and their family members.Results:Two novel mutations,c.202T>C(chr11:61722628,p.Y68H)and c.867+97G>A,in the BEST1 gene were identified in the two Chinese ARB families.The novel missense mutation BEST1 c.202T>C(p.Y68H)resulted in the substitution of tyrosine with histidine in the N-terminal region of transmembrane domain 2 of bestrophin-1.Another novel variant,BEST1 c.867+97G>A(chr11:61725867),located in intron 7,might be considered a regulatory variant that changes allele-specific binding affinity based on motifs of important transcriptional regulators.Conclusion:Our findings represent the first use of third-generation sequencing(TGS)to identify novel BEST1 mutations in patients with ARB,indicating that TGS can be a more accurate and efficient tool for identifying mutations in specific genes.The novel variants identified further broaden the mutation spectrum of BEST1 in the Chinese population.展开更多
AIM:To describe the clinical heterogeneity of patients with novel mutations in BEST1.METHODS:All the members in the two Chinese families underwent detailed clinical evaluations including best-corrected visual acuity,s...AIM:To describe the clinical heterogeneity of patients with novel mutations in BEST1.METHODS:All the members in the two Chinese families underwent detailed clinical evaluations including best-corrected visual acuity,slit-lamp examination,applanation tonometry,and dilated fundus examination.Fundus autofluorescence,fundus fluorescein angiography,spectral-domain optical coherence tomography,electrooculography,and electroretinogram were also performed.Genomic DNA was extracted from venous blood for all the participants.The targeted next-generation sequencing of inherited retinal disease-associated genes was conducted to identify the causative mutation.RESULTS:A novel BEST1 missense mutation c.41T>C(p.Leu14Ser) was identified in Family 1.It was co-segregated with the phenotype of best vitelliform macular dystrophy(BVMD) and bioinformatics analysis confirmed it was harmful.Another novel BEST1 frameshift mutation c.345_(3)46insGGCAAGGACG(p.Glu119Glyfs*116) and a novel USH2A missense mutation c.12560G>A,p.Arg4187 His were identified in family 2 with retinitis pigmentosa(RP),which might interact and lead to the phenotype of RP.CONCLUSION:Two novel mutations in the BEST1 gene in two unrelated families with distinct phenotypes and BEST1 mutation accompanied with USH2A mutation would result in RP,which could be enormously helpful in understanding the pathogenesis of the inherited retinal disease caused by a BEST1 mutation.展开更多
Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke.The narrow treatment time window is still to be solved.Given that the ischemic core expanded ove...Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke.The narrow treatment time window is still to be solved.Given that the ischemic core expanded over days,treatment with an extended time window is anticipated.Bestrophin1(BEST1)belongs to a bestrophin family of calcium-activated chloride channels.We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice.Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits.Using electrophysiological recordings,we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity.Finally,we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6—72 h post-ischemia in rodents.This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions.Our study identifies the glutamatereleasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.展开更多
We study two instances of polynomial optimization problem over a single sphere. The first problem is to compute the best rank-1 tensor approximation. We show the equivalence between two recent semidefinite relaxations...We study two instances of polynomial optimization problem over a single sphere. The first problem is to compute the best rank-1 tensor approximation. We show the equivalence between two recent semidefinite relaxations methods. The other one arises from Bose-Einstein condensates(BEC), whose objective function is a summation of a probably nonconvex quadratic function and a quartic term. These two polynomial optimization problems are closely connected since the BEC problem can be viewed as a structured fourth-order best rank-1 tensor approximation. We show that the BEC problem is NP-hard and propose a semidefinite relaxation with both deterministic and randomized rounding procedures. Explicit approximation ratios for these rounding procedures are presented. The performance of these semidefinite relaxations are illustrated on a few preliminary numerical experiments.展开更多
文摘Objective:Autosomal recessive bestrophinopathy(ARB),a retinal degenerative disease,is characterized by central visual loss,yellowish multifocal diffuse subretinal deposits,and a dramatic decrease in the light peak on electrooculogram.The potential pathogenic mechanism involves mutations in the BEST1 gene,which encodes Ca2+-activated Cl−channels in the retinal pigment epithelium(RPE),resulting in degeneration of RPE and photoreceptor.In this study,the complete clinical characteristics of two Chinese ARB families were summarized.Methods:Pacific Biosciences(PacBio)single-molecule real-time(SMRT)sequencing was performed on the probands to screen for disease-causing gene mutations,and Sanger sequencing was applied to validate variants in the patients and their family members.Results:Two novel mutations,c.202T>C(chr11:61722628,p.Y68H)and c.867+97G>A,in the BEST1 gene were identified in the two Chinese ARB families.The novel missense mutation BEST1 c.202T>C(p.Y68H)resulted in the substitution of tyrosine with histidine in the N-terminal region of transmembrane domain 2 of bestrophin-1.Another novel variant,BEST1 c.867+97G>A(chr11:61725867),located in intron 7,might be considered a regulatory variant that changes allele-specific binding affinity based on motifs of important transcriptional regulators.Conclusion:Our findings represent the first use of third-generation sequencing(TGS)to identify novel BEST1 mutations in patients with ARB,indicating that TGS can be a more accurate and efficient tool for identifying mutations in specific genes.The novel variants identified further broaden the mutation spectrum of BEST1 in the Chinese population.
基金Supported by the Health Special Research Projects of Military Commission (No.19BJZ39)the Key Research Plan of Hainan Province (No.ZDYF2020031)。
文摘AIM:To describe the clinical heterogeneity of patients with novel mutations in BEST1.METHODS:All the members in the two Chinese families underwent detailed clinical evaluations including best-corrected visual acuity,slit-lamp examination,applanation tonometry,and dilated fundus examination.Fundus autofluorescence,fundus fluorescein angiography,spectral-domain optical coherence tomography,electrooculography,and electroretinogram were also performed.Genomic DNA was extracted from venous blood for all the participants.The targeted next-generation sequencing of inherited retinal disease-associated genes was conducted to identify the causative mutation.RESULTS:A novel BEST1 missense mutation c.41T>C(p.Leu14Ser) was identified in Family 1.It was co-segregated with the phenotype of best vitelliform macular dystrophy(BVMD) and bioinformatics analysis confirmed it was harmful.Another novel BEST1 frameshift mutation c.345_(3)46insGGCAAGGACG(p.Glu119Glyfs*116) and a novel USH2A missense mutation c.12560G>A,p.Arg4187 His were identified in family 2 with retinitis pigmentosa(RP),which might interact and lead to the phenotype of RP.CONCLUSION:Two novel mutations in the BEST1 gene in two unrelated families with distinct phenotypes and BEST1 mutation accompanied with USH2A mutation would result in RP,which could be enormously helpful in understanding the pathogenesis of the inherited retinal disease caused by a BEST1 mutation.
基金supported by STI2030-Major Project(2022ZD0211700,China)National Natural Science Foundation of China(82171293,82090042 and 82171368)Natural Science Foundation of Jiangsu Province(BK20211255,China)。
文摘Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke.The narrow treatment time window is still to be solved.Given that the ischemic core expanded over days,treatment with an extended time window is anticipated.Bestrophin1(BEST1)belongs to a bestrophin family of calcium-activated chloride channels.We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice.Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits.Using electrophysiological recordings,we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity.Finally,we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6—72 h post-ischemia in rodents.This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions.Our study identifies the glutamatereleasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.
基金supported by National Natural Science Foundation of China (Grant Nos. 11401364, 11322109, 11331012, 11471325 and 11461161005)the National High Technology Research and Development Program of China (863 Program) (Grant No. 2013AA122902)+1 种基金the National Center for Mathematics and Interdisciplinary Sciences, Chinese Academy of SciencesNational Basic Research Program of China (973 Program) (Grant No. 2015CB856002)
文摘We study two instances of polynomial optimization problem over a single sphere. The first problem is to compute the best rank-1 tensor approximation. We show the equivalence between two recent semidefinite relaxations methods. The other one arises from Bose-Einstein condensates(BEC), whose objective function is a summation of a probably nonconvex quadratic function and a quartic term. These two polynomial optimization problems are closely connected since the BEC problem can be viewed as a structured fourth-order best rank-1 tensor approximation. We show that the BEC problem is NP-hard and propose a semidefinite relaxation with both deterministic and randomized rounding procedures. Explicit approximation ratios for these rounding procedures are presented. The performance of these semidefinite relaxations are illustrated on a few preliminary numerical experiments.
