Background:Bacillus cereus is an important pathogen that causes human food poisoning,specifically diarrhea and vomiting.B.cereus can also induce mastitis in dairy cows and has a strong survival ability in milk,as it c...Background:Bacillus cereus is an important pathogen that causes human food poisoning,specifically diarrhea and vomiting.B.cereus can also induce mastitis in dairy cows and has a strong survival ability in milk,as it cannot be inactivated by high-temperature short-time pasteurization.Therefore,B.cereus can enter the market through pasteurized milk and other dairy products,imposing enormous hidden dangers on food safety and human health.Results:In this study,B.cereus 2101(BC)was isolated from milk samples of cows with mastitis.BC grew rapidly with strong hemolysis,making it difficult to prevent mastitis and ensure food security.MAC-T cells were treated with BC and/or Lactobacillus rhamnosus GR-1(LGR-1).Pretreatment with LGR-1 protected the integrity of tight junctions and the expression of zonula occludens-1(ZO-1)and occludin destroyed by BC.Furthermore,LGR-1 pretreatment reduced the expression of NOD-like receptor family member pyrin domain-containing protein 3(NLRP3),caspase recruitment and activation domain(ASC),Caspase-1 p20,gasdermin D(GSDMD)p30,inflammatory factors(interleukin(IL)-1βand IL-18),and cell death induced by BC.Moreover,LGR-1 pretreatment reduced NLRP3 inflammasome activity and increased expressions of ZO-1 and occludin induced by lipopolysaccharides(LPS)+ATP stimulation.MAC-T cells were transfected with NLRP3 si RNA or MCC950 and/or treated with BC and/or LGR-1.NLRP3-si RNA transfection and MCC950 attenuated BC-induced NLRP3 inflammasome activity.Expression of inflammatory cytokines and cell death suggested that the inflammatory pathway might play an important role in the induction of the NLRP3 inflammasome by BC and the protection of LGR-1.Conclusions:These results suggest that LGR-1 might be a probiotic alternative to antibiotics and could be administered to prevent mastitis in dairy cows,thus ensuring food security.展开更多
Chromium yeast(CY)supplementation has the potential to alleviate the negative effects of heat stress in dairy cows,but the mechanism remains elusive.We aimed to identify the metabolic mechanisms whereby CY supplementa...Chromium yeast(CY)supplementation has the potential to alleviate the negative effects of heat stress in dairy cows,but the mechanism remains elusive.We aimed to identify the metabolic mechanisms whereby CY supplementation alleviates the negative effects of heat stress in mid-lactation dairy cows.Twelve Holstein dairy cows with similar milk yield(24.6±1.5 kg/d),parity(2 or 3)and days in milk(125±8 d)were fed the same basal diet containing 0.09 mg of Cr/kg DM.They were allocated randomly to 2 groups:a control group(CON,without CY supplementation)and a CY group(CY,administered 0.36 mg Cr/kg DM).The experiment was performed over 8 weeks during a hot summer,in which the mean temperature-humidity index was 79.0±3.13(>72),indicating that the dairy cows were exposed to heat stress.Chromium yeast supplementation reduced rectal temperature(P=0.032),and increased the lactation performance by increasing the yield of milk(+2.6 kg/d),protein,lactose and total solid,and protein and lactose percentages in the milk of the heat-stressed dairy cows(P<0.05).Supplementation with CY increased the serum glucose and thyroxine concentrations,but reduced the urea nitrogen,in-sulin,and triiodothyronine concentrations on d 56(P<0.05).Furthermore,plasma metabolomic analysis was performed using liquid chromatography tandem-mass spectrometry,which identified 385 metab-olites in the two groups.Subsequently,16 significantly different metabolites in the plasma,were significantly higher in the CY group(variable importance for the projection>1.0,P<0.05),and found to be involved in 6 Kyoto Encyclopedia of Genes and Genomes pathways,including those involved in nicotinate and nicotinamide metabolism.Specifically,plasma concentration of nicotinamide was higher after CY supplementation,which might also contribute to the reduction of rectal temperature,the regulation of glucose homeostasis,and an improvement in the lactation performance of heat-stressed dairy cows.In conclusion,CY supplementation reduces rectal temperature,influences metabolism by reducing serum insulin concentration and increasing serum glucose and plasma nicotinamide concen-trations,and finally increases lactation performance of heat-stressed dairy cows.展开更多
Exhausted CD8^(+)T(Tex)cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts.A stem cell-like Tex(Tex-stem)subset can self-renew and differentiate into terminally exh...Exhausted CD8^(+)T(Tex)cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts.A stem cell-like Tex(Tex-stem)subset can self-renew and differentiate into terminally exhausted(Tex-term)cells.Here,we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor models.Tcf1 overexpression diminished coinhibitory receptor expression and enhanced polycytokine-producing capacity while retaining a heightened responses to checkpoint blockade,leading to enhanced viral and tumor control.Mechanistically,ectopically expressed Tcf1 exploited existing and novel chromatin accessible sites as transcriptional enhancers or repressors and modulated the transcriptome by enforcing pre-existing expression patterns in Tex-stem cells,such as enhanced suppression of Blimp1 and Bim and acquisition of new downstream genes,including Mx1,Tox2,and Runx3.These findings reveal a pronounced impact of ectopic Tcf1 expression on Tex functional restoration and highlight the therapeutic potential of harnessing Tcf1-enforced transcriptional programs.展开更多
Transcription factors and DNA/histone modification enzymes work in concert to establish and maintain cell identity. CD4^＋ and CD8^＋ T cells are key players in cellular immunity with distinct functions. Recent studie...Transcription factors and DNA/histone modification enzymes work in concert to establish and maintain cell identity. CD4^＋ and CD8^＋ T cells are key players in cellular immunity with distinct functions. Recent studies offer novel insights into how their identities are established in the thymus and maintained in the periphery during immune responses. During thymic maturation, Thpok, HDAC1 and HDAC2 guard CD4^＋ T cells from activation of CD8^＋ cytotoxic genes, and Tcfl and Left utilize their intrinsic HDAC activity to shut down CD4^＋ lineage-associated genes in CD8^＋ T cells. In activated CD4＋ T cells, Tcfl and Left act upstream of the Bc16-Blimpl axis to direct differentiation of follicular helper T （Tfh） cells, and prevent diversion of Tfh to IL-17-producing cells. In parallel, T-bet, together with Eomes or Blimpl, ensures proper induction of the cytotoxic program in CD8^＋ effectors elicited by acute infection, and prevents generation of pathogenic, IL-17-producing CD8^＋ effector T cells. Antigen persistence due to chronic viral infection leads to CD8^＋ T cell exhaustion. A portion of exhausted CD8^＋ T cells has the capacity to activate the Tfh program in a Tcfl-dependent manner. Those Tfh-like CD8^＋ T cells exhibit enhanced proliferative capacity in response to PD-1 blockage therapy and are more effective in curtailing viral replication. Thus, dissecting the molecular aspects of T cell identity, during development and immune responses, may lead to new therapies for treating autoimmunity, tumors, and persistent infections.展开更多
基金the following funds:the National Key R&D Program of China(Project No.2017YFD0502200)the National Natural Science Foundation of China(Project No.31960721)the National Natural Science Foundation of China(Project No.31873034)。
文摘Background:Bacillus cereus is an important pathogen that causes human food poisoning,specifically diarrhea and vomiting.B.cereus can also induce mastitis in dairy cows and has a strong survival ability in milk,as it cannot be inactivated by high-temperature short-time pasteurization.Therefore,B.cereus can enter the market through pasteurized milk and other dairy products,imposing enormous hidden dangers on food safety and human health.Results:In this study,B.cereus 2101(BC)was isolated from milk samples of cows with mastitis.BC grew rapidly with strong hemolysis,making it difficult to prevent mastitis and ensure food security.MAC-T cells were treated with BC and/or Lactobacillus rhamnosus GR-1(LGR-1).Pretreatment with LGR-1 protected the integrity of tight junctions and the expression of zonula occludens-1(ZO-1)and occludin destroyed by BC.Furthermore,LGR-1 pretreatment reduced the expression of NOD-like receptor family member pyrin domain-containing protein 3(NLRP3),caspase recruitment and activation domain(ASC),Caspase-1 p20,gasdermin D(GSDMD)p30,inflammatory factors(interleukin(IL)-1βand IL-18),and cell death induced by BC.Moreover,LGR-1 pretreatment reduced NLRP3 inflammasome activity and increased expressions of ZO-1 and occludin induced by lipopolysaccharides(LPS)+ATP stimulation.MAC-T cells were transfected with NLRP3 si RNA or MCC950 and/or treated with BC and/or LGR-1.NLRP3-si RNA transfection and MCC950 attenuated BC-induced NLRP3 inflammasome activity.Expression of inflammatory cytokines and cell death suggested that the inflammatory pathway might play an important role in the induction of the NLRP3 inflammasome by BC and the protection of LGR-1.Conclusions:These results suggest that LGR-1 might be a probiotic alternative to antibiotics and could be administered to prevent mastitis in dairy cows,thus ensuring food security.
基金supported by the National Key Research and Development Program of China(2022YFD1300505,2022YFD1301101)the earmarked fund for China Agriculture Research System(CARS-37)the Agricultural Science and Technology Innovation Program(cxgc-ias-07).
文摘Chromium yeast(CY)supplementation has the potential to alleviate the negative effects of heat stress in dairy cows,but the mechanism remains elusive.We aimed to identify the metabolic mechanisms whereby CY supplementation alleviates the negative effects of heat stress in mid-lactation dairy cows.Twelve Holstein dairy cows with similar milk yield(24.6±1.5 kg/d),parity(2 or 3)and days in milk(125±8 d)were fed the same basal diet containing 0.09 mg of Cr/kg DM.They were allocated randomly to 2 groups:a control group(CON,without CY supplementation)and a CY group(CY,administered 0.36 mg Cr/kg DM).The experiment was performed over 8 weeks during a hot summer,in which the mean temperature-humidity index was 79.0±3.13(>72),indicating that the dairy cows were exposed to heat stress.Chromium yeast supplementation reduced rectal temperature(P=0.032),and increased the lactation performance by increasing the yield of milk(+2.6 kg/d),protein,lactose and total solid,and protein and lactose percentages in the milk of the heat-stressed dairy cows(P<0.05).Supplementation with CY increased the serum glucose and thyroxine concentrations,but reduced the urea nitrogen,in-sulin,and triiodothyronine concentrations on d 56(P<0.05).Furthermore,plasma metabolomic analysis was performed using liquid chromatography tandem-mass spectrometry,which identified 385 metab-olites in the two groups.Subsequently,16 significantly different metabolites in the plasma,were significantly higher in the CY group(variable importance for the projection>1.0,P<0.05),and found to be involved in 6 Kyoto Encyclopedia of Genes and Genomes pathways,including those involved in nicotinate and nicotinamide metabolism.Specifically,plasma concentration of nicotinamide was higher after CY supplementation,which might also contribute to the reduction of rectal temperature,the regulation of glucose homeostasis,and an improvement in the lactation performance of heat-stressed dairy cows.In conclusion,CY supplementation reduces rectal temperature,influences metabolism by reducing serum insulin concentration and increasing serum glucose and plasma nicotinamide concen-trations,and finally increases lactation performance of heat-stressed dairy cows.
基金supported by grants from the NIH(AI112579,AI121080 and AI139874 to H.-H.X.,GM133712 to C.Z.,and GM113961,AI147064 and AI114543 to V.P.B.)the Veteran Affairs BLR&D Merit Review Program(BX002903)to H.-H.X.
文摘Exhausted CD8^(+)T(Tex)cells are dysfunctional due to persistent antigen exposure in chronic viral infection and tumor contexts.A stem cell-like Tex(Tex-stem)subset can self-renew and differentiate into terminally exhausted(Tex-term)cells.Here,we show that ectopic Tcf1 expression potently promoted the generation of Tex-stem cells in both a chronic viral infection and preclinical tumor models.Tcf1 overexpression diminished coinhibitory receptor expression and enhanced polycytokine-producing capacity while retaining a heightened responses to checkpoint blockade,leading to enhanced viral and tumor control.Mechanistically,ectopically expressed Tcf1 exploited existing and novel chromatin accessible sites as transcriptional enhancers or repressors and modulated the transcriptome by enforcing pre-existing expression patterns in Tex-stem cells,such as enhanced suppression of Blimp1 and Bim and acquisition of new downstream genes,including Mx1,Tox2,and Runx3.These findings reveal a pronounced impact of ectopic Tcf1 expression on Tex functional restoration and highlight the therapeutic potential of harnessing Tcf1-enforced transcriptional programs.
文摘Transcription factors and DNA/histone modification enzymes work in concert to establish and maintain cell identity. CD4^＋ and CD8^＋ T cells are key players in cellular immunity with distinct functions. Recent studies offer novel insights into how their identities are established in the thymus and maintained in the periphery during immune responses. During thymic maturation, Thpok, HDAC1 and HDAC2 guard CD4^＋ T cells from activation of CD8^＋ cytotoxic genes, and Tcfl and Left utilize their intrinsic HDAC activity to shut down CD4^＋ lineage-associated genes in CD8^＋ T cells. In activated CD4＋ T cells, Tcfl and Left act upstream of the Bc16-Blimpl axis to direct differentiation of follicular helper T （Tfh） cells, and prevent diversion of Tfh to IL-17-producing cells. In parallel, T-bet, together with Eomes or Blimpl, ensures proper induction of the cytotoxic program in CD8^＋ effectors elicited by acute infection, and prevents generation of pathogenic, IL-17-producing CD8^＋ effector T cells. Antigen persistence due to chronic viral infection leads to CD8^＋ T cell exhaustion. A portion of exhausted CD8^＋ T cells has the capacity to activate the Tfh program in a Tcfl-dependent manner. Those Tfh-like CD8^＋ T cells exhibit enhanced proliferative capacity in response to PD-1 blockage therapy and are more effective in curtailing viral replication. Thus, dissecting the molecular aspects of T cell identity, during development and immune responses, may lead to new therapies for treating autoimmunity, tumors, and persistent infections.
