With the emerging diverse applications in data centers,the demands on quality of service in data centers also become diverse,such as high throughput of elephant flows and low latency of deadline-sensitive flows.Howeve...With the emerging diverse applications in data centers,the demands on quality of service in data centers also become diverse,such as high throughput of elephant flows and low latency of deadline-sensitive flows.However,traditional TCPs are ill-suited to such situations and always result in the inefficiency(e.g.missing the flow deadline,inevitable throughput collapse)of data transfers.This further degrades the user-perceived quality of service(QoS)in data centers.To reduce the flow completion time of mice and deadline-sensitive flows along with promoting the throughput of elephant flows,an efficient and deadline-aware priority-driven congestion control(PCC)protocol,which grants mice and deadline-sensitive flows the highest priority,is proposed in this paper.Specifically,PCC computes the priority of different flows according to the size of transmitted data,the remaining data volume,and the flows’deadline.Then PCC adjusts the congestion window according to the flow priority and the degree of network congestion.Furthermore,switches in data centers control the input/output of packets based on the flow priority and the queue length.Different from existing TCPs,to speed up the data transfers of mice and deadline-sensitive flows,PCC provides an effective method to compute and encode the flow priority explicitly.According to the flow priority,switches can manage packets efficiently and ensure the data transfers of high priority flows through a weighted priority scheduling with minor modification.The experimental results prove that PCC can improve the data transfer performance of mice and deadline-sensitive flows while guaranting the throughput of elephant flows.展开更多
Traditional simulators have deficiencies of scalability, thus they are not so efficient in running simulations with large-scale networks. In this paper, we present a new simulator, namely EasiSim, specifically for eva...Traditional simulators have deficiencies of scalability, thus they are not so efficient in running simulations with large-scale networks. In this paper, we present a new simulator, namely EasiSim, specifically for evalu-ating sensor net-works on a large scale. EasiSim is featured by organizing its core components, including nodes, topology and scenario, in a hierarchically structured approach. The hierarchically structured organiza-tion enables nodes to process all the concurrent events in one batch, hence reducing the running time by an order of magnitude. Moreover, we propose a visualization scheme based on a Client/Server model which separates the graphical user interface (GUI) from the simulation engine, and therefore the scalability of the simulator will not be decreased by complex GUI. Extensive simulations show that EasiSim outperforms ns-2 in terms of real running time and memory usage.展开更多
Food hygiene incidents in hot pot restaurants were studied,and a relationship model between corporate reputation and consumers behavioral intention was established.Hot pot consumers of hot pot restaurants were surveye...Food hygiene incidents in hot pot restaurants were studied,and a relationship model between corporate reputation and consumers behavioral intention was established.Hot pot consumers of hot pot restaurants were surveyed through questionnaires.The results show that corporate reputation positively affects service recovery and repurchase intention,and service recovery positively influences repurchase intention,while corporate reputation affects repurchase intention through service recovery.In other words,under the situation of enterprise crises,the service recovery of an enterprise can restore its image and reputation.Therefore,when an enterprise has a crisis,it should positively respond to the crisis incident,and take timely crisis recovery to maintain its positive image.展开更多
The national strategy of"Guangdong-Hong Kong-Macao Greater Bay Area"has replaced the original Pearl River Delta economic circle.As one of them,the economic development of Zhaoqing City ushered in a historic ...The national strategy of"Guangdong-Hong Kong-Macao Greater Bay Area"has replaced the original Pearl River Delta economic circle.As one of them,the economic development of Zhaoqing City ushered in a historic opportunity.Other cities in Greater Bay Area provide sufficient tourist resources for the development of Zhaoqing’s tourism industry.Under the new situation,Seven Star Cave,the leading scenic spot in Zhaoqing,should firmly grasp the national strategic dividend of the"Guangdong-Hong Kong-Macao Greater Bay Area",accelerate the transformation and upgrading,and enhance the market competitiveness.In this paper,the data are collected by nominal group technique,and are integrated into SWOT matrix for analysis.The development strategy of Zhaoqing Seven Star Cave Scenic Area is obtained by matching internal and external factors.展开更多
Taking wine culture and quality of life as the research object,this paper analyzes the relationship between wine culture and quality of life.The research data were collected by questionnaire survey online,and a total ...Taking wine culture and quality of life as the research object,this paper analyzes the relationship between wine culture and quality of life.The research data were collected by questionnaire survey online,and a total of 315 valid questionnaires were collected.And then the software SPSS 21.0 is used for descriptive analysis and regression analysis.The results show that among the 12 hypotheses of the three dimensions of wine culture to the four dimensions of quality of life,9 hypotheses are valid and 3 hypotheses are not.This study is helpful for people to clearly understand the influence and mechanism of wine culture on the quality of life.展开更多
With the overall promotion of the rural revitalization strategy,rural tourism has become an effective way to help rural revitalization.Xuwen pineapple field has a unique pineapple planting sightseeing belt in China,wh...With the overall promotion of the rural revitalization strategy,rural tourism has become an effective way to help rural revitalization.Xuwen pineapple field has a unique pineapple planting sightseeing belt in China,which is nicknamed the"sea of pineapple".It has high ornamental value and tourism attraction,and is very suitable for developing rural tourism.In this paper,Xuwen pineapple field is taken as research object.By literature research method and nominal cluster method,the factors influencing the development of rural tourism in Xuwen pineapple field are collected.Using 4P model analysis method and PEST model analysis method,the internal and external factors of rural tourism in Xuwen pineapple field are carefully combed.Finally,SWOT matrix analysis on the development of rural tourism in Xuwen pineapple field is carried out,and the development strategy of rural tourism in Xuwen pineapple field under the background of rural revitalization is obtained.展开更多
In Ambient Assistant Living(AAL) systems, it is a fundamental problem to ensure prompt delivery of detected events, such as irregular heart rate or fall of elderly, to a central processing device(e.g. gateway node). M...In Ambient Assistant Living(AAL) systems, it is a fundamental problem to ensure prompt delivery of detected events, such as irregular heart rate or fall of elderly, to a central processing device(e.g. gateway node). Most of recently proposed MAC protocols for low-power embedded sensing systems(e.g. wireless sensor networks) are designed with energy efficiency as the first goal, so they are not suitable for AAL systems. Although some multi-channel MAC protocols have been proposed to address the problem, most of those protocols ignore the cost of channel switching, which can have reverse effect on network performance, especially latency of data delivery. In this paper, we propose a Delay-Sensitive Multi-channel MAC protocol(DS-MMAC) for AAL systems, which can provide high packet delivery ratio and bound low latency for data delivered to the gateway node. The novelty of the protocol is that an efficient distributed time slot scheduling and channel assignment algorithm is combined with the process of route establishment, which takes the channel switching cost into account and reduces endto-end delay to meet the required delay bound of each data flow. The performance of the proposed protocol is evaluated through extensive simulations. Results show that DS-MMAC can bound low latency for delivering detected events in AAL system to the gateway, while providing high delivery reliability and low energy consumption.展开更多
By constructing a research framework of theoretical concepts such as leisure involvement, authenticity experience, place attachment, and willingness to revisit, the aim is to explore the authenticity experience and it...By constructing a research framework of theoretical concepts such as leisure involvement, authenticity experience, place attachment, and willingness to revisit, the aim is to explore the authenticity experience and its influencing mechanisms in shared accommodation consumption. Research data are collected by using questionnaire survey method, and statistical analysis of data is conducted using SPSS 21.0. Research has found that leisure involvement has a significant positive impact on authenticity experience, place attachment, and willingness to revisit;authenticity experience has a significant positive impact on place attachment and willingness to revisit;place attachment has a significant positive impact on willingness to revisit. Therefore, shared accommodation owners need to strengthen the editing and publishing of leisure strategies on we media to enhance customers sense of leisure involvement;pay attention to enhancing the local authentic cultural experience of tenants, in order to increase their sense of attachment to the place and thereby enhance their willingness to stay.展开更多
Limitations of current electronic textiles(e-textiles),including poor washability,instability,and inferior sensing capability,are concerns hindering their broad and practical applications in personal health care manag...Limitations of current electronic textiles(e-textiles),including poor washability,instability,and inferior sensing capability,are concerns hindering their broad and practical applications in personal health care management,virtual games,sports,and more.Here,we report an RGO/PANI e-textile via alternative coatings of in situ reduced graphene oxides(RGO)and in situ polymerized polyaniline(PANI),establishing a laminated structure on a knitted textile substrate.As a result of an in situ lamination strategy,our e-textile exhibits excellent breathability(1428 mm s^(-1),greater than that of bare cotton fabric)and outstanding sensitivity(gage factor of 39.7)over a wide strain range(~0.0625–200%).Importantly,we observed exceptional sensing durability even after severe mechanical disturbance of stretching,bending,or twisting(>1500 cycles)and daily machine washes.Detailed analysis revealed that our proposed in situ lamination approach enabled the physical and chemical interactions between sensing active materials and the textile substrate.Furthermore,the electromechanical behavior of our RGO/PANI e-textile was thoroughly analyzed based on an equivalent electrical circuit,which agreed well with the experi-mental data.Example applications of the e-textile were demonstrated for personal health care management,including body motion monitoring,emotional sensing,and flatfoot gait correction.The RGO/PANI e-textile presented in this study holds significant implications for the evolution of health care applications utilizing smart e-textiles.展开更多
The role of the delta isobar degrees of freedom in nucleon–nucleon scattering is revisited.We attempt to understand why the dimensionally regularized two-pion exchanges with the explicit delta isobar is much stronger...The role of the delta isobar degrees of freedom in nucleon–nucleon scattering is revisited.We attempt to understand why the dimensionally regularized two-pion exchanges with the explicit delta isobar is much stronger than the ones with spectral function regularization.When the cutoff value of spectral function regularization is varied,the isoscalar central component exhibits a rather large cut-off variation.This reveals a surprisingly large numerical factor of the deltaful two-pion exchange potentials.The power counting is adjusted accordingly and we discuss the results and how to improve upon this finding.展开更多
Linalool,a major component of aromatic plant essential oils,has an antibacterial effect against Hafnia alvei,which can induce food spoilage.In this study,we aimed to investigate the antibacterial effect and mechanism ...Linalool,a major component of aromatic plant essential oils,has an antibacterial effect against Hafnia alvei,which can induce food spoilage.In this study,we aimed to investigate the antibacterial effect and mechanism of linalool against H.alvei.Linalool treatment resulted in excessive reactive oxygen species(ROS)accumulation,which resulted in destruction of the cell membrane.According to the field emission scanning electron microscopy(FESEM)and flow cytometry(FCM)results,it was confirmed that the membrane structure of H.alvei was destroyed.Moreover,metabolomics analysis showed that there were 64 and 73 differentially expressed metabolites screened by mass spectrometry in positive and negative ion modes,respectively,suggesting that nucleic acid metabolism,the respiratory chain and energy metabolism were negatively affected by linalool.Biochemical validation confirmed that the activities of malate dehydrogenase(MDH),and succinate dehydrogenase(SDH)and respiratory metabolism were reduced after linalool treatment.It was therefore concluded that the cell membrane was damaged,nucleic acid metabolism was disturbed,and energy metabolism was reduced by inhibition of the respiratory chain and tricarboxylic acid(TCA)cycle.These results revealed the antibacterial mechanism of linalool against H.alvei,and support the use of linalool as a potential natural preservative to control H.alvei.展开更多
Background:Recurrence and metastasis remain significant challenges in lung adenocarcinoma(LUAD)after radical resection.The mechanisms behind the recurrence and metastasis of LUAD remain elusive,and deregulated cellul...Background:Recurrence and metastasis remain significant challenges in lung adenocarcinoma(LUAD)after radical resection.The mechanisms behind the recurrence and metastasis of LUAD remain elusive,and deregulated cellular metabolism is suspected to play a significant role.This study explores the metabolic and epigenetic regulation mediated by nicotinamide N-methyl transferase(NNMT)in LUAD.Methods:Untargeted metabolomic analyses were performed to detect metabolism irregularities.Single-cell RNA sequencing(RNA-seq)databases and multiplex immunofluorescence analysis were used to identify the location of NNMT within the tumor microenvironment.The biological functions of NNMT were investigated both in vitro and in vivo,with RNA-seq and chromatin immunoprecipitation-PCR providing insights into underlying mechanisms.Finally,single-cell RNA-seq data and immunohistochemistry of primary tumors were analyzed to validate the main findings.Results:Untargeted metabolomic analyses revealed metabolic aberrations in amino acids,organic acids,lipids,and nicotinamide pathways,which are linked to metastasis of non-small cell lung cancer.NNMT is a key enzyme in nicotinamide metabolism,and we found the bulk tissue mRNA level of NNMT gene was inversely associated with LUAD metastasis.NNMT was proved to be predominantly expressed in cancer-associated fibroblasts(CAFs)within the stromal regions of LUAD,and a low stromal NNMT expression was identified as a predictor of poor disease-free survival following radical resection of LUAD.The isolation and primary culture of CAFs from LUAD enabled in vitro and in vivo experiments,which confirmed that NNMT negatively regulated the metastasispromoting properties of CAFs in LUAD.Mechanistically,the downregulation of NNMT led to an increase in intracellular methyl groups by reducing the activity of the methionine cycle,resulting in heightened methylation at H3K4me3.This alteration triggered the upregulation of genes involved in extracellular matrix remodeling in CAFs,including those encoding collagens,integrins,laminins,and matrix metalloproteinases,thereby facilitating cancer cell invasion and metastasis.Reanalysis of single-cell RNA-seq data and immunohistochemistry assays of primary LUAD tissues substantiated NNMT’s negative regulation of these genes in CAFs.Conclusions:This study provides novel insights into the metabolic and epigenetic regulatory functions of NNMT in CAFs,expanding the current understanding of LUAD metastasis regulation and suggesting potential avenues for future research and therapeutic development.展开更多
基金supported part by the National Natural Science Foundation of China(61601252,61801254)Public Technology Projects of Zhejiang Province(LG-G18F020007)+1 种基金Zhejiang Provincial Natural Science Foundation of China(LY20F020008,LY18F020011,LY20F010004)K.C.Wong Magna Fund in Ningbo University。
文摘With the emerging diverse applications in data centers,the demands on quality of service in data centers also become diverse,such as high throughput of elephant flows and low latency of deadline-sensitive flows.However,traditional TCPs are ill-suited to such situations and always result in the inefficiency(e.g.missing the flow deadline,inevitable throughput collapse)of data transfers.This further degrades the user-perceived quality of service(QoS)in data centers.To reduce the flow completion time of mice and deadline-sensitive flows along with promoting the throughput of elephant flows,an efficient and deadline-aware priority-driven congestion control(PCC)protocol,which grants mice and deadline-sensitive flows the highest priority,is proposed in this paper.Specifically,PCC computes the priority of different flows according to the size of transmitted data,the remaining data volume,and the flows’deadline.Then PCC adjusts the congestion window according to the flow priority and the degree of network congestion.Furthermore,switches in data centers control the input/output of packets based on the flow priority and the queue length.Different from existing TCPs,to speed up the data transfers of mice and deadline-sensitive flows,PCC provides an effective method to compute and encode the flow priority explicitly.According to the flow priority,switches can manage packets efficiently and ensure the data transfers of high priority flows through a weighted priority scheduling with minor modification.The experimental results prove that PCC can improve the data transfer performance of mice and deadline-sensitive flows while guaranting the throughput of elephant flows.
文摘Traditional simulators have deficiencies of scalability, thus they are not so efficient in running simulations with large-scale networks. In this paper, we present a new simulator, namely EasiSim, specifically for evalu-ating sensor net-works on a large scale. EasiSim is featured by organizing its core components, including nodes, topology and scenario, in a hierarchically structured approach. The hierarchically structured organiza-tion enables nodes to process all the concurrent events in one batch, hence reducing the running time by an order of magnitude. Moreover, we propose a visualization scheme based on a Client/Server model which separates the graphical user interface (GUI) from the simulation engine, and therefore the scalability of the simulator will not be decreased by complex GUI. Extensive simulations show that EasiSim outperforms ns-2 in terms of real running time and memory usage.
基金Supported by the Innovative Training Program Project for Students of Zhaoqing University"The Influence of Corporate Image of Hotpot Restaurants on Repurchase Intention" (X202310580161).
文摘Food hygiene incidents in hot pot restaurants were studied,and a relationship model between corporate reputation and consumers behavioral intention was established.Hot pot consumers of hot pot restaurants were surveyed through questionnaires.The results show that corporate reputation positively affects service recovery and repurchase intention,and service recovery positively influences repurchase intention,while corporate reputation affects repurchase intention through service recovery.In other words,under the situation of enterprise crises,the service recovery of an enterprise can restore its image and reputation.Therefore,when an enterprise has a crisis,it should positively respond to the crisis incident,and take timely crisis recovery to maintain its positive image.
基金Supported by the Characteristic Innovation Projects of Ordinary Colleges and Universities in Guangdong Province(2018WTSCX154)。
文摘The national strategy of"Guangdong-Hong Kong-Macao Greater Bay Area"has replaced the original Pearl River Delta economic circle.As one of them,the economic development of Zhaoqing City ushered in a historic opportunity.Other cities in Greater Bay Area provide sufficient tourist resources for the development of Zhaoqing’s tourism industry.Under the new situation,Seven Star Cave,the leading scenic spot in Zhaoqing,should firmly grasp the national strategic dividend of the"Guangdong-Hong Kong-Macao Greater Bay Area",accelerate the transformation and upgrading,and enhance the market competitiveness.In this paper,the data are collected by nominal group technique,and are integrated into SWOT matrix for analysis.The development strategy of Zhaoqing Seven Star Cave Scenic Area is obtained by matching internal and external factors.
基金Supported by Characteristic Innovation Program of Colleges and Universities in Guangdong Province (2018WTSCX154).
文摘Taking wine culture and quality of life as the research object,this paper analyzes the relationship between wine culture and quality of life.The research data were collected by questionnaire survey online,and a total of 315 valid questionnaires were collected.And then the software SPSS 21.0 is used for descriptive analysis and regression analysis.The results show that among the 12 hypotheses of the three dimensions of wine culture to the four dimensions of quality of life,9 hypotheses are valid and 3 hypotheses are not.This study is helpful for people to clearly understand the influence and mechanism of wine culture on the quality of life.
基金Supported by the Characteristic Innovation Projects of Ordinary Colleges and Universities in Guangdong Province(2018WTSCX154)。
文摘With the overall promotion of the rural revitalization strategy,rural tourism has become an effective way to help rural revitalization.Xuwen pineapple field has a unique pineapple planting sightseeing belt in China,which is nicknamed the"sea of pineapple".It has high ornamental value and tourism attraction,and is very suitable for developing rural tourism.In this paper,Xuwen pineapple field is taken as research object.By literature research method and nominal cluster method,the factors influencing the development of rural tourism in Xuwen pineapple field are collected.Using 4P model analysis method and PEST model analysis method,the internal and external factors of rural tourism in Xuwen pineapple field are carefully combed.Finally,SWOT matrix analysis on the development of rural tourism in Xuwen pineapple field is carried out,and the development strategy of rural tourism in Xuwen pineapple field under the background of rural revitalization is obtained.
基金supported by the International S&T Cooperation Program of China (ISTCP) under Grant No. 2013DFA10690the National Science Foundation of China (NSFC) under Grant No. 61100180
文摘In Ambient Assistant Living(AAL) systems, it is a fundamental problem to ensure prompt delivery of detected events, such as irregular heart rate or fall of elderly, to a central processing device(e.g. gateway node). Most of recently proposed MAC protocols for low-power embedded sensing systems(e.g. wireless sensor networks) are designed with energy efficiency as the first goal, so they are not suitable for AAL systems. Although some multi-channel MAC protocols have been proposed to address the problem, most of those protocols ignore the cost of channel switching, which can have reverse effect on network performance, especially latency of data delivery. In this paper, we propose a Delay-Sensitive Multi-channel MAC protocol(DS-MMAC) for AAL systems, which can provide high packet delivery ratio and bound low latency for data delivered to the gateway node. The novelty of the protocol is that an efficient distributed time slot scheduling and channel assignment algorithm is combined with the process of route establishment, which takes the channel switching cost into account and reduces endto-end delay to meet the required delay bound of each data flow. The performance of the proposed protocol is evaluated through extensive simulations. Results show that DS-MMAC can bound low latency for delivering detected events in AAL system to the gateway, while providing high delivery reliability and low energy consumption.
基金Supported by 2022 Students Entrepreneurship Training Program Project of Zhaoqing University(X202210580160X).
文摘By constructing a research framework of theoretical concepts such as leisure involvement, authenticity experience, place attachment, and willingness to revisit, the aim is to explore the authenticity experience and its influencing mechanisms in shared accommodation consumption. Research data are collected by using questionnaire survey method, and statistical analysis of data is conducted using SPSS 21.0. Research has found that leisure involvement has a significant positive impact on authenticity experience, place attachment, and willingness to revisit;authenticity experience has a significant positive impact on place attachment and willingness to revisit;place attachment has a significant positive impact on willingness to revisit. Therefore, shared accommodation owners need to strengthen the editing and publishing of leisure strategies on we media to enhance customers sense of leisure involvement;pay attention to enhancing the local authentic cultural experience of tenants, in order to increase their sense of attachment to the place and thereby enhance their willingness to stay.
基金supported by the Public Welfare Project of Zhejiang Province(LGF21E030005)the National Natural Science Foundation of China(NSFC 51803185)+2 种基金the Fundamental Research Funds of Zhejiang Sci-Tech University(22202301-Y)the Opening Project of Key Laboratory of Clean Dyeing and Finishing Technology of Zhejiang Province(QJRZ2214)the China Scholarships Council for the overseas scholarship(202008330177).
文摘Limitations of current electronic textiles(e-textiles),including poor washability,instability,and inferior sensing capability,are concerns hindering their broad and practical applications in personal health care management,virtual games,sports,and more.Here,we report an RGO/PANI e-textile via alternative coatings of in situ reduced graphene oxides(RGO)and in situ polymerized polyaniline(PANI),establishing a laminated structure on a knitted textile substrate.As a result of an in situ lamination strategy,our e-textile exhibits excellent breathability(1428 mm s^(-1),greater than that of bare cotton fabric)and outstanding sensitivity(gage factor of 39.7)over a wide strain range(~0.0625–200%).Importantly,we observed exceptional sensing durability even after severe mechanical disturbance of stretching,bending,or twisting(>1500 cycles)and daily machine washes.Detailed analysis revealed that our proposed in situ lamination approach enabled the physical and chemical interactions between sensing active materials and the textile substrate.Furthermore,the electromechanical behavior of our RGO/PANI e-textile was thoroughly analyzed based on an equivalent electrical circuit,which agreed well with the experi-mental data.Example applications of the e-textile were demonstrated for personal health care management,including body motion monitoring,emotional sensing,and flatfoot gait correction.The RGO/PANI e-textile presented in this study holds significant implications for the evolution of health care applications utilizing smart e-textiles.
基金supported by the National Natural Science Foundation of China(NSFC)under Grant Nos.12275185,12335002(BL),and 12347154(RP)。
文摘The role of the delta isobar degrees of freedom in nucleon–nucleon scattering is revisited.We attempt to understand why the dimensionally regularized two-pion exchanges with the explicit delta isobar is much stronger than the ones with spectral function regularization.When the cutoff value of spectral function regularization is varied,the isoscalar central component exhibits a rather large cut-off variation.This reveals a surprisingly large numerical factor of the deltaful two-pion exchange potentials.The power counting is adjusted accordingly and we discuss the results and how to improve upon this finding.
基金the National Natural Science Foundation of China(No.32160591)for financial support.
文摘Linalool,a major component of aromatic plant essential oils,has an antibacterial effect against Hafnia alvei,which can induce food spoilage.In this study,we aimed to investigate the antibacterial effect and mechanism of linalool against H.alvei.Linalool treatment resulted in excessive reactive oxygen species(ROS)accumulation,which resulted in destruction of the cell membrane.According to the field emission scanning electron microscopy(FESEM)and flow cytometry(FCM)results,it was confirmed that the membrane structure of H.alvei was destroyed.Moreover,metabolomics analysis showed that there were 64 and 73 differentially expressed metabolites screened by mass spectrometry in positive and negative ion modes,respectively,suggesting that nucleic acid metabolism,the respiratory chain and energy metabolism were negatively affected by linalool.Biochemical validation confirmed that the activities of malate dehydrogenase(MDH),and succinate dehydrogenase(SDH)and respiratory metabolism were reduced after linalool treatment.It was therefore concluded that the cell membrane was damaged,nucleic acid metabolism was disturbed,and energy metabolism was reduced by inhibition of the respiratory chain and tricarboxylic acid(TCA)cycle.These results revealed the antibacterial mechanism of linalool against H.alvei,and support the use of linalool as a potential natural preservative to control H.alvei.
基金National Natural Science Foundation of China,Grant/Award Numbers:92059203,82173386National Key R&D Program of China,Grant/Award Number:2023YFF0723500+3 种基金Research Unit of Intelligence Diagnosis and Treatment in Early Non-small Cell Lung Cancer,Chinese Academy of Medical Sciences,Grant/Award Number:2021RU002Medical and Health Science and Technology Innovation project,Grant/Award Number:2021-I2M-002Beijing Nova Program,Grant/Award Number:20230484314Innovation Fund for Excellent PhD student of Peking University Health Science Center,Grant/Award Number:2022-58。
文摘Background:Recurrence and metastasis remain significant challenges in lung adenocarcinoma(LUAD)after radical resection.The mechanisms behind the recurrence and metastasis of LUAD remain elusive,and deregulated cellular metabolism is suspected to play a significant role.This study explores the metabolic and epigenetic regulation mediated by nicotinamide N-methyl transferase(NNMT)in LUAD.Methods:Untargeted metabolomic analyses were performed to detect metabolism irregularities.Single-cell RNA sequencing(RNA-seq)databases and multiplex immunofluorescence analysis were used to identify the location of NNMT within the tumor microenvironment.The biological functions of NNMT were investigated both in vitro and in vivo,with RNA-seq and chromatin immunoprecipitation-PCR providing insights into underlying mechanisms.Finally,single-cell RNA-seq data and immunohistochemistry of primary tumors were analyzed to validate the main findings.Results:Untargeted metabolomic analyses revealed metabolic aberrations in amino acids,organic acids,lipids,and nicotinamide pathways,which are linked to metastasis of non-small cell lung cancer.NNMT is a key enzyme in nicotinamide metabolism,and we found the bulk tissue mRNA level of NNMT gene was inversely associated with LUAD metastasis.NNMT was proved to be predominantly expressed in cancer-associated fibroblasts(CAFs)within the stromal regions of LUAD,and a low stromal NNMT expression was identified as a predictor of poor disease-free survival following radical resection of LUAD.The isolation and primary culture of CAFs from LUAD enabled in vitro and in vivo experiments,which confirmed that NNMT negatively regulated the metastasispromoting properties of CAFs in LUAD.Mechanistically,the downregulation of NNMT led to an increase in intracellular methyl groups by reducing the activity of the methionine cycle,resulting in heightened methylation at H3K4me3.This alteration triggered the upregulation of genes involved in extracellular matrix remodeling in CAFs,including those encoding collagens,integrins,laminins,and matrix metalloproteinases,thereby facilitating cancer cell invasion and metastasis.Reanalysis of single-cell RNA-seq data and immunohistochemistry assays of primary LUAD tissues substantiated NNMT’s negative regulation of these genes in CAFs.Conclusions:This study provides novel insights into the metabolic and epigenetic regulatory functions of NNMT in CAFs,expanding the current understanding of LUAD metastasis regulation and suggesting potential avenues for future research and therapeutic development.
