Human cardiac organoids have revolutionized the study of cardiac development,disease modeling,drug discovery,and regenerative therapies.This review systematically discusses strategies and progress in the construction ...Human cardiac organoids have revolutionized the study of cardiac development,disease modeling,drug discovery,and regenerative therapies.This review systematically discusses strategies and progress in the construction of cardiac organoids,categorizing them into three main types:cardiac spheroids,self-organizing/assembloid organoids,and organoid-on-a-chip systems.This review uniquely integrates the advances in vascularization,organ-on-chip design,and environmental cardiotoxicity modeling within cardiac organoid platforms,offering a critical synthesis that is absent in the literature.In the context of escalating environmental threats to cardiovascular health,there is an urgent need for physiologically relevant models to accurately identify cardiac toxicants and elucidate their underlying mechanisms of action.This review highlights advances in cardiac organoid applications for disease modeling—including congenital heart defects and acquired cardiovascular diseases—drug development,toxicity screening,and the study of environmentally induced cardiovascular pathogenesis.In addition,it critically examines ongoing challenges and underscores opportunities brought by bioengineering approaches.Finally,we propose future directions for developing standardized cardiac organoid platforms with clinical predictability,aiming to expand the utility of this technology across broader research applications.展开更多
Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism rem...Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.展开更多
Rett syndrome(RTT)is a progressive neurodevelopmental disorder that occurs mainly in girls with a range of typical symptoms of autism spectrum disorders.MeCP2 protein loss-of-function in neural lineage cells is the ma...Rett syndrome(RTT)is a progressive neurodevelopmental disorder that occurs mainly in girls with a range of typical symptoms of autism spectrum disorders.MeCP2 protein loss-of-function in neural lineage cells is the main cause of RTT pathogenicity.As it is still hard to understand the mechanism of RTT on the basis of only clinical patients or animal models,cell models cultured in vitro play indispensable roles.Here we reviewed the research progress in the pathogenesis of RTT at the cellular level,summarized the preclinical-research-related applications,and prospected potential future development.展开更多
There is a critical need to develop animal models to alleviate vaccine and drug development difficulties against zoonotic viral infections.The coronavirus family,which includes severe acute respiratory syndrome corona...There is a critical need to develop animal models to alleviate vaccine and drug development difficulties against zoonotic viral infections.The coronavirus family,which includes severe acute respiratory syndrome coronavirus 1 and severe acute respiratory syndrome coronavirus 2,crossed the species barrier and infected humans,causing a global outbreak in the 21st century.Because humans do not have pre-existing immunity against these viral infections and with ethics governing clinical trials,animal models are therefore being used in clinical studies to facilitate drug discovery and testing efficacy of vaccines.The ideal animal models should reflect the viral replication,clinical signs,and pathological responses observed in humans.Different animal species should be tested to establish an appropriate animal model to study the disease pathology,transmission and evaluation of novel vaccine and drug candidates to treat coronavirus disease 2019.In this context,the present review summarizes the recent progress in developing animal models for these two pathogenic viruses and highlights the utility of these models in studying SARS-associated coronavirus diseases.展开更多
Liver cirrhosis is the final pathological result of various chronic liver diseases,and fibrosis is the precursor of cirrhosis.Many types of cells,cytokines and miRNAs are involved in the initiation and progression of ...Liver cirrhosis is the final pathological result of various chronic liver diseases,and fibrosis is the precursor of cirrhosis.Many types of cells,cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis.Activation of hepatic stellate cells(HSCs)is a pivotal event in fibrosis.Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis.Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs.Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis.At the molecular level,many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis.Recently,miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis.Robust animal models of liver fibrosis and cirrhosis,as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.展开更多
Alcoholic hepatitis(AH)is an acute hepatic inflammation associated with significant morbidity and mortality.Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol me...Alcoholic hepatitis(AH)is an acute hepatic inflammation associated with significant morbidity and mortality.Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol metabolism,inflammation and innate immunity.Several clinical scoring systems have been derived to predict the clinical outcomes of patients with AH;such as Child-Turcotte-Pugh score,the Maddrey discriminant function,the Lille Model,the model for end stage liver disease scores,and the Glasgow alcoholic hepatitis score.At present,Corticosteroids or pentoxifylline are the current pharmacologic treatment options;though the outcomes from the therapies are poor.Liver trans-plantation as the treatment of alcoholic hepatitis remains controversial,and in an era of organ shortage current guidelines do not recommend transplantation as the treatment option.Because of the limitations in the therapeutic options,it is no doubt that there is a critical need for the newer and more effective pharmacological agents to treat AH.展开更多
Nonalcoholic steatohepatitis(NASH)is a common clinical condition that can lead to advanced liver diseases.The mechanism of the diaease progression,which is lacking effective therapy,remains obsure.Therefore,there is a...Nonalcoholic steatohepatitis(NASH)is a common clinical condition that can lead to advanced liver diseases.The mechanism of the diaease progression,which is lacking effective therapy,remains obsure.Therefore,there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies.To accomplish this goal,experimental animal models that recapitulate the human disease are necessary.Currently,an increasing number of studies have focused on natural constituents from medicinal plants which have been emerged as a new hope for NASH.This review summarized the pathogenesis of NASH,animal models commonly used,and the promising targets for therapeutics.We also reviewed the natural constituents as potential NASH therapeutic agents.展开更多
Tauopathies represent a class of neurodegenerative diseases(NDs),including Alzheimer’s disease(AD),progressive supranuclear palsy(PSP),Pick’s disease(PiD),and corticobasal degeneration(CBD),defined by intracellular ...Tauopathies represent a class of neurodegenerative diseases(NDs),including Alzheimer’s disease(AD),progressive supranuclear palsy(PSP),Pick’s disease(PiD),and corticobasal degeneration(CBD),defined by intracellular accumulation of misfolded and hyperphosphorylated tau protein.The pathogenic cascade involves hyperphosphorylation,conformational changes,and aggregation into neurofibrillary tangles(NFTs),which are spatially and functionally linked to neuronal dysfunction,synaptic loss,and progressive cognitive and motor decline.To elucidate tau-mediated mechanisms,diverse transgenic rodent models expressing wild-type or mutant forms of human TAU have been generated.Although these models have advanced understanding of tau aggregation and propagation,tau-targeting therapies have failed to produce clinical benefits,raising concerns about the precise mechanism underlying tauopathies and the fidelity of animal models in evaluating therapeutic targets.This review systematically examines the neuropathological and behavioral phenotypes across established rodent and non-human primate(NHP)tauopathy models,highlighting mechanistic insights into tau-driven pathology.The advantages,limitations,and translational barriers of each model are critically evaluated to inform the development of more predictive preclinical platforms for therapeutic discovery.展开更多
Understanding microbial-host interactions in the oral cavity is essential for elucidating oral disease pathogenesis and its systemic implications.In vitro bacteria-host cell coculture models have enabled fundamental s...Understanding microbial-host interactions in the oral cavity is essential for elucidating oral disease pathogenesis and its systemic implications.In vitro bacteria-host cell coculture models have enabled fundamental studies to characterize bacterial infection and host responses in a reductionist yet reproducible manner.However,existing in vitro coculture models fail to establish conditions that are suitable for the growth of both mammalian cells and anaerobes,thereby hindering a comprehensive understanding of their interactions.Here,we present an asymmetric gas coculture system that simulates the oral microenvironment by maintaining distinct normoxic and anaerobic conditions for gingival epithelial cells and anaerobic bacteria,respectively.Using a key oral pathobiont,Fusobacterium nucleatum,as the primary test bed,we demonstrate that the system preserves bacterial viability and supports the integrity of telomerase-immortalized gingival keratinocytes.Compared to conventional models,this system enhanced bacterial invasion,elevated intracellular bacterial loads,and elicited more robust host pro-inflammatory responses,including increased secretion of CXCL10,IL-6,and IL-8.In addition,the model enabled precise evaluation of antibiotic efficacy against intracellular pathogens.Finally,we validate the ability of the asymmetric system to support the proliferation of a more oxygen-sensitive oral pathobiont,Porphyromonas gingivalis.These results underscore the utility of this coculture platform for studying oral microbial pathogenesis and screening therapeutics,offering a physiologically relevant approach to advance oral and systemic health research.展开更多
Anxiety disorders have become one of the most severe psychiatric disorders,and the incidence is increasing every year.They impose an extraordinary personal and socioeconomic burden.Anxiety disorders are influenced by ...Anxiety disorders have become one of the most severe psychiatric disorders,and the incidence is increasing every year.They impose an extraordinary personal and socioeconomic burden.Anxiety disorders are influenced by multiple complex and interacting genetic,psychological,social,and environmental factors,which contribute to disruption or imbalance in homeostasis and eventually cause pathologic anxiety.The selection of a suitable animal model is important for the exploration of disease etiology and pathophysiology,and the development of new drugs.Therefore,a more comprehensive understanding of the advantages and limitations of existing animal models of anxiety disorders is helpful to further study the underlying pathological mechanisms of the disease.This review summarizes animal models and the pathogenesis of anxiety disorders,and discusses the current research status to provide insights for further study of anxiety disorders.展开更多
The dynamic errors of gyros are the important error sources of a strapdown inertial navigation system. In order to identify the dynamic error model coefficients accurately, the static error model coefficients which la...The dynamic errors of gyros are the important error sources of a strapdown inertial navigation system. In order to identify the dynamic error model coefficients accurately, the static error model coefficients which lay a foundation for compensating while identifying the dynamic error model are identified in the gravity acceleration fields by using angular position function of the three-axis turntable. The angular acceleration and angular velocity are excited on the input, output and spin axis of the gyros when the outer axis and the middle axis of a three-axis turntable are in the uniform angular velocity state simultaneously, while the inner axis of the turntable is in different static angular positions. 8 groups of data are sampled when the inner axis is in 8 different angular positions. These data are the function of the middle axis positions and the inner axis positions. For these data, harmonic analysis method is applied two times versus the middle axis positions and inner axis positions respectively so that the dynamic error model coefficients are finally identified through the least square method. In the meantime the optimal angular velocity of the outer axis and the middle axis are selected by computing the determination value of the information matrix.展开更多
The exact causes of inflammatory bowel disease(IBD)are not yet fully defined.From a vast body of literature,we know that the immune response has long been involved in the pathogenesis of IBD,including both ulcerative ...The exact causes of inflammatory bowel disease(IBD)are not yet fully defined.From a vast body of literature,we know that the immune response has long been involved in the pathogenesis of IBD,including both ulcerative colitis and Crohn’s disease.A variety of specific alterations can lead to immune activation and inflammation directed to the colon,as revealed by some animal models.Current research has focused on the role of antibodies in downstream events and mechanisms of autoimmunity and inflammation.It is not well known whether the production of antibodies is a serologic consequence of IBD,or if it is a result of barrier dysfunction induced by inflammation.Here,we present a new hypothesis to distinguish the complex links between genetic susceptibility,barrier dysfunction,commensal and pathologic microbial factors and inflammatory response(especially autoantibodies)in the pathogenesis of IBD.To ascertain the hypothesis,we developed a pilot model with the concept of the presence of antibodies against enteric bacterial antigens in IBD.Results confirmed our hypothesis.Our hypothesis suggests the possibility of subcutaneous vaccination of animals with administration of all or specific enteric bacterial antigens.展开更多
The Angolan strain of Marburg virus （MARV/Ang） can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previo...The Angolan strain of Marburg virus （MARV/Ang） can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previous work includes the development and characterization of a MARV/Ang variant that can cause lethal disease in mice （MARV/Ang-MA）, with the aim of using this tool to screen for promising prophylactic and therapeutic candidates. An intermediate animal model is needed to confirm any findings from mice studies before testing in the gold-standard non-human primate （NHP） model. In this study, we serially passaged the clinical isolate of MARV/Ang in the livers and spleens of guinea pigs until a variant emerged that causes 100% lethality in guinea pigs （MARV/Ang- GA）. Animals infected with MARV/Ang-GA showed signs of filovirus infection including lymphocytopenia, thrombocytopenia, and high viremia leading to spread to major organs, including the liver, spleen, lungs, and kidneys. The MARV/Ang-GA guinea pigs died between 7-9 days after infection, and the LD50 was calculated to be 1.1x10-1 TCID50 （median tissue culture infective dose）. Mutations in MARV/Ang-GA were identified and compared to sequences of known rodent-adapted MARV/Ang variants, which may benefit future studies characterizing important host adaptation sites in the MARV/Ang viral genome.展开更多
Hepatitis E virus(HEV)is one of the leading causes of acute viral hepatitis worldwide.Although most of HEV infections are asymptomatic,some patients will develop the symptoms,especially pregnant women,the elderly,and ...Hepatitis E virus(HEV)is one of the leading causes of acute viral hepatitis worldwide.Although most of HEV infections are asymptomatic,some patients will develop the symptoms,especially pregnant women,the elderly,and patients with preexisting liver diseases,who often experience anorexia,nausea,vom-iting,malaise,abdominal pain,and jaundice.HEV infection may become chronic in immunosuppressed individuals.In addition,HEV infection can also cause several extrahepatic manifestations.HEV exists in a wide range of hosts in nature and can be transmitted across species.Hence,animals susceptible to HEV can be used as models.The establishment of animal models is of great significance for studying HEV transmission,clinical symptoms,extrahepatic manifestations,and therapeutic strategies,which will help us understand the pathogenesis,prevention,and treatment of hepatitis E.This review summarized the animal models of HEV,including pigs,monkeys,rabbits,mice,rats,and other animals.For each animal species,we provided a concise summary of the HEV genotypes that they can be infected with,the cross-species transmission pathways,as well as their role in studying extrahepatic manifestations,prevention,and treatment of HEV infection.The advantages and disadvantages of these animal models were also emphasized.This review offers new perspectives to enhance the current understanding of the research landscape surrounding HEV animal models.展开更多
Antineutrophil cytoplasmic autoantibody(ANCA)-associated vasculitis(AAV)is a rare and severe systemic autoimmune disease characterized by pauci-immune necrotizing inflammation of small blood vessels.AAV involves multi...Antineutrophil cytoplasmic autoantibody(ANCA)-associated vasculitis(AAV)is a rare and severe systemic autoimmune disease characterized by pauci-immune necrotizing inflammation of small blood vessels.AAV involves multiple organ systems throughout the body.Our knowledge of the pathogenesis of AAV has increased considerably in recent years,involving cellular,molecular and genetic factors.Because of the controlled environment with no other confounding factors,animal models are beneficial for studying the mechanistic details of disease development and for providing novel therapeutic targets with fewer toxic side effects.However,the complexity and heterogeneity of AAV make it very difficult to establish a single animal model that can fully represent the entire clinical spectrum found in patients.The aim of this review is to overview the current status of animal models for AAV,outline the pros and cons of methods,and propose potential directions for future research.展开更多
基金supported by the Innovation Promotion Program of NHC and Shanghai Key Labs,SIBPT(grant number PT2025-01)。
文摘Human cardiac organoids have revolutionized the study of cardiac development,disease modeling,drug discovery,and regenerative therapies.This review systematically discusses strategies and progress in the construction of cardiac organoids,categorizing them into three main types:cardiac spheroids,self-organizing/assembloid organoids,and organoid-on-a-chip systems.This review uniquely integrates the advances in vascularization,organ-on-chip design,and environmental cardiotoxicity modeling within cardiac organoid platforms,offering a critical synthesis that is absent in the literature.In the context of escalating environmental threats to cardiovascular health,there is an urgent need for physiologically relevant models to accurately identify cardiac toxicants and elucidate their underlying mechanisms of action.This review highlights advances in cardiac organoid applications for disease modeling—including congenital heart defects and acquired cardiovascular diseases—drug development,toxicity screening,and the study of environmentally induced cardiovascular pathogenesis.In addition,it critically examines ongoing challenges and underscores opportunities brought by bioengineering approaches.Finally,we propose future directions for developing standardized cardiac organoid platforms with clinical predictability,aiming to expand the utility of this technology across broader research applications.
文摘Neuromyelitis optica spectrum disorders are neuroinflammatory demyelinating disorders that lead to permanent visual loss and motor dysfunction.To date,no effective treatment exists as the exact causative mechanism remains unknown.Therefore,experimental models of neuromyelitis optica spectrum disorders are essential for exploring its pathogenesis and in screening for therapeutic targets.Since most patients with neuromyelitis optica spectrum disorders are seropositive for IgG autoantibodies against aquaporin-4,which is highly expressed on the membrane of astrocyte endfeet,most current experimental models are based on aquaporin-4-IgG that initially targets astrocytes.These experimental models have successfully simulated many pathological features of neuromyelitis optica spectrum disorders,such as aquaporin-4 loss,astrocytopathy,granulocyte and macrophage infiltration,complement activation,demyelination,and neuronal loss;however,they do not fully capture the pathological process of human neuromyelitis optica spectrum disorders.In this review,we summarize the currently known pathogenic mechanisms and the development of associated experimental models in vitro,ex vivo,and in vivo for neuromyelitis optica spectrum disorders,suggest potential pathogenic mechanisms for further investigation,and provide guidance on experimental model choices.In addition,this review summarizes the latest information on pathologies and therapies for neuromyelitis optica spectrum disorders based on experimental models of aquaporin-4-IgG-seropositive neuromyelitis optica spectrum disorders,offering further therapeutic targets and a theoretical basis for clinical trials.
基金The Major Basic Research Project of Science and Technology of YunnanGrant/Award Number:202001BC070001 and 202105AC160041+3 种基金National Natural Science Foundation of ChinaGrant/Award Number:81930121 and 31960120The National Key Research and Development Program of ChinaGrant/Award Number:2018YFA0107902 and 2018YFA0801403。
文摘Rett syndrome(RTT)is a progressive neurodevelopmental disorder that occurs mainly in girls with a range of typical symptoms of autism spectrum disorders.MeCP2 protein loss-of-function in neural lineage cells is the main cause of RTT pathogenicity.As it is still hard to understand the mechanism of RTT on the basis of only clinical patients or animal models,cell models cultured in vitro play indispensable roles.Here we reviewed the research progress in the pathogenesis of RTT at the cellular level,summarized the preclinical-research-related applications,and prospected potential future development.
基金COVID Therapeutics,Department of Biotechnology,Government of India,Ref.No.BT/PR4094/COT/142/20/2021.
文摘There is a critical need to develop animal models to alleviate vaccine and drug development difficulties against zoonotic viral infections.The coronavirus family,which includes severe acute respiratory syndrome coronavirus 1 and severe acute respiratory syndrome coronavirus 2,crossed the species barrier and infected humans,causing a global outbreak in the 21st century.Because humans do not have pre-existing immunity against these viral infections and with ethics governing clinical trials,animal models are therefore being used in clinical studies to facilitate drug discovery and testing efficacy of vaccines.The ideal animal models should reflect the viral replication,clinical signs,and pathological responses observed in humans.Different animal species should be tested to establish an appropriate animal model to study the disease pathology,transmission and evaluation of novel vaccine and drug candidates to treat coronavirus disease 2019.In this context,the present review summarizes the recent progress in developing animal models for these two pathogenic viruses and highlights the utility of these models in studying SARS-associated coronavirus diseases.
文摘Liver cirrhosis is the final pathological result of various chronic liver diseases,and fibrosis is the precursor of cirrhosis.Many types of cells,cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis.Activation of hepatic stellate cells(HSCs)is a pivotal event in fibrosis.Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis.Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs.Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis.At the molecular level,many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis.Recently,miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis.Robust animal models of liver fibrosis and cirrhosis,as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
基金Supported by K08 AA016570 from the NIH/NIAAA,1I01-CX000361-01 from the Veterans Affairs Research and Admin-istration,Indiana University Research Support Fund GrantW81XWH-12-1-0497 from United States Department of Defense(all to Liangpunsakul S)
文摘Alcoholic hepatitis(AH)is an acute hepatic inflammation associated with significant morbidity and mortality.Current evidence suggests that the pathogenesis is the end result of the complex interplay between ethanol metabolism,inflammation and innate immunity.Several clinical scoring systems have been derived to predict the clinical outcomes of patients with AH;such as Child-Turcotte-Pugh score,the Maddrey discriminant function,the Lille Model,the model for end stage liver disease scores,and the Glasgow alcoholic hepatitis score.At present,Corticosteroids or pentoxifylline are the current pharmacologic treatment options;though the outcomes from the therapies are poor.Liver trans-plantation as the treatment of alcoholic hepatitis remains controversial,and in an era of organ shortage current guidelines do not recommend transplantation as the treatment option.Because of the limitations in the therapeutic options,it is no doubt that there is a critical need for the newer and more effective pharmacological agents to treat AH.
基金supported by the National Natural Science Foundation of China(No.81872889)the Drug Innovation Major Project(Nos.2018ZX09711-001-007 and 2018ZX09735002-003)。
文摘Nonalcoholic steatohepatitis(NASH)is a common clinical condition that can lead to advanced liver diseases.The mechanism of the diaease progression,which is lacking effective therapy,remains obsure.Therefore,there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies.To accomplish this goal,experimental animal models that recapitulate the human disease are necessary.Currently,an increasing number of studies have focused on natural constituents from medicinal plants which have been emerged as a new hope for NASH.This review summarized the pathogenesis of NASH,animal models commonly used,and the promising targets for therapeutics.We also reviewed the natural constituents as potential NASH therapeutic agents.
基金supported by the National Key Research and Development Program of China(2021YFF0702201,2021YFF0702204)Natural Science Foundation of Guangdong Province(2022A1515012651)。
文摘Tauopathies represent a class of neurodegenerative diseases(NDs),including Alzheimer’s disease(AD),progressive supranuclear palsy(PSP),Pick’s disease(PiD),and corticobasal degeneration(CBD),defined by intracellular accumulation of misfolded and hyperphosphorylated tau protein.The pathogenic cascade involves hyperphosphorylation,conformational changes,and aggregation into neurofibrillary tangles(NFTs),which are spatially and functionally linked to neuronal dysfunction,synaptic loss,and progressive cognitive and motor decline.To elucidate tau-mediated mechanisms,diverse transgenic rodent models expressing wild-type or mutant forms of human TAU have been generated.Although these models have advanced understanding of tau aggregation and propagation,tau-targeting therapies have failed to produce clinical benefits,raising concerns about the precise mechanism underlying tauopathies and the fidelity of animal models in evaluating therapeutic targets.This review systematically examines the neuropathological and behavioral phenotypes across established rodent and non-human primate(NHP)tauopathy models,highlighting mechanistic insights into tau-driven pathology.The advantages,limitations,and translational barriers of each model are critically evaluated to inform the development of more predictive preclinical platforms for therapeutic discovery.
基金supported by National Science Foundation CAREER (2238972)National Institute of Dental and Craniofacial Research awards (R03DE031329 and R01DE030943)The Translational Tissue Modeling Laboratory is supported by the University of Michigan (Center for Gastrointestinal Research,Office of the Dean, Comprehensive Cancer Center, and the Departments of Pathology, Pharmacology, and Internal Medicine) with additional funding from the Endowment for Basic Sciences
文摘Understanding microbial-host interactions in the oral cavity is essential for elucidating oral disease pathogenesis and its systemic implications.In vitro bacteria-host cell coculture models have enabled fundamental studies to characterize bacterial infection and host responses in a reductionist yet reproducible manner.However,existing in vitro coculture models fail to establish conditions that are suitable for the growth of both mammalian cells and anaerobes,thereby hindering a comprehensive understanding of their interactions.Here,we present an asymmetric gas coculture system that simulates the oral microenvironment by maintaining distinct normoxic and anaerobic conditions for gingival epithelial cells and anaerobic bacteria,respectively.Using a key oral pathobiont,Fusobacterium nucleatum,as the primary test bed,we demonstrate that the system preserves bacterial viability and supports the integrity of telomerase-immortalized gingival keratinocytes.Compared to conventional models,this system enhanced bacterial invasion,elevated intracellular bacterial loads,and elicited more robust host pro-inflammatory responses,including increased secretion of CXCL10,IL-6,and IL-8.In addition,the model enabled precise evaluation of antibiotic efficacy against intracellular pathogens.Finally,we validate the ability of the asymmetric system to support the proliferation of a more oxygen-sensitive oral pathobiont,Porphyromonas gingivalis.These results underscore the utility of this coculture platform for studying oral microbial pathogenesis and screening therapeutics,offering a physiologically relevant approach to advance oral and systemic health research.
基金National Natural Science Foundation of ChinaGrant/Award Number:82104793 and 82104836+5 种基金Natural Science Foundation of Hunan ProvinceGrant/Award Number:2023JJ60482Openof TCM First-class Disciplines in HNUCMGrant/Award Number:2022ZYX18Science and Technology talent promotion Project of Hunan ProvinceGrant/Award Number:2023TJ-N22。
文摘Anxiety disorders have become one of the most severe psychiatric disorders,and the incidence is increasing every year.They impose an extraordinary personal and socioeconomic burden.Anxiety disorders are influenced by multiple complex and interacting genetic,psychological,social,and environmental factors,which contribute to disruption or imbalance in homeostasis and eventually cause pathologic anxiety.The selection of a suitable animal model is important for the exploration of disease etiology and pathophysiology,and the development of new drugs.Therefore,a more comprehensive understanding of the advantages and limitations of existing animal models of anxiety disorders is helpful to further study the underlying pathological mechanisms of the disease.This review summarizes animal models and the pathogenesis of anxiety disorders,and discusses the current research status to provide insights for further study of anxiety disorders.
文摘The dynamic errors of gyros are the important error sources of a strapdown inertial navigation system. In order to identify the dynamic error model coefficients accurately, the static error model coefficients which lay a foundation for compensating while identifying the dynamic error model are identified in the gravity acceleration fields by using angular position function of the three-axis turntable. The angular acceleration and angular velocity are excited on the input, output and spin axis of the gyros when the outer axis and the middle axis of a three-axis turntable are in the uniform angular velocity state simultaneously, while the inner axis of the turntable is in different static angular positions. 8 groups of data are sampled when the inner axis is in 8 different angular positions. These data are the function of the middle axis positions and the inner axis positions. For these data, harmonic analysis method is applied two times versus the middle axis positions and inner axis positions respectively so that the dynamic error model coefficients are finally identified through the least square method. In the meantime the optimal angular velocity of the outer axis and the middle axis are selected by computing the determination value of the information matrix.
文摘The exact causes of inflammatory bowel disease(IBD)are not yet fully defined.From a vast body of literature,we know that the immune response has long been involved in the pathogenesis of IBD,including both ulcerative colitis and Crohn’s disease.A variety of specific alterations can lead to immune activation and inflammation directed to the colon,as revealed by some animal models.Current research has focused on the role of antibodies in downstream events and mechanisms of autoimmunity and inflammation.It is not well known whether the production of antibodies is a serologic consequence of IBD,or if it is a result of barrier dysfunction induced by inflammation.Here,we present a new hypothesis to distinguish the complex links between genetic susceptibility,barrier dysfunction,commensal and pathologic microbial factors and inflammatory response(especially autoantibodies)in the pathogenesis of IBD.To ascertain the hypothesis,we developed a pilot model with the concept of the presence of antibodies against enteric bacterial antigens in IBD.Results confirmed our hypothesis.Our hypothesis suggests the possibility of subcutaneous vaccination of animals with administration of all or specific enteric bacterial antigens.
基金supported by the Public Health Agency of Canada(PHAC)partially supported by the NIH and CIHR grants to X.G.Qiu(U19 AI109762-1 and CIHR-IER-143487,respectively)+1 种基金grants from the National Natural Science Foundation of China International Cooperation and Exchange Program(8161101193)National Science and Technology Major Project(2016ZX10004222)to G.Wong
文摘The Angolan strain of Marburg virus （MARV/Ang） can cause lethal disease in humans with a case fatality rate of up to 90%, but infection of immunocompetent rodents do not result in any observable symptoms. Our previous work includes the development and characterization of a MARV/Ang variant that can cause lethal disease in mice （MARV/Ang-MA）, with the aim of using this tool to screen for promising prophylactic and therapeutic candidates. An intermediate animal model is needed to confirm any findings from mice studies before testing in the gold-standard non-human primate （NHP） model. In this study, we serially passaged the clinical isolate of MARV/Ang in the livers and spleens of guinea pigs until a variant emerged that causes 100% lethality in guinea pigs （MARV/Ang- GA）. Animals infected with MARV/Ang-GA showed signs of filovirus infection including lymphocytopenia, thrombocytopenia, and high viremia leading to spread to major organs, including the liver, spleen, lungs, and kidneys. The MARV/Ang-GA guinea pigs died between 7-9 days after infection, and the LD50 was calculated to be 1.1x10-1 TCID50 （median tissue culture infective dose）. Mutations in MARV/Ang-GA were identified and compared to sequences of known rodent-adapted MARV/Ang variants, which may benefit future studies characterizing important host adaptation sites in the MARV/Ang viral genome.
基金This study was supported by grants from the National Natural Science Foundation of China(82272396)the Fundamental Research Funds for the Central Universities(226-2022-00061).
文摘Hepatitis E virus(HEV)is one of the leading causes of acute viral hepatitis worldwide.Although most of HEV infections are asymptomatic,some patients will develop the symptoms,especially pregnant women,the elderly,and patients with preexisting liver diseases,who often experience anorexia,nausea,vom-iting,malaise,abdominal pain,and jaundice.HEV infection may become chronic in immunosuppressed individuals.In addition,HEV infection can also cause several extrahepatic manifestations.HEV exists in a wide range of hosts in nature and can be transmitted across species.Hence,animals susceptible to HEV can be used as models.The establishment of animal models is of great significance for studying HEV transmission,clinical symptoms,extrahepatic manifestations,and therapeutic strategies,which will help us understand the pathogenesis,prevention,and treatment of hepatitis E.This review summarized the animal models of HEV,including pigs,monkeys,rabbits,mice,rats,and other animals.For each animal species,we provided a concise summary of the HEV genotypes that they can be infected with,the cross-species transmission pathways,as well as their role in studying extrahepatic manifestations,prevention,and treatment of HEV infection.The advantages and disadvantages of these animal models were also emphasized.This review offers new perspectives to enhance the current understanding of the research landscape surrounding HEV animal models.
基金the Ethics Committee of Tongji Hospital,Huazhong University of Science and Technology,China(TJ-IRB20191012).
文摘Antineutrophil cytoplasmic autoantibody(ANCA)-associated vasculitis(AAV)is a rare and severe systemic autoimmune disease characterized by pauci-immune necrotizing inflammation of small blood vessels.AAV involves multiple organ systems throughout the body.Our knowledge of the pathogenesis of AAV has increased considerably in recent years,involving cellular,molecular and genetic factors.Because of the controlled environment with no other confounding factors,animal models are beneficial for studying the mechanistic details of disease development and for providing novel therapeutic targets with fewer toxic side effects.However,the complexity and heterogeneity of AAV make it very difficult to establish a single animal model that can fully represent the entire clinical spectrum found in patients.The aim of this review is to overview the current status of animal models for AAV,outline the pros and cons of methods,and propose potential directions for future research.
