Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand...Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.展开更多
Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HN...Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels,but the mechanisms remain unclear.This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways.Methods A stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A.RNA sequencing(RNA-seq)was performed to analyze transcriptional differences.Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes.Results RNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5(TM4SF5)mRNA in HNF4A-overexpressing cells.Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter.Finally,we confirmed that the DR1 site in the-57 to-48 region of the TM4SF5 promoter is the key binding motif for HNF4A.Conclusion This study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation.Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion,which closely aligns with phenotypes observed in MODY1 patients,our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.展开更多
Discoidin domain receptors(DDRs)are single-pass transmembrane proteins belonging to receptor tyrosine kinases(RTKs)family,which are activated by collagen ligands with unusual slow,sustained kinetics,distinguishing the...Discoidin domain receptors(DDRs)are single-pass transmembrane proteins belonging to receptor tyrosine kinases(RTKs)family,which are activated by collagen ligands with unusual slow,sustained kinetics,distinguishing them from canonical RTKs.While DDRs play critical roles in cell adhesion,differentiation,and cancer progression,their activation mechanisms remain partly understood.Here,we investigated the transmembrane domains(TMDs)of DDR1 and DDR2 to elucidate their interaction dynamics in membrane.Using bacterial adenylate cyclase two-hybrid(BACTH)assays,we demonstrated robust homotypic interactions and even stronger heterotypic associations between DDRTMDs.NMR spectroscopy of DDR1TMD and DDR2TMD reconstituted in lipid bilayer-mimetic bicelles showed obvious chemical shift alterations,further validating the stability of their heterocomplex formation.Systematic mutagenesis identified leucine zipper motifs rather than GXXXA motifs mediated both homo-and hetero-associations of DDR1TMD and DDR2TMD.These findings demonstrated the TMD as a critical mediator of DDRs oligomerization and revealed their interaction patterns within membrane.Our study advances the understanding of DDR signaling regulation and highlights transmembrane domain interactions as potential targets for modulating DDR-related pathologies.展开更多
Infections of many viruses induce caspase activation to regulate multiple cellular pathways,including programmed cell death,immune signaling and etc.Characterizations of caspase cleavage sites and substrates are impor...Infections of many viruses induce caspase activation to regulate multiple cellular pathways,including programmed cell death,immune signaling and etc.Characterizations of caspase cleavage sites and substrates are important for understanding the regulation mechanisms of caspase activation.Here,we identified and analyzed a novel caspase cleavage motif AEAD,and confirmed its caspase dependent cleavage activity in natural substrate,such as nitric oxide-associated protein 1(NOA1).Fusing the enhanced green fluorescent protein(EGFP)with the mitochondrial marker protein Tom20 through the AEAD motif peptide localized EGFP to the mitochondria.Upon the activation of caspase triggered by Sendai virus(SeV)or herpes simplex virus type 1(HSV-1)infection,EGFP diffusely localized to the cell due to the caspase-mediated cleavage,thus allowing visual detection of the virusinduced caspase activation.An AEAD peptide-derived inhibitor Z-AEAD-FMK were developed,which significantly inhibited the activities of caspases-1,-3,-6,-7,-8 and-9,exhibiting a broad caspase inhibition effect.The inhibitor further prevented caspases-mediated cleavage of downstream substrates,including BID,PARP1,LMNA,pro-IL-1β,pro-IL-18,GSDMD and GSDME,protecting cells from virus-induced apoptotic and pyroptotic cell death.Together,our findings provide a new perspective for the identification of novel caspase cleavage motifs and the development of new caspase inhibitors and anti-inflammatory drugs.展开更多
Interconnection of all things challenges the traditional communication methods,and Semantic Communication and Computing(SCC)will become new solutions.It is a challenging task to accurately detect,extract,and represent...Interconnection of all things challenges the traditional communication methods,and Semantic Communication and Computing(SCC)will become new solutions.It is a challenging task to accurately detect,extract,and represent semantic information in the research of SCC-based networks.In previous research,researchers usually use convolution to extract the feature information of a graph and perform the corresponding task of node classification.However,the content of semantic information is quite complex.Although graph convolutional neural networks provide an effective solution for node classification tasks,due to their limitations in representing multiple relational patterns and not recognizing and analyzing higher-order local structures,the extracted feature information is subject to varying degrees of loss.Therefore,this paper extends from a single-layer topology network to a multi-layer heterogeneous topology network.The Bidirectional Encoder Representations from Transformers(BERT)training word vector is introduced to extract the semantic features in the network,and the existing graph neural network is improved by combining the higher-order local feature module of the network model representation network.A multi-layer network embedding algorithm on SCC-based networks with motifs is proposed to complete the task of end-to-end node classification.We verify the effectiveness of the algorithm on a real multi-layer heterogeneous network.展开更多
Plasmodium (P.) falciparum is a pathogen that causes severe forms of malaria. Protein interactions have been shown to occur between P. falciparum and human erythrocytes in human blood. The Band 3 Anion Transporter (B3...Plasmodium (P.) falciparum is a pathogen that causes severe forms of malaria. Protein interactions have been shown to occur between P. falciparum and human erythrocytes in human blood. The Band 3 Anion Transporter (B3AT) protein is considered the main invasive pathway for the parasite in erythrocytes that causes clinical symptoms for malaria in humans. The interactions between P. falciparum parasites and erythrocytes along this receptor have previously been explored. Short linear motifs (SLIMs) are short linear mediator sequences that involve several biological processes, acting as mediators of protein interactions identifiable by computational tools such as SLiMFinder. For a given protein, the identification of SLIMs allows predicting its interactors. Using the SLIMs approach, protein-protein interaction network analyses between P. falciparum and its human host, were used to identify a tryptophan-rich protein, A5K5E5_PLAVS as an essential interactor of B3AT. To better understand the interaction mechanism, a guided protein-protein docking approach based on SLIM motifs was performed for human B3AT and A5K5E5_PLAVS. The highlights of this important interaction between P. falciparum and its human host have the potential to pave the way to identify new therapeutic candidates.展开更多
This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore t...This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.展开更多
The image of Mulan is well known to the public as an important symbol in the dissemination of Chinese excellent traditional culture.This paper aims to summarise the mother-title from traditional canonical texts,to exp...The image of Mulan is well known to the public as an important symbol in the dissemination of Chinese excellent traditional culture.This paper aims to summarise the mother-title from traditional canonical texts,to explore the content and value of sustainable IP development,and to study a large number of derivatives with the image of Mulan as the mother-title,based on the wide circulation of the prototype of the mother-title“The Poem of Mulan”(木兰辞)and the positive values conveyed by the content.Through the processing and imagination of scholars and writers on the mother text in the past generations,the image of Mulan has gradually formed a relatively stable cultural communication theme in the process of dissemination in China’s historical period,and many adaptations with international influence based on the mother title of Mulan have emerged in the foreign dissemination,so through the combing and summarisation of the textual works of various periods both at home and abroad,we will dig out the textual transmission of the mother title of Mulan,which is representative of the mother title of China’s excellent traditional culture,and the development of the Chinese spiritual core.The Development of the Chinese Spiritual Kernel.This paper adopts research methods such as documentary evidence method and discourse analysis to show the textual flow of Mulan’s parent theme in a more diversified form.展开更多
基金supported by the National Natural Science Foundation of China(Key Program),No.11932013the National Natural Science Foundation of China(General Program),No.82272255+2 种基金Armed Police Force High-Level Science and Technology Personnel ProjectThe Armed Police Force Focuses on Supporting Scientific and Technological Innovation TeamsKey Project of Tianjin Science and Technology Plan,No.20JCZDJC00570(all to XC)。
文摘Spinal cord injury involves non-reversible damage to the central nervous system that is characterized by limited regenerative capacity and secondary inflammatory damage.The expression of the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis exhibits significant differences before and after injury.Recent studies have revealed that the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis is closely associated with secondary inflammatory responses and the recruitment of immune cells following spinal cord injury,suggesting that this axis is a novel target and regulatory control point for treatment.This review comprehensively examines the therapeutic strategies targeting the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis,along with the regenerative and repair mechanisms linking the axis to spinal cord injury.Additionally,we summarize the upstream and downstream inflammatory signaling pathways associated with spinal cord injury and the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review primarily elaborates on therapeutic strategies that target the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the latest progress of research on antagonistic drugs,along with the approaches used to exploit new therapeutic targets within the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis and the development of targeted drugs.Nevertheless,there are presently no clinical studies relating to spinal cord injury that are focusing on the C-C motif chemokine ligand 2/C-C motif chemokine receptor 2 axis.This review aims to provide new ideas and therapeutic strategies for the future treatment of spinal cord injury.
文摘随着智能交通系统(Intelligent Transportation Systems, ITS)的发展,城市交通车辆轨迹预测技术在交通管理和智能导航中具有重要的应用价值。在城市交通中,车辆出行轨迹受路网约束,将路网引入轨迹预测模型中有助于提高预测精度,但目前已有的基于路网的轨迹预测模型尚未充分利用路网中的高阶结构。因此,本文提出了一种基于路网motif图注意力网络的轨迹预测模型(Graph Attention Network for Trajectory Prediction based on Road Network Motifs, GRAM),该模型依靠真实路网中的motif来挖掘路网的高阶结构属性。GRAM基于路网motif构建交通流图,并利用图注意力网络从基于motif的交通流图和局部个体轨迹图中学习特征,同时通过结合不同motif对同一位置的影响训练模型,以获得最优比例。在3个真实轨迹数据集(波尔图、成都、北京)上的实验结果表明,本文的GRAM展示出了更好的性能。
文摘Objective Hepatocyte nuclear factor 4-alpha(HNF4A)is a critical transcription factor in the liver and pancreas.Dysfunctions of HNF4A lead to maturity onset diabetes of the young 1(MODY1).Notably,MODY1 patients with HNF4A pathogenic mutations exhibit decreased responses to arginine and reduced plasma triglyceride levels,but the mechanisms remain unclear.This study aims to investigate the potential target genes transcriptionally regulated by HNF4A and explore its role in these metabolic pathways.Methods A stable 293T cell line expressing the HNF1A reporter was overexpressed with HNF4A.RNA sequencing(RNA-seq)was performed to analyze transcriptional differences.Transcription factor binding site prediction was then conducted to identify HNF4A binding motifs in the promoter regions of relevant target genes.Results RNA-seq results revealed a significant upregulation of transmembrane 4 L six family member 5(TM4SF5)mRNA in HNF4A-overexpressing cells.Transcription factor binding predictions suggested the presence of five potential HNF4A binding motifs in the TM4SF5 promoter.Finally,we confirmed that the DR1 site in the-57 to-48 region of the TM4SF5 promoter is the key binding motif for HNF4A.Conclusion This study identified TM4SF5 as a target gene of HNF4A and determined the key binding motif involved in its regulation.Given the role of TM4SF5 as an arginine sensor in mTOR signaling activation and triglyceride secretion,which closely aligns with phenotypes observed in MODY1 patients,our findings provide novel insights into the possible mechanisms by which HNF4A regulates triglyceride secretion in the liver and arginine-stimulated insulin secretion in the pancreas.
基金supported by the National Natural Science Foundation of China(32471354 to T.C.and 82260400 to J.L)Natural Science Foundation of Hainan Province(No.822RC703 to J.L)。
文摘Discoidin domain receptors(DDRs)are single-pass transmembrane proteins belonging to receptor tyrosine kinases(RTKs)family,which are activated by collagen ligands with unusual slow,sustained kinetics,distinguishing them from canonical RTKs.While DDRs play critical roles in cell adhesion,differentiation,and cancer progression,their activation mechanisms remain partly understood.Here,we investigated the transmembrane domains(TMDs)of DDR1 and DDR2 to elucidate their interaction dynamics in membrane.Using bacterial adenylate cyclase two-hybrid(BACTH)assays,we demonstrated robust homotypic interactions and even stronger heterotypic associations between DDRTMDs.NMR spectroscopy of DDR1TMD and DDR2TMD reconstituted in lipid bilayer-mimetic bicelles showed obvious chemical shift alterations,further validating the stability of their heterocomplex formation.Systematic mutagenesis identified leucine zipper motifs rather than GXXXA motifs mediated both homo-and hetero-associations of DDR1TMD and DDR2TMD.These findings demonstrated the TMD as a critical mediator of DDRs oligomerization and revealed their interaction patterns within membrane.Our study advances the understanding of DDR signaling regulation and highlights transmembrane domain interactions as potential targets for modulating DDR-related pathologies.
基金supported by the National Key R&D Program of China(2021YFC2300700)National Science and Technology Major Project(No.2018ZX10101004001005)National Natural Science Foundation of China(numbers 32070179).We thank Dr.Qinxue Hu(Wuhan Institute of Virology)and Dr.Yuchen Xia(Wuhan University)for help with materials.We thank Ding Gao from Center for Instrumental Analysis and Metrology at Wuhan Institute of Virology for his help with the Leica confocal microscope and the Operetta.
文摘Infections of many viruses induce caspase activation to regulate multiple cellular pathways,including programmed cell death,immune signaling and etc.Characterizations of caspase cleavage sites and substrates are important for understanding the regulation mechanisms of caspase activation.Here,we identified and analyzed a novel caspase cleavage motif AEAD,and confirmed its caspase dependent cleavage activity in natural substrate,such as nitric oxide-associated protein 1(NOA1).Fusing the enhanced green fluorescent protein(EGFP)with the mitochondrial marker protein Tom20 through the AEAD motif peptide localized EGFP to the mitochondria.Upon the activation of caspase triggered by Sendai virus(SeV)or herpes simplex virus type 1(HSV-1)infection,EGFP diffusely localized to the cell due to the caspase-mediated cleavage,thus allowing visual detection of the virusinduced caspase activation.An AEAD peptide-derived inhibitor Z-AEAD-FMK were developed,which significantly inhibited the activities of caspases-1,-3,-6,-7,-8 and-9,exhibiting a broad caspase inhibition effect.The inhibitor further prevented caspases-mediated cleavage of downstream substrates,including BID,PARP1,LMNA,pro-IL-1β,pro-IL-18,GSDMD and GSDME,protecting cells from virus-induced apoptotic and pyroptotic cell death.Together,our findings provide a new perspective for the identification of novel caspase cleavage motifs and the development of new caspase inhibitors and anti-inflammatory drugs.
基金supported by National Natural Science Foundation of China(62101088,61801076,61971336)Natural Science Foundation of Liaoning Province(2022-MS-157,2023-MS-108)+1 种基金Key Laboratory of Big Data Intelligent Computing Funds for Chongqing University of Posts and Telecommunications(BDIC-2023-A-003)Fundamental Research Funds for the Central Universities(3132022230).
文摘Interconnection of all things challenges the traditional communication methods,and Semantic Communication and Computing(SCC)will become new solutions.It is a challenging task to accurately detect,extract,and represent semantic information in the research of SCC-based networks.In previous research,researchers usually use convolution to extract the feature information of a graph and perform the corresponding task of node classification.However,the content of semantic information is quite complex.Although graph convolutional neural networks provide an effective solution for node classification tasks,due to their limitations in representing multiple relational patterns and not recognizing and analyzing higher-order local structures,the extracted feature information is subject to varying degrees of loss.Therefore,this paper extends from a single-layer topology network to a multi-layer heterogeneous topology network.The Bidirectional Encoder Representations from Transformers(BERT)training word vector is introduced to extract the semantic features in the network,and the existing graph neural network is improved by combining the higher-order local feature module of the network model representation network.A multi-layer network embedding algorithm on SCC-based networks with motifs is proposed to complete the task of end-to-end node classification.We verify the effectiveness of the algorithm on a real multi-layer heterogeneous network.
文摘Plasmodium (P.) falciparum is a pathogen that causes severe forms of malaria. Protein interactions have been shown to occur between P. falciparum and human erythrocytes in human blood. The Band 3 Anion Transporter (B3AT) protein is considered the main invasive pathway for the parasite in erythrocytes that causes clinical symptoms for malaria in humans. The interactions between P. falciparum parasites and erythrocytes along this receptor have previously been explored. Short linear motifs (SLIMs) are short linear mediator sequences that involve several biological processes, acting as mediators of protein interactions identifiable by computational tools such as SLiMFinder. For a given protein, the identification of SLIMs allows predicting its interactors. Using the SLIMs approach, protein-protein interaction network analyses between P. falciparum and its human host, were used to identify a tryptophan-rich protein, A5K5E5_PLAVS as an essential interactor of B3AT. To better understand the interaction mechanism, a guided protein-protein docking approach based on SLIM motifs was performed for human B3AT and A5K5E5_PLAVS. The highlights of this important interaction between P. falciparum and its human host have the potential to pave the way to identify new therapeutic candidates.
文摘This editorial summarizes the latest literature on the roles of neuronal PAS domain protein 2 and KN motif/ankyrin repeat domain 1 in type 2 diabetes(T2D).We highlight their involvement inβ-cell dysfunction,explore their potential as therapeutic targets,and discuss the implications for new treatment strategies.We offer valuable insights into relevant gene regulation and cellular mechanisms relevant for the targeted management of T2D.
文摘The image of Mulan is well known to the public as an important symbol in the dissemination of Chinese excellent traditional culture.This paper aims to summarise the mother-title from traditional canonical texts,to explore the content and value of sustainable IP development,and to study a large number of derivatives with the image of Mulan as the mother-title,based on the wide circulation of the prototype of the mother-title“The Poem of Mulan”(木兰辞)and the positive values conveyed by the content.Through the processing and imagination of scholars and writers on the mother text in the past generations,the image of Mulan has gradually formed a relatively stable cultural communication theme in the process of dissemination in China’s historical period,and many adaptations with international influence based on the mother title of Mulan have emerged in the foreign dissemination,so through the combing and summarisation of the textual works of various periods both at home and abroad,we will dig out the textual transmission of the mother title of Mulan,which is representative of the mother title of China’s excellent traditional culture,and the development of the Chinese spiritual core.The Development of the Chinese Spiritual Kernel.This paper adopts research methods such as documentary evidence method and discourse analysis to show the textual flow of Mulan’s parent theme in a more diversified form.
