Low back pain(LBP),as a leading cause of disability,is a common musculoskeletal disorder that results in major social and economic burdens.Recent research has identified inflammation and related signaling pathways as ...Low back pain(LBP),as a leading cause of disability,is a common musculoskeletal disorder that results in major social and economic burdens.Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration,a significant contributor to LBP.Inflammatory mediators also play an indispensable role in discogenic LBP.The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies.Here,an overview of the advances in inflammation-related pain in disc degeneration is provided,with a discussion on the role of inflammation in IVD degeneration and pain induction.Puncture models,mechanical models,and spontaneous models as the main animal models to study painful disc degeneration are discussed,and the underlying signaling pathways are summarized.Furthermore,potential drug candidates,either under laboratory investigation or undergoing clinical trials,to suppress discogenic LBP by eliminating inflammation are explored.We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.展开更多
The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin(IL)-1β, and is one of the main causes of intervertebral disc degeneration(IVDD). NLR pyrin domain containing 3(...The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin(IL)-1β, and is one of the main causes of intervertebral disc degeneration(IVDD). NLR pyrin domain containing 3(NLRP3) inflammasome activation is an important source of IL-1β. As an anti-inflammatory neuroendocrine hormone, melatonin plays various roles in different pathophysiological conditions. However, its roles in IVDD are still not well understood and require more examination. First, we demonstrated that melatonin delayed the progression of IVDD and relieved IVDD-related low back pain in a rat needle puncture IVDD model;moreover, NLRP3 inflammasome activation(NLRP3, p20, and IL-1β levels) was significantly upregulated in severely degenerated human discs and a rat IVDD model. Subsequently, an IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop was found in nucleus pulposus(NP) cells that were treated with IL-1β. In these cells, expression of NLRP3 and p20 was significantly increased, NF-κB signaling was involved in this regulation, and mitochondrial reactive oxygen species(mt ROS)production increased. Furthermore, we found that melatonin disrupted the IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop in vitro and in vivo. Melatonin treatment decreased NLRP3, p20, and IL-1β levels by inhibiting NF-κB signaling and downregulating mt ROS production. Finally, we showed that melatonin mediated the disruption of the positive feedback loop of IL-1β in vivo. In this study, we showed for the first time that IL-1β promotes its own expression by upregulating NLRP3 inflammasome activation. Furthermore, melatonin disrupts the IL-1β positive feedback loop and may be a potential therapeutic agent for IVDD.展开更多
The dockless bike-sharing system has rapidly expanded worldwide and has been widely used as an intermodal transport to connect with public transportation.However,higher flexibility may cause an imbalance between suppl...The dockless bike-sharing system has rapidly expanded worldwide and has been widely used as an intermodal transport to connect with public transportation.However,higher flexibility may cause an imbalance between supply and demand during daily operation,especially around the metro stations.A stable and efficient rebalancing model requires spatio-temporal usage patterns as fundamental inputs.Therefore,understanding the spatio-temporal patterns and correlates is important for optimizing and rescheduling bike-sharing systems.This study proposed a dynamic time warping distance-based two-dimensional clustering method to quantify spatio-temporal patterns of dockless shared bikes in Wuhan and further applied the multiclass explainable boosting machine to explore the main related factors of these patterns.The results found six patterns on weekdays and four patterns on weekends.Three patterns show the imbalance of arrival and departure flow in the morning and evening peak hours,while these phenomena become less intensive on weekends.Road density,living service facility density and residential density are the top influencing factors on both weekdays and weekends,which means that the comprehensive impact of built-up environment attraction,facility suitability and riding demand leads to the different usage patterns.The nonlinear influence universally exists,and the probability of a certain pattern varies in different value ranges of variables.When the densities of living facilities and roads are moderate and the relationship between job and housing is relatively balanced,it can effectively promote the balanced usage of dockless shared bikes while maintaining high riding flow.The spatio-temporal patterns can identify the associated problems such as imbalance or lack of users,which could be mitigated by corresponding solutions.The relative importance and nonlinear effects help planners prioritize strategies and identify effective ranges on different patterns to promote the usage and efficiency of the bike-sharing system.展开更多
The virulence of influenza viruses is a complex multigenic trait.Previous studies about the virulence determinants of influenza viruses mainly focused on amino acid sites,ignoring the influence of nucleotide mutations...The virulence of influenza viruses is a complex multigenic trait.Previous studies about the virulence determinants of influenza viruses mainly focused on amino acid sites,ignoring the influence of nucleotide mutations.In this study,we collected>200 viral strains from 21 subtypes of influenza A viruses with virulence in mammals and obtained over 100 mammalian virulence-related nucleotide sites across the genome by computational analysis.Fifty of these nucleotide sites only experienced synonymous mutations.Experiments showed that synonymous mutations in three high-scoring nucleotide sites,i.e.,PB1–2031,PB1–633,and PB1–720,enhanced the pathogenicity of the influenza A(H1N1)viruses in mice.Besides,machine-learning models with accepted accuracy for predicting mammalian virulence of influenza A viruses were built.Overall,this study highlighted the importance of nucleotide mutations,especially synonymous mutations in viral virulence,and provided rapid methods for evaluating the virulence of influenza A viruses.It could be helpful for early warning of newly emerging influenza A viruses.展开更多
基金the National Natural Science Foundation of China(81772386,81702191,81572175,81371984,and 81071511)the Guangdong-Hong Kong Joint Innovation Project of Guangdong Province(2017A050506019)the Natural Science Foundation of Guangdong Province,China(2020A1515011031).
文摘Low back pain(LBP),as a leading cause of disability,is a common musculoskeletal disorder that results in major social and economic burdens.Recent research has identified inflammation and related signaling pathways as important factors in the onset and progression of disc degeneration,a significant contributor to LBP.Inflammatory mediators also play an indispensable role in discogenic LBP.The suppression of LBP is a primary goal of clinical practice but has not received enough attention in disc research studies.Here,an overview of the advances in inflammation-related pain in disc degeneration is provided,with a discussion on the role of inflammation in IVD degeneration and pain induction.Puncture models,mechanical models,and spontaneous models as the main animal models to study painful disc degeneration are discussed,and the underlying signaling pathways are summarized.Furthermore,potential drug candidates,either under laboratory investigation or undergoing clinical trials,to suppress discogenic LBP by eliminating inflammation are explored.We hope to attract more research interest to address inflammation and pain in IDD and contribute to promoting more translational research.
基金supported by grants from the Natural Science Foundation of Guangdong Province (Grant no: 2017A030313670)the National Natural Science Foundation of China (81572175 and 81772386)。
文摘The inflammatory response is induced by the overexpression of inflammatory cytokines, mainly interleukin(IL)-1β, and is one of the main causes of intervertebral disc degeneration(IVDD). NLR pyrin domain containing 3(NLRP3) inflammasome activation is an important source of IL-1β. As an anti-inflammatory neuroendocrine hormone, melatonin plays various roles in different pathophysiological conditions. However, its roles in IVDD are still not well understood and require more examination. First, we demonstrated that melatonin delayed the progression of IVDD and relieved IVDD-related low back pain in a rat needle puncture IVDD model;moreover, NLRP3 inflammasome activation(NLRP3, p20, and IL-1β levels) was significantly upregulated in severely degenerated human discs and a rat IVDD model. Subsequently, an IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop was found in nucleus pulposus(NP) cells that were treated with IL-1β. In these cells, expression of NLRP3 and p20 was significantly increased, NF-κB signaling was involved in this regulation, and mitochondrial reactive oxygen species(mt ROS)production increased. Furthermore, we found that melatonin disrupted the IL-1β/NF-κB-NLRP3 inflammasome activation positive feedback loop in vitro and in vivo. Melatonin treatment decreased NLRP3, p20, and IL-1β levels by inhibiting NF-κB signaling and downregulating mt ROS production. Finally, we showed that melatonin mediated the disruption of the positive feedback loop of IL-1β in vivo. In this study, we showed for the first time that IL-1β promotes its own expression by upregulating NLRP3 inflammasome activation. Furthermore, melatonin disrupts the IL-1β positive feedback loop and may be a potential therapeutic agent for IVDD.
基金supported by the National Key Research and Development Program of China[grant number 2017YFB0503601]。
文摘The dockless bike-sharing system has rapidly expanded worldwide and has been widely used as an intermodal transport to connect with public transportation.However,higher flexibility may cause an imbalance between supply and demand during daily operation,especially around the metro stations.A stable and efficient rebalancing model requires spatio-temporal usage patterns as fundamental inputs.Therefore,understanding the spatio-temporal patterns and correlates is important for optimizing and rescheduling bike-sharing systems.This study proposed a dynamic time warping distance-based two-dimensional clustering method to quantify spatio-temporal patterns of dockless shared bikes in Wuhan and further applied the multiclass explainable boosting machine to explore the main related factors of these patterns.The results found six patterns on weekdays and four patterns on weekends.Three patterns show the imbalance of arrival and departure flow in the morning and evening peak hours,while these phenomena become less intensive on weekends.Road density,living service facility density and residential density are the top influencing factors on both weekdays and weekends,which means that the comprehensive impact of built-up environment attraction,facility suitability and riding demand leads to the different usage patterns.The nonlinear influence universally exists,and the probability of a certain pattern varies in different value ranges of variables.When the densities of living facilities and roads are moderate and the relationship between job and housing is relatively balanced,it can effectively promote the balanced usage of dockless shared bikes while maintaining high riding flow.The spatio-temporal patterns can identify the associated problems such as imbalance or lack of users,which could be mitigated by corresponding solutions.The relative importance and nonlinear effects help planners prioritize strategies and identify effective ranges on different patterns to promote the usage and efficiency of the bike-sharing system.
基金This work was supported by the National Key Plan for Scientific Research and Development of China(2016YFC1200200 and 2016YFD0500300)the National Natural Science Foundation of China(31671371)+1 种基金the Chinese Academy of Medical Sciences(2016-I2M-1-005)the Fundamental Research Funds for the Central Universities of China.
文摘The virulence of influenza viruses is a complex multigenic trait.Previous studies about the virulence determinants of influenza viruses mainly focused on amino acid sites,ignoring the influence of nucleotide mutations.In this study,we collected>200 viral strains from 21 subtypes of influenza A viruses with virulence in mammals and obtained over 100 mammalian virulence-related nucleotide sites across the genome by computational analysis.Fifty of these nucleotide sites only experienced synonymous mutations.Experiments showed that synonymous mutations in three high-scoring nucleotide sites,i.e.,PB1–2031,PB1–633,and PB1–720,enhanced the pathogenicity of the influenza A(H1N1)viruses in mice.Besides,machine-learning models with accepted accuracy for predicting mammalian virulence of influenza A viruses were built.Overall,this study highlighted the importance of nucleotide mutations,especially synonymous mutations in viral virulence,and provided rapid methods for evaluating the virulence of influenza A viruses.It could be helpful for early warning of newly emerging influenza A viruses.
