This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of wood...This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, andfor the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.展开更多
The effects of dietary supplementation with Clostridium butyricum on growth performance and humoral immune response in Miichthys miiuy were evaluated. One hundred and fifty Miichthys miiuy weighing approximately 200-2...The effects of dietary supplementation with Clostridium butyricum on growth performance and humoral immune response in Miichthys miiuy were evaluated. One hundred and fifty Miichthys miiuy weighing approximately 200-260 g were divided into five groups and reared in 15 tanks with closed circuiting culture system. The animals were fed 5 diets： basal diet only （control） or supplemented of the basal diet with C. butyricum at doses of 10^3 （CB1）, 10^5 （CB2）, 10^7 （CB3） or 10^9 （CB4） CFU/g. Compared with the control, the serum phenoloxidase activity was significantly increased by the supplementation （P〈0.05）, acid phosphatases activity was increased significantly （P〈0.05） at the doses of 10^9 CFU/g. Serum lysozyme activity peaked at dose of 10^7 CFU/g and in the skin mucus at dose of 10^9 CFU/g. Immunoglobulin M level in the serum and skin mucus was increased except at dose of 10^3 CFU/g （P〈0.05）. The growth at the dose of 10^9 CFU/g was higher than that of the control （P〈0.05）. It is concluded that supplementation of C. butyricum can mediate the humoral immune responses and improve the growth performance in Miichthys miiuy.展开更多
AIM: To investigate the cellular defects by analyzing the (Th1/Th2) cytokine levels in vaccine responders and non-responders. METHODS: Peripheral blood mononuclear cell (PBMC) from responders and non-responders were s...AIM: To investigate the cellular defects by analyzing the (Th1/Th2) cytokine levels in vaccine responders and non-responders. METHODS: Peripheral blood mononuclear cell (PBMC) from responders and non-responders were stimulated with or with out recombinant HBsAg or PHA. Broad spectrum of cytokines viz (Th1) IFN-γ, IL-2, TNF-α, IL-12 and (Th2) IL-10, IL-4 were measured after in vitro stimulation with recombinant HBsAg and were compared with respective antibody titers. RESULTS: A significant decrease (P = 0.001) in Th1 and Th2 cytokines namely, IL-2, INF-γ, TNF-α and IL-10in non-responders was observed. The level of IL-4 was not significant between the three groups. Furthermore, despite a strong Th1 and Th2 cytokine response, the level of IL-12 was elevated in high-responders compared to other groups (P = 0.001) and demonstrated a positive correlation with anti-HBs titers and Th1 cytokine response. CONCLUSION: Our findings suggest that unrespon-siveness to recombinant hepatitis B vaccines (rHB) is multifactorial, including specific failure of antigen presentation or the lack of both T helper Th1 and Th2 response.展开更多
Introduction: Following the COVID-19 pandemic, vaccination has been proposed in several countries as the main preventive measure despite very limited data, particularly in dialysis patients. We conducted this study to...Introduction: Following the COVID-19 pandemic, vaccination has been proposed in several countries as the main preventive measure despite very limited data, particularly in dialysis patients. We conducted this study to assess the immunological response to vaccination in Senegalese hemodialysis patients. Patients and Methods: We conducted a prospective study, in two dialysis centers in Dakar from March 30<sup>th</sup> to August 30<sup>th</sup>, 2021 including patients on hemodialysis for >6 months, vaccinated against SARS-CoV-2 according to the vaccination schedule recommended by WHO. A vaccine response was considered positive when seroconversion was observed after one dose of vaccine. The clinical efficacy of immunization was defined as the absence of new COVID-19 infection in patients who received a complete vaccination. Results: Among the 81 patients included in the study, 7.4% had anti-Spike IgM antibodies before their first vaccination. Seroprevalence of IgM antibodies was 38.3% one month after the first vaccine dose (at M1) and 8.6% one month after the second dose (at M4). Anti-Spike IgG antibodies were present in 40.3% of patients before vaccination, in 90.1% at M1, and in 59.7% at M4. Among patients previously infected with SARS-CoV-2, 10.2% had IgM antibodies at M0, 31.6% at M1, and 10.5% at M4 post-vaccination. Similarly, seroprevalences of IgG antibodies in this subgroup were 31.5%, 61.3%, and 50.0% respectively at M0, M1, and M4 post-vaccination. A comparison of seroconversion rates between M0 and M4 showed significant differences only for IgG in COVID-19 naive patients. Mean duration in dialysis and the existence of previous COVID-19 infection were associated with patients’ vaccinal response after the two doses. Age, gender and the use of immunosuppressive treatment did not influence post-vaccinal antibody production. Conclusion: Vaccination against COVID-19 in Senegalese hemodialysis patients induced a low seroconversion rate but it was well tolerated. Moreover, the induced protection was neither st展开更多
Understanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection against reinfection and,thus,for public health policy and vaccine development for COVID-19.In this study,using eit...Understanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection against reinfection and,thus,for public health policy and vaccine development for COVID-19.In this study,using either live SARS-CoV-2 particles or retroviruses pseudotyped with the SARS-CoV-2 S viral surface protein(Spike),we studied the neutralizing antibody(nAb)response in serum samples from a cohort of 140 SARS-CoV-2 qPCR-confirmed infections,including patients with mild symptoms and also more severe forms,including those that required intensive care.We show that nAb titers correlated strongly with disease severity and with anti-spike IgG levels.Indeed,patients from intensive care units exhibited high nAb titers;conversely,patients with milder disease symptoms had heterogeneous nAb titers,and asymptomatic or exclusive outpatient-care patients had no or low nAbs.We found that nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery compared to individuals infected with other coronaviruses.Moreover,we found an absence of cross-neutralization between endemic coronaviruses and SARS-CoV-2,indicating that previous infection by human coronaviruses may not generate protective nAbs against SARS-CoV-2.Finally,we found that the D614G mutation in the spike protein,which has recently been identified as the current major variant in Europe,does not allow neutralization escape.Altogether,our results contribute to our understanding of the immune correlates of SARS-CoV-2-induced disease,and rapid evaluation of the role of the humoral response in the pathogenesis of SARS-CoV-2 is warranted.展开更多
Background:The impact of corticosteroids on humoral responses in coronavirus disease 2019(COVID-19)sur-vivors during the acute phase and subsequent 6-month period remains unknown.This study aimed to determine how the ...Background:The impact of corticosteroids on humoral responses in coronavirus disease 2019(COVID-19)sur-vivors during the acute phase and subsequent 6-month period remains unknown.This study aimed to determine how the use of corticosteroids influences the initiation and duration of humoral responses in COVID-19 survivors 6 months after infection onset.Methods:We used kinetic antibody data from the lopinavir-ritonavir trial conducted at Jin Yin-Tan Hospital in January 2020,which involved adults hospitalized with severe COVID-19(LOTUS,ChiCTR2000029308).Anti-body samples were collected from 192 patients during hospitalization,and kinetic antibodies were monitored at all available time points after recruitment.Additionally,plasma samples were collected from 101 COVID-19 survivors for comprehensive humoral immune measurement at the half-year follow-up visit.The main focus was comparing the humoral responses between patients treated with systemic corticosteroid therapy and the non-corticosteroid group.Results:From illness onset to day 30,the median antibody titre areas under the receiver operating characteristic curve(AUCs)of nucleoprotein(N),spike protein(S),and receptor-binding domain(RBD)immunoglobulin G(IgG)were significantly lower in the corticosteroids group.The AUCs of N-,S-,and RBD-IgM as well as neutralizing antibodies(NAbs)were numerically lower in the corticosteroids group compared with the non-corticosteroid group.However,peak titres of N,S,RBD-IgM and-IgG and NAbs were not influenced by corticosteroids.During 6-month follow-up,we observed a delayed decline for most binding antibodies,except N-IgM(𝛽−0.05,95%CI[−0.10,0.00])in the corticosteroids group,though not reaching statistical significance.No significant difference was observed for NAbs.However,for the half-year seropositive rate,corticosteroids significantly accelerated the decay of IgA and IgM but made no difference to N-,S-,and RBD-IgG or NAbs.Additionally,corticosteroids group showed a trend towards delayed viral clearance compared with the n展开更多
Objective To break immune tolerance to prion （PrP） proteins using DNA vaccines.Methods Four different human prion DNA vaccine candidates were constructed based on the pcDNA3.1 vector：PrP‐WT expressing wild‐type P...Objective To break immune tolerance to prion （PrP） proteins using DNA vaccines.Methods Four different human prion DNA vaccine candidates were constructed based on the pcDNA3.1 vector：PrP‐WT expressing wild‐type PrP,Ubiq‐PrP expressing PrP fused to ubiquitin,PrP‐LII expressing PrP fused to the lysosomal integral membrane protein type II lysosome‐targeting signal,and PrP‐ER expressing PrP locating the ER.Using a prime‐boost strategy,three‐doses of DNA vaccine were injected intramuscularly into Balb/c mice,followed by two doses of PrP protein.Two weeks after the last immunization,sera and spleens were collected and PrP‐specific humoral and cellular immune responses evaluated by ELISA and ELISPOT tests.Results Higher levels of serum PrP antibodies were detected in mice vaccinated using the strategy of DNA priming followed by protein boosting.Of these,WT‐PrP,Ubiq‐PrP,and PrP‐LII induced significantly higher humoral responses.ELISPOT tests showed markedly increased numbers of IFN‐γ‐secreting T cells in mice vaccinated using the strategy of DNA priming followed by protein boosting after stimulation with recombinant PrP23‐90 and PrP23‐231.PrP‐ER inducedthe strongest T‐cell response.Conclusion Prion vaccines can break tolerance to PrP proteins and induce PrP‐specific humoral and cellular immune responses.展开更多
In this paper, we consider two nonlinear models for viral infection with humoraL immu- nity. The first model contains four compartments; uninfected target cells, actively infected cells, free virus particles and B cel...In this paper, we consider two nonlinear models for viral infection with humoraL immu- nity. The first model contains four compartments; uninfected target cells, actively infected cells, free virus particles and B cells. The second model is a modification of the first one by including the latently infected cells. The incidence rate, removal rate of infected cells, production rate of viruses and the latent-to-active conversion rate are given by more general nonlinear functions. We have established a set of conditions on these general functions and determined two threshold parameters for each model which are sufficient to determine the global dynamics of the models. The global asymptotic stability of all equilibria of the models has been proven by using Lyapunov theory and applying LaSalle＇s invariance principle. We have performed some numerical simulations for the models with specific forms of the general functions. We have shown that, the numerical results are consistent with the theoretical results.展开更多
基金Supported by contract N01-AI-05399 to the College of Veterinary Medicine, Cornell University from the National Institute of Allergy and Infectious Diseases. PC and SM also have been supported by contract N01-AI-95390 to the Georgetown University Medical Center, Georgetown University from the National Institute of Allergy and Infectious Diseases
文摘This review describes the woodchuck and the woodchuck hepatitis virus (WHV) as an animal model for pathogenesis and therapy of chronic hepatitis B virus (HBV) infection and disease in humans. The establishment of woodchuck breeding colonies, and use of laboratory-reared woodchucks infected with defined WHV inocula, have enhanced our understanding of the virology and immunology of HBV infection and disease pathogenesis, including major sequelae like chronic hepatitis and hepatocellular carcinoma. The role of persistent WHV infection and of viral load on the natural history of infection and disease progression has been firmly established along the way. More recently, the model has shed new light on the role of host immune responses in these natural processes, and on how the immune system of the chronic carrier can be manipulated therapeutically to reduce or delay serious disease sequelae through induction of the recovery phenotype. The woodchuck is an outbred species and is not well defined immunologically due to a limitation of available host markers. However, the recent development of several key host response assays for woodchucks provides experimental opportunities for further mechanistic studies of outcome predictors in neonatal- and adult-acquired infections. Understanding the virological and immunological mechanisms responsible for resolution of self-limited infection, andfor the onset and maintenance of chronic infection, will greatly facilitate the development of successful strategies for the therapeutic eradication of established chronic HBV infection. Likewise, the results of drug efficacy and toxicity studies in the chronic carrier woodchucks are predictive for responses of patients chronically infected with HBV. Therefore, chronic WHV carrier woodchucks provide a well-characterized mammalian model for preclinical evaluation of the safety and efficacy of drug candidates, experimental therapeutic vaccines, and immunomodulators for the treatment and prevention of HBV disease sequelae.
基金Project supported by the Bureau of Science and Technology of Zhejiang Province (No. 2004201), China and the Youth Fund of Ningbo City (No. 2004A620008), China
文摘The effects of dietary supplementation with Clostridium butyricum on growth performance and humoral immune response in Miichthys miiuy were evaluated. One hundred and fifty Miichthys miiuy weighing approximately 200-260 g were divided into five groups and reared in 15 tanks with closed circuiting culture system. The animals were fed 5 diets： basal diet only （control） or supplemented of the basal diet with C. butyricum at doses of 10^3 （CB1）, 10^5 （CB2）, 10^7 （CB3） or 10^9 （CB4） CFU/g. Compared with the control, the serum phenoloxidase activity was significantly increased by the supplementation （P〈0.05）, acid phosphatases activity was increased significantly （P〈0.05） at the doses of 10^9 CFU/g. Serum lysozyme activity peaked at dose of 10^7 CFU/g and in the skin mucus at dose of 10^9 CFU/g. Immunoglobulin M level in the serum and skin mucus was increased except at dose of 10^3 CFU/g （P〈0.05）. The growth at the dose of 10^9 CFU/g was higher than that of the control （P〈0.05）. It is concluded that supplementation of C. butyricum can mediate the humoral immune responses and improve the growth performance in Miichthys miiuy.
基金Serum Institute of India, Pune, India and Indian Council for Medical Research (ICMR) New Delhi, India
文摘AIM: To investigate the cellular defects by analyzing the (Th1/Th2) cytokine levels in vaccine responders and non-responders. METHODS: Peripheral blood mononuclear cell (PBMC) from responders and non-responders were stimulated with or with out recombinant HBsAg or PHA. Broad spectrum of cytokines viz (Th1) IFN-γ, IL-2, TNF-α, IL-12 and (Th2) IL-10, IL-4 were measured after in vitro stimulation with recombinant HBsAg and were compared with respective antibody titers. RESULTS: A significant decrease (P = 0.001) in Th1 and Th2 cytokines namely, IL-2, INF-γ, TNF-α and IL-10in non-responders was observed. The level of IL-4 was not significant between the three groups. Furthermore, despite a strong Th1 and Th2 cytokine response, the level of IL-12 was elevated in high-responders compared to other groups (P = 0.001) and demonstrated a positive correlation with anti-HBs titers and Th1 cytokine response. CONCLUSION: Our findings suggest that unrespon-siveness to recombinant hepatitis B vaccines (rHB) is multifactorial, including specific failure of antigen presentation or the lack of both T helper Th1 and Th2 response.
文摘Introduction: Following the COVID-19 pandemic, vaccination has been proposed in several countries as the main preventive measure despite very limited data, particularly in dialysis patients. We conducted this study to assess the immunological response to vaccination in Senegalese hemodialysis patients. Patients and Methods: We conducted a prospective study, in two dialysis centers in Dakar from March 30<sup>th</sup> to August 30<sup>th</sup>, 2021 including patients on hemodialysis for >6 months, vaccinated against SARS-CoV-2 according to the vaccination schedule recommended by WHO. A vaccine response was considered positive when seroconversion was observed after one dose of vaccine. The clinical efficacy of immunization was defined as the absence of new COVID-19 infection in patients who received a complete vaccination. Results: Among the 81 patients included in the study, 7.4% had anti-Spike IgM antibodies before their first vaccination. Seroprevalence of IgM antibodies was 38.3% one month after the first vaccine dose (at M1) and 8.6% one month after the second dose (at M4). Anti-Spike IgG antibodies were present in 40.3% of patients before vaccination, in 90.1% at M1, and in 59.7% at M4. Among patients previously infected with SARS-CoV-2, 10.2% had IgM antibodies at M0, 31.6% at M1, and 10.5% at M4 post-vaccination. Similarly, seroprevalences of IgG antibodies in this subgroup were 31.5%, 61.3%, and 50.0% respectively at M0, M1, and M4 post-vaccination. A comparison of seroconversion rates between M0 and M4 showed significant differences only for IgG in COVID-19 naive patients. Mean duration in dialysis and the existence of previous COVID-19 infection were associated with patients’ vaccinal response after the two doses. Age, gender and the use of immunosuppressive treatment did not influence post-vaccinal antibody production. Conclusion: Vaccination against COVID-19 in Senegalese hemodialysis patients induced a low seroconversion rate but it was well tolerated. Moreover, the induced protection was neither st
基金The laboratory of FLC received financial support from the LabEx Ecofect(ANR-11-LABX-0048)the“Universitéde Lyon,”within the program“Investissements d’Avenir”(ANR-11-IDEX-0007)+1 种基金operated by the French National Research Agency(ANR),the ANR(grant from RA-Covid-19)the Fondation pour la Recherche Médicale(FRM),and Inserm Transfert.We thank D.Lavillette for providing the SARS-CoV-2 spike expression vector and B.La Scola for providing a clone of Vero-E6 cells.We acknowledge the contribution of SFR Biosciences(UMS3444/CNRS,US8/Inserm,ENS de Lyon,UCBL)ANIRA-Cytometry facility for excellent technical assistance and support.
文摘Understanding the immune responses elicited by SARS-CoV-2 infection is critical in terms of protection against reinfection and,thus,for public health policy and vaccine development for COVID-19.In this study,using either live SARS-CoV-2 particles or retroviruses pseudotyped with the SARS-CoV-2 S viral surface protein(Spike),we studied the neutralizing antibody(nAb)response in serum samples from a cohort of 140 SARS-CoV-2 qPCR-confirmed infections,including patients with mild symptoms and also more severe forms,including those that required intensive care.We show that nAb titers correlated strongly with disease severity and with anti-spike IgG levels.Indeed,patients from intensive care units exhibited high nAb titers;conversely,patients with milder disease symptoms had heterogeneous nAb titers,and asymptomatic or exclusive outpatient-care patients had no or low nAbs.We found that nAb activity in SARS-CoV-2-infected patients displayed a relatively rapid decline after recovery compared to individuals infected with other coronaviruses.Moreover,we found an absence of cross-neutralization between endemic coronaviruses and SARS-CoV-2,indicating that previous infection by human coronaviruses may not generate protective nAbs against SARS-CoV-2.Finally,we found that the D614G mutation in the spike protein,which has recently been identified as the current major variant in Europe,does not allow neutralization escape.Altogether,our results contribute to our understanding of the immune correlates of SARS-CoV-2-induced disease,and rapid evaluation of the role of the humoral response in the pathogenesis of SARS-CoV-2 is warranted.
基金supported by the National Natural Science Foundation of China(No.82200009)the National Key Research and Development Program of China(No.2021YFC0864700)+1 种基金the National Natural Science Foundation of China(No.81930063)the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(CIFMS No.2021-I2M-1-048).
文摘Background:The impact of corticosteroids on humoral responses in coronavirus disease 2019(COVID-19)sur-vivors during the acute phase and subsequent 6-month period remains unknown.This study aimed to determine how the use of corticosteroids influences the initiation and duration of humoral responses in COVID-19 survivors 6 months after infection onset.Methods:We used kinetic antibody data from the lopinavir-ritonavir trial conducted at Jin Yin-Tan Hospital in January 2020,which involved adults hospitalized with severe COVID-19(LOTUS,ChiCTR2000029308).Anti-body samples were collected from 192 patients during hospitalization,and kinetic antibodies were monitored at all available time points after recruitment.Additionally,plasma samples were collected from 101 COVID-19 survivors for comprehensive humoral immune measurement at the half-year follow-up visit.The main focus was comparing the humoral responses between patients treated with systemic corticosteroid therapy and the non-corticosteroid group.Results:From illness onset to day 30,the median antibody titre areas under the receiver operating characteristic curve(AUCs)of nucleoprotein(N),spike protein(S),and receptor-binding domain(RBD)immunoglobulin G(IgG)were significantly lower in the corticosteroids group.The AUCs of N-,S-,and RBD-IgM as well as neutralizing antibodies(NAbs)were numerically lower in the corticosteroids group compared with the non-corticosteroid group.However,peak titres of N,S,RBD-IgM and-IgG and NAbs were not influenced by corticosteroids.During 6-month follow-up,we observed a delayed decline for most binding antibodies,except N-IgM(𝛽−0.05,95%CI[−0.10,0.00])in the corticosteroids group,though not reaching statistical significance.No significant difference was observed for NAbs.However,for the half-year seropositive rate,corticosteroids significantly accelerated the decay of IgA and IgM but made no difference to N-,S-,and RBD-IgG or NAbs.Additionally,corticosteroids group showed a trend towards delayed viral clearance compared with the n
基金supported by Chinese National Natural Science Foundation Grants 30771914 and 30800975Institution Technique R&D Grant (2008EG150300)+2 种基金National Basic Research Program of China (973 Program) (2007CB310505)China Mega-Project for Infectious Disease (2009ZX10004‐101, 2008ZX10004‐001, and 2008ZX10004‐002)the SKLID Development Grant (2008SKLID102 and 2008SKLID202)
文摘Objective To break immune tolerance to prion （PrP） proteins using DNA vaccines.Methods Four different human prion DNA vaccine candidates were constructed based on the pcDNA3.1 vector：PrP‐WT expressing wild‐type PrP,Ubiq‐PrP expressing PrP fused to ubiquitin,PrP‐LII expressing PrP fused to the lysosomal integral membrane protein type II lysosome‐targeting signal,and PrP‐ER expressing PrP locating the ER.Using a prime‐boost strategy,three‐doses of DNA vaccine were injected intramuscularly into Balb/c mice,followed by two doses of PrP protein.Two weeks after the last immunization,sera and spleens were collected and PrP‐specific humoral and cellular immune responses evaluated by ELISA and ELISPOT tests.Results Higher levels of serum PrP antibodies were detected in mice vaccinated using the strategy of DNA priming followed by protein boosting.Of these,WT‐PrP,Ubiq‐PrP,and PrP‐LII induced significantly higher humoral responses.ELISPOT tests showed markedly increased numbers of IFN‐γ‐secreting T cells in mice vaccinated using the strategy of DNA priming followed by protein boosting after stimulation with recombinant PrP23‐90 and PrP23‐231.PrP‐ER inducedthe strongest T‐cell response.Conclusion Prion vaccines can break tolerance to PrP proteins and induce PrP‐specific humoral and cellular immune responses.
文摘In this paper, we consider two nonlinear models for viral infection with humoraL immu- nity. The first model contains four compartments; uninfected target cells, actively infected cells, free virus particles and B cells. The second model is a modification of the first one by including the latently infected cells. The incidence rate, removal rate of infected cells, production rate of viruses and the latent-to-active conversion rate are given by more general nonlinear functions. We have established a set of conditions on these general functions and determined two threshold parameters for each model which are sufficient to determine the global dynamics of the models. The global asymptotic stability of all equilibria of the models has been proven by using Lyapunov theory and applying LaSalle＇s invariance principle. We have performed some numerical simulations for the models with specific forms of the general functions. We have shown that, the numerical results are consistent with the theoretical results.
