The majority of individuals maintain normal physiological and behavioral function despite experiencing severe traumatic stress,demonstrating psychological resilience.Yet a clinically significant proportion develops in...The majority of individuals maintain normal physiological and behavioral function despite experiencing severe traumatic stress,demonstrating psychological resilience.Yet a clinically significant proportion develops increased vulnerability,often presenting as stress-related psychiatric conditions such as major depressive disorder(MDD)[1].The global prevalence of MDD is surging unprecedentedly,contributing substantially to the global burden of disease and disability.展开更多
Background:This study was conducted to investigate the effects of each phytogenic feed additive(PFA;PFA1,bitter citrus extract;PFA2,a microencapsulated blend of thymol and carvacrol;PFA3,a mixture of bitter citrus ext...Background:This study was conducted to investigate the effects of each phytogenic feed additive(PFA;PFA1,bitter citrus extract;PFA2,a microencapsulated blend of thymol and carvacrol;PFA3,a mixture of bitter citrus extract,thymol,and carvacrol;PFA4,a premixture of grape seed,grape marc extract,green tea,and hops;PFA5,fenugreek seed powder)on the growth performance,nutrient digestibility,intestinal morphology,and immune response in weaned pigs infected with Escherichia coli(E.coli).Results:A total of 634-week-old weaned pigs were placed in individual metabolic cages and assigned to seven treatment groups.The seven treatments were as follows:1)NC;basal diet without E.coli challenge,2)PC;basal diet with E.coli challenge,3)T1;PC+0.04%PFA1,4)T2;PC+0.01%PFA2,5)T3;PC+0.10%PFA3,6)T4;PC+0.04%PFA4,7)T5;PC+0.10%PFA5.The experiments lasted in 21 d,including 7 d before and 14 d after the first E.coli challenge.In the E.coli challenge treatments,all pigs were orally inoculated by dividing a total of 10 mL of E.coli F18 for 3 consecutive days.The PFA-added groups significantly increased(P<0.05)average daily gain and feed efficiency and decreased(P<0.05)the fecal score at d 0 to 14 post-inoculation(PI).Tumor necrosis factorαwas significantly lower(P<0.05)in the PFA-added groups except for T1 in d 14 PI compared to the PC treatment.The T3 had a higher(P<0.05)immunoglobulin G and immunoglobulin A concentration compared to the PC treatment at d 7 PI.Also,T3 showed significantly higher(P<0.05)villus height:crypt depth and claudin 1 expression in ileal mucosa,and significantly downregulated(P<0.05)the expression of calprotectin compared to the PC treatment.Conclusions:Supplementation of PFA in weaned pigs challenged with E.coli alleviated the negative effects of E.coli and improved growth performance.Among them,the mixed additive of bitter citrus extract,thymol,and carvacrol showed the most effective results,improving immune response,intestinal morphology,and expression of tight junctions.展开更多
There is growing evidence that acute hypoxia can be hazardous to health by causing damage to a variety of human organs.Gastrointestinal dysfunction is a common symptom of acute mountain sickness,and the pathogenesis o...There is growing evidence that acute hypoxia can be hazardous to health by causing damage to a variety of human organs.Gastrointestinal dysfunction is a common symptom of acute mountain sickness,and the pathogenesis of acute hypoxic gastrointestinal injury is complex.Additionally,the incidence of gastrointestinal disorders in people travelling to highland areas increases with altitude.展开更多
This experiment was conducted to investigate the effects of benzoic acid,Bacillus coagulans and oregano oil combined supplementation on growth performance,immune status and intestinal barrier integrity of piglets.In a...This experiment was conducted to investigate the effects of benzoic acid,Bacillus coagulans and oregano oil combined supplementation on growth performance,immune status and intestinal barrier integrity of piglets.In a 26-d experiment,25 piglets were randomly assigned to 5 treatments:1)a basal diet,negative control(NC),2)NC added with antibiotics,positive control(PC);3)NC added with benzoic acid at 3,000 g/t and Bacillus coagulans at 400 g/t(AB);4)NC added with benzoic acid at 3,000 g/t and o regano oil at 400 g/t(AO);5)NC added with 3,000 g/t benzoic acid and Bacillus coagulans at 400 g/t and oregano oil at 400 g/t(ABO);On d 27,all piglets were euthanized to obtain jejunal mucosa to measure immune status and intestinal barrier integrity.Results showed that pigs fed AB diet increased the final body weight and average daily body weight gain and decreased the ratio of feed to gain co mpared with NC group(P<0.05).Co mpared with NC group,AB,AO and ABO decreased serum tumor necrosis factor-a concentration and ABO decreased interleukin-1βconcentration in serum and jejunal mucosa(P<0.05).Compared with NC group,AB upregulated mRNA expressions of sodium-glucose cotransportel,claudin-1,occludin and mucin2 in jejunal mucosa and the populations of Bifidobacterium and Bacillus in cecal digesta(P<0.05).Compared with NC group,ABO increased jejunal mucosal occludin mRNA abundance and Bifidobacterium population in cecal digesta,and decreased Escherichia coli population in cecal digesta(P<0.05).Furthermore,AB and ABO increased Bacillus population in cecal digesta compared with PC group(P<0.05).These results indicated that dietary AB supplementation could improve growth performance and intestinal barrier integrity of piglets when fed antibiotic-free diets,which was possibly associated with the improvement of immune status and intestinal microflora.Dietary ABO supplementation is also beneficial to improve immune status and intestinal barrier integrity and micro flora of piglets.展开更多
The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood components.The mechanistic basis of this barrier...The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood components.The mechanistic basis of this barrier is found at multiple levels,including the adherens and tight junction proteins that tightly bind adjacent endothelial cells and the influence of neighboring pericytes,microglia,and astrocyte endfeet.In addition,extracellular matrix components of the vascular basement membrane play a critical role in establishing and maintaining blood-brain barrier integrity,not only by providing an adhesive substrate for blood-brain barrier cells to adhere to,but also by providing guidance cues that strongly influence vascular cell behavior.The extracellular matrix protein laminin is one of the most abundant components of the basement membrane,and several lines of evidence suggest that it plays a key role in directing blood-brain barrier behavior.In this review,we describe the basic structure of laminin and its receptors,the expression patterns of these molecules in central nervous system blood vessels and how they are altered in disease states,and most importantly,how genetic deletion of different laminin isoforms or their receptors reveals the contribution of these molecules to blood-brain barrier function and integrity.Finally,we discuss some of the important unanswered questions in the field and provide a“to-do”list of some of the critical outstanding experiments.展开更多
A new fuzzy adaptive control method is proposed for a class of strict feedback nonlinear systems with immeasurable states and full constraints.The fuzzy logic system is used to design the approximator,which deals with...A new fuzzy adaptive control method is proposed for a class of strict feedback nonlinear systems with immeasurable states and full constraints.The fuzzy logic system is used to design the approximator,which deals with uncertain and continuous functions in the process of backstepping design.The use of an integral barrier Lyapunov function not only ensures that all states are within the bounds of the constraint,but also mixes the states and errors to directly constrain the state,reducing the conservativeness of the constraint satisfaction condition.Considering that the states in most nonlinear systems are immeasurable,a fuzzy adaptive states observer is constructed to estimate the unknown states.Combined with adaptive backstepping technique,an adaptive fuzzy output feedback control method is proposed.The proposed control method ensures that all signals in the closed-loop system are bounded,and that the tracking error converges to a bounded tight set without violating the full state constraint.The simulation results prove the effectiveness of the proposed control scheme.展开更多
Hypoxemia is a common pathological state characterized by low oxygen saturation in the blood.This condition compromises mucosal barrier integrity particularly in the gut and oral cavity.However,the mechanisms underlyi...Hypoxemia is a common pathological state characterized by low oxygen saturation in the blood.This condition compromises mucosal barrier integrity particularly in the gut and oral cavity.However,the mechanisms underlying this association remain unclear.This study used periodontitis as a model to investigate the role of platelet activation in oral mucosal immunopathology under hypoxic conditions.Hypoxia upregulated methyltransferase-like protein 4(METTL4)expression in platelets,resulting in N6-methyladenine modification of mitochondrial DNA(mtDNA).This modification impaired mitochondrial transcriptional factor A-dependent cytosolic mtDNA degradation,leading to cytosolic mtDNA accumulation.Excess cytosolic mt-DNA aberrantly activated the cGAS-STING pathway in platelets.This resulted in excessive platelet activation and neutrophil extracellular trap formation that ultimately exacerbated periodontitis.Targeting platelet METTL4 and its downstream pathways offers a potential strategy for managing oral mucosa immunopathology.Further research is needed to examine its broader implications for mucosal inflammation under hypoxic conditions.展开更多
Tricellulin,a key tricellular tight junction(TJ)protein,is essential for maintaining the barrier integrity of acinar epithelia against macromolecular passage in salivary glands.This study aims to explore the role and ...Tricellulin,a key tricellular tight junction(TJ)protein,is essential for maintaining the barrier integrity of acinar epithelia against macromolecular passage in salivary glands.This study aims to explore the role and regulatory mechanism of tricellulin in the development of salivary gland hypofunction in Sjögren’s syndrome(SS).Employing a multifaceted approach involving patient biopsies,non-obese diabetic(NOD)mice as a SS model,salivary gland acinar cell-specific tricellulin conditional knockout(TricCKO)mice,and IFN-γ-stimulated salivary gland epithelial cells,we investigated the role of tricellulin in SS-related hyposalivation.Our data revealed diminished levels of tricellulin in salivary glands of SS patients.Similarly,NOD mice displayed a reduction in tricellulin expression from the onset of the disease,concomitant with hyposecretion and an increase in salivary albumin content.Consistent with these findings,TricCKO mice exhibited both hyposecretion and leakage of macromolecular tracers when compared to control animals.Mechanistically,the JAK/STAT1/miR-145 axis was identified as mediating the IFN-γ-induced downregulation of tricellulin.Treatment with AT1001,a TJ sealer,ameliorated epithelial barrier dysfunction,restored tricellulin expression,and consequently alleviated hyposalivation in NOD mice.Importantly,treatment with miR-145 antagomir to specifically recover the expression of tricellulin in NOD mice significantly alleviated hyposalivation and macromolecular leakage.Collectively,we identified that tricellulin deficiency in salivary glands contributed to hyposalivation in SS.Our findings highlight tricellulin as a potential therapeutic target for hyposecretion,particularly in the context of reinforcing epithelial barrier function through preventing leakage of macromolecules in salivary glands.展开更多
Although the etiology of inflammatory bowel disease (IBD) remains unclear,compromised epithelial barrier integrity is believed to promote susceptibility toIBD and be associated with disease severity, suggesting that i...Although the etiology of inflammatory bowel disease (IBD) remains unclear,compromised epithelial barrier integrity is believed to promote susceptibility toIBD and be associated with disease severity, suggesting that improving gut barrierintegrity may palliate or treat IBD. Such a notion gets support from the clinicalfindings that mucosal healing in IBD patients is associated with improvedprognosis, and reduced risk of relapse or colitis-associated cancer. It thereforebecomes critical to understand the intracellular signals that regulate mucosalhealing and gut barrier integrity. Focal adhesion kinase (FAK) is a non-receptortyrosine kinase that critically modulates epithelial cell growth and mobility andhas been associated with carcinogenesis. However, studies also suggest that FAKactivation may promote mucosal healing under conditions of colitis, which shouldreduce the risk of colitis-associated cancer. These findings highlight a potentiallytransformative role for FAK in the context of IBD. Understanding the molecularmechanisms by which FAK influences gut barrier repair and mucosal integritycould offer novel therapeutic avenues for treating IBD and preventing its longtermcomplications. This review focuses on the potential role of FAK in promotingcolitis-associated mucosal healing and the underlying molecular mechanismsdriving these processes, offering critical insights into IBD pathogenesis and therapy.展开更多
BACKGROUND The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis.Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease(NAFLD)by modul...BACKGROUND The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis.Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease(NAFLD)by modulating gut microbiota.Partially hydrolyzed guar gum(PHGG),a water-soluble dietary fiber,has been reported to alleviate the symptoms of various intestinal diseases and metabolic syndromes.However,its effects on NAFLD remain to be fully elucidated.To determine whether treatment with PHGG attenuates NAFLD development in mice through the gut-liver axis.METHODS Seven-week-old male C57BL/6J mice with increased intestinal permeability were fed a control or atherogenic(Ath)diet(a mouse model of NAFLD)for 8 wk,with or without 5%PHGG.Increased intestinal permeability was induced through chronic intermittent administration of low-dose dextran sulfate sodium.Body weight,liver weight,macroscopic findings in the liver,blood biochemistry[aspartate aminotransferase(AST)and alanine aminotransferase(ALT),total cholesterol,triglyceride,free fatty acids,and glucose levels],liver histology,myeloperoxidase activity in liver tissue,mRNA expression in the liver and intestine,serum endotoxin levels in the portal vein,intestinal permeability,and microbiota and short-chain fatty acid(SCFA)profiles in the cecal samples were investigated.RESULTS Mice with increased intestinal permeability subjected to the Ath diet showed significantly increased serum AST and ALT levels,liver fat accumulation,liver inflammatory(tumor necrosis factor-αand monocyte chemotactic protein-1)and fibrogenic(collagen 1a1 andαsmooth muscle actin)marker levels,and liver myeloperoxidase activity,which were significantly attenuated by PHGG treatment.Furthermore,the Ath diet combined with increased intestinal permeability resulted in elevated portal endotoxin levels and activated toll-like receptor(TLR)4 and TLR9 expression,confirming that intestinal permeability was significantly elevated,as observed by evaluating the lumen-to-blood clearance of fluorescein isothiocyanate-conjugated dextran.PHGG treatment did not affect fatty acid metabolism in the liver.However,it decreased lipopolysaccharide signaling through the gut-liver axis.In addition,it significantly increased the abundance of cecal Bacteroides and Clostridium subcluster XIVa.Treatment with PHGG markedly increased the levels of SCFAs,particularly,butyric acid,acetic acid,propionic acid,and formic acid,in the cecal samples.CONCLUSION PHGG partially prevented NAFLD development in mice through the gut-liver axis by modulating microbiota and downstream SCFA profiles.展开更多
In the ANSICHT project that was jointly carried out by DBE TECHNOLOGY Gmb H,BGR,and GRS g Gmb H,two generic geological site models were used to develop a first draft of a methodology to demonstrate the safety of a hig...In the ANSICHT project that was jointly carried out by DBE TECHNOLOGY Gmb H,BGR,and GRS g Gmb H,two generic geological site models were used to develop a first draft of a methodology to demonstrate the safety of a high-level waste(HLW) repository in argillaceous formations in Germany,taking into account the regulatory requirements.The main results of the project are characterised by the developed repository concepts adapted to the geological conditions.The specific quantifications of the integrity criteria and their exemplary application with calculational proofs were used to demonstrate the integrity of the host rocks.The development of site-specific FEP(features,events,and processes) cataloges provided a complete system description for evaluation of the repository evolution.The developed work flow of the demonstration concept illustrated the complete sequence of the safety proof in a transparent way.It shows that various steps have to be performed,possibly iteratively,to provide a successful safety proof.The results form a useful tool in the pending search for a HLW repository site,especially when providing a basis for comparing safety analyses of different sites in Germany.展开更多
To evaluate the measurement of zonulin level and antibodies of zonulin and other tight junction proteins in the blood of controls and celiac disease patients.METHODSThis study was conducted to assess the variability o...To evaluate the measurement of zonulin level and antibodies of zonulin and other tight junction proteins in the blood of controls and celiac disease patients.METHODSThis study was conducted to assess the variability or stability of zonulin levels vs IgA and IgG antibodies against zonulin in blood samples from 18 controls at 0,6,24 and 30 h after blood draw.We also measured zonulin level as well as zonulin,occludin,vinculin,aquaporin 4 and glial fibrillary acidic protein antibodies in the sera of 30 patients with celiac disease and 30 controls using enzyme-linked immunosorbent assay methodology.RESULTSThe serum zonulin level in 6 out of 18 subjects was low or<2.8 ng/mL and was very close to the detection limit of the assay.The other 12 subjects had zonulin levels of>2.8 ng/mL and showed significant fluctuation from sample to sample.Comparatively,zonulin antibody measured in all samples was highly stable and reproducible from sample to sample.Celiac disease patients showed zonulin levels with a mean of 8.5 ng/mL compared to 3.7 ng/mL in controls(P<0.0001).Elevation of zonulin level at 2SD above the mean was demonstrated in 37%of celiac disease patients,while antibodies against zonulin,occludin and other tight junction proteins was detected in up to 86%of patients with celiac disease.CONCLUSIONDue to its fluctuation,a single measurement of zonulin level is not recommended for assessment of intestinal barrier integrity.Measurement of IgG and IgA antibodies against zonulin,occludin,and other tight junction proteins is proposed for the evaluation of the loss of intestinal barrier integrity.展开更多
The intestinal barrier is the primary defense that separates the host from the external environ-ment,possessing several crucial physiological functions,including nutrient digestion,absorption,and protection against po...The intestinal barrier is the primary defense that separates the host from the external environ-ment,possessing several crucial physiological functions,including nutrient digestion,absorption,and protection against potentially harmful dietary antigens and pathogenic microorganisms.Nevertheless,various factors,such as diet,medications,circadian rhythm disturbances,gut microbiota,microbial me-tabolites,and genetic predisposition,can disrupt the intestinal barrier.Such disruption may lead to bac-terial translocation,subsequently triggering enterohepatic and systemic inflammation.Impaired intestinal barrier has been implicated in the pathogenesis of numerous diseases,particularly chronic gut and liver diseases.In this review,we will summarize the fundamental functions of intestinal barrier and discuss clinical correlations between intestinal barrier dysfunction and diseases such as colitis,colorectal cancer,and chronic liver diseases including metabolic dysfunction-associated steatohepatitis,alcohol-associated liver disease,and primary sclerosing cholangitis.Additionally,we will also highlight some potential ther-apeutic strategies aimed at restoring barrier integrity to improve disease management.展开更多
In this paper,a study of control for an uncertain2-degree of freedom(DOF)helicopter system is given.The2-DOF helicopter is subject to input deadzone and output constraints.In order to cope with system uncertainties an...In this paper,a study of control for an uncertain2-degree of freedom(DOF)helicopter system is given.The2-DOF helicopter is subject to input deadzone and output constraints.In order to cope with system uncertainties and input deadzone,the neural network technique is introduced because of its capability in approximation.In order to update the weights of the neural network,an adaptive control method is utilized to improve the system adaptability.Furthermore,the integral barrier Lyapunov function(IBLF)is adopt in control design to guarantee the condition of output constraints and boundedness of the corresponding tracking errors.The Lyapunov direct method is applied in the control design to analyze system stability and convergence.Finally,numerical simulations are conducted to prove the feasibility and effectiveness of the proposed control based on the model of Quanser's 2-DOF helicopter.展开更多
In this paper,an integrated estimation guidance and control(IEGC)system is designed based on the command filtered backstepping approach for circular field-of-view(FOV)strapdown missiles.The threedimensional integrated...In this paper,an integrated estimation guidance and control(IEGC)system is designed based on the command filtered backstepping approach for circular field-of-view(FOV)strapdown missiles.The threedimensional integrated estimation guidance and control nonlinear model with limited actuator deflection angle is established considering the seeker's FOV constraint.The boundary time-varying integral barrier Lyapunov function(IBLF)is employed in backstepping design to constrain the body line-of-sight(BLOS)in IEGC system to fit a circular FOV.Then,the nonlinear adaptive controller is designed to estimate the changing aerodynamic parameters.The generalized extended state observer(GESO)is designed to estimate the acceleration of the maneuvering targets and the unmatched time-varying disturbances for improving tracking accuracy.Furthermore,the command filters are used to solve the"differential expansion"problem during the backstepping design.The Lyapunov theory is used to prove the stability of the overall closed-loop IEGC system.Finally,the simulation results validate the integrated system's effectiveness,achieving high accuracy strikes against maneuvering targets.展开更多
This paper investigates the issue of adaptive optimal tracking control for nonlinear systems with dynamic state constraints.An asymmetric time-varying integral barrier Lyapunov function(ATIBLF)based integral reinforce...This paper investigates the issue of adaptive optimal tracking control for nonlinear systems with dynamic state constraints.An asymmetric time-varying integral barrier Lyapunov function(ATIBLF)based integral reinforcement learning(IRL)control algorithm with an actor–critic structure is first proposed.The ATIBLF items are appropriately arranged in every step of the optimized backstepping control design to ensure that the dynamic full-state constraints are never violated.Thus,optimal virtual/actual control in every backstepping subsystem is decomposed with ATIBLF items and also with an adaptive optimized item.Meanwhile,neural networks are used to approximate the gradient value functions.According to the Lyapunov stability theorem,the boundedness of all signals of the closed-loop system is proved,and the proposed control scheme ensures that the system states are within predefined compact sets.Finally,the effectiveness of the proposed control approach is validated by simulations.展开更多
Emerging research underscores the pivotal role of the gut-immune-brain axis,a dynamic bidirectional communication system involving intricate interactions between the gut microbiota,immune responses,and the central ner...Emerging research underscores the pivotal role of the gut-immune-brain axis,a dynamic bidirectional communication system involving intricate interactions between the gut microbiota,immune responses,and the central nervous system.Gut microbes and their metabolites have profound effects on immune and neurological homeostasis,influencing the development and function of multiple physiological systems.Disruption of the composition of the gut microbiota and barrier integrity has been implicated in various neurological and psychiatric disorders,including autism spectrum disorder,Alzheimer's disease,Parkinson's disease,depression,and anxiety.Most insights into these host-microbiota interactions come from preclinical models,revealing both the complexity and potential therapeutic opportunities of the gut-brain communication pathways.This review synthesizes the current understanding of these intricate interactions,exploring how microbiota-driven modulation of the gut and brain barriers,immune signaling,and neuronal pathways,such as those through the vagus nerve,contributes to health and disease.We further explore therapeutic implications,including personalized precision microbiota interventions,microbiome-derived biomarkers,and barrierstrengthening strategies.Advancing this field offers transformative potential for developing innovative,personalized therapies tailored to individual microbiomes and immune profiles,ultimately redefining clinical approaches to neurological and immunemediated diseases.展开更多
基金supported by the National Natural Science Foundation of China(32300851)Zhejiang Provincial Natural Science Foundation(LQ24h310008).
文摘The majority of individuals maintain normal physiological and behavioral function despite experiencing severe traumatic stress,demonstrating psychological resilience.Yet a clinically significant proportion develops increased vulnerability,often presenting as stress-related psychiatric conditions such as major depressive disorder(MDD)[1].The global prevalence of MDD is surging unprecedentedly,contributing substantially to the global burden of disease and disability.
基金carried out with the support of“Cooperative Research Program for Agriculture Science&Technology Development(Project No.PJ01622001)”Rural Development Administration,Korea。
文摘Background:This study was conducted to investigate the effects of each phytogenic feed additive(PFA;PFA1,bitter citrus extract;PFA2,a microencapsulated blend of thymol and carvacrol;PFA3,a mixture of bitter citrus extract,thymol,and carvacrol;PFA4,a premixture of grape seed,grape marc extract,green tea,and hops;PFA5,fenugreek seed powder)on the growth performance,nutrient digestibility,intestinal morphology,and immune response in weaned pigs infected with Escherichia coli(E.coli).Results:A total of 634-week-old weaned pigs were placed in individual metabolic cages and assigned to seven treatment groups.The seven treatments were as follows:1)NC;basal diet without E.coli challenge,2)PC;basal diet with E.coli challenge,3)T1;PC+0.04%PFA1,4)T2;PC+0.01%PFA2,5)T3;PC+0.10%PFA3,6)T4;PC+0.04%PFA4,7)T5;PC+0.10%PFA5.The experiments lasted in 21 d,including 7 d before and 14 d after the first E.coli challenge.In the E.coli challenge treatments,all pigs were orally inoculated by dividing a total of 10 mL of E.coli F18 for 3 consecutive days.The PFA-added groups significantly increased(P<0.05)average daily gain and feed efficiency and decreased(P<0.05)the fecal score at d 0 to 14 post-inoculation(PI).Tumor necrosis factorαwas significantly lower(P<0.05)in the PFA-added groups except for T1 in d 14 PI compared to the PC treatment.The T3 had a higher(P<0.05)immunoglobulin G and immunoglobulin A concentration compared to the PC treatment at d 7 PI.Also,T3 showed significantly higher(P<0.05)villus height:crypt depth and claudin 1 expression in ileal mucosa,and significantly downregulated(P<0.05)the expression of calprotectin compared to the PC treatment.Conclusions:Supplementation of PFA in weaned pigs challenged with E.coli alleviated the negative effects of E.coli and improved growth performance.Among them,the mixed additive of bitter citrus extract,thymol,and carvacrol showed the most effective results,improving immune response,intestinal morphology,and expression of tight junctions.
基金supported by the Specialized Scientific Research Projects for Military Laboratory Animals(China)(No.SYDW_KY[2021]06)the Military Medical Research Institute Young Talent Fund Program(China)(No.AMMS-QNPY-2022-019).
文摘There is growing evidence that acute hypoxia can be hazardous to health by causing damage to a variety of human organs.Gastrointestinal dysfunction is a common symptom of acute mountain sickness,and the pathogenesis of acute hypoxic gastrointestinal injury is complex.Additionally,the incidence of gastrointestinal disorders in people travelling to highland areas increases with altitude.
基金supported by the National Key Research and Development Program of China(2018YFD0500605)the Science and Technology Support Program of Sichuan Province(2014NZ0043,2016NZ0006)
文摘This experiment was conducted to investigate the effects of benzoic acid,Bacillus coagulans and oregano oil combined supplementation on growth performance,immune status and intestinal barrier integrity of piglets.In a 26-d experiment,25 piglets were randomly assigned to 5 treatments:1)a basal diet,negative control(NC),2)NC added with antibiotics,positive control(PC);3)NC added with benzoic acid at 3,000 g/t and Bacillus coagulans at 400 g/t(AB);4)NC added with benzoic acid at 3,000 g/t and o regano oil at 400 g/t(AO);5)NC added with 3,000 g/t benzoic acid and Bacillus coagulans at 400 g/t and oregano oil at 400 g/t(ABO);On d 27,all piglets were euthanized to obtain jejunal mucosa to measure immune status and intestinal barrier integrity.Results showed that pigs fed AB diet increased the final body weight and average daily body weight gain and decreased the ratio of feed to gain co mpared with NC group(P<0.05).Co mpared with NC group,AB,AO and ABO decreased serum tumor necrosis factor-a concentration and ABO decreased interleukin-1βconcentration in serum and jejunal mucosa(P<0.05).Compared with NC group,AB upregulated mRNA expressions of sodium-glucose cotransportel,claudin-1,occludin and mucin2 in jejunal mucosa and the populations of Bifidobacterium and Bacillus in cecal digesta(P<0.05).Compared with NC group,ABO increased jejunal mucosal occludin mRNA abundance and Bifidobacterium population in cecal digesta,and decreased Escherichia coli population in cecal digesta(P<0.05).Furthermore,AB and ABO increased Bacillus population in cecal digesta compared with PC group(P<0.05).These results indicated that dietary AB supplementation could improve growth performance and intestinal barrier integrity of piglets when fed antibiotic-free diets,which was possibly associated with the improvement of immune status and intestinal microflora.Dietary ABO supplementation is also beneficial to improve immune status and intestinal barrier integrity and micro flora of piglets.
文摘The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood components.The mechanistic basis of this barrier is found at multiple levels,including the adherens and tight junction proteins that tightly bind adjacent endothelial cells and the influence of neighboring pericytes,microglia,and astrocyte endfeet.In addition,extracellular matrix components of the vascular basement membrane play a critical role in establishing and maintaining blood-brain barrier integrity,not only by providing an adhesive substrate for blood-brain barrier cells to adhere to,but also by providing guidance cues that strongly influence vascular cell behavior.The extracellular matrix protein laminin is one of the most abundant components of the basement membrane,and several lines of evidence suggest that it plays a key role in directing blood-brain barrier behavior.In this review,we describe the basic structure of laminin and its receptors,the expression patterns of these molecules in central nervous system blood vessels and how they are altered in disease states,and most importantly,how genetic deletion of different laminin isoforms or their receptors reveals the contribution of these molecules to blood-brain barrier function and integrity.Finally,we discuss some of the important unanswered questions in the field and provide a“to-do”list of some of the critical outstanding experiments.
基金supported in part by the National Natural Science Foundation of China(6202530361973147)the LiaoNing Revitalization Talents Program(XLYC1907050)。
文摘A new fuzzy adaptive control method is proposed for a class of strict feedback nonlinear systems with immeasurable states and full constraints.The fuzzy logic system is used to design the approximator,which deals with uncertain and continuous functions in the process of backstepping design.The use of an integral barrier Lyapunov function not only ensures that all states are within the bounds of the constraint,but also mixes the states and errors to directly constrain the state,reducing the conservativeness of the constraint satisfaction condition.Considering that the states in most nonlinear systems are immeasurable,a fuzzy adaptive states observer is constructed to estimate the unknown states.Combined with adaptive backstepping technique,an adaptive fuzzy output feedback control method is proposed.The proposed control method ensures that all signals in the closed-loop system are bounded,and that the tracking error converges to a bounded tight set without violating the full state constraint.The simulation results prove the effectiveness of the proposed control scheme.
基金supported by the National Natural Science Foundation of China(82325012)the Youth Fund of the National Natural Science Foundation of China(82301043)+1 种基金the Natural Science Basic Research Program of Shaanxi (Program No.2024JC-YBQN-0980)the Shaanxi Key Scientific and Technological Innovation Team(2020TD-033).
文摘Hypoxemia is a common pathological state characterized by low oxygen saturation in the blood.This condition compromises mucosal barrier integrity particularly in the gut and oral cavity.However,the mechanisms underlying this association remain unclear.This study used periodontitis as a model to investigate the role of platelet activation in oral mucosal immunopathology under hypoxic conditions.Hypoxia upregulated methyltransferase-like protein 4(METTL4)expression in platelets,resulting in N6-methyladenine modification of mitochondrial DNA(mtDNA).This modification impaired mitochondrial transcriptional factor A-dependent cytosolic mtDNA degradation,leading to cytosolic mtDNA accumulation.Excess cytosolic mt-DNA aberrantly activated the cGAS-STING pathway in platelets.This resulted in excessive platelet activation and neutrophil extracellular trap formation that ultimately exacerbated periodontitis.Targeting platelet METTL4 and its downstream pathways offers a potential strategy for managing oral mucosa immunopathology.Further research is needed to examine its broader implications for mucosal inflammation under hypoxic conditions.
基金supported by the National Natural Science Foundation of China(grants 31972908,81991500,81991502,and 32030010)Beijing Natural Science Foundation(grant 7202082).
文摘Tricellulin,a key tricellular tight junction(TJ)protein,is essential for maintaining the barrier integrity of acinar epithelia against macromolecular passage in salivary glands.This study aims to explore the role and regulatory mechanism of tricellulin in the development of salivary gland hypofunction in Sjögren’s syndrome(SS).Employing a multifaceted approach involving patient biopsies,non-obese diabetic(NOD)mice as a SS model,salivary gland acinar cell-specific tricellulin conditional knockout(TricCKO)mice,and IFN-γ-stimulated salivary gland epithelial cells,we investigated the role of tricellulin in SS-related hyposalivation.Our data revealed diminished levels of tricellulin in salivary glands of SS patients.Similarly,NOD mice displayed a reduction in tricellulin expression from the onset of the disease,concomitant with hyposecretion and an increase in salivary albumin content.Consistent with these findings,TricCKO mice exhibited both hyposecretion and leakage of macromolecular tracers when compared to control animals.Mechanistically,the JAK/STAT1/miR-145 axis was identified as mediating the IFN-γ-induced downregulation of tricellulin.Treatment with AT1001,a TJ sealer,ameliorated epithelial barrier dysfunction,restored tricellulin expression,and consequently alleviated hyposalivation in NOD mice.Importantly,treatment with miR-145 antagomir to specifically recover the expression of tricellulin in NOD mice significantly alleviated hyposalivation and macromolecular leakage.Collectively,we identified that tricellulin deficiency in salivary glands contributed to hyposalivation in SS.Our findings highlight tricellulin as a potential therapeutic target for hyposecretion,particularly in the context of reinforcing epithelial barrier function through preventing leakage of macromolecules in salivary glands.
文摘Although the etiology of inflammatory bowel disease (IBD) remains unclear,compromised epithelial barrier integrity is believed to promote susceptibility toIBD and be associated with disease severity, suggesting that improving gut barrierintegrity may palliate or treat IBD. Such a notion gets support from the clinicalfindings that mucosal healing in IBD patients is associated with improvedprognosis, and reduced risk of relapse or colitis-associated cancer. It thereforebecomes critical to understand the intracellular signals that regulate mucosalhealing and gut barrier integrity. Focal adhesion kinase (FAK) is a non-receptortyrosine kinase that critically modulates epithelial cell growth and mobility andhas been associated with carcinogenesis. However, studies also suggest that FAKactivation may promote mucosal healing under conditions of colitis, which shouldreduce the risk of colitis-associated cancer. These findings highlight a potentiallytransformative role for FAK in the context of IBD. Understanding the molecularmechanisms by which FAK influences gut barrier repair and mucosal integritycould offer novel therapeutic avenues for treating IBD and preventing its longtermcomplications. This review focuses on the potential role of FAK in promotingcolitis-associated mucosal healing and the underlying molecular mechanismsdriving these processes, offering critical insights into IBD pathogenesis and therapy.
基金Scientific Research(KAKENHI)(C),No.25460958Japan Society for the Promotion of Science,No.20K11513and Adaptable and Seamless Technology Transfer Program through target driven R&D from the Japan Agency for Medical Research and Development.
文摘BACKGROUND The gut-liver axis has attracted much interest in the context of chronic liver disease pathogenesis.Prebiotics such as dietary fibers were shown to attenuate non-alcoholic fatty liver disease(NAFLD)by modulating gut microbiota.Partially hydrolyzed guar gum(PHGG),a water-soluble dietary fiber,has been reported to alleviate the symptoms of various intestinal diseases and metabolic syndromes.However,its effects on NAFLD remain to be fully elucidated.To determine whether treatment with PHGG attenuates NAFLD development in mice through the gut-liver axis.METHODS Seven-week-old male C57BL/6J mice with increased intestinal permeability were fed a control or atherogenic(Ath)diet(a mouse model of NAFLD)for 8 wk,with or without 5%PHGG.Increased intestinal permeability was induced through chronic intermittent administration of low-dose dextran sulfate sodium.Body weight,liver weight,macroscopic findings in the liver,blood biochemistry[aspartate aminotransferase(AST)and alanine aminotransferase(ALT),total cholesterol,triglyceride,free fatty acids,and glucose levels],liver histology,myeloperoxidase activity in liver tissue,mRNA expression in the liver and intestine,serum endotoxin levels in the portal vein,intestinal permeability,and microbiota and short-chain fatty acid(SCFA)profiles in the cecal samples were investigated.RESULTS Mice with increased intestinal permeability subjected to the Ath diet showed significantly increased serum AST and ALT levels,liver fat accumulation,liver inflammatory(tumor necrosis factor-αand monocyte chemotactic protein-1)and fibrogenic(collagen 1a1 andαsmooth muscle actin)marker levels,and liver myeloperoxidase activity,which were significantly attenuated by PHGG treatment.Furthermore,the Ath diet combined with increased intestinal permeability resulted in elevated portal endotoxin levels and activated toll-like receptor(TLR)4 and TLR9 expression,confirming that intestinal permeability was significantly elevated,as observed by evaluating the lumen-to-blood clearance of fluorescein isothiocyanate-conjugated dextran.PHGG treatment did not affect fatty acid metabolism in the liver.However,it decreased lipopolysaccharide signaling through the gut-liver axis.In addition,it significantly increased the abundance of cecal Bacteroides and Clostridium subcluster XIVa.Treatment with PHGG markedly increased the levels of SCFAs,particularly,butyric acid,acetic acid,propionic acid,and formic acid,in the cecal samples.CONCLUSION PHGG partially prevented NAFLD development in mice through the gut-liver axis by modulating microbiota and downstream SCFA profiles.
基金the Federal Ministry for Economic Affairs and Energy(BMWi=Bundesministerium für Wirtschaft und Energie)represented by the Project Management Agency Karlsruhe(Karlsruhe Institute of Technology,KIT)for funding the research work performed in this project
文摘In the ANSICHT project that was jointly carried out by DBE TECHNOLOGY Gmb H,BGR,and GRS g Gmb H,two generic geological site models were used to develop a first draft of a methodology to demonstrate the safety of a high-level waste(HLW) repository in argillaceous formations in Germany,taking into account the regulatory requirements.The main results of the project are characterised by the developed repository concepts adapted to the geological conditions.The specific quantifications of the integrity criteria and their exemplary application with calculational proofs were used to demonstrate the integrity of the host rocks.The development of site-specific FEP(features,events,and processes) cataloges provided a complete system description for evaluation of the repository evolution.The developed work flow of the demonstration concept illustrated the complete sequence of the safety proof in a transparent way.It shows that various steps have to be performed,possibly iteratively,to provide a successful safety proof.The results form a useful tool in the pending search for a HLW repository site,especially when providing a basis for comparing safety analyses of different sites in Germany.
文摘To evaluate the measurement of zonulin level and antibodies of zonulin and other tight junction proteins in the blood of controls and celiac disease patients.METHODSThis study was conducted to assess the variability or stability of zonulin levels vs IgA and IgG antibodies against zonulin in blood samples from 18 controls at 0,6,24 and 30 h after blood draw.We also measured zonulin level as well as zonulin,occludin,vinculin,aquaporin 4 and glial fibrillary acidic protein antibodies in the sera of 30 patients with celiac disease and 30 controls using enzyme-linked immunosorbent assay methodology.RESULTSThe serum zonulin level in 6 out of 18 subjects was low or<2.8 ng/mL and was very close to the detection limit of the assay.The other 12 subjects had zonulin levels of>2.8 ng/mL and showed significant fluctuation from sample to sample.Comparatively,zonulin antibody measured in all samples was highly stable and reproducible from sample to sample.Celiac disease patients showed zonulin levels with a mean of 8.5 ng/mL compared to 3.7 ng/mL in controls(P<0.0001).Elevation of zonulin level at 2SD above the mean was demonstrated in 37%of celiac disease patients,while antibodies against zonulin,occludin and other tight junction proteins was detected in up to 86%of patients with celiac disease.CONCLUSIONDue to its fluctuation,a single measurement of zonulin level is not recommended for assessment of intestinal barrier integrity.Measurement of IgG and IgA antibodies against zonulin,occludin,and other tight junction proteins is proposed for the evaluation of the loss of intestinal barrier integrity.
基金supported by National Natural Science Foundation of China(82530024 and 82222071)National Key Research and Development Program of China(2021YFA1301200)+1 种基金Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0830402,China)Shanghai Municipal Science and Technology Major Project,to Cen Xie.
文摘The intestinal barrier is the primary defense that separates the host from the external environ-ment,possessing several crucial physiological functions,including nutrient digestion,absorption,and protection against potentially harmful dietary antigens and pathogenic microorganisms.Nevertheless,various factors,such as diet,medications,circadian rhythm disturbances,gut microbiota,microbial me-tabolites,and genetic predisposition,can disrupt the intestinal barrier.Such disruption may lead to bac-terial translocation,subsequently triggering enterohepatic and systemic inflammation.Impaired intestinal barrier has been implicated in the pathogenesis of numerous diseases,particularly chronic gut and liver diseases.In this review,we will summarize the fundamental functions of intestinal barrier and discuss clinical correlations between intestinal barrier dysfunction and diseases such as colitis,colorectal cancer,and chronic liver diseases including metabolic dysfunction-associated steatohepatitis,alcohol-associated liver disease,and primary sclerosing cholangitis.Additionally,we will also highlight some potential ther-apeutic strategies aimed at restoring barrier integrity to improve disease management.
基金supported by the National Natural Science Foundation of China(61803085,61806052,U1713209)the Natural Science Foundation of Jiangsu Province of China(BK20180361)
文摘In this paper,a study of control for an uncertain2-degree of freedom(DOF)helicopter system is given.The2-DOF helicopter is subject to input deadzone and output constraints.In order to cope with system uncertainties and input deadzone,the neural network technique is introduced because of its capability in approximation.In order to update the weights of the neural network,an adaptive control method is utilized to improve the system adaptability.Furthermore,the integral barrier Lyapunov function(IBLF)is adopt in control design to guarantee the condition of output constraints and boundedness of the corresponding tracking errors.The Lyapunov direct method is applied in the control design to analyze system stability and convergence.Finally,numerical simulations are conducted to prove the feasibility and effectiveness of the proposed control based on the model of Quanser's 2-DOF helicopter.
文摘In this paper,an integrated estimation guidance and control(IEGC)system is designed based on the command filtered backstepping approach for circular field-of-view(FOV)strapdown missiles.The threedimensional integrated estimation guidance and control nonlinear model with limited actuator deflection angle is established considering the seeker's FOV constraint.The boundary time-varying integral barrier Lyapunov function(IBLF)is employed in backstepping design to constrain the body line-of-sight(BLOS)in IEGC system to fit a circular FOV.Then,the nonlinear adaptive controller is designed to estimate the changing aerodynamic parameters.The generalized extended state observer(GESO)is designed to estimate the acceleration of the maneuvering targets and the unmatched time-varying disturbances for improving tracking accuracy.Furthermore,the command filters are used to solve the"differential expansion"problem during the backstepping design.The Lyapunov theory is used to prove the stability of the overall closed-loop IEGC system.Finally,the simulation results validate the integrated system's effectiveness,achieving high accuracy strikes against maneuvering targets.
基金Project supported by the National Natural Science Foundation of China(Nos.62203392 and 62373329)the Natural Science Foundation of Zhejiang Province,China(No.LY23F030009)the Baima Lake Laboratory Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(No.LBMHD24F030002)。
文摘This paper investigates the issue of adaptive optimal tracking control for nonlinear systems with dynamic state constraints.An asymmetric time-varying integral barrier Lyapunov function(ATIBLF)based integral reinforcement learning(IRL)control algorithm with an actor–critic structure is first proposed.The ATIBLF items are appropriately arranged in every step of the optimized backstepping control design to ensure that the dynamic full-state constraints are never violated.Thus,optimal virtual/actual control in every backstepping subsystem is decomposed with ATIBLF items and also with an adaptive optimized item.Meanwhile,neural networks are used to approximate the gradient value functions.According to the Lyapunov stability theorem,the boundedness of all signals of the closed-loop system is proved,and the proposed control scheme ensures that the system states are within predefined compact sets.Finally,the effectiveness of the proposed control approach is validated by simulations.
基金supported by grants from the National Research Foundation of Korea funded by the Korea Ministry of Science and ICT(MSIT):L.C.and H.-K.K.were supported by RS-2024-00361620,RS-2019-NR040072,RS-2025-00561456,and RS2024-00438443.S.-H.I was supported by RS-2024-00345575.We would like to thank MID(Medical Illustration&Design),a member of the Medical Research Support Services of Yonsei University College of Medicine,for providing excellent support with medical illustrations.
文摘Emerging research underscores the pivotal role of the gut-immune-brain axis,a dynamic bidirectional communication system involving intricate interactions between the gut microbiota,immune responses,and the central nervous system.Gut microbes and their metabolites have profound effects on immune and neurological homeostasis,influencing the development and function of multiple physiological systems.Disruption of the composition of the gut microbiota and barrier integrity has been implicated in various neurological and psychiatric disorders,including autism spectrum disorder,Alzheimer's disease,Parkinson's disease,depression,and anxiety.Most insights into these host-microbiota interactions come from preclinical models,revealing both the complexity and potential therapeutic opportunities of the gut-brain communication pathways.This review synthesizes the current understanding of these intricate interactions,exploring how microbiota-driven modulation of the gut and brain barriers,immune signaling,and neuronal pathways,such as those through the vagus nerve,contributes to health and disease.We further explore therapeutic implications,including personalized precision microbiota interventions,microbiome-derived biomarkers,and barrierstrengthening strategies.Advancing this field offers transformative potential for developing innovative,personalized therapies tailored to individual microbiomes and immune profiles,ultimately redefining clinical approaches to neurological and immunemediated diseases.
