OBJECTIVE Takeda G protein-coupled receptor 5(TGR5)is recognized as a promising target for type 2 diabetes and metabolic syndrome;its expression has been demonstrat⁃ed in the brain and is thought to be neuroprotec⁃tiv...OBJECTIVE Takeda G protein-coupled receptor 5(TGR5)is recognized as a promising target for type 2 diabetes and metabolic syndrome;its expression has been demonstrat⁃ed in the brain and is thought to be neuroprotec⁃tive.Here,we hypothesize that dysfunction of central TGR5 may contribute to the pathogene⁃sis of depression.METHODS In well-established chronic social defeat stress(CSDS)and chronic restraint stress(CRS)models of depression,we investigated the functional roles of TGR5 in CA3 pyramidal neurons(PyNs)and underlying mech⁃anisms of the neuronal circuit in depression(for in vivo studies,n=10;for in vitro studies,n=5-10)using fiber photometry;optogenetic,chemoge⁃netic,pharmacological,and molecular profiling techniques;and behavioral tests.RESULTS Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs.Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777,a specific agonist,protected against CSDS and CRS,exerting sig⁃nificant antidepressant-like effects that were mediated via CA3 PyN activation.Conversely,genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behav⁃iors.Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in Tgr5 knockout mice exposed to CSDS or CRS.Silencing and stimula⁃tion of CA3 PyNs→somatostatin-GABAergic(gamma-aminobutyric acidergic)neurons of the dorsolateral septum circuit bidirectionally regulat⁃ed depression-like behaviors,and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs.CON⁃CLUSION TGR5 can regulate depression via CA3 PyNs→somatostatin-GABAergic neurons of dorsolateral septum transmission,suggesting that TGR5 could be a novel target for developing antidepressants.展开更多
Dengue fever,caused by the dengue virus(DENV),poses a significant public health challenge globally,with Nigeria experiencing sporadic outbreaks.A clear understanding of the dengue burden has not been achieved in Niger...Dengue fever,caused by the dengue virus(DENV),poses a significant public health challenge globally,with Nigeria experiencing sporadic outbreaks.A clear understanding of the dengue burden has not been achieved in Nigeria,just as in other African countries.Understanding the epidemiology and burden of dengue fever is essential for effective prevention and control strategies.This paper examines the recent dengue outbreaks in northern Nigeria,particularly in Sokoto state,and evaluates the recommended Takeda dengue vaccine(TDV)along with future prevention strategies.Despite limited surveillance and underreporting,dengue fever is endemic in Nigeria(with over 5 million cases and 5000 dengue-related deaths in 2023),with recent outbreaks indicating a growing concern.The TDV,a live attenuated tetravalent vaccine,has shown promise in preventing dengue fever,but challenges such as vaccine acceptance and access-ibility need to be addressed.Global urbanization contributes to the disease's spread,which is influenced by factors such as population density,cultural beliefs,water storage practices,hygiene,and water supply accessibility.Future prevention strategies must focus on government intervention,community practices,and innovative vector control measures to mitigate the spread of DENV in Nigeria.This study will serve as a valuable reference for policy-makers,researchers,and clinicians in the management and control of DENV in Nigeria and Africa as a whole.展开更多
Takeda Taijun(1912-1976)is a representative of the Japanese postwar writers,who has a special affinity for China.During his whole lifetime,he stayed in China for two long periods,of which the period from June,1944 to ...Takeda Taijun(1912-1976)is a representative of the Japanese postwar writers,who has a special affinity for China.During his whole lifetime,he stayed in China for two long periods,of which the period from June,1944 to February,1946 was spent in Shanghai.He was quite productive and created quite a few works focusing on China,especially Shanghai before and after Japan’s being defeated in the Second World War,which became the background of many works.This paper attempts to interpret Takeda Taijun’s experience in Shanghai of that time on the basis of the masterpiece Firefly in Shanghai in his later years.展开更多
Background Ruminants and monogastric animals exhibit significant differences in gluconeogenic efficiency.In dairy cows,hepatic gluconeogenesis serves as the primary source of glucose.Metabolites modulate gluconeogenes...Background Ruminants and monogastric animals exhibit significant differences in gluconeogenic efficiency.In dairy cows,hepatic gluconeogenesis serves as the primary source of glucose.Metabolites modulate gluconeogenesis efficiency through allosteric regulation,redox state,and signal transduction pathways.However,the liver-enriched metabolites that regulate hepatic gluconeogenesis in dairy cows and their specific regulatory mechanisms remain incompletely characterized.Results Six Holstein dairy cows and six Duroc×(Landrace×Yorkshire)(DLY)crossbred pigs served as research subjects.Employing non-targeted and targeted metabolomics,we discovered that three bile acids—taurodeoxycholic acid(TDCA),taurocholic acid(TCA),and glycocholic acid(GCA)—were highly enriched in Holstein dairy cows'livers.In bovine hepatocytes,individual or combined stimulation of these bile acids significantly upregulated the expression of gluconeogenesis genes(FBP1,PCK1 and G6PC)and enhanced glucose production.In fasting mice with induced gluconeogenesis,TDCA,TCA,and GCA increased fasting blood glucose levels,and pyruvate tolerance tests further revealed their capacity to enhance hepatic gluconeogenesis,enabling more efficient glucose synthesis from pyruvate.Mechanistically,these bile acids activated Takeda G protein-coupled receptor 5(TGR5),elevated intracellular cAMP levels,and ultimately enhanced gluconeogenesis via the transcription factor cAMP-response element binding protein(CREB).Notably,a TGR5 inhibitor abrogated the stimulatory effects of TDCA,TCA,and GCA on hepatic gluconeogenesis in fasting mice.Conclusion TDCA,TCA,and GCA are key metabolites promoting hepatic gluconeogenesis in dairy cows,with TGR5 as the pivotal receptor and the cAMP/PKA/CREB pathway as the critical downstream mechanism.展开更多
Background and aims:Diet-induced obesity and metabolic syndrome can trigger the progression of fatty liver disease to non-alcoholic steatohepatitis and fibrosis,which is a major public health concern.Bile acids regula...Background and aims:Diet-induced obesity and metabolic syndrome can trigger the progression of fatty liver disease to non-alcoholic steatohepatitis and fibrosis,which is a major public health concern.Bile acids regulate metabolic homeostasis and inflammation in the liver and gut via the activation of nuclear farnesoid X receptor(Fxr)and the membrane receptor Takeda G protein-coupled receptor 5(Tgr5).Tgr5 is highly expressed in the gut and skeletal muscle,and in cholangiocytes and Kupffer cells of the liver.Tgr5 is implicated in the mediation of liver and gut inflammation,as well as the maintenance of energy homeostasis.Here,we used a high fat,high fructose,and high sucrose(HFS)diet to determine how bile acid signaling through Tgr5 may regulate metabolism during the progression from fatty liver to non-alcoholic steatohepatitis and fibrosis.Materials and methods:Female C57BL/6J control wild type(WT)and Tgr5 knockout(Tgr5^(-/-))mice were fed HFS(high fat(40%kcal),high fructose,and 20%sucrose water)diet for 20 weeks.Metabolic phe-notypes were characterized through examination of bile acid synthesis pathways,lipid and cholesterol metabolism pathways,and fibrosis and inflammation pathways.Results:Tgr5^(-/-)mice were more glucose intolerant when fed HFS diet,despite gaining the same amount of weight as WT mice.Tgr5^(-/-)mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice,and gene expression of lipogenic genes was significantly upregulated.Hepatic cholesterol 7alpha-hydroxylase(Cyp7a1)gene expression was consistently elevated in Tgr5^(-/-)mice,while oxysterol 7alpha-hydroxylase(Cyp7b1),sterol 27-hydroxylase(Cyp27a1),Fxr,and small heterodimer partner(Shp)were downregulated by HFS diet.Surprisingly,hepatic inflammation and fibrosis were also significantly reduced in Tgr5^(-/-)mice fed HFS diet,which may be due to altered se-rotonin signaling in the liver.Conclusions:Tgr5^(-/-)mice may be protected from high fat,high sugar-induced hepatic inflammation and injury due to altered serotonin metabolism.展开更多
Many countries throughout the world have experienced large earthquakes,which cause building damage or collapse.After such earthquakes,structures must be inspected rapidly to judge whether they are safe to reoccupy.To ...Many countries throughout the world have experienced large earthquakes,which cause building damage or collapse.After such earthquakes,structures must be inspected rapidly to judge whether they are safe to reoccupy.To facilitate the inspection process,the authors previously developed a rapid building safety assessment system using sparse acceleration measurements for steel framed buildings.The proposed system modeled nonlinearity in the measurement data using a calibrated simplified lumped-mass model and convolutional neural networks(CNNs),based on which the buildinglevel damage index was estimated rapidly after earthquakes.The proposed system was validated for a nonlinear 3D numerical model of a five-story steel building,and later for a large-scale specimen of an 18-story building in Japan tested on the E-Defense shaking table.However,the applicability of the safety assessment system for reinforced concrete(RC)structures with complex hysteretic material nonlinearity has yet to be explored;the previous approach based on a simplified lumpedmass model with a Bouc-Wen hysteretic model does not accurately represent the inherent nonlinear behavior and resulting damage states of RC structures.This study extends the rapid building safety assessment system to low-rise RC moment resisting frame structures representing typical residential apartments in Japan.First,a safety classification for RC structures based on a damage index consistent with the current state of practice is defined.Then,a 3D nonlinear numerical model of a two-story moment frame structure is created.A simplified lumped-mass nonlinear model is developed and calibrated using the 3D model,incorporating the Takeda degradation model for the RC material nonlinearity.This model is used to simulate the seismic response and associated damage sensitive features(DSF)for random ground motion.The resulting database of responses is used to train a convolutional neural network(CNN)that performs rapid safety assessment.The developed system is validated using the 3D nonlinear analysis model subjected to historical earthquakes.The results indicate the applicability of the proposed system for RC structures following seismic events.展开更多
BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profil...BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profiles of fecal bile acids(BAs).It was observed that BA receptors Takeda G-protein-coupled receptor 5(TGR5)and vitamin D receptor(VDR)participate in intestinal inflammatory responses by regulating NF-ĸB signaling.We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.AIM To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.METHODS The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls(HCs).Fecal BAs were measured by targeted metabolomics approaches.Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry,and serum inflammatory cytokine levels were detected by ELISA.RESULTS Thirty-two UC patients and twenty-three HCs were enrolled in this study.It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs.Firmicutes,Clostridium IV,Butyricicoccus,Clostridium XlVa,Faecalibacterium,and Roseburia were significantly decreased in patients with UC(P=3.75E-05,P=8.28E-07,P=0.0002,P=0.003,P=0.0003,and P=0.0004,respectively).Proteobacteria,Escherichia,Enterococcus,Klebsiella,and Streptococcus were significantly enriched in the UC group(P=2.99E-09,P=3.63E-05,P=8.59E-05,P=0.003,and P=0.016,respectively).The concentrations of fecal secondary BAs,such as lithocholic acid,deoxycholic acid,glycodeoxycholic acid,glycolithocholic acid,and taurolithocholate,in UC patients were significantly lower than those in HCs(P=8.1E-08,P=1.2E-07,P=3.5E-04,P=1.9E-03,and P=1.8E-02,respectively)and were positively correlated with Butyricicoccus,Roseburia,Clostridium IV,Faecalibacterium,and Clostridium XlVb(P<0.01).The concentrations of primary BAs,such as taurocholic acid,cholic acid,taurochenodeoxycholate,and glycochenodeoxycholate,in UC patients were significantly higher than those in HCs(P=5.3E-03,P=4E-02,P=0.042,and P=0.045,respectively)and were positively related to Enterococcus,Klebsiella,Streptococcus,Lactobacillus,and pro-inflammatory cytokines(P<0.01).The expression of TGR5 was significantly elevated in UC patients(0.019±0.013 vs 0.006±0.003,P=0.0003).VDR expression in colonic mucosal specimens was significantly decreased in UC patients(0.011±0.007 vs 0.016±0.004,P=0.033).CONCLUSION Fecal BA profiles are closely related to the gut microbiota and serum inflammatory cytokines.Dysregulation of the gut microbiota and altered constitution of fecal BAs may participate in regulating inflammatory responses via the BA receptors TGR5 and VDR.展开更多
Parkinson’s disease(PD)is a common neurodegenerative disease in middle-aged and elderly people.In particular,increasing evidence has showed that astrocyte-mediated neuroinflammation is involved in the pathogenesis of...Parkinson’s disease(PD)is a common neurodegenerative disease in middle-aged and elderly people.In particular,increasing evidence has showed that astrocyte-mediated neuroinflammation is involved in the pathogenesis of PD.As a precious traditional Chinese medicine,bear bile powder(BBP)has a long history of use in clinical practice.It has numerous activities,such as clearing heat,calming the liver wind and anti-inflammation,and also exhibits good therapeutic effect on convulsive epilepsy.However,whether BBP can prevent the development of PD has not been elucidated.Hence,this study was designed to explore the effect and mechanism of BBP on suppressing astrocyte-mediated neuroinflammation in a mouse model of PD.PD-like behavior was induced in the mice by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)(30 mg·kg−1)for five days,followed by BBP(50,100,and 200 mg·kg−1)treatment daily for ten days.LPS stimulated rat C6 astrocytic cells were used as a cell model of neuroinflammation.THe results indicated that BBP treatment significantly ameliorated dyskinesia,increased the levels of tyrosine hydroxylase(TH)and inhibited astrocyte hyperactivation in the substantia nigra(SN)of PD mice.Furthermore,BBP decreased the protein levels of glial fibrillary acidic protein(GFAP),cyclooxygenase 2(COX2)and inducible nitric oxide synthase(iNOS),and up-regulated the protein levels of takeda G protein-coupled receptor 5(TGR5)in the SN.Moreover,BBP significantly activated TGR5 in a dose-dependent manner,and decreased the protein levels of GFAP,iNOS and COX2,as well as the mRNA levels of GFAP,iNOS,COX2,interleukin(IL)-1β,IL-6 and tumor necrosis factor-α(TNF-α)in LPS-stimulated C6 cells.Notably,BBP suppressed the phosphorylation of protein kinase B(AKT),inhibitor of NF-κB(IκBα)and nuclear factor-κB(NF-κB)proteins in vivo and in vitro.We also observed that TGR5 inhibitor triamterene attenuated the anti-neuroinflammatory effect of BBP on LPS-stimulated C6 cells.Taken together,BBP alleviates the progression of PD mice by suppressing astrocyte-mediated inflammation via TGR5.展开更多
文摘OBJECTIVE Takeda G protein-coupled receptor 5(TGR5)is recognized as a promising target for type 2 diabetes and metabolic syndrome;its expression has been demonstrat⁃ed in the brain and is thought to be neuroprotec⁃tive.Here,we hypothesize that dysfunction of central TGR5 may contribute to the pathogene⁃sis of depression.METHODS In well-established chronic social defeat stress(CSDS)and chronic restraint stress(CRS)models of depression,we investigated the functional roles of TGR5 in CA3 pyramidal neurons(PyNs)and underlying mech⁃anisms of the neuronal circuit in depression(for in vivo studies,n=10;for in vitro studies,n=5-10)using fiber photometry;optogenetic,chemoge⁃netic,pharmacological,and molecular profiling techniques;and behavioral tests.RESULTS Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs.Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777,a specific agonist,protected against CSDS and CRS,exerting sig⁃nificant antidepressant-like effects that were mediated via CA3 PyN activation.Conversely,genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behav⁃iors.Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in Tgr5 knockout mice exposed to CSDS or CRS.Silencing and stimula⁃tion of CA3 PyNs→somatostatin-GABAergic(gamma-aminobutyric acidergic)neurons of the dorsolateral septum circuit bidirectionally regulat⁃ed depression-like behaviors,and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs.CON⁃CLUSION TGR5 can regulate depression via CA3 PyNs→somatostatin-GABAergic neurons of dorsolateral septum transmission,suggesting that TGR5 could be a novel target for developing antidepressants.
文摘Dengue fever,caused by the dengue virus(DENV),poses a significant public health challenge globally,with Nigeria experiencing sporadic outbreaks.A clear understanding of the dengue burden has not been achieved in Nigeria,just as in other African countries.Understanding the epidemiology and burden of dengue fever is essential for effective prevention and control strategies.This paper examines the recent dengue outbreaks in northern Nigeria,particularly in Sokoto state,and evaluates the recommended Takeda dengue vaccine(TDV)along with future prevention strategies.Despite limited surveillance and underreporting,dengue fever is endemic in Nigeria(with over 5 million cases and 5000 dengue-related deaths in 2023),with recent outbreaks indicating a growing concern.The TDV,a live attenuated tetravalent vaccine,has shown promise in preventing dengue fever,but challenges such as vaccine acceptance and access-ibility need to be addressed.Global urbanization contributes to the disease's spread,which is influenced by factors such as population density,cultural beliefs,water storage practices,hygiene,and water supply accessibility.Future prevention strategies must focus on government intervention,community practices,and innovative vector control measures to mitigate the spread of DENV in Nigeria.This study will serve as a valuable reference for policy-makers,researchers,and clinicians in the management and control of DENV in Nigeria and Africa as a whole.
文摘Takeda Taijun(1912-1976)is a representative of the Japanese postwar writers,who has a special affinity for China.During his whole lifetime,he stayed in China for two long periods,of which the period from June,1944 to February,1946 was spent in Shanghai.He was quite productive and created quite a few works focusing on China,especially Shanghai before and after Japan’s being defeated in the Second World War,which became the background of many works.This paper attempts to interpret Takeda Taijun’s experience in Shanghai of that time on the basis of the masterpiece Firefly in Shanghai in his later years.
基金supported by the National Science Fund for Excellent Young Scholars(grant number 32422082)the Natural Science Basic Research Plan in Shaanxi Province(grant number 2025JC-QYXQ-009)。
文摘Background Ruminants and monogastric animals exhibit significant differences in gluconeogenic efficiency.In dairy cows,hepatic gluconeogenesis serves as the primary source of glucose.Metabolites modulate gluconeogenesis efficiency through allosteric regulation,redox state,and signal transduction pathways.However,the liver-enriched metabolites that regulate hepatic gluconeogenesis in dairy cows and their specific regulatory mechanisms remain incompletely characterized.Results Six Holstein dairy cows and six Duroc×(Landrace×Yorkshire)(DLY)crossbred pigs served as research subjects.Employing non-targeted and targeted metabolomics,we discovered that three bile acids—taurodeoxycholic acid(TDCA),taurocholic acid(TCA),and glycocholic acid(GCA)—were highly enriched in Holstein dairy cows'livers.In bovine hepatocytes,individual or combined stimulation of these bile acids significantly upregulated the expression of gluconeogenesis genes(FBP1,PCK1 and G6PC)and enhanced glucose production.In fasting mice with induced gluconeogenesis,TDCA,TCA,and GCA increased fasting blood glucose levels,and pyruvate tolerance tests further revealed their capacity to enhance hepatic gluconeogenesis,enabling more efficient glucose synthesis from pyruvate.Mechanistically,these bile acids activated Takeda G protein-coupled receptor 5(TGR5),elevated intracellular cAMP levels,and ultimately enhanced gluconeogenesis via the transcription factor cAMP-response element binding protein(CREB).Notably,a TGR5 inhibitor abrogated the stimulatory effects of TDCA,TCA,and GCA on hepatic gluconeogenesis in fasting mice.Conclusion TDCA,TCA,and GCA are key metabolites promoting hepatic gluconeogenesis in dairy cows,with TGR5 as the pivotal receptor and the cAMP/PKA/CREB pathway as the critical downstream mechanism.
基金This work was supported by the USA National Institutes of Health(NIH)(AA015951,DK044442,and DK058379).
文摘Background and aims:Diet-induced obesity and metabolic syndrome can trigger the progression of fatty liver disease to non-alcoholic steatohepatitis and fibrosis,which is a major public health concern.Bile acids regulate metabolic homeostasis and inflammation in the liver and gut via the activation of nuclear farnesoid X receptor(Fxr)and the membrane receptor Takeda G protein-coupled receptor 5(Tgr5).Tgr5 is highly expressed in the gut and skeletal muscle,and in cholangiocytes and Kupffer cells of the liver.Tgr5 is implicated in the mediation of liver and gut inflammation,as well as the maintenance of energy homeostasis.Here,we used a high fat,high fructose,and high sucrose(HFS)diet to determine how bile acid signaling through Tgr5 may regulate metabolism during the progression from fatty liver to non-alcoholic steatohepatitis and fibrosis.Materials and methods:Female C57BL/6J control wild type(WT)and Tgr5 knockout(Tgr5^(-/-))mice were fed HFS(high fat(40%kcal),high fructose,and 20%sucrose water)diet for 20 weeks.Metabolic phe-notypes were characterized through examination of bile acid synthesis pathways,lipid and cholesterol metabolism pathways,and fibrosis and inflammation pathways.Results:Tgr5^(-/-)mice were more glucose intolerant when fed HFS diet,despite gaining the same amount of weight as WT mice.Tgr5^(-/-)mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice,and gene expression of lipogenic genes was significantly upregulated.Hepatic cholesterol 7alpha-hydroxylase(Cyp7a1)gene expression was consistently elevated in Tgr5^(-/-)mice,while oxysterol 7alpha-hydroxylase(Cyp7b1),sterol 27-hydroxylase(Cyp27a1),Fxr,and small heterodimer partner(Shp)were downregulated by HFS diet.Surprisingly,hepatic inflammation and fibrosis were also significantly reduced in Tgr5^(-/-)mice fed HFS diet,which may be due to altered se-rotonin signaling in the liver.Conclusions:Tgr5^(-/-)mice may be protected from high fat,high sugar-induced hepatic inflammation and injury due to altered serotonin metabolism.
基金supported by a fellowship from Design Department of Taisei Corporation。
文摘Many countries throughout the world have experienced large earthquakes,which cause building damage or collapse.After such earthquakes,structures must be inspected rapidly to judge whether they are safe to reoccupy.To facilitate the inspection process,the authors previously developed a rapid building safety assessment system using sparse acceleration measurements for steel framed buildings.The proposed system modeled nonlinearity in the measurement data using a calibrated simplified lumped-mass model and convolutional neural networks(CNNs),based on which the buildinglevel damage index was estimated rapidly after earthquakes.The proposed system was validated for a nonlinear 3D numerical model of a five-story steel building,and later for a large-scale specimen of an 18-story building in Japan tested on the E-Defense shaking table.However,the applicability of the safety assessment system for reinforced concrete(RC)structures with complex hysteretic material nonlinearity has yet to be explored;the previous approach based on a simplified lumpedmass model with a Bouc-Wen hysteretic model does not accurately represent the inherent nonlinear behavior and resulting damage states of RC structures.This study extends the rapid building safety assessment system to low-rise RC moment resisting frame structures representing typical residential apartments in Japan.First,a safety classification for RC structures based on a damage index consistent with the current state of practice is defined.Then,a 3D nonlinear numerical model of a two-story moment frame structure is created.A simplified lumped-mass nonlinear model is developed and calibrated using the 3D model,incorporating the Takeda degradation model for the RC material nonlinearity.This model is used to simulate the seismic response and associated damage sensitive features(DSF)for random ground motion.The resulting database of responses is used to train a convolutional neural network(CNN)that performs rapid safety assessment.The developed system is validated using the 3D nonlinear analysis model subjected to historical earthquakes.The results indicate the applicability of the proposed system for RC structures following seismic events.
基金Supported by National Key Technology Support Program during“12th Five-Year Plan”Period of China,No.2014BAI08B00National Key Research and Development Plan for Precision Medicine Research,No.2017YFC0910002and Leapforward Development Program for Beijing Biopharmaceutical Industry(G20),No.Z171100001717008.
文摘BACKGROUND Gut microbiota and its metabolites may be involved in the pathogenesis of inflammatory bowel disease.Several clinical studies have recently shown that patients with ulcerative colitis(UC)have altered profiles of fecal bile acids(BAs).It was observed that BA receptors Takeda G-protein-coupled receptor 5(TGR5)and vitamin D receptor(VDR)participate in intestinal inflammatory responses by regulating NF-ĸB signaling.We hypothesized that altered profiles of fecal BAs might be correlated with gut microbiota and inflammatory responses in patients with UC.AIM To investigate the changes in fecal BAs and analyze the relationship of BAs with gut microbiota and inflammation in patients with UC.METHODS The present study used 16S rDNA sequencing technology to detect the differences in the intestinal flora between UC patients and healthy controls(HCs).Fecal BAs were measured by targeted metabolomics approaches.Mucosal TGR5 and VDR expression was analyzed using immunohistochemistry,and serum inflammatory cytokine levels were detected by ELISA.RESULTS Thirty-two UC patients and twenty-three HCs were enrolled in this study.It was found that the diversity of gut microbiota in UC patients was reduced compared with that in HCs.Firmicutes,Clostridium IV,Butyricicoccus,Clostridium XlVa,Faecalibacterium,and Roseburia were significantly decreased in patients with UC(P=3.75E-05,P=8.28E-07,P=0.0002,P=0.003,P=0.0003,and P=0.0004,respectively).Proteobacteria,Escherichia,Enterococcus,Klebsiella,and Streptococcus were significantly enriched in the UC group(P=2.99E-09,P=3.63E-05,P=8.59E-05,P=0.003,and P=0.016,respectively).The concentrations of fecal secondary BAs,such as lithocholic acid,deoxycholic acid,glycodeoxycholic acid,glycolithocholic acid,and taurolithocholate,in UC patients were significantly lower than those in HCs(P=8.1E-08,P=1.2E-07,P=3.5E-04,P=1.9E-03,and P=1.8E-02,respectively)and were positively correlated with Butyricicoccus,Roseburia,Clostridium IV,Faecalibacterium,and Clostridium XlVb(P<0.01).The concentrations of primary BAs,such as taurocholic acid,cholic acid,taurochenodeoxycholate,and glycochenodeoxycholate,in UC patients were significantly higher than those in HCs(P=5.3E-03,P=4E-02,P=0.042,and P=0.045,respectively)and were positively related to Enterococcus,Klebsiella,Streptococcus,Lactobacillus,and pro-inflammatory cytokines(P<0.01).The expression of TGR5 was significantly elevated in UC patients(0.019±0.013 vs 0.006±0.003,P=0.0003).VDR expression in colonic mucosal specimens was significantly decreased in UC patients(0.011±0.007 vs 0.016±0.004,P=0.033).CONCLUSION Fecal BA profiles are closely related to the gut microbiota and serum inflammatory cytokines.Dysregulation of the gut microbiota and altered constitution of fecal BAs may participate in regulating inflammatory responses via the BA receptors TGR5 and VDR.
基金the Organizational Key Research and Development Program of Shanghai University of Traditional Chinese Medicine(No.2023YZZ02).
文摘Parkinson’s disease(PD)is a common neurodegenerative disease in middle-aged and elderly people.In particular,increasing evidence has showed that astrocyte-mediated neuroinflammation is involved in the pathogenesis of PD.As a precious traditional Chinese medicine,bear bile powder(BBP)has a long history of use in clinical practice.It has numerous activities,such as clearing heat,calming the liver wind and anti-inflammation,and also exhibits good therapeutic effect on convulsive epilepsy.However,whether BBP can prevent the development of PD has not been elucidated.Hence,this study was designed to explore the effect and mechanism of BBP on suppressing astrocyte-mediated neuroinflammation in a mouse model of PD.PD-like behavior was induced in the mice by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)(30 mg·kg−1)for five days,followed by BBP(50,100,and 200 mg·kg−1)treatment daily for ten days.LPS stimulated rat C6 astrocytic cells were used as a cell model of neuroinflammation.THe results indicated that BBP treatment significantly ameliorated dyskinesia,increased the levels of tyrosine hydroxylase(TH)and inhibited astrocyte hyperactivation in the substantia nigra(SN)of PD mice.Furthermore,BBP decreased the protein levels of glial fibrillary acidic protein(GFAP),cyclooxygenase 2(COX2)and inducible nitric oxide synthase(iNOS),and up-regulated the protein levels of takeda G protein-coupled receptor 5(TGR5)in the SN.Moreover,BBP significantly activated TGR5 in a dose-dependent manner,and decreased the protein levels of GFAP,iNOS and COX2,as well as the mRNA levels of GFAP,iNOS,COX2,interleukin(IL)-1β,IL-6 and tumor necrosis factor-α(TNF-α)in LPS-stimulated C6 cells.Notably,BBP suppressed the phosphorylation of protein kinase B(AKT),inhibitor of NF-κB(IκBα)and nuclear factor-κB(NF-κB)proteins in vivo and in vitro.We also observed that TGR5 inhibitor triamterene attenuated the anti-neuroinflammatory effect of BBP on LPS-stimulated C6 cells.Taken together,BBP alleviates the progression of PD mice by suppressing astrocyte-mediated inflammation via TGR5.
