Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student...Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student–teacher learning framework was designed to classify images. 2,317 images from 189 participants were included. Of these, 1,126 images revealed IRDs, 533 were normal samples, and 658 were control samples.Results The FSL model achieved a total accuracy of 0.974–0.983, total sensitivity of 0.934–0.957, total specificity of 0.984–0.990, and total F1 score of 0.935–0.957, which were superior to the total accuracy of the baseline model of 0.943–0.954, total sensitivity of 0.866–0.886, total specificity of 0.962–0.971,and total F1 score of 0.859–0.885. The performance of most subclassifications also exhibited advantages. Moreover, the FSL model had a higher area under curves(AUC) of the receiver operating characteristic(ROC) curves in most subclassifications.Conclusion This study demonstrates the effective use of the FSL model for the classification of OCT images from patients with IRDs, normal, and control participants with a smaller volume of data. The general principle and similar network architectures can also be applied to other retinal diseases with a low prevalence.展开更多
Advancements in genome editing enable permanent changes of DNA sequences in a site-specific manner,providing promising approaches for treating human genetic disorders caused by gene mutations.Recently,genome editing h...Advancements in genome editing enable permanent changes of DNA sequences in a site-specific manner,providing promising approaches for treating human genetic disorders caused by gene mutations.Recently,genome editing has been applied and achieved significant progress in treating inherited genetic disorders that remain incurable by conventional therapy.Here,we present a review of various programmable genome editing systems with their principles,advantages,and limitations.We introduce their recent applications for treating inherited diseases in the clinic,including sickle cell disease(SCD),β-thalassemia,Leber congenital amaurosis(LCA),heterozygous familial hypercholesterolemia(HeFH),etc.We also discuss the paradigm of ex vivo and in vivo editing and highlight the promise of somatic editing and the challenge of germline editing.Finally,we propose future directions in delivery,cutting,and repairing to improve the scope of clinical applications.展开更多
Inherited retinal diseases(IRD)are a leading cause of blindness in the working age population.The advances in ocular genetics,retinal imaging and molecular biology,have conspired to create the ideal environment for es...Inherited retinal diseases(IRD)are a leading cause of blindness in the working age population.The advances in ocular genetics,retinal imaging and molecular biology,have conspired to create the ideal environment for establishing treatments for IRD,with the first approved gene therapy and the commencement of multiple therapy trials.The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD.Herein we present in a comprehensive and concise manner the imaging findings of:(I)macular dystrophies(MD)[Stargardt disease(ABCA4),X-linked retinoschisis(RS1),Best disease(BEST1),pattern dystrophy(PRPH2),Sorsby fundus dystrophy(TIMP3),and autosomal dominant drusen(EFEMP1)],(II)cone and cone-rod dystrophies(GUCA1A,PRPH2,ABCA4 and RPGR),(III)cone dysfunction syndromes[achromatopsia(CNGA3,CNGB3,PDE6C,PDE6H,GNAT2,ATF6],blue-cone monochromatism(OPN1LW/OPN1MW array),oligocone trichromacy,bradyopsia(RGS9/R9AP)and Bornholm eye disease(OPN1LW/OPN1MW),(IV)Leber congenital amaurosis(GUCY2D,CEP290,CRB1,RDH12,RPE65,TULP1,AIPL1 and NMNAT1),(V)rod-cone dystrophies[retinitis pigmentosa,enhanced S-Cone syndrome(NR2E3),Bietti crystalline corneoretinal dystrophy(CYP4V2)],(VI)rod dysfunction syndromes(congenital stationary night blindness,fundus albipunctatus(RDH5),Oguchi disease(SAG,GRK1),and(VII)chorioretinal dystrophies[choroideremia(CHM),gyrate atrophy(OAT)].展开更多
Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum(L. barbarum) polysaccharide(LBP) protects degenerated photo...Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum(L. barbarum) polysaccharide(LBP) protects degenerated photoreceptors in rd1, a transgenic mouse model of retinitis pigmentosa. L. barbarum glycopeptide(Lb GP) is an immunoreactive glycoprotein extracted from LBP. In this study, we investigated the potential protective effect of Lb GP on a chemically induced photoreceptor-degenerative mouse model. Wild-type mice received the following: oral administration of Lb GP as a protective pre-treatment on days 1–7;intraperitoneal administration of 40 mg/kg N-methylN-nitrosourea to induce photoreceptor injury on day 7;and continuation of orally administered Lb GP on days 8–14. Treatment with Lb GP increased photoreceptor survival and improved the structure of photoreceptors, retinal photoresponse, and visual behaviors of mice with photoreceptor degeneration. Lb GP was also found to partially inhibit the activation of microglia in N-methyl-N-nitrosourea-injured retinas and significantly decreased the expression of two pro-inflammatory cytokines. In conclusion, Lb GP effectively slowed the rate of photoreceptor degeneration in N-methyl-N-nitrosourea-injured mice, possibly through an anti-inflammatory mechanism, and has potential as a candidate drug for the clinical treatment of photoreceptor degeneration.展开更多
Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology.However,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a m...Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology.However,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a maladaptive response.Thus "pure" genetic and "pure" xenobiotic liver diseases are modified by each other and other factors,identified or unknown.The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes.This exercise is not to argue that all liver diseases have an environmental component,but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility.This review also discusses key new tools and approaches that will likely be critical to address this question in the future.Taken together,identifying the key gaps in our understanding is critical for the field to move forward,or at the very least to "know what we don't know."展开更多
Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)continuum.However,the role of NPS as an early marker of pathophysiological p...Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)continuum.However,the role of NPS as an early marker of pathophysiological progression in AD remains unclear.Dominantly inherited AD(DIAD)mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation.Hence,the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies.In this longitudinal study,we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers.Methods:We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier status.The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire(NPI-Q),age,and estimated years to symptom onset(EYO)as a function of metabolism measured by[^(18)F]flurodeoxyglucose([^(18)F]FDG)positron emission tomography,were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers.Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q subcomponents.Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.Results:A total of 119 mutation carriers and 102 non-carriers were studied.The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional[18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices,the bilateral parietal lobes and the right insula in DIAD mutation carriers.The neuropsychiatric subsyndromes of agitation,disinhibition,irritability and depression interacted with the EYO to drive the[^(18)F]FDG uptake decline in the DIAD mutation carriers.The interaction of NPI and EYO was not associated with[^(18)F]FDG uptake in DIAD mutation non-carriers.Conclusions:The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD,which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD.Further studies using different methodological approaches to identify NPS in predinical AD are needed to validate our findings.展开更多
Erythropoietic protoporphyria(EPP)is a rare inherited disease caused by partial deficiency activity of the enzyme ferrochelatase(FECH),resulting in excessive accumulation of protoporphyrin IX in erythrocyte and tissue...Erythropoietic protoporphyria(EPP)is a rare inherited disease caused by partial deficiency activity of the enzyme ferrochelatase(FECH),resulting in excessive accumulation of protoporphyrin IX in erythrocyte and tissues.Here,we report a patient with photosensitive dermatitis and acute icteric hepatitis caused by EPP,whose clinical and biochemical results successfully improved following 2-month treatment with glucose load,ursodeoxycholic acid capsules,and cholestyramine powder.This case provides a reference for a combination therapy strategy for patients with liver and skin injury caused by EPP.展开更多
基金supported by National Natural Science Foundation of China [No.82171073]。
文摘Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student–teacher learning framework was designed to classify images. 2,317 images from 189 participants were included. Of these, 1,126 images revealed IRDs, 533 were normal samples, and 658 were control samples.Results The FSL model achieved a total accuracy of 0.974–0.983, total sensitivity of 0.934–0.957, total specificity of 0.984–0.990, and total F1 score of 0.935–0.957, which were superior to the total accuracy of the baseline model of 0.943–0.954, total sensitivity of 0.866–0.886, total specificity of 0.962–0.971,and total F1 score of 0.859–0.885. The performance of most subclassifications also exhibited advantages. Moreover, the FSL model had a higher area under curves(AUC) of the receiver operating characteristic(ROC) curves in most subclassifications.Conclusion This study demonstrates the effective use of the FSL model for the classification of OCT images from patients with IRDs, normal, and control participants with a smaller volume of data. The general principle and similar network architectures can also be applied to other retinal diseases with a low prevalence.
基金supported by the Genome Tagging Project and grants from the National Natural Science Foundation of China(31821004,32030029,31730062,and 3210060158)CAS Special Research Assistant Program.
文摘Advancements in genome editing enable permanent changes of DNA sequences in a site-specific manner,providing promising approaches for treating human genetic disorders caused by gene mutations.Recently,genome editing has been applied and achieved significant progress in treating inherited genetic disorders that remain incurable by conventional therapy.Here,we present a review of various programmable genome editing systems with their principles,advantages,and limitations.We introduce their recent applications for treating inherited diseases in the clinic,including sickle cell disease(SCD),β-thalassemia,Leber congenital amaurosis(LCA),heterozygous familial hypercholesterolemia(HeFH),etc.We also discuss the paradigm of ex vivo and in vivo editing and highlight the promise of somatic editing and the challenge of germline editing.Finally,we propose future directions in delivery,cutting,and repairing to improve the scope of clinical applications.
基金Supported by grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology,Macular Society(UK),Fight for Sight(UK),Onassis Foundation,Leventis Foundation,The Wellcome Trust(099173/Z/12/Z)Moorfields Eye Hospital Special Trustees,Moorfields Eye Charity,Retina UK,and the Foundation Fighting Blindness(USA).
文摘Inherited retinal diseases(IRD)are a leading cause of blindness in the working age population.The advances in ocular genetics,retinal imaging and molecular biology,have conspired to create the ideal environment for establishing treatments for IRD,with the first approved gene therapy and the commencement of multiple therapy trials.The scope of this review is to familiarize clinicians and scientists with the current landscape of retinal imaging in IRD.Herein we present in a comprehensive and concise manner the imaging findings of:(I)macular dystrophies(MD)[Stargardt disease(ABCA4),X-linked retinoschisis(RS1),Best disease(BEST1),pattern dystrophy(PRPH2),Sorsby fundus dystrophy(TIMP3),and autosomal dominant drusen(EFEMP1)],(II)cone and cone-rod dystrophies(GUCA1A,PRPH2,ABCA4 and RPGR),(III)cone dysfunction syndromes[achromatopsia(CNGA3,CNGB3,PDE6C,PDE6H,GNAT2,ATF6],blue-cone monochromatism(OPN1LW/OPN1MW array),oligocone trichromacy,bradyopsia(RGS9/R9AP)and Bornholm eye disease(OPN1LW/OPN1MW),(IV)Leber congenital amaurosis(GUCY2D,CEP290,CRB1,RDH12,RPE65,TULP1,AIPL1 and NMNAT1),(V)rod-cone dystrophies[retinitis pigmentosa,enhanced S-Cone syndrome(NR2E3),Bietti crystalline corneoretinal dystrophy(CYP4V2)],(VI)rod dysfunction syndromes(congenital stationary night blindness,fundus albipunctatus(RDH5),Oguchi disease(SAG,GRK1),and(VII)chorioretinal dystrophies[choroideremia(CHM),gyrate atrophy(OAT)].
基金supported by Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology,No.20200730009 (to YX)the National Natural Science Foundation of China,No.82074169 (to XM)+2 种基金the Guangdong Basic and Applied Basic Research Foundation,No.2021A1515012473 (to XM)Project of Administration of Traditional Chinese Medicine of Guangdong Province,No.20202045 (to XM)Aier Eye Hospital Group,No.AF2019001 (to ST,KFS,YX,XM)。
文摘Photoreceptor cell degeneration leads to blindness, for which there is currently no effective treatment. Our previous studies have shown that Lycium barbarum(L. barbarum) polysaccharide(LBP) protects degenerated photoreceptors in rd1, a transgenic mouse model of retinitis pigmentosa. L. barbarum glycopeptide(Lb GP) is an immunoreactive glycoprotein extracted from LBP. In this study, we investigated the potential protective effect of Lb GP on a chemically induced photoreceptor-degenerative mouse model. Wild-type mice received the following: oral administration of Lb GP as a protective pre-treatment on days 1–7;intraperitoneal administration of 40 mg/kg N-methylN-nitrosourea to induce photoreceptor injury on day 7;and continuation of orally administered Lb GP on days 8–14. Treatment with Lb GP increased photoreceptor survival and improved the structure of photoreceptors, retinal photoresponse, and visual behaviors of mice with photoreceptor degeneration. Lb GP was also found to partially inhibit the activation of microglia in N-methyl-N-nitrosourea-injured retinas and significantly decreased the expression of two pro-inflammatory cytokines. In conclusion, Lb GP effectively slowed the rate of photoreceptor degeneration in N-methyl-N-nitrosourea-injured mice, possibly through an anti-inflammatory mechanism, and has potential as a candidate drug for the clinical treatment of photoreceptor degeneration.
基金Supported, in part, by grants from NIH (R01 AA021978, P30 DK120531, and R21 ES031531, USA)。
文摘Liver diseases are considered to predominantly possess an inherited or xenobiotic etiology.However,inheritance drives the ability to appropriately adapt to environmental stressors,and disease is the culmination of a maladaptive response.Thus "pure" genetic and "pure" xenobiotic liver diseases are modified by each other and other factors,identified or unknown.The purpose of this review is to highlight the knowledgebase of environmental exposure as a potential risk modifying agent for the development of liver disease by other causes.This exercise is not to argue that all liver diseases have an environmental component,but to challenge the assumption that the current state of our knowledge is sufficient in all cases to conclusively dismiss this as a possibility.This review also discusses key new tools and approaches that will likely be critical to address this question in the future.Taken together,identifying the key gaps in our understanding is critical for the field to move forward,or at the very least to "know what we don't know."
文摘Background:Neuropsychiatric symptoms(NPS)are increasingly recognized as early non-cognitive manifestations in the Alzheimer's disease(AD)continuum.However,the role of NPS as an early marker of pathophysiological progression in AD remains unclear.Dominantly inherited AD(DIAD)mutation carriers are young individuals who are destined to develop AD in future due to the full penetrance of the genetic mutation.Hence,the study of DIAD mutation carriers enables the evaluation of the associations between pure AD pathophysiology and metabolic correlates of NPS without the confounding effects of co-existing pathologies.In this longitudinal study,we aimed to identify regional brain metabolic dysfunctions associated with NPS in cognitively intact DIAD mutation carriers.Methods:We stratified 221 cognitively intact participants from the Dominantly Inherited Alzheimer's Network according to their mutation carrier status.The interactions of NPS measured by the Neuropsychiatric Inventory-Questionnaire(NPI-Q),age,and estimated years to symptom onset(EYO)as a function of metabolism measured by[^(18)F]flurodeoxyglucose([^(18)F]FDG)positron emission tomography,were evaluated by the mixed-effects regression model with family-level random effects in DIAD mutation carriers and non-carriers.Exploratory factor analysis was performed to identify the neuropsychiatric subsyndromes in DIAD mutation carriers using the NPI-Q subcomponents.Then the effects of interactions between specific neuropsychiatric subsyndromes and EYO on metabolism were evaluated with the mixed-effects regression model.Results:A total of 119 mutation carriers and 102 non-carriers were studied.The interaction of higher NPI-Q and shorter EYO was associated with more rapid declines of global and regional[18F]FDG uptake in the posterior cingulate and ventromedial prefrontal cortices,the bilateral parietal lobes and the right insula in DIAD mutation carriers.The neuropsychiatric subsyndromes of agitation,disinhibition,irritability and depression interacted with the EYO to drive the[^(18)F]FDG uptake decline in the DIAD mutation carriers.The interaction of NPI and EYO was not associated with[^(18)F]FDG uptake in DIAD mutation non-carriers.Conclusions:The NPS in cognitively intact DIAD mutation carriers may be a clinical indicator of subsequent metabolic decline in brain networks vulnerable to AD,which supports the emerging conceptual framework that NPS represent early manifestations of neuronal injury in AD.Further studies using different methodological approaches to identify NPS in predinical AD are needed to validate our findings.
基金the Guangdong Key Field R&D Plan of China(2019B020228001)the 5010 Project of Clinical Research in Sun Yat-sen University,China(No.2018024).
文摘Erythropoietic protoporphyria(EPP)is a rare inherited disease caused by partial deficiency activity of the enzyme ferrochelatase(FECH),resulting in excessive accumulation of protoporphyrin IX in erythrocyte and tissues.Here,we report a patient with photosensitive dermatitis and acute icteric hepatitis caused by EPP,whose clinical and biochemical results successfully improved following 2-month treatment with glucose load,ursodeoxycholic acid capsules,and cholestyramine powder.This case provides a reference for a combination therapy strategy for patients with liver and skin injury caused by EPP.