The endosomal trafficking of signaling membrane proteins, such as receptors, transporters and channels, is mediated by the retromer-mediated sorting machinery, composed of a cargo-selective vacuolar protein sorting tr...The endosomal trafficking of signaling membrane proteins, such as receptors, transporters and channels, is mediated by the retromer-mediated sorting machinery, composed of a cargo-selective vacuolar protein sorting trimer and a membrane-deforming subunit of sorting nexin proteins. Recent studies have shown that the isoforms, sorting nexin 5 (SNX5) and SNX6, have played distinctive regulatory roles in retrograde membrane trafficking. However, the molecular insight determined functional differences within the proteins remains unclear. We reported that SNX5 and SNX6 had distinct binding affinity to the cargo protein vesicular monoamine transporter 2 (VMAT2). SNX5, but not SNX6, specifically interacted with VMAT2 through the Phox domain, which contains an alpha-helix binding motif. Using chimeric mutagenesis, we identified that several key residues within this domain were unique in SNX5, but not SNX6, and played an auxiliary role in its binding to VMAT2. Importantly, we generated a set of mutant SNX6, in which the corresponding key residues were mutated to those in SNX5. In addition to the gain in binding affinity to VMAT2, their overexpression functionally rescued the altered retrograde trafficking of VMAT2 induced by siRNA-mediated depletion of SNX5. These data strongly suggest that SNX5 and SNX6 have different functions in retrograde membrane trafficking, which is determined by the different structural elements within the Phox domain of two proteins. Our work provides a new information on the role of SNX5 and SNX6 in the molecular regulation of retrograde membrane trafficking and vesicular membrane targeting in monoamine neurotransmission and neurological diseases.展开更多
Percutaneous endoscopic gastrostomy is an established method to provide nutrition to patients with restricted oral uptake of fluids and calories.Here,we review the methods,indications and complications of this procedu...Percutaneous endoscopic gastrostomy is an established method to provide nutrition to patients with restricted oral uptake of fluids and calories.Here,we review the methods,indications and complications of this procedure.While gastrostomy can be safely and easily performed during gastroscopy,the right patients and timing for this intervention are not always chosen.Especially in patients with dementia,the indication for and timing of gastrostomies are often improper.In this patient group,clear data for enteral nutrition are lacking;however,some evidence suggests that patients with advanced dementia do not benefit,whereas patients with mild to moderate dementia might benefit from early enteral nutrition.Additionally,other patient groups with temporary or permanent restriction of oral uptake might be a useful target population for early enteral nutrition to maintain mobilization and muscle strength.We plead for a coordinated study program for these patient groups to identify suitable patients and the best timing for tube implantation.展开更多
The many-banded krait,Bungarus multicinctus,has been recorded as the animal resource of JinQianBaiHuaShe in the Chinese Pharmacopoeia.Characterization of its venoms classified chief phyla of modern animal neurotoxins....The many-banded krait,Bungarus multicinctus,has been recorded as the animal resource of JinQianBaiHuaShe in the Chinese Pharmacopoeia.Characterization of its venoms classified chief phyla of modern animal neurotoxins.However,the evolutionary origin and diversification of its neurotoxins as well as biosynthesis of its active compounds remain largely unknown due to the lack of its high-quality genome.Here,we present the 1.58 Gbp genome of B.multicinctus assembled into 18 chromosomes with contig/scaffold N50 of 7.53 Mbp/149.8 Mbp.Major bungarotoxin-coding genes were clustered within genome by family and found to be associated with ancient local duplications.The truncation of glycosylphosphatidylinositol anchor in the 3'-terminal of a LY6E paralog released modern three-finger toxins(3FTxs)from membrane tethering before the Colubroidea divergence.Subsequent expansion and mutations diversified and recruited these 3FTxs.After the cobra/krait divergence,the modern unit-B ofβ-bungarotoxin emerged with an extra cysteine residue.A subsequent point substitution in unit-A enabled theβ-bungarotoxin covalent linkage.The B.multicinctus gene expression,chromatin topological organization,and histone modification characteristics were featured by transcriptome,proteome,chromatin conformation capture sequencing,and ChIP-seq.The results highlighted that venom production was under a sophisticated regulation.Our findings provide new insights into snake neurotoxin research,meanwhile will facilitate antivenom development,toxin-driven drug discovery and the quality control of JinQianBaiHuaShe.展开更多
Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modif...Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.展开更多
We investigate the critical properties of the Ising S=1/2 and S=1 model on(3,4,6,4)and(34,6)Archimedean lattices.The system is studied through the extensive Monte Carlo simulations.We calculate the critical temperatur...We investigate the critical properties of the Ising S=1/2 and S=1 model on(3,4,6,4)and(34,6)Archimedean lattices.The system is studied through the extensive Monte Carlo simulations.We calculate the critical temperature as well as the critical point exponentsγ/ν,β/ν,andνbasing on finite size scaling analysis.The calculated values of the critical temperature for S=1 are kBTC/J=1.590(3),and kBTC/J=2.100(4)for(3,4,6,4)and(34,6)Archimedean lattices,respectively.The critical exponentsβ/ν,γ/ν,and 1/ν,for S=1 areβ/ν=0.180(20),γ/ν=1.46(8),and 1/ν=0.83(5),for(3,4,6,4)and 0.103(8),1.44(8),and 0.94(5),for(34,6)Archimedean lattices.Obtained results differ from the Ising S=1/2 model on(3,4,6,4),(34,6)and square lattice.The evaluated effective dimensionality of the system for S=1 are Deff=1.82(4),for(3,4,6,4),and Deff=1.64(5)for(34,6).展开更多
Ever since the Cold Spring Pavilion (Lengquan ting 冷泉亭) was built, it has been extolled by scholar-literati as a place of purity, where the dust of the mundane world could be cleansed by the cold spring water flo...Ever since the Cold Spring Pavilion (Lengquan ting 冷泉亭) was built, it has been extolled by scholar-literati as a place of purity, where the dust of the mundane world could be cleansed by the cold spring water flowing beside it. For centuries, people tried to reinforce the image of the pavilion as an innocent haven through writing poems, stories, and essays about their visits there. But they were unaware, or refused to admit, that their admiration of the place also possessed the power to destroy whatever sacredness and serenity it stood for. This paper examines representations of the Cold Spring Pavilion in Chinese literature through the lens of a paradox that has haunted the pavilion since it was first built. The paper argues that, ever since the pavilion was built, it has, through its literary-historical representation, been slowly but inevitably absorbed or assimilated into what it had originally been built to fend off. Like the Cold Spring, which flowed into West Lake, the Cold Spring Pavilion, which was created to help people resist the temptations of city life, was inevitably absorbed into the very fabric of the city.展开更多
基金This work was supported by the National Natural Science Foundation of China(Grant Nos.31371436 and 8157051134 to Y.L.)by the laboratory start-up grant from Nanjing Medical University(to Y.L.).
文摘The endosomal trafficking of signaling membrane proteins, such as receptors, transporters and channels, is mediated by the retromer-mediated sorting machinery, composed of a cargo-selective vacuolar protein sorting trimer and a membrane-deforming subunit of sorting nexin proteins. Recent studies have shown that the isoforms, sorting nexin 5 (SNX5) and SNX6, have played distinctive regulatory roles in retrograde membrane trafficking. However, the molecular insight determined functional differences within the proteins remains unclear. We reported that SNX5 and SNX6 had distinct binding affinity to the cargo protein vesicular monoamine transporter 2 (VMAT2). SNX5, but not SNX6, specifically interacted with VMAT2 through the Phox domain, which contains an alpha-helix binding motif. Using chimeric mutagenesis, we identified that several key residues within this domain were unique in SNX5, but not SNX6, and played an auxiliary role in its binding to VMAT2. Importantly, we generated a set of mutant SNX6, in which the corresponding key residues were mutated to those in SNX5. In addition to the gain in binding affinity to VMAT2, their overexpression functionally rescued the altered retrograde trafficking of VMAT2 induced by siRNA-mediated depletion of SNX5. These data strongly suggest that SNX5 and SNX6 have different functions in retrograde membrane trafficking, which is determined by the different structural elements within the Phox domain of two proteins. Our work provides a new information on the role of SNX5 and SNX6 in the molecular regulation of retrograde membrane trafficking and vesicular membrane targeting in monoamine neurotransmission and neurological diseases.
文摘Percutaneous endoscopic gastrostomy is an established method to provide nutrition to patients with restricted oral uptake of fluids and calories.Here,we review the methods,indications and complications of this procedure.While gastrostomy can be safely and easily performed during gastroscopy,the right patients and timing for this intervention are not always chosen.Especially in patients with dementia,the indication for and timing of gastrostomies are often improper.In this patient group,clear data for enteral nutrition are lacking;however,some evidence suggests that patients with advanced dementia do not benefit,whereas patients with mild to moderate dementia might benefit from early enteral nutrition.Additionally,other patient groups with temporary or permanent restriction of oral uptake might be a useful target population for early enteral nutrition to maintain mobilization and muscle strength.We plead for a coordinated study program for these patient groups to identify suitable patients and the best timing for tube implantation.
基金the Fundamental Research Funds for the Central Public Welfare Research Institutes(ZZ13-YQ-047,ZXKT22006,China)quality standard system construction for the whole industry chain of Chinese medicine from Guangdong Provincial Drug Administration of China(002009/2019KT1261/2020ZDB25)+2 种基金the National Major Science and Technology Projects(2019ZX09201005,China)the Open Research Fund of Chengdu University of Traditional Chinese Medicino state Key Laboratory scluthwestern Chinese Medicine Resources(2022ZYXK2011006,China)the National Key R&D Program of China(2019YFC1711100)。
文摘The many-banded krait,Bungarus multicinctus,has been recorded as the animal resource of JinQianBaiHuaShe in the Chinese Pharmacopoeia.Characterization of its venoms classified chief phyla of modern animal neurotoxins.However,the evolutionary origin and diversification of its neurotoxins as well as biosynthesis of its active compounds remain largely unknown due to the lack of its high-quality genome.Here,we present the 1.58 Gbp genome of B.multicinctus assembled into 18 chromosomes with contig/scaffold N50 of 7.53 Mbp/149.8 Mbp.Major bungarotoxin-coding genes were clustered within genome by family and found to be associated with ancient local duplications.The truncation of glycosylphosphatidylinositol anchor in the 3'-terminal of a LY6E paralog released modern three-finger toxins(3FTxs)from membrane tethering before the Colubroidea divergence.Subsequent expansion and mutations diversified and recruited these 3FTxs.After the cobra/krait divergence,the modern unit-B ofβ-bungarotoxin emerged with an extra cysteine residue.A subsequent point substitution in unit-A enabled theβ-bungarotoxin covalent linkage.The B.multicinctus gene expression,chromatin topological organization,and histone modification characteristics were featured by transcriptome,proteome,chromatin conformation capture sequencing,and ChIP-seq.The results highlighted that venom production was under a sophisticated regulation.Our findings provide new insights into snake neurotoxin research,meanwhile will facilitate antivenom development,toxin-driven drug discovery and the quality control of JinQianBaiHuaShe.
文摘Significant cellular senescence has been observed in cartilage harvested from patients with osteoarthritis(OA).In this study,we aim to develop a senescence-relevant OA-like cartilage model for developing disease-modifying OA drugs(DMOADs).Spe-cifically,human bone marrow-derived mesenchymal stromal cells(MSCs)were expanded in vitro up to passage 10(P10-MSCs).Following their senescent phenotype formation,P10-MSCs were subjected to pellet culture in chondrogenic medium.Results from qRT-PCR,histology,and immunostaining indicated that cartilage generated from P10-MSCs displayed both senescent and OA-like phenotypes without using other OA-inducing agents,when compared to that from normal passage 4(P4)-MSCs.Interestingly,the same gene expression differences observed between P4-MSCs and P10-MSC-derived cartilage tissues were also observed between the preserved and damaged OA cartilage regions taken from human samples,as demonstrated by RNA sequencing data and other analysis methods.Lastly,the utility of this senescence-initiated OA-like cartilage model in drug development was assessed by testing several potential DMOADs and senolytics.The results suggest that pre-existing cellular senescence can induce the generation of OA-like changes in cartilage.The P4-and P10-MSCs derived cartilage models also represent a novel platform for predicting the efficacy and toxicity of potential DMOADs on both preserved and damaged cartilage in humans.
基金the Brazilian agency FAPEPI(Teresina,Piaui,Brazil)and the Polish Ministry of Science and Higher Education for their financial support。
文摘We investigate the critical properties of the Ising S=1/2 and S=1 model on(3,4,6,4)and(34,6)Archimedean lattices.The system is studied through the extensive Monte Carlo simulations.We calculate the critical temperature as well as the critical point exponentsγ/ν,β/ν,andνbasing on finite size scaling analysis.The calculated values of the critical temperature for S=1 are kBTC/J=1.590(3),and kBTC/J=2.100(4)for(3,4,6,4)and(34,6)Archimedean lattices,respectively.The critical exponentsβ/ν,γ/ν,and 1/ν,for S=1 areβ/ν=0.180(20),γ/ν=1.46(8),and 1/ν=0.83(5),for(3,4,6,4)and 0.103(8),1.44(8),and 0.94(5),for(34,6)Archimedean lattices.Obtained results differ from the Ising S=1/2 model on(3,4,6,4),(34,6)and square lattice.The evaluated effective dimensionality of the system for S=1 are Deff=1.82(4),for(3,4,6,4),and Deff=1.64(5)for(34,6).
文摘Ever since the Cold Spring Pavilion (Lengquan ting 冷泉亭) was built, it has been extolled by scholar-literati as a place of purity, where the dust of the mundane world could be cleansed by the cold spring water flowing beside it. For centuries, people tried to reinforce the image of the pavilion as an innocent haven through writing poems, stories, and essays about their visits there. But they were unaware, or refused to admit, that their admiration of the place also possessed the power to destroy whatever sacredness and serenity it stood for. This paper examines representations of the Cold Spring Pavilion in Chinese literature through the lens of a paradox that has haunted the pavilion since it was first built. The paper argues that, ever since the pavilion was built, it has, through its literary-historical representation, been slowly but inevitably absorbed or assimilated into what it had originally been built to fend off. Like the Cold Spring, which flowed into West Lake, the Cold Spring Pavilion, which was created to help people resist the temptations of city life, was inevitably absorbed into the very fabric of the city.