Background Despite growing concerns about the adverse effects of antibiotics in farm animals,there has been little investigation of the effects of florfenicol in laying hens.This study examined the effect of florfenic...Background Despite growing concerns about the adverse effects of antibiotics in farm animals,there has been little investigation of the effects of florfenicol in laying hens.This study examined the effect of florfenicol on the intestinal homeostasis,immune system,and pathogen susceptibility of laying hens.Results The oral administration of florfenicol at field-relevant levels for 5 d resulted in a decrease in the gut microbiota genera Lactobacillus,Bacillus,and Bacteroides,indicating the development of intestinal dysbiosis.The dysbiosis led to decreased mRNA levels of key regulators peroxisome proliferator-activated receptor gamma(PPAR-γ)and hypoxia-inducible factor-1α(HIF-1α),compromising intestinal hypoxia.Intestinal homeostasis was also disrupted,with decreased expression of Occludin and Mucin 2(Muc2)genes combined with increased gut epithelial permeability.The breakdown in intestinal homeostasis and immune function provided a favorable environment for opportunistic bacteria like avian pathogenic Escherichia coli(APEC),culminating in systemic infection.Immunologically,florfenicol treatment resulted in increased proportion and absolute number of MRC1L-B^(+)monocytes/macrophages in the spleen,indicating an exacerbated infection.Furthermore,both the proportion and absolute number ofγδT cells in the lamina propria of the cecum decreased.Treatment with florfenicol reduced butyrate levels in the cecum.However,the administration of butyrate before and during florfenicol treatment restored factors associated with intestinal homeostasis,including PPAR-γ,Occludin,and Muc2,while partially restoring HIF-1α,normalized intestinal hypoxia and gut permeability,and reversed immune cell changes,suppressing APEC systemic infection.Conclusion The uncontrolled and widespread use of florfenicol can negatively affect intestinal health in chickens.Specifically,florfenicol was found to impair intestinal homeostasis and immune function in laying hens,including by reducing butyrate levels,thereby increasing their susceptibility to systemic APEC infection.The development of strategies for mitigating the adverse effects of florfenicol on gut health and pathogen susceptibility in laying hens is therefore essential.展开更多
Bone destruction induced by breast cancer metastasis causes severe complications,including death,in breast cancer patients.Communication between cancer cells and skeletal cells in metastatic bone microenvironments is ...Bone destruction induced by breast cancer metastasis causes severe complications,including death,in breast cancer patients.Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis.Tumor-derived factors play fundamental roles in this form of communication.To identify soluble factors released from cancer cells in bone metastasis,we established a highly bone-metastatic subline of MDA-MB-231 breast cancer cells.This subline(mtMDA)showed a markedly elevated ability to secrete S100A4 protein,which directly stimulated osteoclast formation via surface receptor RAGE.Recombinant S100A4 stimulated osteoclastogenesis in vitro and bone loss in vivo.Conditioned medium from mtMDA cells in which S100A4 was knocked down had a reduced ability to stimulate osteoclasts.Furthermore,the S100A4 knockdown cells elicited less bone destruction in mice than the control knockdown cells.In addition,administration of an anti-S100A4 monoclonal antibody(mAb)that we developed attenuated the stimulation of osteoclastogenesis and bone loss by mtMDA in mice.Taken together,our results suggest that S100A4 released from breast cancer cells is an important player in the osteolysis caused by breast cancer bone metastasis.展开更多
Human immunodeficiency virus-1(HIV-1)exploits the viral gp120 protein and host CD4/CCR5 receptors for the pandemic infection to humans.The host co-receptors of not only humans but also several primates and HIV-model m...Human immunodeficiency virus-1(HIV-1)exploits the viral gp120 protein and host CD4/CCR5 receptors for the pandemic infection to humans.The host co-receptors of not only humans but also several primates and HIV-model mice can interact with the HIV receptor.However,the molecular mechanisms of these interactions remain unclear.Using Shaik et al.(2019)'s gp120/CD4/CCR5 structure of HIV-1B and human,here,we investigate the molecular dynamics between HIV sub-lineages(B,C,N,and O)and potential hosts in Euarchontoglires(primates and rodents).Although both host genes show similar protein structures conserved in all animals,CD4 gene demonstrates significantly stronger binding affinities in Catarrhini(apes and Old-World monkeys).Its known candidate residues interacted with gp120 fail to explain these affinity variations.Therefore,we identified novel candidate sites under positive selection on the Catarrhini lineage.Among four positively selected sites,residue R58 in humans is located within an antigen-antibody binding domain,exhibiting apomorphic amino acid substitutions as Arginine(R)in Catarrhini,which are mutually exclusive to the other animals where Lysine(K)is prevalent.Applying for artificial mutation test,we validated that K to R substitutions can lead stronger binding affinities of Catarrhini.Ecologically,these dynamics may relate to shared equatorial habitats in Africa and Asia.Our findings suggest a new candidate site R58 driven by the lineage-specific evolution as a molecular foundation on HIV infection.展开更多
Jasmonic acid （JA） functions in plant development, including senescence and immunity. Arabidopsis thaliana CORONATINE INSENSITIVE 1 encodes a JA receptor and functions in the JA‐responsive signaling pathway. The Ar...Jasmonic acid （JA） functions in plant development, including senescence and immunity. Arabidopsis thaliana CORONATINE INSENSITIVE 1 encodes a JA receptor and functions in the JA‐responsive signaling pathway. The Arabidopsis genome harbors a single COI gene, but the rice （Oryza sativa） genome harbors three COI homologs, OsCOI1a, OsCOI1b, and OsCOI2. Thus, it remains unclear whether each OsCOI has distinct, additive, synergistic, or redundant func-tions in development. Here, we use the oscoi1b‐1 knockout mutants to show that OsCOI1b mainly affects leaf senescence under senescence‐promoting conditions. oscoi1b‐1 mutants stayed green during dark‐induced and natural senescence, with substantial retention of chlorophylls and photosyn-thetic capacity. Furthermore, several senescence‐associated genes were downregulated in oscoi1b‐1 mutants, including homologs of Arabidopsis thaliana ETHYLENE INSENSITIVE 3 and ORESARA 1, important regulators of leaf senescence. These results suggest that crosstalk between JA signaling and ethylene signaling affects leaf senescence. The Arabidopsis coi1‐1 plants containing 35S：OsCOI1a or 35S：OsCOI1b rescued the delayed leaf senescence during dark incubation, sug-gesting that both OsCOI1a and OsCOI1b are required for promoting leaf senescence in rice. oscoi1b‐1 mutants showed significant decreases in spikelet fertility and grain weight, leading to severe reduction of grain yield, indicating that OsCOI1‐mediated JA signaling affects spikelet fertility and grain filling.展开更多
Mycobacterium tuberculosis(MTB)is the causative agent of tuberculosis(TB),a prevalent airborne infectious disease.Despite the availability of the Bacille Calmette-Guerin vaccine,its global efficacy remains modest,and ...Mycobacterium tuberculosis(MTB)is the causative agent of tuberculosis(TB),a prevalent airborne infectious disease.Despite the availability of the Bacille Calmette-Guerin vaccine,its global efficacy remains modest,and tuberculosis persists as a significant global public health threat.Addressing this challenge and advancing towards the End MTB Strategy,we developed a multiepitope vaccine(MEV)based on immunoinformatics and compu-tational approaches.Immunoinformatics screening of MBT protein identified immune-dominant epitopes based on Major Histocompatibility Complex(MHC)allele binding,immunogenicity,antigenicity,allergenicity,toxicity,and cytokine inducibility.Selected epitopes were integrated into an MEV construct with adjuvant and linkers,forming a fully immunogenic vaccine candidate.Comprehensive analyses encompassed the evaluation of immunological and physicochemical properties,determination of tertiary structure,molecular docking with Toll-Like Receptors(TLR),molecular dynamics(MD)simulations for all atoms,and immune simulations.Our MEV comprises 534 amino acids,featuring 6 cytotoxic T lymphocyte,8 helper T lymphocyte,and 7 linear B lymphocyte epitopes,demonstrating high antigenicity and stability.Notably,molecular docking studies and triplicate MD simulations revealed enhanced interactions and stability of MEV with the TLR4 complex compared to TLR2.In addition,the immune simulation indicated the capacity to effectively induce elevated levels of an-tibodies and cytokines,emphasizing the vaccine’s robust immunogenic response.This study presents a promising MEV against TB,exhibiting favorable immunological and physicochemical attributes.The findings provide theoretical support for TB vaccine development.Our study aligns with the global initiative of the End MTB Strategy,emphasizing its potential impact on addressing persistent challenges in TB control.展开更多
Respiratory syncytial virus(RSV)poses a significant global health threat,especially affecting infants and the elderly.Addressing this,the present study proposes an innovative approach to vaccine design,utilizing immun...Respiratory syncytial virus(RSV)poses a significant global health threat,especially affecting infants and the elderly.Addressing this,the present study proposes an innovative approach to vaccine design,utilizing immunoinformatics and computational strategies.We analyzed RSV's structural proteins across both subtypes A and B,identifying potential helper T lymphocyte,cytotoxic T lymphocyte,and linear B lymphocyte epitopes.Criteria such as antigenicity,allergenicity,toxicity,and cytokine-inducing potential were rigorously examined.Additionally,we evaluated the conservancy of these epitopes and their population coverage across various RSV strains.The comprehensive analysis identified six major histocompatibility complex class I(MHC-I)binding,five MHC-II binding,and three B-cell epitopes.These were integrated with suitable linkers and adjuvants to form the vaccine.Further,molecular docking and molecular dynamics simulations demonstrated stable interactions between the vaccine candidate and human Toll-like receptors(TLR4 and TLR5),with a notable preference for TLR4.Immune simulation analysis underscored the vaccine's potential to elicit a strong immune response.This study presents a promising RSV vaccine candidate and offers theoretical support,marking a significant advancement in vaccine development efforts.However,the promising in silico findings need to be further validated through additional in vivo studies.展开更多
基金supported by a the National Research Foundation(NRF),funded by the Ministry of Science and ICT(RS-2023-00218476,RS-2024-00454619)the Cooperative Research Program for Agriculture Science and Technology Development(RS-2022-RD010165)+1 种基金the Ministry of Health&Welfare,Republic of Korea(RS-2022-KH128577)the BK21 FOUR Program of the Department of Agricultural Biotechnology,Seoul National University,Seoul,Korea.
文摘Background Despite growing concerns about the adverse effects of antibiotics in farm animals,there has been little investigation of the effects of florfenicol in laying hens.This study examined the effect of florfenicol on the intestinal homeostasis,immune system,and pathogen susceptibility of laying hens.Results The oral administration of florfenicol at field-relevant levels for 5 d resulted in a decrease in the gut microbiota genera Lactobacillus,Bacillus,and Bacteroides,indicating the development of intestinal dysbiosis.The dysbiosis led to decreased mRNA levels of key regulators peroxisome proliferator-activated receptor gamma(PPAR-γ)and hypoxia-inducible factor-1α(HIF-1α),compromising intestinal hypoxia.Intestinal homeostasis was also disrupted,with decreased expression of Occludin and Mucin 2(Muc2)genes combined with increased gut epithelial permeability.The breakdown in intestinal homeostasis and immune function provided a favorable environment for opportunistic bacteria like avian pathogenic Escherichia coli(APEC),culminating in systemic infection.Immunologically,florfenicol treatment resulted in increased proportion and absolute number of MRC1L-B^(+)monocytes/macrophages in the spleen,indicating an exacerbated infection.Furthermore,both the proportion and absolute number ofγδT cells in the lamina propria of the cecum decreased.Treatment with florfenicol reduced butyrate levels in the cecum.However,the administration of butyrate before and during florfenicol treatment restored factors associated with intestinal homeostasis,including PPAR-γ,Occludin,and Muc2,while partially restoring HIF-1α,normalized intestinal hypoxia and gut permeability,and reversed immune cell changes,suppressing APEC systemic infection.Conclusion The uncontrolled and widespread use of florfenicol can negatively affect intestinal health in chickens.Specifically,florfenicol was found to impair intestinal homeostasis and immune function in laying hens,including by reducing butyrate levels,thereby increasing their susceptibility to systemic APEC infection.The development of strategies for mitigating the adverse effects of florfenicol on gut health and pathogen susceptibility in laying hens is therefore essential.
基金supported by grants from the National Research Foundation of Korea (NRF2017R1A2A1A17069648 and NRF-2018R1A5A2024418) to H.-H.K.the National Research Foundation of Korea (NRF-2017R1D1A1B03028003) to H.K.
文摘Bone destruction induced by breast cancer metastasis causes severe complications,including death,in breast cancer patients.Communication between cancer cells and skeletal cells in metastatic bone microenvironments is a principal element that drives tumor progression and osteolysis.Tumor-derived factors play fundamental roles in this form of communication.To identify soluble factors released from cancer cells in bone metastasis,we established a highly bone-metastatic subline of MDA-MB-231 breast cancer cells.This subline(mtMDA)showed a markedly elevated ability to secrete S100A4 protein,which directly stimulated osteoclast formation via surface receptor RAGE.Recombinant S100A4 stimulated osteoclastogenesis in vitro and bone loss in vivo.Conditioned medium from mtMDA cells in which S100A4 was knocked down had a reduced ability to stimulate osteoclasts.Furthermore,the S100A4 knockdown cells elicited less bone destruction in mice than the control knockdown cells.In addition,administration of an anti-S100A4 monoclonal antibody(mAb)that we developed attenuated the stimulation of osteoclastogenesis and bone loss by mtMDA in mice.Taken together,our results suggest that S100A4 released from breast cancer cells is an important player in the osteolysis caused by breast cancer bone metastasis.
基金supported by the BK21 FOUR Program of the Department of Agricultural Biotechnology,Seoul National University,Seoul,South Korea and was supported by HHMI,USA。
文摘Human immunodeficiency virus-1(HIV-1)exploits the viral gp120 protein and host CD4/CCR5 receptors for the pandemic infection to humans.The host co-receptors of not only humans but also several primates and HIV-model mice can interact with the HIV receptor.However,the molecular mechanisms of these interactions remain unclear.Using Shaik et al.(2019)'s gp120/CD4/CCR5 structure of HIV-1B and human,here,we investigate the molecular dynamics between HIV sub-lineages(B,C,N,and O)and potential hosts in Euarchontoglires(primates and rodents).Although both host genes show similar protein structures conserved in all animals,CD4 gene demonstrates significantly stronger binding affinities in Catarrhini(apes and Old-World monkeys).Its known candidate residues interacted with gp120 fail to explain these affinity variations.Therefore,we identified novel candidate sites under positive selection on the Catarrhini lineage.Among four positively selected sites,residue R58 in humans is located within an antigen-antibody binding domain,exhibiting apomorphic amino acid substitutions as Arginine(R)in Catarrhini,which are mutually exclusive to the other animals where Lysine(K)is prevalent.Applying for artificial mutation test,we validated that K to R substitutions can lead stronger binding affinities of Catarrhini.Ecologically,these dynamics may relate to shared equatorial habitats in Africa and Asia.Our findings suggest a new candidate site R58 driven by the lineage-specific evolution as a molecular foundation on HIV infection.
基金the support of ‘Cooperative Research Program for Agriculture Science & Technology Development (PJ00812802)’, Rural Development Administration, Republic of Korea
文摘Jasmonic acid （JA） functions in plant development, including senescence and immunity. Arabidopsis thaliana CORONATINE INSENSITIVE 1 encodes a JA receptor and functions in the JA‐responsive signaling pathway. The Arabidopsis genome harbors a single COI gene, but the rice （Oryza sativa） genome harbors three COI homologs, OsCOI1a, OsCOI1b, and OsCOI2. Thus, it remains unclear whether each OsCOI has distinct, additive, synergistic, or redundant func-tions in development. Here, we use the oscoi1b‐1 knockout mutants to show that OsCOI1b mainly affects leaf senescence under senescence‐promoting conditions. oscoi1b‐1 mutants stayed green during dark‐induced and natural senescence, with substantial retention of chlorophylls and photosyn-thetic capacity. Furthermore, several senescence‐associated genes were downregulated in oscoi1b‐1 mutants, including homologs of Arabidopsis thaliana ETHYLENE INSENSITIVE 3 and ORESARA 1, important regulators of leaf senescence. These results suggest that crosstalk between JA signaling and ethylene signaling affects leaf senescence. The Arabidopsis coi1‐1 plants containing 35S：OsCOI1a or 35S：OsCOI1b rescued the delayed leaf senescence during dark incubation, sug-gesting that both OsCOI1a and OsCOI1b are required for promoting leaf senescence in rice. oscoi1b‐1 mutants showed significant decreases in spikelet fertility and grain weight, leading to severe reduction of grain yield, indicating that OsCOI1‐mediated JA signaling affects spikelet fertility and grain filling.
文摘Mycobacterium tuberculosis(MTB)is the causative agent of tuberculosis(TB),a prevalent airborne infectious disease.Despite the availability of the Bacille Calmette-Guerin vaccine,its global efficacy remains modest,and tuberculosis persists as a significant global public health threat.Addressing this challenge and advancing towards the End MTB Strategy,we developed a multiepitope vaccine(MEV)based on immunoinformatics and compu-tational approaches.Immunoinformatics screening of MBT protein identified immune-dominant epitopes based on Major Histocompatibility Complex(MHC)allele binding,immunogenicity,antigenicity,allergenicity,toxicity,and cytokine inducibility.Selected epitopes were integrated into an MEV construct with adjuvant and linkers,forming a fully immunogenic vaccine candidate.Comprehensive analyses encompassed the evaluation of immunological and physicochemical properties,determination of tertiary structure,molecular docking with Toll-Like Receptors(TLR),molecular dynamics(MD)simulations for all atoms,and immune simulations.Our MEV comprises 534 amino acids,featuring 6 cytotoxic T lymphocyte,8 helper T lymphocyte,and 7 linear B lymphocyte epitopes,demonstrating high antigenicity and stability.Notably,molecular docking studies and triplicate MD simulations revealed enhanced interactions and stability of MEV with the TLR4 complex compared to TLR2.In addition,the immune simulation indicated the capacity to effectively induce elevated levels of an-tibodies and cytokines,emphasizing the vaccine’s robust immunogenic response.This study presents a promising MEV against TB,exhibiting favorable immunological and physicochemical attributes.The findings provide theoretical support for TB vaccine development.Our study aligns with the global initiative of the End MTB Strategy,emphasizing its potential impact on addressing persistent challenges in TB control.
基金The authors are thankful to the Research Institute of Agriculture and Life Sciences,Seoul National University,and the BK21 FOUR Program of the Department of Agricultural Biotechnology,Seoul National University,Seoul,Republic of Korea,for supporting the research workThis research was supported by a fund(Project Code No.Z-1543082-2019-20-01)by Research of Animal and Plant Quarantine Agency,Republic of Korea.
文摘Respiratory syncytial virus(RSV)poses a significant global health threat,especially affecting infants and the elderly.Addressing this,the present study proposes an innovative approach to vaccine design,utilizing immunoinformatics and computational strategies.We analyzed RSV's structural proteins across both subtypes A and B,identifying potential helper T lymphocyte,cytotoxic T lymphocyte,and linear B lymphocyte epitopes.Criteria such as antigenicity,allergenicity,toxicity,and cytokine-inducing potential were rigorously examined.Additionally,we evaluated the conservancy of these epitopes and their population coverage across various RSV strains.The comprehensive analysis identified six major histocompatibility complex class I(MHC-I)binding,five MHC-II binding,and three B-cell epitopes.These were integrated with suitable linkers and adjuvants to form the vaccine.Further,molecular docking and molecular dynamics simulations demonstrated stable interactions between the vaccine candidate and human Toll-like receptors(TLR4 and TLR5),with a notable preference for TLR4.Immune simulation analysis underscored the vaccine's potential to elicit a strong immune response.This study presents a promising RSV vaccine candidate and offers theoretical support,marking a significant advancement in vaccine development efforts.However,the promising in silico findings need to be further validated through additional in vivo studies.
