A full understanding of adaptive genetic variation at the genomic level will help address questions of how organisms adapt to diverse climates.Actinidia eriantha is a shade-tolerant species,widely distributed in the s...A full understanding of adaptive genetic variation at the genomic level will help address questions of how organisms adapt to diverse climates.Actinidia eriantha is a shade-tolerant species,widely distributed in the southern tropical region of China,occurring in spatially heterogeneous environments.In the present study we combined population genomic,epigenomic,and environmental association analyses to infer population genetic structure and positive selection across a climatic gradient,and to assess genomic offset to climatic change for A.eriantha.The population structure is strongly shaped by geography and influenced by restricted gene f low resulting from isolation by distance due to habitat fragmentation.In total,we identified 102 outlier loci and annotated 455 candidate genes associated with the genomic basis of climate adaptation,which were enriched in functional categories related to development processes and stress response;both temperature and precipitation are important factors driving adaptive variation.In addition to single-nucleotide polymorphisms(SNPs),a total of 27 single-methylation variants(SMVs)had significant correlation with at least one of four climatic variables and 16 SMVswere located in or adjacent to genes,several of whichwere predicted to be involved in plant response to abiotic or biotic stress.Gradient forest analysis indicated that the central/east populations were predicted to be at higher risk of future population maladaptation under climate change.Our results demonstrate that local climate factors impose strong selection pressures and lead to local adaptation.Such information adds to our understanding of adaptive mechanisms to variable climates revealed by both population genome and epigenome analysis.展开更多
Introduction:Lecanemab has shown promise in treating early Alzheimer’s disease(AD),but its safety and efficacy in Chinese populations remain unexplored.This study aimed to evaluate the safety and 6-month clinical out...Introduction:Lecanemab has shown promise in treating early Alzheimer’s disease(AD),but its safety and efficacy in Chinese populations remain unexplored.This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment(MCI)or mild AD.Methods:In this single-arm,real-world study,participants with MCI due to AD or mild AD received biweekly intravenous lecanemab(10 mg/kg).The study was conducted at Hainan Branch,Ruijin Hospital Shanghai Jiao Tong University School of Medicine.Patient enrollment and baseline assessments commenced in November 2023.Safety assessments included monitoring for amyloid-related imaging abnormalities(ARIA)and other adverse events.Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales(mini-mental state examination[MMSE],montreal cognitive assessment[MoCA],clinical dementia rating-sum of boxes[CDR-SB]),plasma biomarker analysis,and advanced neuroimaging.Results:A total of 64 patients were enrolled in this ongoing real-world study.Safety analysis revealed predominantly mild adverse events,with infusion-related reactions(20.3%,13/64)being the most common.Of these,69.2%(9/13)occurred during the initial infusion and 84.6%(11/13)did not recur.ARIA-H(microhemorrhages/superficial siderosis)and ARIA-E(edema/effusion)were observed in 9.4%(6/64)and 3.1%(2/64)of participants,respectively,with only two symptomatic cases(one ARIA-E presenting with headache and one ARIA-H with visual disturbances).After 6 months of treatment,cognitive scores remained stable compared to baseline(MMSE:22.33±5.58 vs.21.27±4.30,P=0.733;MoCA:16.38±6.67 vs.15.90±4.78,P=0.785;CDR-SB:2.30±1.65 vs.3.16±1.72,P=0.357),while significantly increasing plasma amyloid-β42(Aβ42)(+21.42%)and Aβ40(+23.53%)levels compared to baseline.Conclusions:Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD.Cognitive stability and biomarker changes over 6 months suggest potential efficacy,though high dropout rates and absence of a control group warrant cautious interpretation.These findings provide preliminary real-world evidence for lecanemab’s use in China,supporting further investigation in larger controlled studies.展开更多
Background In Alzheimer’s Disease(AD),about one-third of the risk genes identified by GWAS encode proteins that function predominantly in the endocytic pathways.Among them,the Ras and Rab Interactor 3(RIN3)is a guani...Background In Alzheimer’s Disease(AD),about one-third of the risk genes identified by GWAS encode proteins that function predominantly in the endocytic pathways.Among them,the Ras and Rab Interactor 3(RIN3)is a guanine nucleotide exchange factor(GEF)for the Rab5 small GTPase family and has been implicated to be a risk factor for both late onset AD(LOAD)and sporadic early onset AD(sEOAD).However,how RIN3 is linked to AD pathogenesis is currently undefined.Methods Quantitative PCR and immunoblotting were used to measure the RIN3 expression level in mouse brain tissues and cultured basal forebrain cholinergic neuron(BFCNs).Immunostaining was used to define subcellular localization of RIN3 and to visualize endosomal changes in cultured primary BFCNs and PC12 cells.Recombinant flag-tagged RIN3 protein was purified from HEK293T cells and was used to define RIN3-interactomes by mass spectrometry.RIN3-interacting partners were validated by co-immunoprecipitation,immunofluorescence and yeast two hybrid assays.Live imaging of primary neurons was used to examine axonal transport of amyloid precursor protein(APP)andβ-secretase 1(BACE1).Immunoblotting was used to detect protein expression,processing of APP and phosphorylated forms of Tau.Results We have shown that RIN3 mRNA level was significantly increased in the hippocampus and cortex of APP/PS1 mouse brain.Basal forebrain cholinergic neurons(BFCNs)cultured from E18 APP/PS1 mouse embryos also showed increased RIN3 expression accompanied by early endosome enlargement.In addition,via its proline rich domain,RIN3 recruited BIN1(bridging integrator 1)and CD2AP(CD2 associated protein),two other AD risk factors,to early endosomes.Interestingly,overexpression of RIN3 or CD2AP promoted APP cleavage to increase its carboxyl terminal fragments(CTFs)in PC12 cells.Upregulation of RIN3 or the neuronal isoform of BIN1 increased phosphorylated Tau level.Therefore,upregulation of RIN3 expression promoted accumulation of APP CTFs and increased phosphorylated Tau.These effects by RIN3 was rescued by the expression of a dominant negative Rab5(Rab5S34N)construct.Our study has thus pointed to that RIN3 acts through Rab5 to impact endosomal trafficking and signaling.Conclusion RIN3 is significantly upregulated and correlated with endosomal dysfunction in APP/PS1 mouse.Through interacting with BIN1 and CD2AP,increased RIN3 expression alters axonal trafficking and procession of APP.Together with our previous studies,our current work has thus provided important insights into the role of RIN3 in regulating endosomal signaling and trafficking.展开更多
基金funded by the National Natural Science Foundation of China(grants 31770374 and 32070377)the Key Projects of the Joint Fund of the National Natural Science Foundation of China(grant U1802232).
文摘A full understanding of adaptive genetic variation at the genomic level will help address questions of how organisms adapt to diverse climates.Actinidia eriantha is a shade-tolerant species,widely distributed in the southern tropical region of China,occurring in spatially heterogeneous environments.In the present study we combined population genomic,epigenomic,and environmental association analyses to infer population genetic structure and positive selection across a climatic gradient,and to assess genomic offset to climatic change for A.eriantha.The population structure is strongly shaped by geography and influenced by restricted gene f low resulting from isolation by distance due to habitat fragmentation.In total,we identified 102 outlier loci and annotated 455 candidate genes associated with the genomic basis of climate adaptation,which were enriched in functional categories related to development processes and stress response;both temperature and precipitation are important factors driving adaptive variation.In addition to single-nucleotide polymorphisms(SNPs),a total of 27 single-methylation variants(SMVs)had significant correlation with at least one of four climatic variables and 16 SMVswere located in or adjacent to genes,several of whichwere predicted to be involved in plant response to abiotic or biotic stress.Gradient forest analysis indicated that the central/east populations were predicted to be at higher risk of future population maladaptation under climate change.Our results demonstrate that local climate factors impose strong selection pressures and lead to local adaptation.Such information adds to our understanding of adaptive mechanisms to variable climates revealed by both population genome and epigenome analysis.
基金supported by grants from the Hainan Province Science and Technology Special Fund(No.ZDYF2024LCLH005)National Natural Science Foundation of China(No.82101477)the 2025 Shanghai Natural Science Foundation(No.25ZR1402333).
文摘Introduction:Lecanemab has shown promise in treating early Alzheimer’s disease(AD),but its safety and efficacy in Chinese populations remain unexplored.This study aimed to evaluate the safety and 6-month clinical outcomes of lecanemab in Chinese patients with mild cognitive impairment(MCI)or mild AD.Methods:In this single-arm,real-world study,participants with MCI due to AD or mild AD received biweekly intravenous lecanemab(10 mg/kg).The study was conducted at Hainan Branch,Ruijin Hospital Shanghai Jiao Tong University School of Medicine.Patient enrollment and baseline assessments commenced in November 2023.Safety assessments included monitoring for amyloid-related imaging abnormalities(ARIA)and other adverse events.Clinical and biomarker changes from baseline to 6 months were evaluated using cognitive scales(mini-mental state examination[MMSE],montreal cognitive assessment[MoCA],clinical dementia rating-sum of boxes[CDR-SB]),plasma biomarker analysis,and advanced neuroimaging.Results:A total of 64 patients were enrolled in this ongoing real-world study.Safety analysis revealed predominantly mild adverse events,with infusion-related reactions(20.3%,13/64)being the most common.Of these,69.2%(9/13)occurred during the initial infusion and 84.6%(11/13)did not recur.ARIA-H(microhemorrhages/superficial siderosis)and ARIA-E(edema/effusion)were observed in 9.4%(6/64)and 3.1%(2/64)of participants,respectively,with only two symptomatic cases(one ARIA-E presenting with headache and one ARIA-H with visual disturbances).After 6 months of treatment,cognitive scores remained stable compared to baseline(MMSE:22.33±5.58 vs.21.27±4.30,P=0.733;MoCA:16.38±6.67 vs.15.90±4.78,P=0.785;CDR-SB:2.30±1.65 vs.3.16±1.72,P=0.357),while significantly increasing plasma amyloid-β42(Aβ42)(+21.42%)and Aβ40(+23.53%)levels compared to baseline.Conclusions:Lecanemab demonstrated a favorable safety profile in Chinese patients with early AD.Cognitive stability and biomarker changes over 6 months suggest potential efficacy,though high dropout rates and absence of a control group warrant cautious interpretation.These findings provide preliminary real-world evidence for lecanemab’s use in China,supporting further investigation in larger controlled studies.
基金The project was financially supported by the National Natural Science Foundation of China[#81630029 and#81871005 for JD]the National Key R&D Program of China[#2016YFC13060000 for JD].UCSD ADRC P50 Pilot Grant(Wu).
文摘Background In Alzheimer’s Disease(AD),about one-third of the risk genes identified by GWAS encode proteins that function predominantly in the endocytic pathways.Among them,the Ras and Rab Interactor 3(RIN3)is a guanine nucleotide exchange factor(GEF)for the Rab5 small GTPase family and has been implicated to be a risk factor for both late onset AD(LOAD)and sporadic early onset AD(sEOAD).However,how RIN3 is linked to AD pathogenesis is currently undefined.Methods Quantitative PCR and immunoblotting were used to measure the RIN3 expression level in mouse brain tissues and cultured basal forebrain cholinergic neuron(BFCNs).Immunostaining was used to define subcellular localization of RIN3 and to visualize endosomal changes in cultured primary BFCNs and PC12 cells.Recombinant flag-tagged RIN3 protein was purified from HEK293T cells and was used to define RIN3-interactomes by mass spectrometry.RIN3-interacting partners were validated by co-immunoprecipitation,immunofluorescence and yeast two hybrid assays.Live imaging of primary neurons was used to examine axonal transport of amyloid precursor protein(APP)andβ-secretase 1(BACE1).Immunoblotting was used to detect protein expression,processing of APP and phosphorylated forms of Tau.Results We have shown that RIN3 mRNA level was significantly increased in the hippocampus and cortex of APP/PS1 mouse brain.Basal forebrain cholinergic neurons(BFCNs)cultured from E18 APP/PS1 mouse embryos also showed increased RIN3 expression accompanied by early endosome enlargement.In addition,via its proline rich domain,RIN3 recruited BIN1(bridging integrator 1)and CD2AP(CD2 associated protein),two other AD risk factors,to early endosomes.Interestingly,overexpression of RIN3 or CD2AP promoted APP cleavage to increase its carboxyl terminal fragments(CTFs)in PC12 cells.Upregulation of RIN3 or the neuronal isoform of BIN1 increased phosphorylated Tau level.Therefore,upregulation of RIN3 expression promoted accumulation of APP CTFs and increased phosphorylated Tau.These effects by RIN3 was rescued by the expression of a dominant negative Rab5(Rab5S34N)construct.Our study has thus pointed to that RIN3 acts through Rab5 to impact endosomal trafficking and signaling.Conclusion RIN3 is significantly upregulated and correlated with endosomal dysfunction in APP/PS1 mouse.Through interacting with BIN1 and CD2AP,increased RIN3 expression alters axonal trafficking and procession of APP.Together with our previous studies,our current work has thus provided important insights into the role of RIN3 in regulating endosomal signaling and trafficking.
