Background A deterioration in the meat quality of broilers has attracted much more attention in recent years.L-malic acid(MA)is evidenced to decrease meat drip loss in broilers,but the underlying molecular mechanisms ...Background A deterioration in the meat quality of broilers has attracted much more attention in recent years.L-malic acid(MA)is evidenced to decrease meat drip loss in broilers,but the underlying molecular mechanisms are still unclear.It’s also not sure whether the outputs obtained under experimental conditions can be obtained in a com-mercial condition.Here,we investigated the effects and mechanisms of dietary MA supplementation on chicken meat drip loss at large-scale rearing.Results Results showed that the growth performance and drip loss were improved by MA supplementation.Meat metabolome revealed that L-2-aminoadipic acid,β-aminoisobutyric acid,eicosapentaenoic acid,and nicotinamide,as well as amino acid metabolism pathways connected to the improvements of meat quality by MA addition.The transcriptome analysis further indicated that the effect of MA on drip loss was also related to the proper immune response,evidenced by the enhanced B cell receptor signaling pathway,NF-κB signaling pathway,TNF signaling pathway,and IL-17 signaling pathway.Conclusions We provided evidence that MA decreased chicken meat drip loss under commercial conditions.Metabolome and transcriptome revealed a comprehensive understanding of the underlying mechanisms.Together,MA could be used as a promising dietary supplement for enhancing the water-holding capacity of chicken meat.展开更多
Programmed cell death protein-1(PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors.We generated PD-1 and T cell...Programmed cell death protein-1(PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors.We generated PD-1 and T cell receptor(TCR)deficient mesothelin-specific CAR-T(MPTK-CAR-T)cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study.A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion.No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients.The best overall response was stable disease(2/15 patients).Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month.TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion.We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models.Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.展开更多
Anti-CD19 chimeric antigen receptor-modified T(CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. No...Anti-CD19 chimeric antigen receptor-modified T(CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune-cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines(mainly interleukin 6 and C-reactive protein) were identified in two patients(Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.展开更多
Locally resonant metamaterial plates with subwavelength bandgaps can be exploited for the simultaneous control of structural vibrations and acoustic radiation.The present work theoretically investigates the vibroacous...Locally resonant metamaterial plates with subwavelength bandgaps can be exploited for the simultaneous control of structural vibrations and acoustic radiation.The present work theoretically investigates the vibroacoustic characteristics of a metamaterial plate with periodic lateral local resonance.The high accuracy of the presented method is evident from the consistency of the cross mobility of the metamaterial plate calculated with the finite element technique.The modal superposition approach and Rayleigh integral technique are adopted to formulate the mean square velocity and acoustic radiation power in terms of the structural deflection and sound pressure to capture the vibroacoustic coupling characteristics of the metamaterial plate and the surrounding environment.Large vibration suppression and sound reduction with high radiation efficiency can be observed within the frequency ranges of interest.The near-field sound intensity and far-field acoustic pressure distributions inside and outside the bandgaps are plotted and analyzed.The results from this work can be utilized to set design guidelines for metamaterial design to achieve prescribed vibroacoustic characteristics.展开更多
基金This study was funded by the Key Laboratory of Feed and Livestock and Poultry Products Quality&Safety Control,Ministry of Agriculture(2021202201)Reform and Development Project of BAAFS(XMS202322).
文摘Background A deterioration in the meat quality of broilers has attracted much more attention in recent years.L-malic acid(MA)is evidenced to decrease meat drip loss in broilers,but the underlying molecular mechanisms are still unclear.It’s also not sure whether the outputs obtained under experimental conditions can be obtained in a com-mercial condition.Here,we investigated the effects and mechanisms of dietary MA supplementation on chicken meat drip loss at large-scale rearing.Results Results showed that the growth performance and drip loss were improved by MA supplementation.Meat metabolome revealed that L-2-aminoadipic acid,β-aminoisobutyric acid,eicosapentaenoic acid,and nicotinamide,as well as amino acid metabolism pathways connected to the improvements of meat quality by MA addition.The transcriptome analysis further indicated that the effect of MA on drip loss was also related to the proper immune response,evidenced by the enhanced B cell receptor signaling pathway,NF-κB signaling pathway,TNF signaling pathway,and IL-17 signaling pathway.Conclusions We provided evidence that MA decreased chicken meat drip loss under commercial conditions.Metabolome and transcriptome revealed a comprehensive understanding of the underlying mechanisms.Together,MA could be used as a promising dietary supplement for enhancing the water-holding capacity of chicken meat.
基金This research was supported by grants from the National Key Research and Development Program of China(No.2019YFC1316205 to J.N.)National Natural Science Foundation of China(Nos.31991171 and 81830002 to W.D.H.,81773269 and 31722036 to H.Y.W.)Strategic Priority Research Program of the Chinese Academy of Sciences(No.XDA16010503 to H.Y.W.).
文摘Programmed cell death protein-1(PD-1)-mediated immunosuppression has been proposed to contribute to the limited clinical efficacy of chimeric antigen receptor T(CAR-T)cells in solid tumors.We generated PD-1 and T cell receptor(TCR)deficient mesothelin-specific CAR-T(MPTK-CAR-T)cells using CRISPR-Cas9 technology and evaluated them in a dose-escalation study.A total of 15 patients received one or more infusions of MPTK-CAR-T cells without prior lymphodepletion.No dose-limiting toxicity or unexpected adverse events were observed in any of the 15 patients.The best overall response was stable disease(2/15 patients).Circulating MPTK-CAR-T cells peaked at days 7–14 and became undetectable beyond 1 month.TCR-positive CAR-T cells rather than TCR-negative CAR-T cells were predominantly detected in effusion or peripheral blood from three patients after infusion.We further confirmed the reduced persistence of TCR-deficient CAR-T cells in animal models.Our results establish the preliminary feasibility and safety of CRISPR-engineered CAR-T cells with PD-1 disruption and suggest that the natural TCR plays an important role in the persistence of CAR-T cells when treating solid tumors.
基金supported by the National Science Foundation for Young Scientists of China (81402567, 81402566, 81472612)Bejing Nova Program (XX2016086)+3 种基金China Postdoctoral Science Foundation Grant (201150M1533)Science and Technology Planning Project of Beijing City (Z151100003915076 to Weidong Han)National Natural Science Foundation of China (31270820, 81230061 to Weidong Han)People’s Republic of China Support Fund (2015PC-TSYS-2013 to Suxia Li)
文摘Anti-CD19 chimeric antigen receptor-modified T(CAR-T-19) cells have emerged as a powerful targeted immunotherapy for B-cell lineage acute lymphoblastic leukemia with a remarkable clinical response in recent trials. Nonetheless, few data are available on the subsequent clinical monitoring and treatment of the patients, especially those with disease recurrence after CAR-T-19 cell infusion. Here, we analyzed three patients who survived after our phase I clinical trial and who were studied by means of biomarkers reflecting persistence of CAR-T-19 cells in vivo and predictive factors directing further treatment. One patient achieved 9-week sustained complete remission and subsequently received an allogeneic hematopoietic stem cell transplant. Another patient who showed relapse after 20 weeks without detectable leukemia in the cerebrospinal fluid after CAR-T-19 cell treatment was able to achieve a morphological remission under the influence of stand-alone low-dose chemotherapeutic agents. The third patient gradually developed extensive extramedullary involvement in tissues with scarce immune-cell infiltration during a long period of hematopoietic remission after CAR-T-19 cell therapy. Long-term and discontinuous increases in serum cytokines(mainly interleukin 6 and C-reactive protein) were identified in two patients(Nos. 1 and 6) even though only a low copy number of CAR molecules could be detected in their peripheral blood. This finding was suggestive of persistent functional activity of CAR-T-19 cells. Combined analyses of laboratory biomarkers with their clinical manifestations before and after salvage treatment showed that the persistent immunosurveillance mediated by CAR-T-19 cells would inevitably potentiate the leukemia-killing effectiveness of subsequent chemotherapy in patients who showed relapse after CAR-T-19-induced remission.
基金supported by the National Natural Science Foundation of China(No.52001131 and No.52071152).
文摘Locally resonant metamaterial plates with subwavelength bandgaps can be exploited for the simultaneous control of structural vibrations and acoustic radiation.The present work theoretically investigates the vibroacoustic characteristics of a metamaterial plate with periodic lateral local resonance.The high accuracy of the presented method is evident from the consistency of the cross mobility of the metamaterial plate calculated with the finite element technique.The modal superposition approach and Rayleigh integral technique are adopted to formulate the mean square velocity and acoustic radiation power in terms of the structural deflection and sound pressure to capture the vibroacoustic coupling characteristics of the metamaterial plate and the surrounding environment.Large vibration suppression and sound reduction with high radiation efficiency can be observed within the frequency ranges of interest.The near-field sound intensity and far-field acoustic pressure distributions inside and outside the bandgaps are plotted and analyzed.The results from this work can be utilized to set design guidelines for metamaterial design to achieve prescribed vibroacoustic characteristics.
