Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including...Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs.Peroxisomes are recently found to receive cholesterol from lysosomes through lysosomeperoxisome membrane contacts.However,whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown.Here,by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes,we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1,2 and 3(E-Syts).Depletion of peroxisomal PI(4,5)P2 or ESyts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes.Furthermore,we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro,and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER.Together,our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.展开更多
The significant challenges that urban design faces when moving forward into this new digital era involve the increasingly massive and complex projects that must be analyzed and developed.The need for efficient analysi...The significant challenges that urban design faces when moving forward into this new digital era involve the increasingly massive and complex projects that must be analyzed and developed.The need for efficient analysis tools and rational design methods represent ongoing concerns,while practicable and maneuverable applications rather than experimental studies are scarce.This research implemented a framework of digital description and generative grammar of block form from the perspective of block morphological complexity.The implemented framework was tested in an urban design practice.First,this study adapted the hierarchical structure and access structure theory to analyze the spatial form of target blocks.The characteristics of blocks case samples in Nanjing are extracted as text descriptions.Second,the relevant composition patterns and parameters were employed as features for classificati on and were converted into procedural rules.With the top-down control by rules and bottom-up generation by shape grammar in CityEngine,the texture of the block can be generated as close to the actual block as possible.Furthermore,in a real urban design case located in Nanjing,this work applies the method to construct a three-dimensional scene quickly and accurately.After integrating design factors such as an environment,transportation,and vision and summarizing the intentions of blocks and buildings in corresponding functions and control indexes,the initial generation plan was built by applying the obtained characteristics and procedural rules in specific shape grammar.Finally,designers can adjust the result in detail by employing real-time calculation and interactive operation.展开更多
The rapid urbanization process in China has promoted the active state of urban design practice.In the process of solving complex problems,the practical scope of urban design has gradually expanded.This paper took a de...The rapid urbanization process in China has promoted the active state of urban design practice.In the process of solving complex problems,the practical scope of urban design has gradually expanded.This paper took a design institution in Nanjing as a case study and sorted the trends in design project types and themes over the past 20 years,which presented a partial and diverse state of evolution in urban design practice.Concept,technology and management were extracted as the three main dimensions of cognitive urban design practice development.The relative positions and relationships of different types of urban design work were interpreted through mapping analysis of these three dimensions.This study provided a foundation for the practical orientation of urban design in China and a platform for communication a mong managers,urban design practitioners,scholars of related disciplines,and the public.展开更多
Niemann-Pick type C2(NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of lowdensity lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2(NF-κB2)...Niemann-Pick type C2(NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of lowdensity lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2(NF-κB2) protein is a component of NF-κB transcription factor complex critically implicated in immune and inflammatory responses. Here, we report that NF-κB2 regulates intracellular cholesterol transport by controlling NPC2 expression. RNAi-mediated disruption of NF-κB2, as well as other signaling members of the non-canonical NF-κB pathway, caused intracellular cholesterol accumulation. Blockage of the non-canonical NF-κB pathway suppressed NPC2 expression, whereas Lymphotoxin β receptor(LTβR) activation or Baff receptor(BaffR) stimulation up-regulated the mRNA abundance and protein level of NPC2. Further, NF-κB2 activated NPC2 transcription through direct binding to its promoter region. We also observed cholesterol accumulation in NF-κB2-deficient zebrafish embryo and NF-κB2 mutant mice. Collectively, these data identify a regulatory role for the non-canonical NF-κB pathway in intracellular cholesterol trafficking and suggest a link between cholesterol transport and immune system.展开更多
Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the A...Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene,which encodes a transporter mediating the uptake of very long-chain fatty acids(VLCFAs).The curative approaches for PDs are very limited.Here,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs.We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome.2-Hydroxypropyl-β-cyclodextrin(HPCD)effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes.In ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal levels.In Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex.The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration.Together,our results suggest that defective cholesterol transport underlies most,if not all,PDs,and that HPCD can serve as a novel and effective strategy for the treatment of PDs.展开更多
Dramatic changes in the economic systems and land rights in the recent history of China yielded unique but complex urban forms for many cities.The complexity of urban form is mostly manifested as ambiguous relations b...Dramatic changes in the economic systems and land rights in the recent history of China yielded unique but complex urban forms for many cities.The complexity of urban form is mostly manifested as ambiguous relations between elements of the physical form and between the physical form and human behavior.Currently,these ambiguities become obstacles that increasingly hinder urban regeneration.However,despite the fast-growing research on the morphology of Chinese cities,our understanding of the complexity of their built form is still in its infancy.Taking the city of Nanjing as the case study,this study attempts to decipher the complexity of its built form by investigating its plot patterns.Six samples,dating back to different development periods,are selected and analyzed in terms of both a physical entity and a unit of property.The results show that the complexity of plots is largely attributable to the inconsistency between their spatial boundaries as physical entities and as units of property.Accordingly,the plots of all six samples are re-recognized and two generic types of plot sub-series,co-inflection and embeddedness,are developed as a prism to decipher the built form complexity.The findings contribute to the theory on the compositional hierarchy of urban forms and may shed light on the urban regeneration of Chinese cities as well.展开更多
基金supported by the National Natural Science Foundation of China (91754102, 31771568, 31690102, 31600651, 31701030)National Key Research and Development Project of the Ministry of Science and Technology of China (2016YFA0500100)+2 种基金Shenzhen City Technology Basic Research Program (JCYJ20170818144026198)Science and Technology Department of Hubei Province (2017CFB617)the 111 Project of Ministry of Education of China (B16036)
文摘Most mammalian cells take up cholesterol from low-density lipoproteins(LDLs) via receptor-mediated endocytosis.After reaching lysosomes,LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs.Peroxisomes are recently found to receive cholesterol from lysosomes through lysosomeperoxisome membrane contacts.However,whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown.Here,by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes,we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1,2 and 3(E-Syts).Depletion of peroxisomal PI(4,5)P2 or ESyts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes.Furthermore,we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro,and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER.Together,our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.
基金supported by the National Natural Science Foundation of China under Grant 51778118。
文摘The significant challenges that urban design faces when moving forward into this new digital era involve the increasingly massive and complex projects that must be analyzed and developed.The need for efficient analysis tools and rational design methods represent ongoing concerns,while practicable and maneuverable applications rather than experimental studies are scarce.This research implemented a framework of digital description and generative grammar of block form from the perspective of block morphological complexity.The implemented framework was tested in an urban design practice.First,this study adapted the hierarchical structure and access structure theory to analyze the spatial form of target blocks.The characteristics of blocks case samples in Nanjing are extracted as text descriptions.Second,the relevant composition patterns and parameters were employed as features for classificati on and were converted into procedural rules.With the top-down control by rules and bottom-up generation by shape grammar in CityEngine,the texture of the block can be generated as close to the actual block as possible.Furthermore,in a real urban design case located in Nanjing,this work applies the method to construct a three-dimensional scene quickly and accurately.After integrating design factors such as an environment,transportation,and vision and summarizing the intentions of blocks and buildings in corresponding functions and control indexes,the initial generation plan was built by applying the obtained characteristics and procedural rules in specific shape grammar.Finally,designers can adjust the result in detail by employing real-time calculation and interactive operation.
基金The work described in this paper was sponsored by the National Natural Science Foundation of China(NSFC#51578123).
文摘The rapid urbanization process in China has promoted the active state of urban design practice.In the process of solving complex problems,the practical scope of urban design has gradually expanded.This paper took a design institution in Nanjing as a case study and sorted the trends in design project types and themes over the past 20 years,which presented a partial and diverse state of evolution in urban design practice.Concept,technology and management were extracted as the three main dimensions of cognitive urban design practice development.The relative positions and relationships of different types of urban design work were interpreted through mapping analysis of these three dimensions.This study provided a foundation for the practical orientation of urban design in China and a platform for communication a mong managers,urban design practitioners,scholars of related disciplines,and the public.
基金supported by National Natural Science Foundation of China (91754102, 31771568, 31701030, 31601147, 31600651)111 Project of Ministry of Education of China (B16036)Natural Science Foundation of Hubei Province (2016CFA012)
文摘Niemann-Pick type C2(NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of lowdensity lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2(NF-κB2) protein is a component of NF-κB transcription factor complex critically implicated in immune and inflammatory responses. Here, we report that NF-κB2 regulates intracellular cholesterol transport by controlling NPC2 expression. RNAi-mediated disruption of NF-κB2, as well as other signaling members of the non-canonical NF-κB pathway, caused intracellular cholesterol accumulation. Blockage of the non-canonical NF-κB pathway suppressed NPC2 expression, whereas Lymphotoxin β receptor(LTβR) activation or Baff receptor(BaffR) stimulation up-regulated the mRNA abundance and protein level of NPC2. Further, NF-κB2 activated NPC2 transcription through direct binding to its promoter region. We also observed cholesterol accumulation in NF-κB2-deficient zebrafish embryo and NF-κB2 mutant mice. Collectively, these data identify a regulatory role for the non-canonical NF-κB pathway in intracellular cholesterol trafficking and suggest a link between cholesterol transport and immune system.
基金supported by the China Postdoctoral Science Foundation Grant(2021M692478)the Ministry of Science and Technology of China(2018YFA0800703)+2 种基金the National Natural Science Foundation of China(32293203,31771568)111 Project of Ministry of Education of China(B16036)the support from the Tencent Foundation through the XPLORER PRIZE。
文摘Peroxisomal disorders(PDs)are a heterogenous group of diseases caused by defects in peroxisome biogenesis or functions.Xlinked adrenoleukodystrophy is the most prevalent form of PDs and results from mutations in the ABCD1 gene,which encodes a transporter mediating the uptake of very long-chain fatty acids(VLCFAs).The curative approaches for PDs are very limited.Here,we investigated whether cholesterol accumulation in the lysosomes is a biochemical feature shared by a broad spectrum of PDs.We individually knocked down fifteen PD-associated genes in cultured cells and found ten induced cholesterol accumulation in the lysosome.2-Hydroxypropyl-β-cyclodextrin(HPCD)effectively alleviated the cholesterol accumulation phenotype in PD-mimicking cells through reducing intracellular cholesterol content as well as promoting cholesterol redistribution to other cellular membranes.In ABCD1 knockdown cells,HPCD treatment lowered reactive oxygen species and VLCFA to normal levels.In Abcd1 knockout mice,HPCD injections reduced cholesterol and VLCFA sequestration in the brain and adrenal cortex.The plasma levels of adrenocortical hormones were increased and the behavioral abnormalities were greatly ameliorated upon HPCD administration.Together,our results suggest that defective cholesterol transport underlies most,if not all,PDs,and that HPCD can serve as a novel and effective strategy for the treatment of PDs.
基金the National Natural Science Foundation of China,for project"Analysis and optimization of superblock morphology based on the measurement of‘scaling hierarchy and access structure’"(Program No.52008082),January 2021-December 2023.
文摘Dramatic changes in the economic systems and land rights in the recent history of China yielded unique but complex urban forms for many cities.The complexity of urban form is mostly manifested as ambiguous relations between elements of the physical form and between the physical form and human behavior.Currently,these ambiguities become obstacles that increasingly hinder urban regeneration.However,despite the fast-growing research on the morphology of Chinese cities,our understanding of the complexity of their built form is still in its infancy.Taking the city of Nanjing as the case study,this study attempts to decipher the complexity of its built form by investigating its plot patterns.Six samples,dating back to different development periods,are selected and analyzed in terms of both a physical entity and a unit of property.The results show that the complexity of plots is largely attributable to the inconsistency between their spatial boundaries as physical entities and as units of property.Accordingly,the plots of all six samples are re-recognized and two generic types of plot sub-series,co-inflection and embeddedness,are developed as a prism to decipher the built form complexity.The findings contribute to the theory on the compositional hierarchy of urban forms and may shed light on the urban regeneration of Chinese cities as well.
